Liragl utide 7 10 Date:15 06 March 2012 Novo Nordisk Trial TD: NN8022-1922 8 CONFIDENTIAL11 Version16 : 6.0 Protocol - Revised edition 9 12 Status17: Final EudraCT No.: 2008-002199-88 13 Page:18 I of 133 14 Protocol - Revised edition Trial ID: NN8022- 1922 Revised protocol included: Global Substantial Amendment no. 1 dated 27-Aug-2008 Global Substantial Amendment no. 2 dated 28-Apr-2009 Global Substantial Amendment no. 4 dated 26-Nov-2010 Local Substantional Amendment no. 8 dated 27-Dec-2010 (Israel) Local Substantial Amendment no 11 dated 27 May 201 1 (France) Global Substantial Amendment no. 13 dated 14-Jul-201 l Local Substantial Amendment no. 17 dated 07-Dec-2011 (Israel) Local Substantial Amendment no. 18 dated 03-Jan-2012 (US) Global Substantial Amendment no. 19 dated 06-Mar-2012

SCALETM - Diabetes Satiety and Clinical Adiposity -Liraglutide Evidence in Nondiabetic and Diabetic Subjects

Effect of liraglutide on body weight in overweight or obese subjects with type 2 diabetes

A 56 week randomised, double-blind, placebo- controlled, three armed parallel group, multi-centre, multinational trial with a 12 week observational follow- up period

Trial phase: 3a

Author:

ClinOps, GLPl & Obesity

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51 Liraglutide 56 59 Date: 06 March 2012 Novo Nordisk 52 Trial ID: NN8022-1922 57 CONFIDENTIAL 60 Version: 6.0 53 Protocol - Revised edition 58 61 Status: Final 54 EudraCT No.: 2008-002199-88 62 Page: 2 of 133 6355 64 65 66 This confidential document is the property of Novo Nordisk. No unpublished information contained herein 67 may be disclosed without prior written approval from Novo Nordisk. Access to this document must be 68 restricted to relevant parties.

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69 Liraglutide 76 79 Date: 06 March 2012 Novo Nordisk 70 Trial ID: NN8022-1922 77 CONFIDENTIAL 80 Version: 6.0 71 Protocol - Revised edition 78 81 Status: Final 72 EudraCT No.: 2008-002199-88 82 Page: 3 of 133 73 74 Table of contents 8375 84 Page

85 Table of contents ...... 3 86 Table of tables ...... 8 87 List of abbreviations ...... 9 88 1 Summary ...... 12 89 2 Flow chart ...... 15 90 2.1 Trial design diagram: ...... 19 91 3 Introduction ...... 20 92 3.1 Basic information ...... 20 93 3.1.1 Glucagon-like peptide-1 (GLP-1) ...... 20 94 3.1.2 Liraglutide ...... 20 95 3.2 Rationale for the trial ...... 22 96 4 Objectives and endpoints ...... 24 97 4.1 Objectives ...... 24 98 4.2 Endpoint(s) ...... 24 99 5 Trial design ...... 27 100 5.1 Type of trial ...... 27 101 5.2 Rationale for trial design ...... 28 102 5.3 Treatment of subjects ...... 30 103 5.3.1 Liraglutide/liraglutide placebo...... 30 104 5.3.2 Metformin, sulphonylurea and glitazone ...... 32 105 5.3.3 Counselling on Diet and Physical Activity ...... 32 106 5.3.3.1 Calculation of estimated total energy expenditure ...... 33 107 5.4 Rationale for treatment ...... 33 108 6 Trial population ...... 35 109 6.1 Number of subjects to be studied ...... 35 110 6.2 Inclusion criteria ...... 35 111 6.3 Exclusion criteria ...... 35 112 6.4 Randomisation criteria ...... 37 113 6.5 Rescue criteria ...... 38 114 6.6 Withdrawal criteria ...... 38 115 6.7 Subject replacement ...... 39 116 6.8 Rationale for trial population ...... 40 117 7 Trial schedule ...... 41 118 8 Methods and assessments ...... 42 119 8.1 Visit Procedures...... 42 120 8.1.1 Visit Schedule ...... 44 121 8.1.2 Visit 1, Screening visit ...... 44 122 8.1.3 Visit 2, Randomisation visit ...... 46 123 8.1.4 Visit 3, Dose escalation visit ...... 48

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124 Liraglutide 129 132 Date: 06 March 2012 Novo Nordisk 125 Trial ID: NN8022-1922 130 CONFIDENTIAL 133 Version: 6.0 126 Protocol - Revised edition 131 134 Status: Final 127 EudraCT No.: 2008-002199-88 135 Page: 4 of 133 136128 137 8.1.5 Visit 4, Dose escalation visit/maintenance visit ...... 49 138 8.1.6 Visit 5a, maintenance visit ...... 51 139 8.1.7 Visit 5b, maintenance visit ...... 52 140 8.1.8 Visit 6, maintenance visit ...... 53 141 8.1.9 Visit 7, maintenance visit ...... 54 142 8.1.10 Visit 8, maintenance visit ...... 55 143 8.1.11 Visit 9, maintenance visit ...... 56 144 8.1.12 Visit 10, maintenance visit ...... 58 145 8.1.13 Visit 11, maintenance visit ...... 59 146 8.1.14 Visit 12, maintenance visit ...... 60 147 8.1.15 Visit 13, maintenance visit ...... 61 148 8.1.16 Visit 14, maintenance visit ...... 62 149 8.1.17 Visit 15, maintenance visit ...... 64 150 8.1.18 Visit 16, End of treatment/premature discontinuation before Visit 16 ...... 65 151 8.1.19 Visit 16x, Body weight/MESI recording visit ...... 67 152 8.1.20 Visit 17, follow-up visit/premature discontinuation at Visit 17 ...... 67 153 8.1.21 Visit 18, follow-up ...... 68 154 8.1.22 Visit 19, follow-up ...... 69 155 8.1.23 Visit 20, follow-up/premature discontinuation after Visit 17 ...... 70 156 8.2 Assessments for efficacy ...... 71 157 8.2.1 Body measurements ...... 72 158 8.2.1.1 Weight and height ...... 72 159 8.2.1.2 Waist circumference ...... 72 160 8.2.2 HbA1c ...... 73 161 8.2.3 Fasting plasma glucose ...... 73 162 8.2.4 Self-monitored fasting plasma glucose...... 73 163 8.2.4.1 7-Point plasma glucose profiles ...... 73 164 8.2.5 Glucose metabolism ...... 74 165 8.2.6 Vital signs ...... 74 166 8.2.6.1 Blood pressure ...... 74 167 8.2.6.2 Pulse ...... 74 168 8.2.7 Lipids ...... 74 169 8.2.8 Cardiovascular biomarkers ...... 74 170 8.2.9 Patient reported outcomes (PRO) questionnaires ...... 75 171 8.2.9.1 IWOoL-Lite ...... 75 172 8.2.9.2 Diabetes treatment satisfaction questionnaire ...... 75 173 8.2.10 Urinary Albumin-to-Creatinine ratio ...... 75 174 8.3 Assessments for safety ...... 75 175 8.3.1 Physical examination ...... 75 176 8.3.2 Hypoglycaemic episodes ...... 76 177 8.3.3 ECG 12 lead ...... 78 178 8.3.4 Adverse events (AEs) ...... 78 179 8.3.5 Haematology and biochemistry ...... 78 180 8.3.6 Pregnancy test ...... 79 181 8.3.7 Liraglutide antibodies ...... 80 182 8.3.8 Suspicion of Acute Hypersensitivity (allergic reaction) to Trial Product ...... 80 183 8.3.9 Suspicion of Immune-complex Disease ...... 80

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184 Liraglutide 189 192 Date: 06 March 2012 Novo Nordisk 185 Trial ID: NN8022-1922 190 CONFIDENTIAL 193 Version: 6.0 186 Protocol - Revised edition 191 194 Status: Final 187 EudraCT No.: 2008-002199-88 195 Page: 5 of 133 196188 197 8.3.10 Mental Health questionnaires ...... 80 198 8.3.10.1 C-SSRS ...... 81 199 8.3.10.2 PHQ-9 ...... 81 200 8.3.11 Thyroidectomy Pathology Slides...... 81 201 8.3.12 Thyroid Tissue Sample Collection in Case of Thyroidectomy ...... 82 202 8.3.13 Genetic Testing in case of Confirmed C-cell Pathology ...... 82 203 8.3.14 Eye examination ...... 82 204 8.3.15 Binge Eating Scale questionnaire ...... 82 205 8.4 Other assessments ...... 83 206 8.4.1 Smoking habits ...... 83 207 8.4.2 Diabetes diary ...... 83 208 8.4.3 3-day food diary ...... 8 3 209 8.4.4 Dietary compliance and physical activity ...... 83 210 8.4.5 Liraglutide concentration (population PK) ...... 83 211 8.4.6 History of diabetes complications ...... 84 212 8.4.7 History of Concomitant Cardiovascular Disease ...... 84 213 8.4.8 History of Gallbladder Disease ...... 84 214 8.4.9 History of Psychiatric Disorders ...... 84 215 8.5 Subject compliance ...... 84 216 9 Trial supplies ...... 86 217 9.1 Trial product(s) ...... 86 218 9.2 Packaging and labelling of trial product(s) ...... 86 219 9.3 Storage and drug accountability of trial product(s) ...... 86 220 9.4 Auxiliary supply ...... 87 221 10 Randomisation, breaking of blinded codes and interactive voice/web response system 222 (IV/WRS) ...... 88 223 10.1 Randomisation ...... 88 224 10.2 Breaking of blinded codes ...... 88 225 10.3 Interactive voice/web response system (IV/WRS) ...... 88 226 11 Concomitant illnesses/Medical history and concomitant medication ...... 90 227 12 Adverse events and Pregnancies ...... 91 228 12.1 Definitions ...... 91 229 12.1.1 Technical complaints ...... 93 230 12.2 Collection, recording and reporting of adverse events ...... 93 231 12.2.1 Medical events of special interest ...... 94 232 12.2.2 External independent event adjudication committee ...... 96 233 12.3 Follow-up of adverse events ...... 97 234 12.3.1 Collection and reporting of technical complaints ...... 98 235 12.3.2 Collection, storage and shipment of technical complaint samples ...... 99 236 12.4 Pregnancy ...... 99 237 12.5 Precautions/over-dosage ...... 100 238 12.6 Safety committee ...... 100 239 12.6.1 Internal Novo Nordisk safety committee ...... 100 240 12.6.2 Calcitonin Monitoring Committee ...... 101 241 13 Case report forms ...... 102

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242 Liraglutide 247 250 Date: 06 March 2012 Novo Nordisk 243 Trial ID: NN8022-1922 248 CONFIDENTIAL 251 Version: 6.0 244 Protocol - Revised edition 249 252 Status: Final 245 EudraCT No.: 2008-002199-88 253 Page: 6 of 133 254246 255 13.1 Rules for completing eCRFs ...... 102 256 13.2 Corrections to eCRFs ...... 102 257 13.3 eCRF flow ...... 102 258 14 Monitoring procedures ...... 103 259 15 Data management ...... 105 260 16 Computerised systems ...... 106 261 17 Evaluability of subjects for analysis ...... 107 262 18 Statistical considerations ...... 108 263 18.1 Sample size calculation ...... 108 264 18.2 Statistical methods ...... 108 265 18.2.1 Primary efficacy endpoints ...... 109 266 18.2.1.1 Primary analysis of the co-primary endpoints ...... 109 267 18.2.1.2 Sensitivity analyses of the co-primary endpoints ...... 111 268 18.2.2 Analysis of secondary efficacy endpoints ...... 112 269 18.2.3 Analysis of safety endpoints ...... 114 270 18.3 Interim analysis ...... 117 271 18.4 Sequential safety analysis/safety monitoring ...... 117 272 18.5 Explorative statistical analysis for pharmacogenetics and biomarkers...... 117 273 18.6 Health economics and/or subject reported outcome ...... 118 274 18.7 PK and/or PD modelling ...... 118 275 19 Ethics ...... 119 276 19.1 Informed consent form for trial subjects ...... 121 277 19.2 Data Handling ...... 121 278 19.3 Institutional review boards/independent ethics committee ...... 121 279 19.4 Regulatory authorities ...... 122 280 20 Premature termination of the trial/ trial site ...... 123 281 21 Protocol compliance ...... 124 282 21.1 Audits and inspections ...... 124 283 22 Critical documents ...... 125 284 23 Responsibilities ...... 126 285 24 Reports and publications ...... 127 286 24.1 Communication and publication ...... 127 287 24.1.1 Authorship ...... 127 288 24.1.2 Publication(s) ...... 128 289 24.1.3 Site-specific publication(s) by Investigator(s) ...... 128 290 24.2 Investigator access to data and review of results ...... 128 291 25 Retention of clinical trial documentation ...... 129 292 26 Indemnity statement ...... 130 293 References ...... 131

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294 Liraglutide 299 302 Date: 06 March 2012 Novo Nordisk 295 Trial ID: NN8022-1922 300 CONFIDENTIAL 303 Version: 6.0 296 Protocol - Revised edition 301 304 Status: Final 297 EudraCT No.: 2008-002199-88 305 Page: 7 of 133 306298 307 Appendix A Approval of final protocol (Not applicable for consolidated protocol) 308 Appendix B Agreement on the final protocol 309 Appendix C New York Heart Association Criteria for Functional Capacity 310 Appendix D Instruction for Blood Pressure Measurement 311 Appendix E Extended Flow Chart 312 Appendix F PRO questionnaires 313 Appendix G Mental Health questionnaires 314 Appendix H Medical Events of Special Interest (MESI) 315 Appendix I Calcitonin Monitoring Committee 316 Attachment I - global List of key staff and relevant departments 317 Attachment II - country List of key staff and relevant departments

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318 Liraglutide 325 328 Date: 06 March 2012 Novo Nordisk 319 Trial ID: NN8022-1922 326 CONFIDENTIAL 329 Version: 6.0 320 Protocol - Revised edition 327 330 Status: Final 321 EudraCT No.: 2008-002199-88 331 Page: 8 of 133 322 332 333 323 Table of tables 334 324 335 Page 336 337 Table 5–1 Treatment of subjects ...... 30 338 Table 5–2 Equations for estimating basal metabolic rate (BMR) in kcal/day* ...... 33 339 Table 8–1 Visit schedule ...... 44

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340 Liraglutide 347 350 Date: 06 March 2012 Novo Nordisk 341 Trial ID: NN8022-1922 348 CONFIDENTIAL 351 Version: 6.0 342 Protocol - Revised edition 349 352 Status: Final 343 EudraCT No.: 2008-002199-88 353 Page: 9 of 133 344 345 List of abbreviations 346 354 ADA American Diabetes Association 355 AE adverse event 356 ALAT alanine aminotransferase 357 ANCOVA Analysis of Covariance 358 ASAT aspartate aminotransferase 359 ATP-III adult treatment panel III 360 BES binge eating scale 361 BMI body mass index 362 BMR basal metabolic rate 363 BP blood pressure 364 CABG coronary artery bypass graft surgery 365 C-cell parafollicular cell 366 DFU Direction for Use 367 CPK creatine phosphokinase (creatinine kinase) 368 CRD Novo Nordisk clinical research department 369 eCRF electronic case report form 370 C-SSRS Columbia suicidality severity rating scale 371 CTA clinical trial application 372 CTR clinical trial report 373 DPP-4 dipeptidyl peptidase-4 374 DTSQs diabetes treatment satisfaction questionnaire (status version) 375 DUN dispensing unit number 376 ECG electrocardiogram 377 EDC electronic data capture 378 EOT end of trial 379 EAP Events Adjudication Panel 380 FAS full analysis set 381 FDA Food and Drug Administration 382 FFA free fatty acids 383 FMTC familial medullary thyroid carcinoma 384 FPFV first patient first visit 385 FPG fasting plasma glucose (fasting glucose) 386 GCP good clinical practice 387 GI gastro intestitinal 388 GLP-1 glucagon-like peptide-1 389 HbA1c glycosylated haemoglobin 390 hCG human chorionic gonadotropin 391 HDL high density lipoprotein 392 HOMA homeostasis model assessment 393 hsCRP high sensitivity C reactive protein 394 i.v. intravenous 395 IB investigator brochure

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396 Liraglutide 401 404 Date: 06 March 2012 Novo Nordisk 397 Trial ID: NN8022-1922 402 CONFIDENTIAL 405 Version: 6.0 398 Protocol - Revised edition 403 406 Status: Final 399 EudraCT No.: 2008-002199-88 407 Page: 10 of 133 408400 409 ICH international conference on harmonisation 410 ICMJE International Committee of Medical Journal Editors 411 IEC independent ethics committee 412 IMP Investigational Medical Product 413 INN international non-proprietary name 414 IRB institutional review board 415 ITT intention to treat 416 IV/WRS interactive voice response system/interactive web response system 417 IWQoL-Lite impact of weight on quality of life questionnaire – lite version 418 LDL low density lipoprotein 419 LR logistic regression 420 LLOQ lower limit of quantification 421 LOCF last observation carried forward 422 LPLV last patient last visit 423 MedDRA medical dictionary for regulatory activities 424 MEN2 multiple endocrine neoplasia type 2 425 MHP Mental Health Professional 426 MESI Medical Event of Special Interest 427 NCEP National Cholesterol Education Program 428 NCR no carbon required 429 NGSP national glycohemoglobin standardisation program 430 NYHA New York Heart Association 431 OAD oral antidiabetic drug 432 PAI-1 Plasminogen activator inhibitor-1 433 PAL physical activity level 434 PCI percutaneous coronary intervention 435 PHQ patient health questionnaire 436 PK Pharmacokinetics 437 PP per protocol 438 PPG postprandial glucose 439 PRO patient reported outcome 440 s.c. subcutaneous 441 SAE serious adverse event 442 SIF Safety information form 443 SD Standard deviation 444 SU sulphonylurea 445 t½ the elimination half-life 446 TC total cholesterol (cholesterol) 447 TEAE treatment emergent adverse event 448 TEE total energy expenditure 449 TG triglycerides 450 tmax the time to reach maximum concentration of drug in plasma 451 TMM trial materials manual

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452 Liraglutide 457 460 Date: 06 March 2012 Novo Nordisk 453 Trial ID: NN8022-1922 458 CONFIDENTIAL 461 Version: 6.0 454 Protocol - Revised edition 459 462 Status: Final 455 EudraCT No.: 2008-002199-88 463 Page: 11 of 133 464456 465 TSH thyroid-stimulating hormone 466 TVP trial validation plan 467 UNR upper normal range 468 VLDL very low density lipoprotein

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469 Liraglutide 476 479 Date: 06 March 2012 Novo Nordisk 470 Trial ID: NN8022-1922 477 CONFIDENTIAL 480 Version: 6.0 471 Protocol - Revised edition 478 481 Status: Final 472 EudraCT No.: 2008-002199-88 482 Page: 12 of 133 473 474 1 Summary 483475 484 485 Primary objective: 486 To investigate the efficacy of liraglutide compared to liraglutide placebo in inducing and maintaining weight 487 loss in overweight or obese subjects with type 2 diabetes after 56 weeks. 488 489 Secondary objectives: 490 To assess and compare the effect of liraglutide versus liraglutide placebo on parameters of glycaemic 491 control, waist circumference, cardiovascular risk factors and patient reported outcomes (PRO) in overweight 492 or obese subjects with type 2 diabetes. 493 494 Safety objective: 495 To evaluate the safety and tolerability of liraglutide. 496 497 Trial design: 498 This is a 56 week, randomised, double-blind, placebo-controlled, three armed, parallel group, multi-centre, 499 multinational trial with a 12-week observational follow-up period. 500 501 This paragraph applies to all countries except France: Subjects will be randomised in a 2:1:1 manner to 502 receive 3.0 mg of liraglutide, 1.8 mg of liraglutide or liraglutide placebo (1.8 mg or 3.0 mg) as an add-on to 503 their background diabetes treatment of either diet and exercise only or single compound oral antidiabetic 504 drug (OAD) treatment (metformin, sulphonylurea [SU] or glitazone) or any combination OAD treatment 505 (metformin+SU, metformin+glitazone, SU+glitazone, metformin+SU+glitazone). 506 507 This paragraph is only applicable to France: Subjects will be randomised in a 2:1:1 manner to receive 3.0 508 mg of liraglutide, 1.8 mg of liraglutide or liraglutide placebo (1.8 mg or 3.0 mg) as an add-on to their 509 background diabetes treatment of single compound oral antidiabetic drug (OAD) treatment (metformin as 510 single agent therapy, SU as single agent therapy (if presence of metformin contraindication or intolerance), 511 glitazone as single agent therapy (if presence of metformin contraindication or intolerance)) or combination 512 of two of the above mentioned OAD treatments (metformin+SU, metformin+glitazone, SU+glitazone). 513 514 The background treatment must be stable (same drug(s), dose and dosing frequency) for at least 3 months 515 prior to screening. 516 517 The maximum overall duration of the trial will be 70 weeks including the screening period and the 12-week 518 observational follow-up period. The trial consists of a screening visit, a randomisation visit, 15 treatment 519 visits and 4 follow-up visits. Furthermore, subjects that have discontinued the trial prematurely (before Visit 520 16) will be asked to attend a weight recording visit (16x) which will take place 56 weeks after the 521 randomisation visit. 522 523 PRO recordings will be performed in France, Germany, Spain, Sweden, United Kingdom and USA.

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524 Liraglutide 529 532 Date: 06 March 2012 Novo Nordisk 525 Trial ID: NN8022-1922 530 CONFIDENTIAL 533 Version: 6.0 526 Protocol - Revised edition 531 534 Status: Final 527 EudraCT No.: 2008-002199-88 535 Page: 13 of 133 536528 537 Trial population: 538 It is planned to randomise 800 subjects from 9 different countries. 539 540 Key inclusion criteria: 541 • Informed consent obtained 542 • Subjects diagnosed with type 2 diabetes and treated with either diet and exercise alone, metformin, SU, 543 glitazone as single agent therapy or any combination of the previously mentioned compounds 544 (metformin+SU, metformin+glitazone, SU+glitazone, metformin+SU+glitazone) 545 Only applicable to France: Subjects diagnosed with type 2 diabetes and treated with either metformin as 546 single agent therapy, SU as single agent therapy (if presence of metformin contraindication or 547 intolerance), glitazone as single agent therapy (if presence of metformin contraindication or intolerance) 548 or combination of two of the above mentioned compounds: metformin+SU, metformin+glitazone, 549 SU+glitazone

550 • HbA1c 7.0-10.0% (both inclusive) 2 551 • Body Mass Index (BMI) ≥ 27.0 kg/m 552 • Stable body weight 553 • Preceding failed dietary effort 554 555 Key exclusion criteria: 556 • Treatment with glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) 557 inhibitors or insulin within the last 3 months 558 • Known proliferative retinopathy or maculopathy 559 • History of acute or chronic pancreatitis 560 • Obesity induced by drug treatment 561 • Use of approved weight lowering pharmacotherapy 562 • Previous surgical treatment of obesity 563 • History of major depressive disorder or suicide attempt 564 • Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 565 100 mmHg) 566 • Screening calcitonin ≥ 50 ng/L 567 • Familial or personal history of multiple endocrine neoplasia type 2 (MEN2) or familial medullary 568 thyroid carcinoma (FMTC) 569 • Personal history of non-familial medullary thyroid carcinoma 570 • Only applicable to France: Abnormality of the thyroid identified during the physical exam at screening 571 572 Assessments: 573 The primary efficacy assessment is change in fasting body weight at 56 weeks. The secondary efficacy 574 assessments are HbA1c and other parameters of glycaemic control (proportion of subjects reaching target 575 HbA1c, fasting plasma glucose [FPG], 7-point plasma glucose profile, proportion of subjects with change in 576 concomitant medication (anti-hypertensives, lipid lowering agents, oral antidabetic drugs) at 56 weeks), 577 glucose metabolism related parameters incl. β-cell function, lipid profile, waist circumference, 578 cardiovascular biomarkers, vital signs, and PRO.

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579 Liraglutide 584 587 Date: 06 March 2012 Novo Nordisk 580 Trial ID: NN8022-1922 585 CONFIDENTIAL 588 Version: 6.0 581 Protocol - Revised edition 586 589 Status: Final 582 EudraCT No.: 2008-002199-88 590 Page: 14 of 133 591583 592 The key assessments of safety are physical examination, hypoglycaemic episodes, ECG, adverse events 593 (AE)s, haematology, biochemistry, formation of liraglutide antibodies and mental health assessments. 594 595 Trial product(s): 596 Novo Nordisk, Denmark will supply the following trial products: 597 598 • Liraglutide 6.0 mg/mL, 3 mL FlexPen® for subcutaneous (s.c.) injection 599 • Liraglutide placebo, 3 mL FlexPen® for subcutaneous (s.c.) injection

Downloaded From: https://jamanetwork.com/ on 09/26/2021 600 Liraglutide Protocol - Revised edition Date: 06 March 2012 06 March 2012 Status: Final Novo Nordisk Trial ID: NN8022-1922 EudraCT No.: 2008-002199-88 Version: 6.0 6.0 Page: 15 of 133 601 602 2 Flow chart 603 Dose Randomisa- End of Observational follow- Screen escalation Maintenance tion treat-ment up period

1 Visit Number 1 2 3 4 5a 5b 6 7 8 9 10 11 12 13 14 15 16 16x 17 18 19 20

Weeks in relation to Visit 2 -2 0 2 4 6 8 12 16 20 24 28 32 36 40 44 50 56 56 58 60 64 68 ± Visit Window, days ± 5 ± 3 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 3 ± 5 ± 3 ± 5 ± 5 5 SUBJECTS Informed consent X In/exclusion criteria X X Randomisation criteria X Rescue criteria X X X X X X X X X X X X X X Withdrawal criteria X X X X X X X X X X X X X X X X X X Demography X Date of diagnosis of diabetes X History of diabetes complications X Diabetes treatment history X Medical history and Concomitant X illness History of Concomitant X Cardiovascular Disease History of Gallbladder Disease X History of Psychiatric Disorders X Concomitant medication X X X X X X X X X X X X X X X X X X X X X Smoking habits X Attend visit fasting X X X X X X X X X X X X X EFFICACY 2 Body measurements X X X X X X X X X X X X X X X X X X X X X X HbA1c X X X X X X X Fasting plasma glucose X X X X X X X X X X X X 7-point plasma profile (self- 3 X X X measured) Glucose metabolism X X X

Downloaded From: https://jamanetwork.com/ on 09/26/2021 604 Liraglutide Protocol - Revised edition Date: 06 March 2012 06 March 2012 Status: Final Novo Nordisk Trial ID: NN8022-1922 EudraCT No.: 2008-002199-88 Version: 6.0 6.0 Page: 16 of 133 605 Dose Randomisa- End of Observational follow- Screen escalation Maintenance tion treat-ment up period

1 Visit Number 1 2 3 4 5a 5b 6 7 8 9 10 11 12 13 14 15 16 16x 17 18 19 20

Weeks in relation to Visit 2 -2 0 2 4 6 8 12 16 20 24 28 32 36 40 44 50 56 56 58 60 64 68 ± Visit Window, days ± 5 ± 3 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 3 ± 5 ± 3 ± 5 ± 5 5 Urinary Albumin-to-Creatinine X X X X X ratio Vital signs X X X X X X X X X X X X X X X X X X X X Lipids X X X X Cardiovascular biomarkers X X X 4, 5 PRO questionnaires X X X SAFETY Physical examination X X Hypoglycaemic episodes X X X X X X X X X X X X X X X X X X X X ECG X X X X Eye examination X 4,5 Binge Eating Scale questionnaire X X X Adverse Events X X X X X X X X X X X X X X X X X X X X Haematology X X X X X X X X X Biochemistry X X X X X X X X X 6 Pregnancy test X (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) X (X) (X) (X) X Liraglutide antibodies X X7 X 8,9 Mental health questionnaires X X X X X X X X X X X X X X X X X X X X X OTHER ASSESSMENTS PK (liraglutide plasma X X X concentration) TRIAL MATERIAL Dispense trial card X 10 Diabetes diary X X X X X X X X X X X X X X X X X X X X X 11 3-day food diary X X X X X X X X X X X X X X. X X Diet and physical activity X12 X X12 X X12 X X12 X X12 X X12 X X X12 X X12 X counselling Recording of dietary compliance X X X X X X X X

Downloaded From: https://jamanetwork.com/ on 09/26/2021 606 Liraglutide Protocol - Revised edition Date: 06 March 2012 06 March 2012 Status: Final Novo Nordisk Trial ID: NN8022-1922 EudraCT No.: 2008-002199-88 Version: 6.0 6.0 Page: 17 of 133 607 Dose Randomisa- End of Observational follow- Screen escalation Maintenance tion treat-ment up period

1 Visit Number 1 2 3 4 5a 5b 6 7 8 9 10 11 12 13 14 15 16 16x 17 18 19 20

Weeks in relation to Visit 2 -2 0 2 4 6 8 12 16 20 24 28 32 36 40 44 50 56 56 58 60 64 68 ± Visit Window, days ± 5 ± 3 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 3 ± 5 ± 3 ± 5 ± 5 5 13 and physical activity 14 Supply of device(s)/ancillaries X X Dispense trial drug X X X X X X X X X X X X X Drug accountability X X X X X X X X X X X X X IV/WRS call X X X X X X X X X X X X X X X X X End of treatment/ X X X 15 End of Trial 608 609 610 1 Only subjects discontinuing the trial prematurely before Visit 16 will be asked to attend Visit 16x 56 weeks after their randomisation date for the assessment of body 611 weight and MESI 612 2 Height will only be measured at Visit 1. Waist circumference will not be measured at Visit 16x. 613 3 On a normal representative day of the week (not on a day when they anticipate unusual strenuous exercise), preferably within one week prior to the visit 614 4 Applicable for subjects in France, Germany, Spain, Sweden, United Kingdom and USA 615 5 The investigator or his delegate must review patient reported outcome(s) for completeness and AEs immediately following administration. For subjects 616 discontinuing the trial prematurely before Visit 16 the questionnaire should be completed at the end of treatment visit (Visit 16) 617 6 For all women of childbearing potential: a serum pregnancy test will be performed at Visit 1, 16 and 20. Furthermore, pregnancy urine tests will be performed at any 618 other clinic visits during the trial if a menstrual period is missed or as required by local law 619 7 For subjects discontinuing the trial prematurely before Visit 16, liraglutide antibodies will be measured at the end of treatment visit (Visit 16) while subjects that 620 complete the treatment will have liraglutide antibodies measured at the first follow-up (Visit 17). 621 8 Mental health will be assessed by the use of PHQ-9 and C-SSRS at all site visits. The Investigator must assess the scores at Visit 1 (screening visit) and Visit 2 622 (randomisation visit) to exclude subjects with major depression (PHQ-9 ≥ 15) and/or any suicidal ideation (of type 4 or type 5) (see section 8.3.10) 623 9 For subjects discontinuing the trial prematurely before Visit 16 the mental health questionnaires will be completed at the end of treatment visit (Visit 16) 624 10 Dispense diabetes diary at Visit 1 to 19 and transcribe into eCRF at Visit 2 to 20 625 11 Dispense 3-day food diary at Visit 1, 4, 6, 8, 10, 12, 15 and 18. Collect 3-day food diary at Visit 2, 5b, 7, 9, 11, 13, 16 and 19. 626 12 Diet counselling based on a 3-day food diary 627 13 At Visit 2 only physical activity will be recorded

Downloaded From: https://jamanetwork.com/ on 09/26/2021 628 Liraglutide Protocol - Revised edition Date: 06 March 2012 06 March 2012 Status: Final Novo Nordisk Trial ID: NN8022-1922 EudraCT No.: 2008-002199-88 Version: 6.0 6.0 Page: 18 of 133 629 630 14 Glucose meter will be dispensed at Visit 1 and pedometer will be dispensed at Visit 2 631 15 Subjects discontinuing the trial prematurely before Visit 16 will be asked to attend a last visit at which procedures according to Visit 16 will be performed and the 632 EOT form completed. For subjects discontinuing the trial prematurely after Visit 16 the following will apply; at Visit 17: procedures according to Visit 17 will be 633 performed and the EOT form completed - after Visit 17; procedures according to Visit 20 will be performed and the EOT form completed

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634 Liraglutide 639 642 Date: 06 March 2012 Novo Nordisk 635 Trial ID: NN8022-1922 640 CONFIDENTIAL 643 Version: 6.0 636 Protocol - Revised edition 641 644 Status: Final 637 EudraCT No.: 2008-002199-88 645 Page: 19 of 133 646638 647 648 2.1 Trial design diagram: 649 650 651

652

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653 Liraglutide 660 663 Date: 06 March 2012 Novo Nordisk 654 Trial ID: NN8022-1922 661 CONFIDENTIAL 664 Version: 6.0 655 Protocol - Revised edition 662 665 Status: Final 656 EudraCT No.: 2008-002199-88 666 Page: 20 of 133 657 658 3 Introduction 667659 668 In this document Investigator refers to the individual overall responsible for the conduct of the clinical trial at 669 a trial site. 670 671 672 3.1 Basic information 673 The prevalence of both obesity and diabetes continues to increase worldwide. More than one billion adults 674 worldwide are overweight and at least 300 million are obese(1). The prevalence of diabetes is also rising, 675 with worldwide prevalence estimated at 4.0% in 2007, and still rising(2). Eighty to ninety percent of people 676 with type 2 diabetes are overweight(3) and obesity worsens the metabolic and physiologic abnormalities 677 associated with diabetes, particularly hyperglycaemia, hyperlipidemia, and hypertension(4). Weight loss is a 678 cornerstone of diabetes care for overweight people, as it improves insulin sensitivity and glycaemic 679 control(5) and in addition improves blood pressure and lipid profiles by decreasing triglycerides and low- 680 density lipoprotein levels(4). 681 682 3.1.1 Glucagon-like peptide-1 (GLP-1) 683 GLP-1 is an incretin hormone secreted from the L-cells in the lower gut in response to meal ingestion, which 684 stimulates endogenous insulin secretion in a glucose-dependent manner. GLP-1 also decreases blood 685 glucagon levels and reduces gastric emptying by decreasing gastric motility and increasing satiety and 686 subsequently reducing food intake, and has been shown to promote β-cell growth and proliferation in animal 687 models(6-8). GLP-1 reduces appetite in lean and normal weight individuals, as well as in obese 688 individuals(9-11), and has been shown to reduce body weight in people with type 2 diabetes(12). The 689 underlying mechanism mediating the weight-reducing effects of GLP-1 is most likely a combination of 690 effects on the gastrointestinal tract and the central nervous system, i.e. decreased gastric motility and reduced 691 appetite/increased satiety with a subsequent reduction in food intake. 692 693 The combination of these mechanisms makes GLP-1 receptor stimulation an attractive mechanism to 694 investigate for weight management and blood glucose lowering(13). 695 696 3.1.2 Liraglutide 697 Liraglutide is a long-acting GLP-1 analogue under development by Novo Nordisk and recently approved for 698 the treatment of type 2 diabetes in the US, EU, Japan and other countries worldwide under the brand name 699 Victoza (1.2 mg or 1.8 mg once-daily). Compared to human GLP-1, liraglutide has a C16 fatty (palmitic) 700 acid chain attached at position 26 (lysine) of the peptide, and has lysine at position 34 replaced by arginine. 701 When administered subcutaneously, these structural modifications result in a compound with protracted 702 kinetic properties suitable for one time daily injection. In vitro receptor studies have shown that liraglutide is 703 a selective, potent and full agonist of the cloned human GLP-1 receptor. The effects of liraglutide include 704 delayed gastric emptying, reduced sensation of hunger and increased satiety leading to decreased food intake 705 and subsequent weight loss. 706 707 A total of 50 clinical trials with liraglutide have been completed (includes doses up to 3.0 mg). The trials 708 were conducted world-wide, with most being conducted in Europe. Out of more than 10000 subjects, more

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709 Liraglutide 714 717 Date: 06 March 2012 Novo Nordisk 710 Trial ID: NN8022-1922 715 CONFIDENTIAL 718 Version: 6.0 711 Protocol - Revised edition 716 719 Status: Final 712 EudraCT No.: 2008-002199-88 720 Page: 21 of 133 721713 722 than 7500 subjects were exposed to liraglutide (including 850 subjects treated for 104 weeks in completed 723 trials). A total of 986 obese subjects without type 2 diabetes (<9% of all subjects) have been included to date 724 in the obesity clinical development programme for liraglutide in the completed phase 2 trial NN8022-1807 725 and the completed phase 3a trial NN8022-1923 (of which 305 subjects were randomised to liraglutide 3.0 726 mg). A further 48 obese subjects were randomised in the ongoing phase 1 trial NN8022-3630. 727 728 Data from finalised trials have shown liraglutide to have a pharmacokinetic profile suitable for one time 729 daily administration, as evidenced by a relatively slow absorption ([tmax] =8-12 hours) with a terminal 730 elimination half-life (t½) of approximately 13 hours. The pharmacokinetic profile is comparable between 731 healthy subjects and subjects with type 2 diabetes. 732 733 Results from a phase 2 trial in obese subjects without type 2 diabetes (NN8022-1807) showed a dose 734 dependent weight loss ranging from 3.8 to 7.8 kg with liraglutide doses of 1.2-3.0 mg administered for 52 735 weeks (20 weeks as double-blind and 32 weeks of open-label treatment (sponsor unblinded at 20 weeks). In 736 addition to weight lowering, there was a decrease in systolic blood pressure and an impact on the number of 737 subjects with pre-diabetes. In addition, of the approximately 30% of subjects who had pre-diabetes at 738 baseline, 85% did not have pre-diabetes after 20 weeks compared to 45% of placebo subjects. Of the 70% of 739 subjects without pre-diabetes at baseline, 20% of placebo subjects developed pre-diabetes, whereas only 2- 740 4% of liraglutide-treated subjects had pre-diabetes after 20 weeks. The safety evaluation was favourable with 741 the main tolerability finding being gastrointestinal side effects (please refer to liraglutide obesity 742 Investigators Brochure (IB), 3rd Edition, 2010) 743 744 The first of three confirmatory phase 3 trials within the liraglutide obesity development programme (Trial 745 NN8022-1923, or SCALE-Maintenance) was recently completed. Reporting is ongoing. The trial was a 56- 746 week randomised, double-blind, placebo-controlled trial investigating treatment of liraglutide 3.0 mg versus 747 placebo as an adjunct to diet and exercise in obese subjects or overweight subjects with co-morbidities who 748 had already lost at least 5% of their body weight during a 4 to 12-week run-in period on a low calorie diet. 749 The mean weight loss for subjects in the run-in period was approximately 6 kg. From a body weight of 750 approximately 100 kg at randomisation, treatment with liraglutide for 56 weeks provided an additional 751 estimated mean weight loss of 6.11% (-5.7 kg), compared to weight-neutrality or maintenance in the placebo 752 group (+0.16 kg vs. baseline). Eighty one (81) percent of liraglutide-treated subjects maintained their run-in 753 weight loss compared to 48% in the placebo group. Moreover, 51% of liraglutide-treated subjects lost 754 additional 5% or more of their baseline body weight, compared to 22% in the placebo group. Treatment with 755 liraglutide maintained and in some instances further improved beneficial effects on markers of glycaemic 756 control and cardiovascular risk. 757 758 Treatment with liraglutide was generally well-tolerated, with high completion rates in groups (75% in 759 liraglutide group, 70% in placebo group). The number of withdrawals due to adverse events was evenly 760 distributed between groups (8.5% in the liraglutide group vs. 8.6% in placebo group). Serious adverse events 761 were relatively uncommon, but were more frequent in liraglutide-treated subjects (4.2%) compared to 762 placebo (2.4%). There were no events of pancreatitis or medullary thyroid cancer, and no treatment-related 763 increases in blood calcitonin levels. Consistent with previous trials with liraglutide, the most commonly 764 reported adverse events were from the gastrointestinal system, with nausea reported by 47% of subjects in the 765 liraglutide group compared to 17% in the placebo groups, and vomiting by 17% vs. 2%, respectively. As

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766 Liraglutide 771 774 Date: 06 March 2012 Novo Nordisk 767 Trial ID: NN8022-1922 772 CONFIDENTIAL 775 Version: 6.0 768 Protocol - Revised edition 773 776 Status: Final 769 EudraCT No.: 2008-002199-88 777 Page: 22 of 133 778770 779 in previous trials, the majority of events were reported in the first 6-8 weeks, were mild or moderate in 780 severity and transient in nature. Please refer to liraglutide obesity Investigators Brochure, 3rd Edition, 2010, 781 or any updates hereof. 782 783 Signs and symptoms of dehydration, including renal impairment and acute renal failure have been reported 784 in patients treated with liraglutide. Patients treated with liraglutide should be advised of the potential risk of 785 dehydration in relation to gastrointestinal side effects and take precautions to avoid fluid depletion. 786 787 Few cases of acute pancreatitis (inflammation of the pancreas) presenting with persistent severe abdominal 788 pain (usually accompanied by vomiting) have been reported with liraglutide and exenatide. Post-marketing 789 surveillance identified at least 30 cases of pancreatitis with exenatide(14). However, a health services 790 registry-based study found no increased frequency of pancreatitis among exenatide users.(15) 791 792 If the investigator suspects acute pancreatitis, all suspected drugs should be discontinued until confirmatory 793 tests have been conducted, and appropriate treatment should be initiated. Subjects diagnosed with acute 794 pancreatitis (as a minimum 2 of 3: characteristic abdominal pain, amylase and/or lipase >3x UNR or 795 characteristic findings on CT/MRI) should be withdrawn from the study. 796 797 Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically 798 relevant exposures in both genders of rats and mice. It is unknown whether liraglutide causes thyroid C-cell 799 tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be ruled 800 out by clinical or nonclinical studies. Liraglutide is contraindicated in patients with a personal or family 801 history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Based on the 802 findings in rodents, monitoring with serum calcitonin or thyroid ultrasound was performed during clinical 803 trials, but this may have increased the number of unnecessary thyroid surgeries. It is unknown whether 804 monitoring with serum calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumors. 805 806 In a 2-year repeat subcutaneous dose carcinogenicity study of liraglutide injected once a day in CD-1 mice, a 807 treatment-related increase in fibrosarcomas was seen on the dorsal skin and subcutis, the body surface used 808 for drug injection, in males in the 3 mg/kg/day group. These fibrosarcomas were attributed to the high local 809 concentration of drug near the injection site. The liraglutide concentration in the clinical formulation (6 810 mg/mL) is 10 times higher than the concentration in the formulation used to administer 3 mg/kg/day 811 liraglutide to mice in the carcinogenicity study (0.6 mg/mL). 812 813 Further information can be obtained in the Liraglutide Investigator's Brochure Obesity, 3rd Edition, 2010 or 814 any updates hereof. 815 816 817 3.2 Rationale for the trial 818 The currently available treatment modalities for inducing weight loss in overweight or obese subjects with 819 type 2 diabetes (i.e. life style interventions and pharmacologic therapy) are still not satisfactory, as they 820 seldom offer adequate glycaemic control, or are associated with safety issues, undesired side effects or offer 821 no improvement in cardiovascular risk factors. Hence, there is a need and a strong incentive for development

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822 Liraglutide 827 830 Date: 06 March 2012 Novo Nordisk 823 Trial ID: NN8022-1922 828 CONFIDENTIAL 831 Version: 6.0 824 Protocol - Revised edition 829 832 Status: Final 825 EudraCT No.: 2008-002199-88 833 Page: 23 of 133 834826 835 of improved weight management agents for subjects with type 2 diabetes that address the unmet medical 836 needs. 837 838 Subjects with type 2 diabetes often have multiple unmet medical needs related to cardiovascular risk, 839 including hypertension and dyslipidemia. It has been consistently demonstrated that weight loss in subjects 840 with type 2 diabetes has a beneficial impact not only on glycaemic control, but also on other cardiovascular 841 risk markers. The present trial has been designed to show the effects of liraglutide in inducing weight loss in 842 overweight or obese subjects with type 2 diabetes, while improving glycaemic control and potentially 843 improving other markers of cardiovascular risk. 844 845 Treatment duration of 56 weeks is considered appropriate to demonstrate weight loss and subsequent weight 846 maintenance. In order to assess the effects of drug cessation on appetite and weight control, possible 847 withdrawal effects and rebound will be ascertained in the 12-week observational follow-up period.

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848 Liraglutide 853 856 Date: 06 March 2012 Novo Nordisk 849 Trial ID: NN8022-1922 854 CONFIDENTIAL 857 Version: 6.0 850 Protocol - Revised edition 855 858 Status: Final 851 EudraCT No.: 2008-002199-88 859 Page: 24 of 133 860852 861 4 Objectives and endpoints 862 863 4.1 Objectives 864 Hypothesis: 865 Liraglutide will induce and maintain weight loss significantly better than liraglutide placebo in overweight or 866 obese subjects with type 2 diabetes. 867 868 Primary objective: 869 To investigate the efficacy of liraglutide compared to liraglutide placebo in inducing and maintaining weight 870 loss in overweight or obese subjects with type 2 diabetes after 56 weeks 871 872 Secondary objectives: 873 To compare liraglutide and liraglutide placebo regarding the effect on: 874 • Parameters of glycaemic control 875 • Waist circumference 876 • Cardiovascular risk factors 877 • Attaining treatment targets of risk factors for subjects with type 2 diabetes 878 • Patient reported outcomes (PRO) 879 • Weight maintenance in the 12-week observational follow-up period 880 881 Safety objectives: 882 • To evaluate the safety and tolerability of liraglutide 883 884 885 4.2 Endpoint(s) 886 Primary efficacy endpoints: 887 • Change from baseline in body weight (fasting body weight) at 56 weeks 888 • Proportion of subjects losing at least 5% of baseline body weight at 56 weeks 889 • Proportion of subjects losing more than 10% of baseline body weight at 56 weeks 890 891 Secondary efficacy endpoints: 892 • Parameters of glycaemic control 893 Change from baseline (Week 0) to Week 56 in: 894 − HbA1c 895 − FPG 896 − 7-point plasma glucose profile (self-measured) 897 − Glucose metabolism related parameters incl. β-cell function (fasting glucagon, fasting insulin, fasting 898 C-peptide, pro-insulin: insulin ratio and homeostasis model assessment [HOMA] parameters(16)) 899 • Parameters of glycaemic control

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900 Liraglutide 905 908 Date: 06 March 2012 Novo Nordisk 901 Trial ID: NN8022-1922 906 CONFIDENTIAL 909 Version: 6.0 902 Protocol - Revised edition 907 910 Status: Final 903 EudraCT No.: 2008-002199-88 911 Page: 25 of 133 912904 913 − Proportion of subjects reaching target HbA1c (< 7% or ≤ 6.5% at Week 56) 914 • Proportion of subjects with change in concomitant medication from baseline to Week 56 in: 915 − Anti-hypertensives 916 − Lipid lowering agents 917 − Oral antidiabetic drugs 918 • Waist circumference 919 • Cardiovascular risk factors 920 Change from baseline (Week 0) to Week 56 in: 921 − Systolic and diastolic blood pressure (Vital signs) 922 − Lipids (cholesterol [TC], low density lipoprotein cholesterol [LDL cholesterol], high density 923 lipoprotein cholesterol [HDL cholesterol], very low density lipoprotein cholesterol [VLDL 924 cholesterol], triglycerides [TG], free fatty acids [FFA]) 925 − Cardiovascular biomarkers (high sensitivity C reactive protein [hsCRP], adiponectin, fibrinogen, 926 PAI-1) 927 − Urinary Albumin-to-Creatinine ratio 928 • Cardiovascular risk factors 929 − Proportion of subjects reaching American Diabetes Association (ADA) treatment targets for LDL 930 cholesterol (< 100 mg/dL) and triglycerides (< 150 mg/dL) 931 − Proportion of subjects who attain ADA treatment targets for blood pressure (< 130/80 mmHg) 932 • PRO assessed by Impact of Weight on Quality of Life – Lite (IWQoL-Lite) questionnaire and Diabetes 933 Treatment Satisfaction Questionnaire status version (DTSQs) 934 935 Observational follow-up efficacy endpoints: 936 • Weight change from baseline (Week 0) to Week 68 (fasting body weight) 937 • Weight change from Week 56 to Week 68 938 • Change in waist circumference from baseline (Week 0) to Week 68 939 • Change in waist circumference from Week 56 to Week 68 940 • Change in fasting plasma glucose from baseline (Week 0) to Week 68 941 • Change in vital signs from baseline (Week 0) to Week 68 942 • Change in vital signs from Week 56 to Week 68 943 • Change in Urinary Albumin-to-Creatinine ratio from Week 0 to Week 68 944 • Change in Urinary Albumin-to-Creatinine ratio from Week 56 to Week 68 945 946 Safety endpoints: 947 • Physical examination (cardiovascular system, respiratory system, abdomen, central and peripheral 948 nervous system, musculo-skeletal system and the thyroid gland) 949 • Hypoglycaemic episodes 950 • Electrocardiogram (ECG) 951 • Adverse events 952 • Haematology and biochemistry including amylase, lipase and calcitonin 953 • Pulse (Vital signs) 954 • Formation of liraglutide antibodies

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955 Liraglutide 960 963 Date: 06 March 2012 Novo Nordisk 956 Trial ID: NN8022-1922 961 CONFIDENTIAL 964 Version: 6.0 957 Protocol - Revised edition 962 965 Status: Final 958 EudraCT No.: 2008-002199-88 966 Page: 26 of 133 967959 968 • Mental health assessed by Columbia Suicidality Severity Rating Scale (C-SSRS) and Patient Health 969 Questionnaire (PHQ-9) 970 971 Observational follow-up safety endpoints: 972 • Hypoglycaemic episodes 973 • Adverse events 974 • Haematology (haemoglobin, haematocrit, thrombocytes, erythrocytes, leucocytes, differential count) 975 • Biochemistry (creatinine, CPK, urea, albumin, bilirubins (total), ALAT, ASAT, alkaline phosphatase, 976 sodium, potassium, calcium [total], amylase, lipase, calcitonin) 977 • In a subset of subjects: Change from baseline (Week 0) in Binge Eating (assessed by Binge Eating 978 Scale [BES]) to Week 56 and 58 979 • Mental health assessed by Columbia Suicidality Severity Rating Scale (C-SSRS) and Patient Health 980 Questionnaire (PHQ-9) 981 982 Other endpoints: 983 Plasma concentrations of liraglutide (PK sampling)

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984 Liraglutide 991 994 Date: 06 March 2012 Novo Nordisk 985 Trial ID: NN8022-1922 992 CONFIDENTIAL 995 Version: 6.0 986 Protocol - Revised edition 993 996 Status: Final 987 EudraCT No.: 2008-002199-88 997 Page: 27 of 133 988 989 5 Trial design 998990 999 1000 5.1 Type of trial 1001 This is a 56-week, randomised, double-blind, placebo-controlled, three armed, parallel group, multi-centre, 1002 multi-national trial comparing once daily administration of 3.0 mg and 1.8 mg of liraglutide with liraglutide 1003 placebo in overweight or obese subjects with type 2 diabetes. 1004 1005 A planned total of 800 subjects will be randomised. Based on an assumption of a 50% screening failure rate, 1006 1600 subjects will be screened. Subjects will be randomised in a 2:1:1 manner to receive 3.0 mg of 1007 liraglutide, 1.8 mg of liraglutide or liraglutide placebo as an add-on to their background diabetes treatment. 1008 The placebo arm will be further subdivided into two arms with different injection volumes corresponding to 1009 the different dose levels of liraglutide (see table Table 5–1). 1010 1011 This paragraph applies to all countries except France: The background treatment (diet and exercise only 1012 or single compound OAD treatment [metformin, SU or glitazone] or any combination OAD treatment 1013 [metformin+SU, metformin+glitazone, SU+glitazone, metformin+SU+glitazone]) must be stable (same drug 1014 or drugs [same INN(s) (International Non-proprietary Name)], dose and dosing frequency) for at least 3 1015 months prior to screening. 1016 1017 This paragraph is only applicable to France: The background treatment (single compound OAD treatment 1018 [metformin; SU (if presence of metformin contraindication or intolerance) or glitazone (if presence of 1019 metformin contraindication or intolerance)] or combination of two of the above mentioned OAD treatments 1020 [metformin+SU, metformin+glitazone, SU+glitazone]) must be stable (same drug or drugs [same INN(s) 1021 (International Non-proprietary Name)], dose and dosing frequency) for at least 3 months prior to screening. 1022 1023 To mitigate sulphonylurea induced hypoglycaemia, subjects treated with SU (either alone or in combination 1024 with other oral antidiabetic drugs [OADs]) will at screening (Visit 1) be asked to reduce the SU dose by 1025 50%. If already on minimum labelled dose at screening, a subject should remain on that dose unless 1026 unacceptable hypoglycaemia occurs, in which case the subject must be withdrawn 1027 1028 In case of consistent hyperglycaemia as described in section 6.5 glycaemic rescue i.e. intensification of 1029 background OAD treatment or addition of new background OADs should be implemented, but how 1030 specifically is at the discretion of the Investigator. 1031 1032 At the time of randomisation (Visit 2) the subjects will be stratified using an Interactive Voice/Web response 1033 system (IV/WRS) according to the following background diabetes treatment categories: 1034 1) diet and exercise only or single compound metformin treatment or 1035 2) single compound OAD treatment (sulphonylurea or glitazone) or combination OAD treatment 1036 (metformin+SU, metformin+glitazone, SU+glitazone, metformin+SU+glitazone). Subjects treated with SU 1037 or any combination of SU must not comprise more than 30% of total subjects

1038 Subjects in the two stratification groups will be further stratified into 2 groups by screening value of HbAlc 1039 (A. <8.5% or B. ≥8.5%).

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1040 Liraglutide 1045 1048 Date: 06 March 2012 Novo Nordisk 1041 Trial ID: NN8022-1922 1046 CONFIDENTIAL 1049 Version: 6.0 1042 Protocol - Revised edition 1047 1050 Status: Final 1043 EudraCT No.: 2008-002199-88 1051 Page: 28 of 133 10521044 1053 Proportion of subjects treated with SU mono- or combination therapy will be restricted to a maximum of 1054 30% of total randomised subjects. When target is reached, subjects treated with SU as background treatment 1055 may not be randomised in the trial. 1056 1057 The duration of the trial from screening to follow up will be 70 weeks per subject with a liraglutide/ 1058 liraglutide placebo treatment duration of 56 weeks. The trial will consist of a screening visit (Visit 1), a 4- 1059 week dose escalation period, a 52-week maintenance period and a 12-week observational follow-up period 1060 after last treatment. 1061 1062 Subjects that have discontinued the trial prematurely (before Visit 16) will be asked to attend the premature 1063 discontinuation Visit 16 and a visit 56 weeks after the randomisation date (Visit 16x). The purpose of this 1064 visit will be recording of the body weight and assessment of MESI. The assessment will be done by asking 1065 the subject if he/she has experienced any MESI (see section 12.2.1 and appendix H) since the last contact. 1066 1067 If the subject is not willing to attend Visit 16x, it should be documented in the patient medical record that the 1068 subject has refused to attend the visit. 1069 1070 PRO recordings will be performed in France, Germany, Spain, Sweden, United Kingdom and USA. 1071 1072 1073 5.2 Rationale for trial design 1074 Obesity is a serious medical condition that is increasing in incidence worldwide. Obesity induces metabolic 1075 abnormalities that contribute to the development of diabetes mellitus and cardiovascular disease, and it is 1076 associated with increased morbidity and mortality risk. The treatment modalities currently available for the 1077 treatment of obesity (i.e. lifestyle interventions, pharmacotherapy and surgery) have limited long-lasting 1078 success in producing major and sustained weight loss and are often associated with undesirable side effects. 1079 A need therefore exists for new and effective therapeutic strategies to prevent and reduce obesity. 1080 1081 Within the last decade, the ability of GLP-1 to decrease appetite and energy intake has been demonstrated in 1082 both lean and obese as well as diabetic and non-diabetic subjects. Furthermore, studies have shown that 1083 obese subjects have attenuated GLP-1 release in response to meals. 1084 1085 Results from a phase 2 trial in obese subjects without type 2 diabetes (NN8022-1807) showed a dose 1086 dependent weight loss ranging from 3.8 to 7.8 kg with liraglutide doses of 1.2-3.0 mg administered for 52 1087 weeks (20 weeks as double-blind and 32 weeks of open-label treatment (sponsor unblinded at 20 weeks). In 1088 addition to weight lowering, there was a decrease in systolic blood pressure and an impact on the number of 1089 subjects with pre-diabetes. In addition, of the approximately 30% of subjects who had pre-diabetes at 1090 baseline, 85% did not have pre-diabetes after 20 weeks compared to 45% of placebo subjects. Of the 70% of 1091 subjects without pre-diabetes at baseline, 20% of placebo subjects developed pre-diabetes, whereas only 2- 1092 4% of liraglutide-treated subjects had pre-diabetes after 20 weeks. The safety evaluation was favourable with 1093 the main tolerability finding being gastrointestinal side effects (please refer to liraglutide obesity 1094 Investigators Brochure (IB), 3rd Edition, 2010)

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1095 Liraglutide 1100 1103 Date: 06 March 2012 Novo Nordisk 1096 Trial ID: NN8022-1922 1101 CONFIDENTIAL 1104 Version: 6.0 1097 Protocol - Revised edition 1102 1105 Status: Final 1098 EudraCT No.: 2008-002199-88 1106 Page: 29 of 133 11071099 1108 The present trial is randomised and conducted as a double-blind trial to avoid bias in subject selection and 1109 the clinical evaluations/assessments. The trial design has been chosen to further investigate the potential of 1110 liraglutide to safely induce long term weight loss in overweight or obese type 2 diabetes. Treatment duration 1111 of 56 weeks is considered appropriate to demonstrate weight loss and subsequent weight maintenance. In 1112 order to assess the effects of drug cessation on appetite and weight control, possible withdrawal effects and 1113 rebound will be ascertained in the 12-week observational follow-up period. 1114 1115 A multi-centre design has been chosen to obtain the required number of subjects within the scheduled 1116 recruitment period. 1117 1118 A placebo-controlled trial design has been chosen to show that liraglutide (as an add-on to background 1119 diabetes treatment) is more effective in type 2 diabetes than lifestyle changes alone. 1120 1121 In order to comply with a regulatory request for bridging the safety and efficacy findings of the upper 1122 liraglutide dose of 3.0 mg in this study to the previously studied safety and efficacy of liraglutide 1.8 mg for 1123 the treatment of type 2 diabetes, a bridging arm consisting of 200 subjects randomised to liraglutide 1.8 mg 1124 per day has been included. The 1.8 mg dose of liraglutide has been demonstrated to be safe and efficacious 1125 for achieving glycaemic control in subjects with type 2 diabetes, but has not generated adequate weight loss 1126 to be selected as the optimal dose (3.0 mg) for weight management. 1127 1128 Subjects will be randomly assigned to one of the three treatment arms, and stratification with regards to the 1129 background treatment will rule out any bias linked to these treatment modalities. 1130 1131 To ensure sufficient exposure to liraglutide is obtained in subjects treated with non-SU based antidiabetic 1132 regimens, the proportion of randomised subjects treated with SU mono- or –combination therapy will be 1133 restricted to a maximum of 30%. 1134 1135 Subjects must have a stable body weight and be in a stable treatment with their background diabetes 1136 medication over a period of at least 3 months prior to screening. This will be done to rule out that change in 1137 safety and efficacy data will be due to changes in weight or background diabetes treatment. 1138 1139 Only subjects sub-optimally controlled on their background therapy are included, as defined by the 1140 requirement for an HbA1c value between 7.0 and 10.0% (both inclusive) at screening (Visit 1). 1141 1142 At screening, subjects treated with an SU, either as monotherapy or in combination with other oral 1143 antidiabetic drugs, will be required to reduce their SU dose by 50% or as close to 50% as possible based on 1144 dose options locally available. This is done to prevent hypoglycaemia induced by the combination of an SU 1145 and liraglutide, and possibly accentuated by weight loss. As a consequence, some subjects may experience 1146 early deterioration of glycaemic control, and to limit the number of subjects who would otherwise meet the 1147 FPG rescue criteria early in the study (and be excluded from analysis), a FPG randomisation criteria of 220 1148 mg/dL (12.2 mmol/L) has been included.

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1149 Liraglutide 1154 1157 Date: 06 March 2012 Novo Nordisk 1150 Trial ID: NN8022-1922 1155 CONFIDENTIAL 1158 Version: 6.0 1151 Protocol - Revised edition 1156 1159 Status: Final 1152 EudraCT No.: 2008-002199-88 1160 Page: 30 of 133 11611153 1162 5.3 Treatment of subjects 1163 Subjects will attend Visit 1 (screening visit) to assess their eligibility. If found eligible the subjects will 1164 return at Visit 2 (randomisation visit, Week 0) where they will be randomised in a 2:1:1 (3.0 mg of 1165 liraglutide, 1.8 mg of liraglutide or liraglutide placebo respectively) manner to one of the three treatment 1166 arms using a telephone/web randomisation system (IV/WRS). The placebo arm will be further subdivided 1167 into two arms with different injection volumes (clicks on the FlexPen®) corresponding to the different dose 1168 levels of liraglutide. See Table 5–1. 1169 1170 Table 5–1 Treatment of subjects 1171 Main- Rando- Dose escalation Scree tenance/ Follow- Trial periods misatio period/Maintenance -ning End of up n treatment Weeks in relation to Visit 2 -2 0 1 2 3 4-56 57-68 (randomisation)

Visit number 1 2 - 3 - 4-16 17-20

Liraglutide 0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg, 3.0 mg, N = 400 3.0 mg 10 clicks 20 clicks 30 clicks 40 clicks 50 clicks Liraglutide 0.6 mg, 1.2 mg, 1.8 mg, 1.8 mg, 1.8 mg, N = 200 1.8 mg Scree- 10 clicks 20 clicks 30 clicks 30 clicks 30 clicks No ning treatment Placebo Placebo, Placebo, Placebo, Placebo, Placebo, N = 150 500 μL 10 clicks 20 clicks 30 clicks 40 clicks 50 clicks Placebo Placebo, Placebo, Placebo, Placebo, Placebo, N = 50 300 μL 10 clicks 20 clicks 30 clicks 30 clicks 30 clicks 1172 1173 Following the end of the treatment, all trial drug treatment will be discontinued and the trial drug collected. 1174 Subjects will be advised with regards to the best possible post-trial treatment option for their weight 1175 management and type 2 diabetes at the discretion of the Investigator (with the exception of treatments listed 1176 in withdrawl criterion no.4 (see section 6.6) in the follow-up period). 1177 1178 5.3.1 Liraglutide/liraglutide placebo 1179 1180 Treatment with liraglutide or liraglutide placebo will be blinded to the subjects, the Investigator and the 1181 Novo Nordisk throughout the trial. 1182 1183 Liraglutide will be available at a concentration of 6.0 mg/mL. Liraglutide and liraglutide placebo will be 1184 supplied in a 3 mL FlexPen®. 1185 1186 Dosing with the liraglutide/liraglutide placebo FlexPen® is controlled by turning the dose selector until the 1187 dose indicator shows the relevant dose (10, 20, 30, 40 or 50 clicks equivalent to 0.6, 1.2, 1.8, 2.4 or 3.0 mg, 1188 respectively or placebo). 1 click equals 0.06 mg. Therefore, the dose level (injection volume) of liraglutide or 1189 placebo is open labelled.

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1190 Liraglutide 1195 1198 Date: 06 March 2012 Novo Nordisk 1191 Trial ID: NN8022-1922 1196 CONFIDENTIAL 1199 Version: 6.0 1192 Protocol - Revised edition 1197 1200 Status: Final 1193 EudraCT No.: 2008-002199-88 1201 Page: 31 of 133 12021194 1203 Liraglutide or liraglutide placebo is administered once daily by subcutaneous injections with the FlexPen®, 1204 either in the abdomen, thigh or upper arm. Injections can be done at any time of day irrespective of meals. 1205 However, it is preferable that liraglutide be injected during the same overall time period on a day to day 1206 basis. 1207 1208 Subjects will be instructed to perform an air shot before the first injection with the FlexPen®. For further 1209 information, please see the direction for use (DFU) for the liraglutide FlexPen®. These DFUs will be provided 1210 in local language together with the trial product. The Investigator must instruct subjects in how to inject 1211 liraglutide or liraglutide placebo, and must ensure that the subjects are familiar with the DFU. It must 1212 be documented in the subject’s medical record that the subject has been instructed in the use of the FlexPen®. 1213 1214 Subjects will follow a fixed dose escalation and in order to reduce the level of side effects, liraglutide is 1215 gradually escalated up to the maintenance dose. Subjects will be instructed to escalate the liraglutide (active 1216 or placebo) dose to 3.0 mg/day over a 4 week period or to 1.8 mg/day over a 2 week period, following an 1217 initial dose of 0.6 mg/day and weekly dose escalation steps of 0.6 mg/day. 1218 1219 If subjects do not tolerate an increase in dose during dose-escalation, the Investigator has the option to 1220 individualise the dose escalation with a total delay of up to 7 days. All subjects must be at the target dose of 1221 50 clicks/day (3.0 mg or placebo) at the latest 35 days after randomisation or 30 clicks/day (1.8 mg or 1222 placebo) at the latest 21 days after randomisation. 1223 1224 After reaching the target dose of 50 clicks per day (3.0 mg liraglutide or liraglutide placebo) or 30 clicks per 1225 day (1.8 mg liraglutide or liraglutide placebo), dose and dosing frequency should not be changed at any time 1226 during the treatment period. If any dose is missed by the subject up to and including 3 consecutive days it 1227 must be documented in the medical record and the Investigator should discuss the importance of treatment 1228 compliance with the subject. After a potential discontinuation up to 3 days the subject must be re-initiated on 1229 trial drug on target dose of 50 clicks per day (3.0 mg liraglutide or liraglutide placebo) or 30 clicks per day 1230 (1.8 mg liraglutide or liraglutide placebo). Missed doses for more than 3 consecutive days should be 1231 discussed with Sponsor and it will be up to Investigator’s judgement if the subject can continue on target dose 1232 or should be withdrawn. 1233 1234 It is always important that the Investigator emphasises to subjects the necessity of compliance with regard to 1235 taking trial drug as described in the protocol. It is the responsibility of the Investigator to access the subject’s 1236 overall compliance throughout the trial and subjects deemed to be non-compliant subjects should be 1237 withdrawn at the Investigator’s discretion. If subjects do not tolerate the target dose, they must be withdrawn 1238 from the trial except if withdrawal criteria no. 7 and/or no. 8 are suspected. 1239 1240 If the investigator suspects acute pancreatitis, all suspected drugs should be discontinued until confirmatory 1241 tests have been conducted. If tests reveal that a subject does not have acute pancreatitis, the subject can 1242 remain in the trial with re-initiation of titration until the target dose is reached. 1243 1244 The exact date, time, dose and site of injection of the 3 doses of trial product immediately prior to Visit 3, 6, 1245 and Visit 10, must be noted in the eCRF for evaluation of PK.

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1246 Liraglutide 1251 1254 Date: 06 March 2012 Novo Nordisk 1247 Trial ID: NN8022-1922 1252 CONFIDENTIAL 1255 Version: 6.0 1248 Protocol - Revised edition 1253 1256 Status: Final 1249 EudraCT No.: 2008-002199-88 1257 Page: 32 of 133 12581250 1259 5.3.2 Metformin, sulphonylurea and glitazone 1260 1261 In this trial, metformin, sulphonylurea and glitazone are characterised as background medication (non- 1262 investigational products) and will be used open-labelled throughout the trial. The drugs will not be provided 1263 by Novo Nordisk. 1264 1265 If FPG is repeatedly above the limits of hyperglycaemia as described in section 6.5, glycaemic rescue with 1266 intensification of background OAD treatment or addition of new background OADs should be implemented, 1267 but how specifically is at the discretion of the Investigator. 1268 1269 Subjects treated with SU (either alone or in combination with other OADs), will at screening (Visit 1) be 1270 required to reduce the SU dose by 50% or as close to 50% as possible based on dose options locally 1271 available. If already on minimum labelled dose at screening, a subject should remain on that dose unless 1272 unacceptable hypoglycaemia occurs, in which case the subject must be withdrawn. 1273 1274 In case a subject is on an OAD (metformin, SU, glitazone) which becomes unavailable during the course of 1275 the trial it is allowed as per the discretion of the investigator to shift to an alternative treatment within the 1276 other OAD classes allowed in the protocol. 1277 1278 If the FPG falls below 6.1 mmol/L (110 mg/dL) as analysed by the central laboratory, it should be 1279 considered to reduce the OAD treatment at the Investigator’s discretion. 1280 1281 The subject should receive the best standard of care at the discretion of the Investigator. Glycaemic goals 1282 should follow recommendations laid out in “Standards of Medical Care in Diabetes”(17), i.e. HbA1c <7%. If 1283 Investigator determines that insulin, GLP-1 receptor agonist (e.g., Byetta® or Victoza®), or DPP-IV 1284 inhibitor, is the best treatment option, the subject must be withdrawn (withdrawal criterion no. 4, see section 1285 6.6). 1286 1287 5.3.3 Counselling on Diet and Physical Activity 1288 1289 At Visit 2 subjects will receive dietary counselling (either in a group or individually) by a qualified dietician 1290 according to local standard and placed on a hypo caloric diet containing max. 30% of energy from fat, 1291 approximately 20% of energy from protein, approximately 50% of energy from carbohydrates and an energy 1292 deficit of approximately 500 kcal/day compared to the subjects’ estimated total energy expenditure (TEE) 1293 (See section 5.3.3.1). 1294 1295 The hypo-caloric diet is continued after randomisation and throughout the treatment period. If after 28 weeks 1296 of treatment the subjects are unable to lose additional weight despite having a BMI ≥25, re-calculation of the 1297 recommended energy intake with no calorie deficit (maintenance diet) is accepted. If a BMI ≤22 is reached 1298 the recommended energy intake should be re-calculated with no calorie deficit (maintenance diet) for the 1299 remainder of the trial. 1300 1301 Counselling on diet and physical activity (either in a group or individually) will be provided every month, 1302 with the exception of Visit 15 and 16 where visits are 6 weeks apart.

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1303 Liraglutide 1308 1311 Date: 06 March 2012 Novo Nordisk 1304 Trial ID: NN8022-1922 1309 CONFIDENTIAL 1312 Version: 6.0 1305 Protocol - Revised edition 1310 1313 Status: Final 1306 EudraCT No.: 2008-002199-88 1314 Page: 33 of 133 13151307 1316 Adherence to the visit schedule is a recommendation as counselling can be done either in a group or 1317 individually at the dietician’s discretion. 1318 1319 All subjects are instructed by dieticians to keep a 3-day diary of food intake between Visits 1 and 2, Visits 4 1320 and 5b, Visits 6 and 7, Visits 8 and 9, Visits 10 and 11, Visits 12 and 13, Visits 15 and 16, Visits 18 and 19. 1321 The 3-day food diaries will be used for counselling at Visit 2, 5b, 7, 9, 11, 13, 16 and 19. 1322 1323 The subject’s dietary compliance and the average daily level of physical activity will be recorded at Visit 2 1324 (only average daily level of physical activity), 5b, 7, 9, 11, 13, 16, and 19. The subject will be questioned 1325 whether they performed less than half an hour, between half an hour and one hour or more than 1 hour of 1326 physical activity per day. An increase in physical activity (recommended minimum 150 minutes/week) will 1327 be encouraged and re-enforced by use of pedometers. 1328 Whether or not the subject is in compliance with the prescribed diet is at the discretion of the dietician after 1329 review of the 3-day food diaries. 1330 1331 5.3.3.1 Calculation of estimated total energy expenditure 1332 The TEE is calculated by multiplying the estimated Basal Metabolic Rate (BMR) (see Table 5–2) with a 1333 Physical Activity Level (PAL) value of 1.3(18): 1334 1335 Total Energy Expenditure (TEE) (kcal/day) = BMR x 1.3 1336

1337 Table 5–2 Equations for estimating basal metabolic rate (BMR) in kcal/day*

13391338 1340 Sex Age BMR (kcal/day)

13421341 1343 Men 18-30 years 15.057 x actual weight in kg + 692.2 1344 31-60 years 11.472 x actual weight in kg + 873.1 1345 ≥ 60 years 11.711 x actual weight in kg + 587.7 1346 1347 Women 18-30 years 14.818 x actual weight in kg + 486.6 1348 31-60 years 8.126 x actual weight in kg + 845.6 1349 ≥ 60 years 9.082 x actual weight in kg + 658.5

13511350 1352 * Revised WHO equations(18). 1353 1354 1355 5.4 Rationale for treatment 1356 Based on a balanced evaluation of the efficacy and safety/tolerability results from the double-blinded phase 1357 2 dose-range finding trial (NN8022-1807) and subsequent 32 week open label extension, a dose of 3.0 mg 1358 has been chosen as the optimal dose for the weight management indication for liraglutide and will therefore 1359 be further investigated in this confirmatory trial. Liraglutide 3.0 mg induced a clinically relevant weight loss 1360 from baseline, while improving weight-related risk factors, such as waist circumference, systolic blood 1361 pressure and glucose control. The safety of 3.0 mg liraglutide was satisfactory with the main tolerability 1362 issue identified being gastro-intestinal side-effects (nausea, diarrhoea and vomiting). The gastro-intestinal

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1363 Liraglutide 1368 1371 Date: 06 March 2012 Novo Nordisk 1364 Trial ID: NN8022-1922 1369 CONFIDENTIAL 1372 Version: 6.0 1365 Protocol - Revised edition 1370 1373 Status: Final 1366 EudraCT No.: 2008-002199-88 1374 Page: 34 of 133 13751367 1376 side effects were predominantly mild to moderate in severity, were mostly transient in nature and were 1377 primarily present during the first 6-8 weeks of treatment. 1378 1379 Liraglutide titration in weekly steps to achieve the target dose of 50 clicks (3.0 mg or placebo) or 30 clicks 1380 (1.8 mg or placebo) is applied in order to reduce the incidence and severity of gastrointestinal side effects. 1381 1382 To increase safety, subjects will be seen more frequently during the initial part of the trial, and they will be 1383 informed to contact the Investigator in the event of any safety issues. Subjects may at all times be withdrawn 1384 from the trial for safety reasons. 1385 1386 All subjects will continue pre-trial treatment. To ensure adequate exposure in subjects treated with other 1387 (non-SU) antidiabetic regimens a proportion of subjects treated with SU mono- or combination therapy at 1388 screening is restricted to a maximum of 30% of randomised subjects. Subjects treated with sulphonylureas 1389 will be asked to reduce the dose by 50% to prevent SU-induced hypoglycaemia. Even though this may 1390 worsen glycaemic control initially, reinforcement of rescue criteria (see section 6.5) to reinstate pre-trial dose 1391 levels and addition of rescue medication should ensure adequate glycaemic control even for subjects on SUs 1392 randomised to liraglutide placebo. 1393 1394 Based on data from the ongoing clinical development program of liraglutide, the current trial is anticipated to 1395 confirm the safety and efficacy of liraglutide in inducing body weight reduction in overweight or obese 1396 subjects with type 2 diabetes. 1397 1398 For further information please refer to the liraglutide obesity Investigators Brochure 3rd edition 2010 and any 1399 subsequent updates thereof.

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1400 Liraglutide 1407 1410 Date: 06 March 2012 Novo Nordisk 1401 Trial ID: NN8022-1922 1408 CONFIDENTIAL 1411 Version: 6.0 1402 Protocol - Revised edition 1409 1412 Status: Final 1403 EudraCT No.: 2008-002199-88 1413 Page: 35 of 133 1404 1405 6 Trial population 14141406 1415 1416 6.1 Number of subjects to be studied 1417 Countries planned to participate: France, Germany, Israel, South Africa, Spain, Sweden, Turkey, United 1418 Kingdom and USA. 1419 Planned number of subjects to be screened: 1600

Planned number of subjects to be randomised/started on trial products: 800

Planned number of subjects to complete the trial: 480

Anticipated number of trial sites: 130 1420 1421 The anticipated screening failure rate of 50% and the anticipated drop-out rate at 56 weeks of 40% are based 1422 on reported rates from obesity and diabetes trials. 1423 1424 1425 6.2 Inclusion criteria 1426 1. Informed consent obtained before any trial-related activities (trial related activities are any procedure that 1427 would not have been performed during the normal management of the subject) 1428 2. Subjects diagnosed with type 2 diabetes and treated with either diet and exercise alone, metformin, 1429 sulphonylurea, glitazone as single agent therapy or any combination of the previously mentioned 1430 compounds (metformin+SU, metformin+glitazone, SU+glitazone, metformin+SU+glitazone). Treatment 1431 should have been stable for at least 3 months prior to screening 1432 Only applicable to France: Subjects diagnosed with type 2 diabetes and treated with either metformin as 1433 single agent therapy, SU as single agent therapy (if presence of metformin contraindication or 1434 intolerance), glitazone as single agent therapy (if presence of metformin contraindication or intolerance), 1435 or combination therapy of two of the above mentioned compounds: metformin+SU, 1436 metformin+glitazone, SU+glitazone. Treatment should have been stable for at least 3 months prior to 1437 screening

1438 3. HbA1c 7.0-10.0% (both inclusive) 2 1439 4. Body Mass Index (BMI) ≥ 27.0 kg/m 1440 5. Stable body weight (less than 5 kg self-reported change during the previous 3 months) 1441 6. Preceding failed dietary effort 1442 7. Age 18 years and above (or as allowed according to local labelling for metformin and sulphonylurea 1443 treatment) 1444 1445 1446 6.3 Exclusion criteria 1447 1. Treatment with GLP-1 receptor agonists (including liraglutide or exenatide), DPP-4 inhibitors or insulin 1448 within the last 3 months

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1449 Liraglutide 1454 1457 Date: 06 March 2012 Novo Nordisk 1450 Trial ID: NN8022-1922 1455 CONFIDENTIAL 1458 Version: 6.0 1451 Protocol - Revised edition 1456 1459 Status: Final 1452 EudraCT No.: 2008-002199-88 1460 Page: 36 of 133 14611453 1462 2. Treatment with any hypoglycaemic agent(s) other than metformin, sulphonylurea and glitazone in the 1463 3 months prior to screening 1464 3. Recurrent major hypoglycaemia or hypoglycaemic unawareness as judged by the Investigator 1465 4. Use of any drug (except for metformin, sulphonylurea or glitazone), which in the Investigator’s opinion 1466 could interfere with glucose level (e.g. systemic corticosteroids) 1467 5. Receipt of any other anti-diabetic investigational drug within 3 months prior to screening for this trial, or 1468 receipt of any investigational drugs not affecting diabetes within 1 month prior to screening for this trial 1469 6. Known proliferative retinopathy or maculopathy requiring acute treatment, as judged by the Investigator 1470 7. Untreated or uncontrolled hypothyroidism/hyperthyroidism defined as TSH > 6 mIU/L or < 0.4 mIU/L 1471 8. History of chronic pancreatitis or idiopathic acute pancreatitis 1472 9. Obesity induced by other endocrinologic disorders (e.g. Cushing Syndrome) 1473 10. Current or history of treatment with medications that may cause significant weight gain, within 3 months 1474 prior to screening for this trial, including systemic corticosteroids (except for a short course of treatment, 1475 i.e., 7- 10 days), tri-cyclic antidepressants, atypical antipsychotic and mood stabilizers (e.g., imipramine, 1476 amitryptiline, mirtazapin, paroxetine, phenelzine, clorpromazine, thioridazine, clozapine, olanzapine, 1477 valproic acid and its derivatives, and lithium) 1478 11. Diet attempts using herbal supplements or over-the-counter medications within 3 months prior to 1479 screening into this trial 1480 12. Current participation in an organised weight reduction program (or within the last 3 months) and/or are 1481 currently using or have used within three months prior to screening for this trial: pramlintide, 1482 sibutramine, orlistat, zonisamide, topiramate or phenteremine (either by prescription or as part of a 1483 clinical trial) 1484 13. Participation in a clinical trial within the last 3 months prior to screening for this trial 1485 14. Previous surgical treatment for obesity (excluding liposuction if performed > one year before trial entry) 1486 15. Screening calcitonin value ≥ 50 ng/L 1487 16. Familial or personal history of multiple endocrine neoplasia type 2 or familial medullary thyroid 1488 carcinoma 1489 17. Personal history of non-familial medullary thyroid carcinoma 1490 18. Simultaneous participation in any other clinical trial of an investigational drug 1491 19. History of Major Depressive Disorder within the last 2 years 1492 20. A PHQ-9 score of ≥ 15 1493 21. History of other severe psychiatric disorders, e.g., schizophrenia, bipolar disorder 1494 22. Any lifetime history of a suicide attempt 1495 23. A history of any suicidal behaviour in the last month prior to randomisation 1496 24. Any suicidal ideation of type 4 or 5 on the C-SSRS in the last month prior to randomisation 1497 25. Surgery scheduled for the trial duration period, except for minor surgical procedures, at the discretion of 1498 the Investigator 1499 26. Uncontrolled treated/untreated hypertension (systolic blood pressure ≥ 160 mmHg and/or diastolic blood 1500 pressure ≥ 100 mmHg). If white coat hypertension is suspected at the screening visit (Visit 1) a repeated 1501 measurement at Visit 2 prior to other trial related activities is allowed 1502 27. Cancer (past or present except basal cell skin cancer or squamous cell skin cancer), which in the 1503 Investigator’s opinion could interfere with the results of the trial 1504 28. Known or suspected hypersensitivity to trial product(s) or related product(s)

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1505 Liraglutide 1510 1513 Date: 06 March 2012 Novo Nordisk 1506 Trial ID: NN8022-1922 1511 CONFIDENTIAL 1514 Version: 6.0 1507 Protocol - Revised edition 1512 1515 Status: Final 1508 EudraCT No.: 2008-002199-88 1516 Page: 37 of 133 15171509 1518 29. Previous participation in the randomised phase of this trial. Re-screening is allowed once within the 1519 limits of the recruitment period 1520 30. Known or suspected abuse of alcohol or narcotics 1521 31. Language barrier, mental incapacity, unwillingness or inability to understand and be able to complete the 1522 mental health questionnaires in the provided language 1523 32. Subjects from the same house hold participating in the trial 1524 33. Females of childbearing potential who are pregnant, breast-feeding or intend to become pregnant or are 1525 not using adequate contraceptive methods (adequate contraceptive measures as required by local law or 1526 practice) US: abstinence and the following methods: diaphragm with spermacide, condom with 1527 spermacide (by male partner), intrauterine device, sponge, spermacide, Norplant®, Depo-Provera® or 1528 oral contraceptives. Germany: adequate contraceptive measures are implants, injectables, combined 1529 oral contraceptives, hormonal IUD, sexual abstinence or vasectomised partner). UK: adequate 1530 contraceptive measures are defined as sterilisation, intra-uterine device, oral contraceptives, consistent 1531 use of barrier methods, male sterilisation or true abstinence 1532 34. The receipt of any investigational product within four weeks prior to screening for this trial (Visit 1) 1533 1534 Only applicable to France: The following exclusion criteria are applicable for France in addition to the 1535 criteria listed above: 1536 • Treatment with diet and exercise only 1537 • Treatment with sulphonylurea as single agent therapy or glitazone as single agent therapy, unless the 1538 patient has metformin contraindication or metformin intolerance 1539 • Treatment with triple oral antidiabetic therapy 1540 • Abnormality of the thyroid identified during the physical exam at screening 1541 1542 Proportion of subjects treated with SU mono- or combination therapy will be restricted to a maximum of 1543 30% of total randomised subjects. When target is reached, subjects treated with SU as background treatment 1544 may not be randomised in the trial. 1545 1546 Subjects who are non-compliant with any of the eligibility criteria, but included in the trial, should be 1547 withdrawn immediately. If extraordinary circumstances speak in favour of maintaining the subject in the trial 1548 then this is only acceptable if justified and approved by the Independents Ethics Committee 1549 (IEC)/Institutional Review Board (IRB), and if the regulatory authorities are notified according to local 1550 requirements 1551 1552 Investigators are recommended to refer screening failure subjects having a calcitonin value of 50 ≥ ng/L to 1553 an endocrinologist for follow-up. 1554 1555 1556 6.4 Randomisation criteria 1557 In order to be eligible for randomisation in the trial, subjects must comply with the following: 1558 1559 1. At the randomisation visit (Visit 2) the fasting plasma glucose (FPG) must be <12.2 mmol/L 1560 (220 mg/dL) as measured by the Investigator at the clinic, by use of a glucose meter. A mean of two

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1561 Liraglutide 1566 1569 Date: 06 March 2012 Novo Nordisk 1562 Trial ID: NN8022-1922 1567 CONFIDENTIAL 1570 Version: 6.0 1563 Protocol - Revised edition 1568 1571 Status: Final 1564 EudraCT No.: 2008-002199-88 1572 Page: 38 of 133 15731565 1574 consecutive measurements (using two strips) should be used. If FPG is above or equal to the limit stated 1575 above the randomisation may be postponed once within the Visit 2 visit window 1576 1577 1578 6.5 Rescue criteria 1579 1. If self measured FPG on three consecutive days/occasions exceeds the limits set below, the subject 1580 should contact the Investigator and come in for an unscheduled visit as soon as possible. The next 1581 scheduled visit should not be awaited. A FPG should be obtained and analysed by the central laboratory. 1582 If this FPG exceeds the limits set below, the background medication dose should initially be escalated to 1583 the maximal approved dose, followed by addition of one of the other allowed background OADs (for 1584 subjects on diet/exercise alone, treatment with a permitted OAD should be initiated at the discretion of 1585 the Investigator): 1586 1587 − From baseline to Week 6: FPG > 15 mmol/L (270 mg/dL) 1588 − From Week 7 to Week 12: FPG > 13.3 mmol/L (240 mg/dL) 1589 − From Week 13 to Week 56: FPG > 11.1 mmol/L (200 mg/dL) 1590 1591 2. If any of the FPG or HbA1c samples analysed by the central laboratory exceeds the limits set below, the 1592 subject should immediately be called in for an unscheduled visit as soon as the result has come to the 1593 knowledge of the Investigator. The next scheduled visit should not be awaited. A new FPG should be 1594 obtained and analysed by the central laboratory and if this FPG exceeds the limits set below the 1595 background medication dose should initially be escalated to the maximal approved dose, followed by 1596 addition of one of the other allowed background OADs (for subjects on diet/exercise alone, treatment 1597 with a permitted OAD should be initiated at the discretion of the Investigator): 1598 1599 − From baseline to Week 6: FPG > 15 mmol/L (270 mg/dL) 1600 − From Week 7 to Week 12: FPG > 13.3 mmol/L (240 mg/dL) 1601 − From Week 13 to Week 56: FPG > 11.1 mmol/L (200 mg/dL) or HbA1c > 8% 1602 1603 1604 6.6 Withdrawal criteria 1605 The subject may be withdrawn from the trial at the discretion of the Investigator or Novo Nordisk due to a 1606 safety concern or if judged non-compliant with trial procedures. 1607 1608 A subject must be withdrawn if the following applies: 1609 1610 1. The subject may withdraw from the trial at will at any time. 1611 2. If the target treatment dose of the randomised trial product is not tolerated by the subject 1612 3. Pregnancy or intention to become pregnant 1613 4. If insulin, GLP-1 receptor agonist (e.g. Byetta® or Victoza®) or DPP-4 inhibitor treatment is initiated 1614 5. If adaptation of background OADs does not result in fasting plasma glucose or HbA1c levels below 1615 those specified as rescue criteria (section 6.5) within 8 weeks.

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1616 Liraglutide 1621 1624 Date: 06 March 2012 Novo Nordisk 1617 Trial ID: NN8022-1922 1622 CONFIDENTIAL 1625 Version: 6.0 1618 Protocol - Revised edition 1623 1626 Status: Final 1619 EudraCT No.: 2008-002199-88 1627 Page: 39 of 133 16281620 1629 6. If a subject despite lowering of background anti-diabetic treatment experiences severe episodes of major 1630 hypoglycaemia or repeated minor hypoglycaemic episodes (as judged by the investigator). 1631 7. If the investigator suspects acute pancreatitis, all suspected drugs should be discontinued until 1632 confirmatory tests have been conducted and appropriate treatment should be initiated. Subjects that are 1633 diagnosed with acute pancreatitis (as a minimum 2 of 3: characteristic abdominal pain, amylase and/or 1634 lipase >3x UNR or characteristic findings on CT/MRI), must be withdrawn from the trial. 1635 8. A subject must be referred to a Mental Health Professional (MHP) if he/she has 1636 1637 • a PHQ-9 score ≥ 10, OR, 1638 • any suicidal behaviour, OR, 1639 • any suicidal ideation of type 4 (active suicidal ideation with some intent to act, without specific plan) 1640 or type 5 (active suicidal ideation with specific plan and intent) on any C-SSRS assessment. 1641 1642 - A referral to a Mental Health Professional (MHP) should also be made if in the opinion of the 1643 Investigator it is necessary for the safety of the subject. If a subject’s psychiatric disorder can be 1644 adequately treated with psycho- and/or pharmacotherapy, then the subject, at the discretion of the 1645 Investigator (in agreement with the MHP), may be continued in the trial on randomised therapy, 1646 otherwise, the subject must be withdrawn. 1647 1648 The Investigator should carefully explain to the subject why the referral and psychiatric evaluation by a 1649 MHP is needed if one or more referral criteria are met. If the subject refuses to be referred to a MHP after the 1650 recommendation and explanation from the Investigator, the subject’s decision should be documented in the 1651 medical record and the Investigator must assess if it is safe for the subject to continue in the trial or if the 1652 subject should be withdrawn. 1653 1654 1655 Only applicable to France: 1656 9. Confirmed calcitonin value ≥ 50 ng/L 1657 1658 In case of withdrawal, the End of Trial (EOT) Form in the case report form (eCRF) must be completed and if 1659 possible, the subject should be called in for a final visit. Procedures according to Visit 16 should be 1660 performed. 1661 1662 Subjects who have discontinued the trial prematurely will be asked to attend a visit taking place 56 weeks 1663 after the randomisation date (Visit 2). The purpose of this visit will be recording of the body weight and 1664 reporting of MESI. 1665 1666 1667 6.7 Subject replacement 1668 Withdrawn subjects will not be replaced. However, re-screening is allowed once within the limits of the 1669 recruitment period, at the Investigator’s discretion. 1670 If a subject is re-screened, a new subject number has to be assigned and new informed consent must be 1671 completed, all screening visit 1 blood sampling and assessments have to be repeated.

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1672 Liraglutide 1677 1680 Date: 06 March 2012 Novo Nordisk 1673 Trial ID: NN8022-1922 1678 CONFIDENTIAL 1681 Version: 6.0 1674 Protocol - Revised edition 1679 1682 Status: Final 1675 EudraCT No.: 2008-002199-88 1683 Page: 40 of 133 16841676 1685 6.8 Rationale for trial population 1686 Overweight or obese subjects with type 2 diabetes have been selected for this trial in line with the trial 1687 objectives of investigating the efficacy of liraglutide compared to placebo with regard to weight loss and 1688 glycaemic control in this population. The intended treatment population is any overweight or obese subject 1689 with type 2 diabetes (treated with either: diet and exercise alone, with a single OAD or combination OAD 1690 (Only applicable to France: treated with a single OAD or dual combination OAD)). To ensure adequate 1691 exposure in subjects treated with other (non-SU) antidiabetic regimens a proportion of subjects treated with 1692 SU mono- or combination therapy at screening is restricted to a maximum of 30% of randomised subjects. 1693 The inclusion criterion defining HbA1c levels will ensure that at the start of the trial, the glycaemic control of 1694 participating subjects is appropriate for treatment intensification. Furthermore, rescue criteria are defined to 1695 ensure that subjects are considered for glycaemic rescue if plasma glucose levels exceed acceptable limits 1696 during trial participation. 1697 1698 The requirement for stable body weight and stable background type 2 diabetes treatment for at least 3 months 1699 prior to screening is implemented in order to ensure that change in glycaemic control and body weight 1700 observed during the trial is solely caused by the trial treatments.

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1701 Liraglutide 1708 1711 Date: 06 March 2012 Novo Nordisk 1702 Trial ID: NN8022-1922 1709 CONFIDENTIAL 1712 Version: 6.0 1703 Protocol - Revised edition 1710 1713 Status: Final 1704 EudraCT No.: 2008-002199-88 1714 Page: 41 of 133 1705 1706 7 Trial schedule 17151707 1716 Planned duration of recruitment period 16 weeks 1717 1718 Planned date for first subject (FPFV) 01-Jun-2011 1719 1720 Planned completion of the last subject (LPLV) Jan-2013 1721 1722 Planned completion of clinical trial report Jun-2013 1723 1724 The end of the clinical trial is defined as the last visit of the last subject (LPLV) globally. 1725 1726 The recruitment will be evaluated by Novo Nordisk on a continuous basis and country and regional specific 1727 contingency measures may be applied. A Competitive recruitment may be applied if deemed needed. 1728 1729 To ensure that only the required number of subjects is randomised, screened subjects will be monitored 1730 closely via IV/WRS. 1731 1732 All Investigators will be notified immediately when the enrolment period comes to an end, after which no 1733 subjects must be screened, and the IV/WRS will be closed for further screening and randomisation. 1734 1735 Protocol information for this trial will be subject to public disclosure at external web sites 1736 (www.clinicaltrials.gov and www.novonordisk-trials.com) according to international regulations e.g. the 1737 International Committee of Medical Journal Editors (ICMJE) (19), the Food and Drug Administration 1738 Amendments Act (FDAAA) (20) - as reflected in Novo Nordisk Code of Conduct for Clinical Trial 1739 Disclosure.

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1740 Liraglutide 1745 1748 Date: 06 March 2012 Novo Nordisk 1741 Trial ID: NN8022-1922 1746 CONFIDENTIAL 1749 Version: 6.0 1742 Protocol - Revised edition 1747 1750 Status: Final 1743 EudraCT No.: 2008-002199-88 1751 Page: 42 of 133 17521744 1753 8 Methods and assessments 1754 1755 8.1 Visit Procedures 1756 Before screening takes place subjects will be provided with written and verbal information about the trial and 1757 the procedures involved. Qualified site staff in accordance with local law will ensure that subjects are fully 1758 informed both verbally and in writing about the practical consequences of participating, of their rights and 1759 responsibilities while participating in the trial as well as any possible advantages and disadvantages in being 1760 treated with the trial products. Subjects will have the opportunity to ask questions to a medically qualified 1761 person and have ample time to consider participation. Subjects who wish to participate must give signed and 1762 dated informed consent. This must be done prior to any trial related activities, i.e. procedures that would not 1763 have been performed during normal management of the subject. 1764 1765 It must be stated in the medical record that the subject is participating in the current trial. Subjects enrolled in 1766 the trial will be provided with a subject ID card, stating that they are participating in a trial and whom to 1767 contact (site address, Investigator’s name and telephone number) for further information, if necessary. The 1768 subjects should be reminded to show the card to other health care providers, as applicable. The subjects 1769 should be instructed to return the card to the Investigator at the last visit of the subject or destroy the card 1770 after the last visit 1771 1772 The Investigator must keep a subject screening log and a subject enrolment log.These can be combined in 1773 one document. 1774 1775 For screening failures (subjects who have given informed consent but who do not meet the inclusion, 1776 exclusion and/or randomisation criteria and hence are not randomised), all data for completed trial 1777 procedures should be recorded in the eCRF, and the reason for exclusion from the trial should be recorded on 1778 the screening failure form. The screening failure form will be entered into the clinical database. Serious and 1779 non-serious adverse events from screening failures will be entered by the Investigator into the electronic 1780 CRFs and consequently transferred to the clinical database. When trial related procedures have been finalised 1781 for screening failures, no more adverse events should be entered in the eCRF. Follow-up of AEs should be 1782 made according to section 12. In addition screening failures should be registered in the IV/WRS. As a 1783 minimum, the reason for screening failure must be recorded in the eCRF 1784 1785 Investigators are recommended to refer screening failure subjects having a calcitonin value of ≥ 50 ng/L to 1786 an endocrinologist for follow-up. 1787 1788 Trial product should be taken once daily at a time convenient to the subject; however, it is preferable that 1789 liraglutide/liraglutide placebo be injected during the same overall time period on a day to day basis. The 1790 injection site does not have to be consistent throughout the trial. 1791 1792 At Visit 2, 3, 4, 5b 7, 8, 10, 13, 15, 16, 16x, 17 and 20 the subject must attend the clinic in a fasting condition 1793 in the morning (i.e., at least eight hours overnight fast without food and/or drink intake, except for water).

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1794 Liraglutide 1799 1802 Date: 06 March 2012 Novo Nordisk 1795 Trial ID: NN8022-1922 1800 CONFIDENTIAL 1803 Version: 6.0 1796 Protocol - Revised edition 1801 1804 Status: Final 1797 EudraCT No.: 2008-002199-88 1805 Page: 43 of 133 18061798 1807 Background medication and the trial product should be withheld on the day of the fasting Visits 2, 3, 4, 5b, 7, 1808 8, 10, 13, 15, 16, 17, and Visit 20, until blood sampling has been done. At all other visits the background 1809 medication and trial product should be taken as usual during the conduct of the trial. 1810 1811 Weight will be measured at all visits to the clinic, hence at those visits subjects attend fasting, weight will be 1812 measured in a fasting state, whereas at all other visits weight will be measured in a non-fasting state. 1813 1814 Trial product will be dispensed at visits 2, 4 and 5b-15. Subjects will be asked to bring all empty, partly used 1815 and unused trial product at visits 4 and 5b-16 for drug accountability. The IV/WRS should be contacted for 1816 trial product dispensing. If the subject attends the clinic for a visit not described in the protocol, then an 1817 Unscheduled Visit Form must be completed. The Unscheduled Visit Form should not be completed if the 1818 sole purpose of the visit is trial product dispensing. If an unscheduled visit is made for the purpose of 1819 dispensing trial products to the subjects then an unscheduled dispensing session must be completed in the 1820 IV/WRS. If the subject attends a fasting visit in a non-fasting state the subject should preferably be called in 1821 for a new visit within the visit window to have the fasting weight and fasting circumference measured and 1822 the fasting blood samples drawn. All other assessments can be performed even though the subject is not 1823 fasting. If it is not possible to attend the new visit within the visit window, the subjects should be called in for 1824 an Unscheduled Visit and the original visit page in the eCRF should be used to obtain information on fasting 1825 weight, fasting circumference and fasting blood samples by overwriting the original date and readings. 1826 1827 In case a subject is being prematurely withdrawn from the trial before or at visit 16, the Investigator will 1828 ensure that the procedures for the End of Treatment visit (Visit 16) are undertaken, if possible. If a subject is 1829 being prematurely withdrawn from the trial after visit 16 or at Visit 17, the Investigator will ensure that the 1830 procedures for Visit 17 are undertaken, if possible. If a subject is being prematurely withdrawn from the trial 1831 after Visit 16 or Visit 17, the Investigator will ensure that the procedures for the follow-up visit (Visit 20) are 1832 undertaken, if possible. The primary reason (adverse event, non-compliance with protocol or other) for 1833 discontinuation must be specified in the eCRF and an IV/WRS withdrawal session should be completed. 1834 Even if the subject is not able to attend a final visit, the End of Trial Form (EOT) must be completed. 1835 1836 Subjects that have discontinued the trial prematurely before Visit 16 will be asked to attend a visit (Visit 1837 16x) taking place 56 weeks after the randomisation date. The purpose of this visit will be recording of the 1838 body weight and assessment of MESI. The assessment will be done by asking the subject if he/she has 1839 experienced any MESI (see section 12.2.1 and appendix H) since the last contact. 1840 1841 If the subject is not willing to attend Visit 16x, it should be documented in the patient medical record that the 1842 subject has refused to attend the visit. 1843 1844 As liraglutide is not available on prescription for the obesity indication after the end of the trial, the subjects 1845 will not be able to receive it when the trial ends. This means that Novo Nordisk will not offer investigational 1846 drug after the end of the trial. At the End of Treatment visit (Visit 16) the Investigator or delegate should 1847 provide counselling on the management of weight control and advise the subjects to commence the 1848 appropriate antidiabetic therapy at her/his discretion (with the exception of the treatments listed in 1849 withdrawal criterion no.4).

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1850 Liraglutide 1855 1858 Date: 06 March 2012 Novo Nordisk 1851 Trial ID: NN8022-1922 1856 CONFIDENTIAL 1859 Version: 6.0 1852 Protocol - Revised edition 1857 1860 Status: Final 1853 EudraCT No.: 2008-002199-88 1861 Page: 44 of 133 18621854 1863 8.1.1 Visit Schedule 1864 Subjects will attend the clinic as stated in Table 8–1. 1865 1866 Table 8–1 Visit schedule 1867 Visit no. Time of Visit Type of Visit Visit 1 Week -2 ± 5 days Screening Visit 2 Day 0, baseline Randomisation, start of liraglutide 0.6 mg /liraglutide placebo Visit 3 Week 2 ± 3 days Dose escalation visit Visit 4 Week 4 ± 5 days Dose escalation visit/Maintenance visit Visit 5a Week 6 ± 5 days Maintenance visit Visit 5b Week 8 ± 5 days Maintenance visit Visit 6 Week 12 ± 5 days Maintenance visit Visit 7 Week 16 ± 5 days Maintenance visit Visit 8 Week 20 ± 5 days Maintenance visit Visit 9 Week 24 ± 5 days Maintenance visit Visit 10 Week 28 ± 5 days Maintenance visit Visit 11 Week 32 ± 5 days Maintenance visit Visit 12 Week 36 ± 5 days Maintenance visit Visit 13 Week 40 ± 5 days Maintenance visit Visit 14 Week 44 ± 5 days Maintenance visit Visit 15 Week 50 ± 5 days Maintenance visit Visit 16x Week 56 ± 5 days Body weight/MESI recording visit Visit 16 Week 56 ± 3 days End of treatment visit/ premature discontinuation before or at Visit 16 Visit 17 Week 58 ± 3 days Follow-up visit/premature discontinuation at Visit 17 Visit 18 Week 60 ± 5 days Follow-up visit Visit 19 Week 64 ± 5 days Follow-up visit Visit 20 Week 68 ± 5 days Follow-up visit/premature discontinuation after Visit 17 1868 1869 1870 The total duration of the trial (for a subject completing the trial) will be up to 70 weeks and will comprise a 1871 total of 21 visits. 1872 1873 8.1.2 Visit 1, Screening visit 1874 Visit 1 will take place 2 weeks ± 5 days before Visit 2. 1875 1876 Subjects must give signed and dated informed consent prior to any trial-related activities. All subjects will be 1877 provided with a copy of the subject information and a copy of their own signed and dated Informed Consent 1878 Form. 1879 1880 The subjects will be allocated the unique lowest consecutive 6 digit subject number available from the range 1881 of subject numbers. The subject number is composed of three digits unique for each trial site and three digits 1882 for each enrolled subject at the trial site. The subject number is maintained throughout the trial.

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1883 Liraglutide 1888 1891 Date: 06 March 2012 Novo Nordisk 1884 Trial ID: NN8022-1922 1889 CONFIDENTIAL 1892 Version: 6.0 1885 Protocol - Revised edition 1890 1893 Status: Final 1886 EudraCT No.: 2008-002199-88 1894 Page: 45 of 133 18951887 1896 The IV/WRS should be called/entered to register the subject as screened (see section 10.3) and the subject 1897 will be provided with a study card indicating that the subject is participating in a trial. 1898 1899 To mitigate SU induced hypoglycaemia, subjects treated with SU (either alone or in combination with other 1900 OADs), will at screening be required to reduce the SU dose by 50% or as close to 50% as possible based on 1901 dose options locally available. If already on minimum labelled dose at screening, a subject should remain on 1902 that dose unless unacceptable hypoglycaemia occurs, in which case the subject must be withdrawn. Other 1903 OAD treatment should remain stable throughout the trial (same drug or drugs [same INN(s)], dose and 1904 dosing frequencies). 1905 1906 The following will be performed and/or recorded in the eCRF: 1907 • Informed consent, signed and dated (see section 19.1) 1908 • Inclusion and exclusion criteria (see section 6.2 and 6.3) 1909 • Demographic information registered in the IV/WRS and/or recorded in the eCRF (date of birth, sex and 1910 race and ethnicity, according to local requirements) 1911 • Diagnosis of type 2 diabetes 1912 • Diabetes treatment history (see section 11) 1913 • Medical history/concomitant illnesses (see section 11) 1914 • Concomitant medication (see section 11) 1915 • Smoking habits (see section 8.4) 1916 • Body measurements (see section 8.2.1) 1917 • Vital signs (see section 8.2.6) 1918 • Physical examination (see section 8.3.1) 1919 • ECG (see section 8.3.3) 1920 • Eye examination (see section 8.3.14) 1921 • Mental Health questionnaires (see section 8.3.10) 1922 • Dispense study card 1923 • Dispense diabetes diary and instruct in the use hereof (see section 8.4.2 and 14) 1924 • History of diabetes complications (see section 8.4.6) 1925 • History of Concomitant Cardiovascular Disease (see section 8.4.7) 1926 • History of Gallbladder Disease (see section 8.4.8) 1927 • History of Psychiatric Disorders (see section 8.4.9) 1928 • Dispense 3-day food diary and instruct the subject in the completion hereof (see section 5.3.3 and 8.4.3) 1929 • Dispense glucose meter and instruct in the use hereof (see section 8.2.4 and 8.3.2) 1930 • Provide collection cup for urine sample 1931 • Record the subjects on the subject screening log or the informed consent log according to local practice 1932 1933 Blood sampling for measurements of:

1934 • HbA1c (see section 8.2.2) 1935 • Lipids (see section 8.2.6) 1936 • Haematology and biochemistry (see section 8.3.5) 1937 • For females of childbearing potential: serum pregnancy test (see section 8.3.6)

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1938 Liraglutide 1943 1946 Date: 06 March 2012 Novo Nordisk 1939 Trial ID: NN8022-1922 1944 CONFIDENTIAL 1947 Version: 6.0 1940 Protocol - Revised edition 1945 1948 Status: Final 1941 EudraCT No.: 2008-002199-88 1949 Page: 46 of 133 19501942 1951 Interact with the IV/WRS to: 1952 • Complete screening session (see section 10.3) 1953 1954 Once all data relating to Visit 1 (screening visit) have been obtained, they must be reviewed by the 1955 Investigator to ensure that the subject is eligible to continue in the trial (see also section 6.2 and 6.3). If the 1956 subject is not eligible to continue, the subject is a screening failure and the IV/WRS must be contacted to 1957 register the subject as a screening failure, and the reason for exclusion must be recorded. 1958 1959 Reminders: 1960 • An appointment for Visit 2 (2 weeks after Visit 1) should be made 1961 • Subjects should be reminded to: 1962 − Continue treatment with background diabetes medication throughout the trial 1963 − Measure FPG on a regular basis, at the Investigator’s discretion (see section 8.2.4) 1964 − Complete their diabetes diary and return it at Visit 2 (see section 8.4.2 and 14) 1965 − Bring their glucose meter at Visit 2 1966 − Bring the urine sample at Visit 2 1967 − Complete their 3-day food diary and return it at Visit 2 (see section 5.3.3 and 8.4.3) 1968 − Attend Visit 2 fasting (i.e., at least eight hours overnight fast without food and/or drink intake, 1969 except for water) 1970 − To withhold treatment with background medication and trial product on the day of Visit 2 until blood 1971 sampling has been done 1972 − Avoid caffeine, smoking and physical activity within 30 minutes prior to the blood pressure 1973 measurement at Visit 2 1974 • Subjects should be reminded to record the following in their diabetes diary: 1975 − Changes in concomitant medication (see section 11) 1976 − A 7-point plasma glucose profile on a normal representative day within a week prior to Visit 2 (see 1977 section 8.2.4) 1978 − Measurements of plasma glucose in any event(s) of hypoglycaemia or hyperglycaemia, including 1979 details about hypoglycaemia (see section 8.3.2) 1980 1981 8.1.3 Visit 2, Randomisation visit 1982 The visit will take place 2 weeks after Visit 1. 1983 1984 The subject should attend the visit fasting (i.e., at least eight hours overnight fast without food and/or drink 1985 intake, except for water). If the subjects attend the visit without being fasting, a new appointment for blood 1986 sampling and body measurements should be made within the visit window. 1987 1988 The subject will receive dietary counselling by a qualified dietician and placed on a hypo caloric diet (see 1989 section 5.3.1). 1990 1991 If the subject is found eligible after review of inclusion, exclusion and randomisation criteria at Visit 2, the 1992 subject will be randomised into one of the three treatment arms (see section 5.1) using IV/WRS (see section

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1993 Liraglutide 1998 2001 Date: 06 March 2012 Novo Nordisk 1994 Trial ID: NN8022-1922 1999 CONFIDENTIAL 2002 Version: 6.0 1995 Protocol - Revised edition 2000 2003 Status: Final 1996 EudraCT No.: 2008-002199-88 2004 Page: 47 of 133 20051997 2006 10.3). The IV/WRS will allocate the Dispensing Unit Number (DUN) of medication to be dispensed to the 2007 subject. 2008 2009 Subjects will have trial products supplied according to randomisation and will be instructed in administration 2010 of daily injections of liraglutide/liraglutide placebo. Injections can be done at anytime of day irrespective of 2011 meals. However, it is preferable that liraglutide/liraglutide placebo be injected during the same overall time 2012 period on a day to day basis. The injection site does not have to be kept consistent throughout the trial. The 2013 trial products dispensed will cover the dose escalation period. Subjects will follow a fixed dose escalation. 2014 The dose will be gradually escalated to 3.0 mg or 1.8 mg starting with 0.6 mg and with a dose level 2015 increment of 0.6 mg every 7 days (see section 5.3.1). 2016 2017 If the subject is not eligible for randomisation, the subject is considered a screening failure and the IV/WRS 2018 must be contacted to register the subject as a screening failure. 2019 2020 The following will be performed and/or recorded in the eCRF: 2021 • Check in- and exclusion criteria (see section 6.1 and 6.2) 2022 • Check randomisation criteria (see section 6.4) 2023 • Stratification group (see section 5.1) 2024 • Concomitant medication (see section 11) 2025 • Body measurements (see section 8.2.1) 2026 • Vital signs (see section 8.2.6) 2027 • Adverse events since last visit (see section 12) 2028 • For females of childbearing potential: urine pregnancy test as applicable (see section 8.3.6) 2029 • Mental Health questionnaires (see section 8.3.10) 2030 • Collect and review diabetes diary and dispense new diabetes diary (see section 8.4.2 and 14) 2031 • Collect and review 3-day food diary (see section 5.3.3 and 8.4.3) 2032 • Diet and physical activity counselling (using the 3-day food diary) (see section 5.3.3) 2033 • Record the subject’s physical activity (see section 5.3.3) 2034 • Dispense pedometer and instruct the subject in the use hereof (see section 5.3.3) 2035 • For subjects in France, Germany, Spain, Sweden, United Kingdom and USA: PRO questionnaires 2036 (see section 8.2.9 and 8.3.15) 2037 2038 Transcription from the diabetes diary: 2039 • Any change in concomitant medication (see section 11) 2040 • Self-measured 7-point plasma glucose profile (see section 8.2.4) 2041 • Hypoglycaemic episodes since last visit (see section 8.3.2) 2042 2043 Blood sampling for measurements of:

2044 • HbA1c (see section 8.2.2) 2045 • FPG (see section 8.2.3) 2046 • Glucose metabolism (see section 8.2.5) 2047 • Lipids (see section 8.2.6) 2048 • Cardiovascular biomarkers (see section 8.2.8)

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2049 Liraglutide 2054 2057 Date: 06 March 2012 Novo Nordisk 2050 Trial ID: NN8022-1922 2055 CONFIDENTIAL 2058 Version: 6.0 2051 Protocol - Revised edition 2056 2059 Status: Final 2052 EudraCT No.: 2008-002199-88 2060 Page: 48 of 133 20612053 2062 • Haematology and biochemistry (see section 8.3.5) 2063 • Liraglutide antibodies (see section 8.3.7) 2064 2065 Urine sampling for measurement of: 2066 • Urinary Albumin-to-Creatinine ratio (see section 8.2.10) 2067 2068 Interact with the IV/WRS to: 2069 • Complete screening failure session, if applicable 2070 • Complete randomisation session 2071 • Complete trial product dispensing session (see section 9.3) 2072 2073 Reminders: 2074 • An appointment for Visit 3 (2 weeks ± 3 days after Visit 2) should be made 2075 • Attend Visit 3 fasting (i.e., at least eight hours overnight fast without food and/or drink intake, except for 2076 water). 2077 • To withhold treatment with background medication and trial product on the day of Visit 3 until blood 2078 sampling has been done 2079 • Subjects should be reminded to: 2080 − Increase the dose by 0.6 mg/day every week until the target dose of 3.0 or 1.8 mg/day has been 2081 reached 2082 − Measure FPG on a regular basis, at the Investigators discretion (see section 8.2.4) 2083 − Complete their diabetes diary and return it at Visit 3 (see section 8.4.2 and 14) 2084 − Bring their glucose meter at Visit 3 2085 • Subjects should be reminded to record the following in their diabetes diary: 2086 − The date of first administration of trial product 2087 − Injection date and time, dose and injection site for the three doses prior to Visit 3 2088 − Changes in concomitant medication (see section 11) 2089 − Measurements of plasma glucose in any event(s) of hypoglycaemia or hyperglycaemia, including 2090 details about hypoglycaemia (see section 8.3.2) 2091 2092 8.1.4 Visit 3, Dose escalation visit 2093 Visit 3 will take place 2 weeks ± 3 days after Visit 2. 2094 2095 The subject should attend the visit fasting (i.e., at least eight hours overnight fast without food and/or drink 2096 intake, except for water). If the subjects attend the visit without being fasting, a new appointment for blood 2097 sampling and body measurements should be made within the visit window. 2098 2099 The following will be performed and/or recorded in the eCRF: 2100 • Rescue criteria (see section 6.5) 2101 • Withdrawal criteria (see section 6.6) 2102 • Subject compliance (see section 8.5) 2103 • Concomitant medication (see section 11) 2104 • Body measurements (see section 8.2.1)

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2105 Liraglutide 2110 2113 Date: 06 March 2012 Novo Nordisk 2106 Trial ID: NN8022-1922 2111 CONFIDENTIAL 2114 Version: 6.0 2107 Protocol - Revised edition 2112 2115 Status: Final 2108 EudraCT No.: 2008-002199-88 2116 Page: 49 of 133 21172109 2118 • AEs since last visit (see section 12) 2119 • Mental Health questionnaires (see section 8.3.10) 2120 • Date and actual time of blood sampling for the measurement of liraglutide plasma concentration (see 2121 section 8.4.5) 2122 • First date on trial product 2123 • For females of childbearing potential: urine pregnancy test as applicable (see section 8.3.6) 2124 • Collect and review diabetes diary and dispense new diabetes diary (see section 8.4.2 and 14) 2125 2126 Transcription from the diabetes diary: 2127 • Any change in concomitant medication (see section 11) 2128 • Hypoglycaemic episodes since last visit (see section 8.3.2) 2129 • Injection date and time, dose and injection site for the three doses prior to visit 3 (see section 8.4.5) 2130 2131 Blood sampling for measurement of: 2132 • FPG (see section 8.2.3) 2133 • Liraglutide plasma concentration (see section 8.4.5) 2134 2135 Interact with the IV/WRS to: 2136 • Complete withdrawal session, if applicable 2137 2138 Reminders: 2139 • An appointment for Visit 4 (4 weeks ± 5 days after Visit 2) should be made 2140 • Subjects should be reminded to: 2141 − Increase the dose 0.6 mg/day every week until the target dose has been reached 2142 − Measure FPG on a regular basis, at the Investigator’s discretion (see section 8.2.4) 2143 − Complete their diabetes diary and return it at Visit 4 (see section 8.4.2 and 14) 2144 − Bring their glucose meter at Visit 4 2145 − Attend Visit 4 fasting (i.e., at least eight hours overnight fast without food and/or drink intake, 2146 except for water) 2147 − To withhold treatment with background medication and trial product on the day of Visit 4 until blood 2148 sampling has been done 2149 − Avoid caffeine, smoking and physical activity within 30 minutes prior to the blood pressure 2150 measurement at Visit 4 2151 − Return all used, partly used and unused trial products, including empty packing, for drug 2152 accountability at Visit 4 2153 • Subjects should be reminded to record the following in their diabetes diary: 2154 − Changes in concomitant medication (see section 11) 2155 − Measurements of plasma glucose in any event(s) of hypoglycaemia or hyperglycaemia, including 2156 details about hypoglycaemia (see section 8.3.2) 2157 2158 8.1.5 Visit 4, Dose escalation visit/maintenance visit 2159 Visit 4 will take place 4 weeks ± 5 days after Visit 2.

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2160 Liraglutide 2165 2168 Date: 06 March 2012 Novo Nordisk 2161 Trial ID: NN8022-1922 2166 CONFIDENTIAL 2169 Version: 6.0 2162 Protocol - Revised edition 2167 2170 Status: Final 2163 EudraCT No.: 2008-002199-88 2171 Page: 50 of 133 21722164 2173 The subject should attend the visit fasting (i.e., at least eight hours overnight fast without food and/or drink 2174 intake, except for water). If the subjects attend the visit without being fasting, a new appointment for blood 2175 sampling and body measurements should be made within the visit window. 2176 2177 The following will be performed and/or recorded in the eCRF: 2178 • Rescue criteria (see section 6.5) 2179 • Withdrawal criteria (see section 6.6) 2180 • Subject compliance (see section 8.5) 2181 • Concomitant medication (see section 11) 2182 • Body measurements (see section 8.2.1) 2183 • Vital signs (see section 8.2.6) 2184 • Mental Health questionnaires (see section 8.3.10) 2185 • AEs since last visit (see section 12) 2186 • For females of childbearing potential: urine pregnancy test as applicable (see section 8.3.6) 2187 • Collect and review diabetes diary and dispense new diabetes diary (see section 8.4.2 and 14) 2188 • Dispense 3-day food diary and instruct the subject in the completion hereof (see section 5.3.3 and 8.4.3) 2189 • Diet and physical activity counselling (see section 5.3.3) 2190 2191 Transcription from the diabetes diary: 2192 • Any change in concomitant medication (see section 11) 2193 • Hypoglycaemic episodes since last visit (see section 8.3.2) 2194 2195 Blood sampling for measurements of:

2196 • HbA1c(see section 8.2.2) 2197 • FPG (see section 8.2.3) 2198 • Haematology and biochemistry (see section 8.3.5) 2199 2200 Interact with the IV/WRS to: 2201 • Complete withdrawal session, if applicable 2202 • Complete trial product dispensing session (see section 9.3) 2203 • Interact with Drug Accountability module (see section 10.3) 2204 2205 Reminders: 2206 • An appointment for Visit 5a (6 weeks ± 5 days after Visit 2) should be made 2207 • Subjects should be reminded to: 2208 − Measure FPG on a regular basis, at the Investigator’s discretion (see section 8.2.4) 2209 − Complete their diabetes diary and return it at Visit 5a (see section 8.4.2 and 14) 2210 − Bring their glucose meter at Visit 5a 2211 − Avoid caffeine, smoking and physical activity within 30 minutes prior to the blood pressure 2212 measurement at Visit 5a 2213 • Subjects should be reminded to record the following in their diabetes diary: 2214 − Changes in concomitant medication (see section 11)

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2215 Liraglutide 2220 2223 Date: 06 March 2012 Novo Nordisk 2216 Trial ID: NN8022-1922 2221 CONFIDENTIAL 2224 Version: 6.0 2217 Protocol - Revised edition 2222 2225 Status: Final 2218 EudraCT No.: 2008-002199-88 2226 Page: 51 of 133 22272219 2228 − Measurements of plasma glucose in any event(s) of hypoglycaemia or hyperglycaemia, including 2229 details about hypoglycaemia (see section 8.3.2) 2230 2231 8.1.6 Visit 5a, maintenance visit 2232 Visit 5a will take place 6 weeks ± 5 days after Visit 2. 2233 2234 The following will be performed and/or recorded in the eCRF: 2235 • Rescue criteria (see section 6.5) 2236 • Withdrawal criteria (see section 6.6) 2237 • Subject compliance (see section 8.5) 2238 • Concomitant medication (see section 11) 2239 • Body measurements (see section 8.2.1) 2240 • Vital signs (see section 8.2.6) 2241 • AEs since last visit (see section 12) 2242 • Mental Health questionnaires (see section 8.3.10) 2243 • For females of childbearing potential: urine pregnancy test as applicable (see section 8.3.6) 2244 • Collect and review diabetes diary and dispense new diabetes diary (see section 8.4.2 and 14) 2245 2246 Transcription from the diabetes diary: 2247 • Any change in concomitant medication (see section 11) 2248 • Hypoglycaemic episodes since last visit (see section 8.3.2) 2249 2250 Interact with the IV/WRS to: 2251 • Complete withdrawal session, if applicable 2252 2253 Reminders: 2254 • An appointment for Visit 5b (8 weeks ± 5 days after Visit 2) should be made 2255 • Subjects should be reminded to: 2256 − Measure FPG on a regular basis, at the Investigator’s discretion (see section 8.2.4) 2257 − Complete their diabetes diary and return it at Visit 5b (see section 8.4.2 and 14) 2258 − Bring their glucose meter at Visit 5b 2259 − Complete their 3-day food diary and return it at Visit 5b (see section 5.3.3 and 8.4.3) 2260 − Attend Visit 5b fasting (i.e., at least eight hours overnight fast without food and/or drink intake, 2261 except for water) 2262 − To withhold treatment with background medication and trial product on the day of Visit 5b until 2263 blood sampling has been done 2264 − Avoid caffeine, smoking and physical activity within 30 minutes prior to the blood pressure 2265 measurement at Visit 5b 2266 − Return all used, partly used and unused trial products, including empty packing, for drug 2267 accountability at Visit 5b 2268 • Subjects should be reminded to record the following in their diabetes diary: 2269 − Changes in concomitant medication (see section 11)

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2270 Liraglutide 2275 2278 Date: 06 March 2012 Novo Nordisk 2271 Trial ID: NN8022-1922 2276 CONFIDENTIAL 2279 Version: 6.0 2272 Protocol - Revised edition 2277 2280 Status: Final 2273 EudraCT No.: 2008-002199-88 2281 Page: 52 of 133 22822274 2283 − Measurements of plasma glucose in any event(s) of hypoglycaemia or hyperglycaemia, including 2284 details about hypoglycaemia (see section 8.3.2) 2285 2286 8.1.7 Visit 5b, maintenance visit 2287 Visit 5b will take place 8 weeks ± 5 days after Visit 2. 2288 2289 The subject should attend the visit fasting (i.e., at least eight hours overnight fast without food and/or drink 2290 intake, except for water). If the subjects attend the visit without being fasting, a new appointment for blood 2291 sampling and body measurements should be made within the visit window. 2292 2293 The following will be performed and/or recorded in the eCRF: 2294 • Rescue criteria (see section 6.5) 2295 • Withdrawal criteria (see section 6.6) 2296 • Subject compliance (see section 8.5) 2297 • Concomitant medication (see section 11) 2298 • Body measurements (see section 8.2.1) 2299 • Vital signs (see section 8.2.6) 2300 • Mental Health questionnaires (see section 8.3.10) 2301 • AEs since last visit (see section 12) 2302 • For females of childbearing potential: urine pregnancy test as applicable (see section 8.3.6) 2303 • Collect and review diabetes diary and dispense new diabetes diary (see section 8.4.2 and 14) 2304 • Collect and review 3-day food diary (see section 5.3.3 and 8.4.3) 2305 • Diet and physical activity counselling (using the 3-day food diary) (see section 5.3.3) 2306 • Record the subject’s dietary compliance and physical activity (see section 5.3.3) 2307 2308 Transcription from the diabetes diary: 2309 • Any change in concomitant medication (see section 11) 2310 • Hypoglycaemic episodes since last visit (see section 8.3.2) 2311 2312 Blood sampling for measurement of: 2313 • FPG (see section 8.2.3) 2314 2315 Interact with the IV/WRS to: 2316 • Complete withdrawal session, if applicable 2317 • Complete trial product dispensing session (see section 9.3) 2318 • Interact with Drug Accountability module (see section 10.3) 2319 2320 Reminders: 2321 • An appointment for Visit 6 (12 weeks ± 5 days after Visit 2) should be made 2322 • Subjects should be reminded to: 2323 − Measure FPG on a regular basis, at the Investigator’s discretion (see section 8.2.4) 2324 − Complete their diabetes diary and return it at Visit 6 (see section 8.4.2 and 14)

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2325 Liraglutide 2330 2333 Date: 06 March 2012 Novo Nordisk 2326 Trial ID: NN8022-1922 2331 CONFIDENTIAL 2334 Version: 6.0 2327 Protocol - Revised edition 2332 2335 Status: Final 2328 EudraCT No.: 2008-002199-88 2336 Page: 53 of 133 23372329 2338 − Bring their glucose meter at Visit 6 2339 − Avoid caffeine, smoking and physical activity within 30 minutes prior to the blood pressure 2340 measurement at Visit 6 2341 − Return all used, partly used and unused trial products, including empty packing, for drug 2342 accountability at Visit 6 2343 • Subjects should be reminded to record the following in their diabetes diary: 2344 − Changes in concomitant medication (see section 11) 2345 − Injection date and time, dose and injection site for the three doses prior to visit 6 2346 − Measurements of plasma glucose in any event(s) of hypoglycaemia or hyperglycaemia, including 2347 details about hypoglycaemia (see section 8.3.2) 2348 2349 8.1.8 Visit 6, maintenance visit 2350 Visit 6 will take place 12 weeks ± 5 days after Visit 2. 2351 2352 The following will be performed and/or recorded in the eCRF: 2353 • Rescue criteria (see section 6.5) 2354 • Withdrawal criteria (see section 6.6) 2355 • Subject compliance (see section 8.5) 2356 • Concomitant medication (see section 11) 2357 • Body measurements (see section 8.2.1) 2358 • Vital signs (see section 8.2.6) 2359 • Mental Health questionnaires (see section 8.3.10) 2360 • Date and actual time of blood sampling for the measurement of liraglutide plasma concentration (see 2361 section 8.4.5) 2362 • AEs since last visit (see section 12) 2363 • For females of childbearing potential: urine pregnancy test as applicable (see section 8.3.6) 2364 • Collect and review diabetes diary and dispense new diabetes diary (see section 8.4.2 and 14) 2365 • Dispense 3-day food diary and instruct the subject in the completion hereof (see section 5.3.3 and 8.4.3) 2366 • Diet and physical activity counselling (see section 5.3.3) 2367 2368 Transcription from the diabetes diary: 2369 • Any change in concomitant medication (see section 11) 2370 • Hypoglycaemic episodes since last visit (see section 8.3.2) 2371 • Injection date and time, dose and injection site for the three doses prior to visit 6 (see section 8.4.5) 2372 2373 Blood sampling for measurement of: 2374 • Liraglutide plasma concentration (see section 8.4.5) 2375 2376 Interact with the IV/WRS to: 2377 • Complete withdrawal session, if applicable 2378 • Complete trial product dispensing session (see section 9.3) 2379 • Interact with Drug Accountability module (see section 10.3)

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2380 Liraglutide 2385 2388 Date: 06 March 2012 Novo Nordisk 2381 Trial ID: NN8022-1922 2386 CONFIDENTIAL 2389 Version: 6.0 2382 Protocol - Revised edition 2387 2390 Status: Final 2383 EudraCT No.: 2008-002199-88 2391 Page: 54 of 133 23922384 2393 Reminders: 2394 • An appointment for Visit 7 (16 weeks ± 5 days after Visit 2) should be made 2395 • Subjects should be reminded to: 2396 − Measure FPG on a regular basis, at the Investigator’s discretion (see section 8.2.4) 2397 − Complete their diabetes diary and return it at Visit 7 (see section 8.4.2 and 14) 2398 − Bring their glucose meter at Visit 7 2399 − Complete their 3-day food diary and return it at Visit 7 (see section 5.3.3 and 8.4.3) 2400 − Attend Visit 7 fasting (i.e., at least eight hours overnight fast without food and/or drink intake, 2401 except for water) 2402 − To withhold treatment with background medication and trial product on the day of Visit 7 until blood 2403 sampling has been done 2404 − Avoid caffeine, smoking and physical activity within 30 minutes prior to the blood pressure 2405 measurement at Visit 7 2406 − Return all used, partly used and unused trial products, including empty packing, for drug 2407 accountability at Visit 7 2408 • Subjects should be reminded to record the following in their diabetes diary: 2409 − Changes in concomitant medication (see section 11) 2410 − Measurements of plasma glucose in any event(s) of hypoglycaemia or hyperglycaemia, including 2411 details about hypoglycaemia (see section 8.3.2) 2412 2413 8.1.9 Visit 7, maintenance visit 2414 Visit 7 will take place 16 weeks ± 5 days after Visit 2. 2415 2416 The subject should attend the visit fasting (i.e., at least eight hours overnight fast without food and/or drink 2417 intake, except for water). If the subjects attend the visit without being fasting, a new appointment for blood 2418 sampling and body measurements should be made within the visit window. 2419 2420 The following will be performed and/or recorded in the eCRF: 2421 • Rescue criteria (see section 6.5) 2422 • Withdrawal criteria (see section 6.6) 2423 • Subject compliance (see section 8.5) 2424 • Concomitant medication (see section 11) 2425 • Body measurements (see section 8.2.1) 2426 • Vital signs (see section 8.2.6) 2427 • AEs since last visit (see section 12) 2428 • For females of childbearing potential: urine pregnancy test as applicable (see section 8.3.6) 2429 • Mental Health questionnaires (see section 8.3.10) 2430 • Collect and review diabetes diary and dispense new diabetes diary (see section 8.4.2 and 14) 2431 • Collect and review 3-day food diary (see section 5.3.3 and 8.4.3) 2432 • Diet and physical activity counselling (based on the 3-day food diary) (see section 5.3.3) 2433 • Record the subject’s dietary compliance and physical activity (see section 5.3.3)

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2434 Liraglutide 2439 2442 Date: 06 March 2012 Novo Nordisk 2435 Trial ID: NN8022-1922 2440 CONFIDENTIAL 2443 Version: 6.0 2436 Protocol - Revised edition 2441 2444 Status: Final 2437 EudraCT No.: 2008-002199-88 2445 Page: 55 of 133 24462438 2447 Transcription from the diabetes diary: 2448 • Any change in concomitant medication (see section 11) 2449 • Hypoglycaemic episodes since last visit (see section 8.3.2) 2450 2451 Blood sampling for measurements of:

2452 • HbA1c (see section 8.2.2) 2453 • FPG (see section 8.2.3) 2454 • Haematology and biochemistry (see section 8.3.5) 2455 2456 Interact with the IV/WRS to: 2457 • Complete withdrawal session, if applicable 2458 • Complete trial product dispensing session (see section 9.3) 2459 • Interact with Drug Accountability module (see section 10.3) 2460 2461 Reminders: 2462 • An appointment for Visit 8 (20 weeks ± 5 days after Visit 2) should be made 2463 • Subjects should be reminded to: 2464 − Measure FPG on a regular basis, at the Investigator’s discretion (see section 8.2.4) 2465 − Complete their diabetes diary and return it at Visit 8 (see section 8.4.2 and 14) 2466 − Bring their glucose meter at Visit 8 2467 − Attend Visit 8 fasting (i.e., at least eight hours overnight fast without food and/or drink intake, 2468 except for water) 2469 − Avoid caffeine, smoking and physical activity within 30 minutes prior to the blood pressure 2470 measurement at Visit 8 2471 − To withhold treatment with background medication and trial product on the day of Visit 8 until 2472 blood sampling has been done 2473 − Return all used, partly used and unused trial products, including empty packing, for drug 2474 accountability at Visit 8 2475 • Subjects should be reminded to record the following in their diabetes diary: 2476 − Changes in concomitant medication (see section 11) 2477 − Measurements of plasma glucose in any event(s) of hypoglycaemia or hyperglycaemia, including 2478 details about hypoglycaemia (see section 8.3.2) 2479 2480 8.1.10 Visit 8, maintenance visit 2481 Visit 8 will take place 20 weeks ± 5 days after Visit 2. 2482 2483 The subject should attend the visit fasting (i.e., at least eight hours overnight fast without food and/or drink 2484 intake, except for water). If the subjects attend the visit without being fasting, a new appointment for blood 2485 sampling and body measurements should be made within the visit window. 2486 2487 The following will be performed and/or recorded in the eCRF: 2488 • Rescue criteria (see section 6.5)

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2489 Liraglutide 2494 2497 Date: 06 March 2012 Novo Nordisk 2490 Trial ID: NN8022-1922 2495 CONFIDENTIAL 2498 Version: 6.0 2491 Protocol - Revised edition 2496 2499 Status: Final 2492 EudraCT No.: 2008-002199-88 2500 Page: 56 of 133 25012493 2502 • Withdrawal criteria (see section 6.6) 2503 • Subject compliance (see section 8.5) 2504 • Concomitant medication (see section 11) 2505 • Body measurements (see section 8.2.1) 2506 • Vital signs (see section 8.2.6) 2507 • Mental Health questionnaires (see section 8.3.10) 2508 • AEs since last visit (see section 12) 2509 • For females of childbearing potential: urine pregnancy test as applicable (see section 8.3.6) 2510 • Collect and review diabetes diary and dispense new diabetes diary (see section 8.4.2 and 14) 2511 • Dispense 3-day food diary and instruct the subject in the completion hereof (see section 5.3.3 and 8.4.3) 2512 • Diet and physical activity counselling (see section 5.3.3) 2513 2514 Transcription from the diabetes diary: 2515 • Any change in concomitant medication (see section 11) 2516 • Hypoglycaemic episodes since last visit (see section 8.3.2) 2517 2518 Blood sampling for measurement of: 2519 • FPG (see section 8.2.3) 2520 2521 Interact with the IV/WRS to: 2522 • Complete withdrawal session, if applicable 2523 • Complete trial product dispensing session (see section 9.3) 2524 • Interact with Drug Accountability module (see section 10.3) 2525 2526 Reminders: 2527 • An appointment for Visit 9 (24 weeks ± 5 days after Visit 2) should be made 2528 • Subjects should be reminded to: 2529 − Measure FPG on a regular basis, at the Investigator’s discretion (see section 8.2.4) 2530 − Complete their diabetes diary and return it at Visit 9 (see section 8.4.2 and 14) 2531 − Bring their glucose meter at Visit 9 2532 − Complete their 3-day food diary and return it at Visit 9 (see section 5.3.3 and 8.4.3) 2533 − Avoid caffeine, smoking and physical activity within 30 minutes prior to the blood pressure 2534 measurement at Visit 9 2535 − Return all used, partly used and unused trial products, including empty packing, for drug 2536 accountability at Visit 9 2537 • Subjects should be reminded to record the following in their diabetes diary: 2538 − Changes in concomitant medication (see section 11) 2539 − Measurements of plasma glucose in any event(s) of hypoglycaemia or hyperglycaemia, including 2540 details about hypoglycaemia (see section 8.3.2) 2541 2542 8.1.11 Visit 9, maintenance visit 2543 Visit 9 will take place 24 weeks ± 5 days after Visit 2.

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2544 Liraglutide 2549 2552 Date: 06 March 2012 Novo Nordisk 2545 Trial ID: NN8022-1922 2550 CONFIDENTIAL 2553 Version: 6.0 2546 Protocol - Revised edition 2551 2554 Status: Final 2547 EudraCT No.: 2008-002199-88 2555 Page: 57 of 133 25562548 2557 The following will be performed and/or recorded in the eCRF: 2558 • Rescue criteria (see section 6.5) 2559 • Withdrawal criteria (see section 6.6) 2560 • Subject compliance (see section 8.5) 2561 • Concomitant medication (see section 11) 2562 • Body measurements (see section 8.2.1) 2563 • Vital signs (see section 8.2.6) 2564 • Mental Health questionnaires (see section 8.3.10) 2565 • AEs since last visit (see section 12) 2566 • For females of childbearing potential: urine pregnancy test as applicable (see section 8.3.6) 2567 • Collect and review diabetes diary and dispense new diabetes diary (see section 8.4.2 and 14) 2568 • Collect and review 3-day food diary (see section 5.3.3 and 8.4.3) 2569 • Diet and physical activity counselling (based on the 3-day food diary) (see section 5.3.3) 2570 • Record the subject’s dietary compliance and physical activity (see section 5.3.3) 2571 • Provide collection cup for urine sample 2572 2573 Transcription from the diabetes diary: 2574 • Any change in concomitant medication (see section 11) 2575 • Hypoglycaemic episodes since last visit (see section 8.3.2) 2576 2577 Interact with the IV/WRS to: 2578 • Complete withdrawal session, if applicable 2579 • Complete trial product dispensing session (see section 9.3) 2580 • Interact with Drug Accountability module (see section 10.3) 2581 2582 Reminders: 2583 • An appointment for Visit 10 (28 weeks ± 5 days after Visit 2) should be made 2584 • Subjects should be reminded to: 2585 − Measure FPG on a regular basis, at the Investigator’s discretion (see section 8.2.4) 2586 − Complete their diabetes diary and return it at Visit 10 (see section 8.4.2 and 14) 2587 − Bring their glucose meter at Visit 10 2588 − Bring the urine sample at Visit 10 2589 − Attend Visit 10 fasting (i.e., at least eight hours overnight fast without food and/or drink intake, 2590 except for water) 2591 − To withhold treatment with background medication and trial product on the day of Visit 10 until 2592 blood sampling has been done 2593 − Avoid caffeine, smoking and physical activity within 30 minutes prior to the blood pressure 2594 measurement at Visit 10 2595 − Return all used, partly used and unused trial products, including empty packing, for drug 2596 accountability at Visit 10 2597 • Subjects should be reminded to record the following in their diabetes diary: 2598 − Changes in concomitant medication (see section 11)

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2599 Liraglutide 2604 2607 Date: 06 March 2012 Novo Nordisk 2600 Trial ID: NN8022-1922 2605 CONFIDENTIAL 2608 Version: 6.0 2601 Protocol - Revised edition 2606 2609 Status: Final 2602 EudraCT No.: 2008-002199-88 2610 Page: 58 of 133 26112603 2612 − A 7-point plasma glucose profile on a normal representative day within a week prior to Visit 10 (see 2613 section 8.2.4) 2614 − Injection date and time, dose and injection site for the three doses prior to visit 10 2615 − Measurements of plasma glucose in any event(s) of hypoglycaemia or hyperglycaemia, including 2616 details about hypoglycaemia (see section 8.3.2) 2617 2618 8.1.12 Visit 10, maintenance visit 2619 Visit 10 will take place 28 weeks ± 5 days after Visit 2. 2620 2621 The subject should attend the visit fasting (i.e., at least eight hours overnight fast without food and/or drink 2622 intake, except for water). If the subjects attend the visit without being fasting, a new appointment for blood 2623 sampling and body measurements should be made within the visit window. 2624 2625 The following will be performed and/or recorded in the eCRF: 2626 • Rescue criteria (see section 6.5) 2627 • Withdrawal criteria (see section 6.6) 2628 • Subject compliance (see section 8.5) 2629 • Concomitant medication (see section 11) 2630 • Body measurements (see section 8.2.1) 2631 • Vital signs (see section 8.2.6) 2632 • Mental Health questionnaires (see section 8.3.10) 2633 • Date and actual time of blood sampling for the measurement of liraglutide plasma concentration (see 2634 section 8.4.5) 2635 • AEs since last visit (see section 12) 2636 • For females of childbearing potential: urine pregnancy test as applicable (see section 8.3.6) 2637 • Collect and review diabetes diary and dispense new diabetes diary (see section 8.4.2 and 14) 2638 • Dispense 3-day food diary and instruct the subject in the completion hereof (see section 5.3.3 and 8.4.3) 2639 • Diet and physical activity counselling (see section 5.3.3) 2640 • For subjects in France, Germany, Spain, Sweden, United Kingdom and USA: PRO questionnaires 2641 (see section 8.2.9). BES is not performed at Visit 10. 2642 2643 Transcription from the diabetes diary: 2644 • Any change in concomitant medication (see section 11) 2645 • Self-measured 7-point plasma glucose profile (see section 8.2.4) 2646 • Hypoglycaemic episodes since last visit (see section 8.3.2) 2647 • Injection date and time, dose and injection site for the three doses prior to visit 10 (see section 8.4.5) 2648 2649 Blood sampling for measurements of:

2650 • HbA1c (see section 8.2.2) 2651 • FPG (see section 8.2.3) 2652 • Glucose metabolism (see section 8.2.5) 2653 • Lipids (see section 8.2.6) 2654 • Cardiovascular biomarkers (see section 8.2.8)

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2655 Liraglutide 2660 2663 Date: 06 March 2012 Novo Nordisk 2656 Trial ID: NN8022-1922 2661 CONFIDENTIAL 2664 Version: 6.0 2657 Protocol - Revised edition 2662 2665 Status: Final 2658 EudraCT No.: 2008-002199-88 2666 Page: 59 of 133 26672659 2668 • Haematology and biochemistry (see section 8.3.5) 2669 • Liraglutide plasma concentration (see section 8.4.5) 2670 2671 Urine sampling for measurement of: 2672 • Urinary Albumin-to-Creatinine ratio (see section 8.2.10) 2673 2674 Interact with the IV/WRS to: 2675 • Complete withdrawal session, if applicable 2676 • Complete trial product dispensing session (see section 9.3) 2677 • Interact with Drug Accountability module (see section 10.3) 2678 2679 Reminders: 2680 • An appointment for Visit 11 (32 weeks ± 5 days after Visit 2) should be made 2681 • Subjects should be reminded to: 2682 − Measure FPG on a regular basis, at the Investigator’s discretion (see section 8.2.4) 2683 − Complete their diabetes diary and return it at Visit 11 (see section 8.4.2 and 14) 2684 − Bring their glucose meter at Visit 11 2685 − Complete their 3-day food diary and return it at Visit 11 (see section 5.3.3 and 8.4.3) 2686 − Avoid caffeine, smoking and physical activity within 30 minutes prior to the blood pressure 2687 measurement at Visit 11 2688 • Subjects should be reminded to record the following in their diabetes diary: 2689 − Changes in concomitant medication (see section 11) 2690 − Measurements of plasma glucose in any event(s) of hypoglycaemia or hyperglycaemia, including 2691 details about hypoglycaemia (see section 8.3.2) 2692 • Subjects should be reminded to return all used, partly used and unused trial products, including empty 2693 packing, for drug accountability at Visit 11 2694 2695 8.1.13 Visit 11, maintenance visit 2696 Visit 11 will take place 32 weeks ± 5 days after Visit 2. 2697 2698 The following will be performed and/or recorded in the eCRF: 2699 • Rescue criteria (see section 6.5) 2700 • Withdrawal criteria (see section 6.6) 2701 • Subject compliance (see section 8.5) 2702 • Concomitant medication (see section 11) 2703 • Body measurements (see section 8.2.1) 2704 • Vital signs (see section 8.2.6) 2705 • AEs since last visit (see section 12) 2706 • For females of childbearing potential: urine pregnancy test as applicable (see section 8.3.6) 2707 • Mental Health questionnaires (see section 8.3.10) 2708 • Collect and review diabetes diary and dispense new diabetes diary (see section 8.4.2 and 14) 2709 • Collect and review 3-day food diary (see section 5.3.3 and 8.4.3) 2710 • Diet and physical activity counselling (based on the 3-day food diary) (see section 5.3.3)

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2711 Liraglutide 2716 2719 Date: 06 March 2012 Novo Nordisk 2712 Trial ID: NN8022-1922 2717 CONFIDENTIAL 2720 Version: 6.0 2713 Protocol - Revised edition 2718 2721 Status: Final 2714 EudraCT No.: 2008-002199-88 2722 Page: 60 of 133 27232715 2724 • Record the subject’s dietary compliance and physical activity (see section 5.3.3) 2725 2726 Transcription from the diabetes diary: 2727 • Any change in concomitant medication (see section 11) 2728 • Hypoglycaemic episodes since last visit (see section 8.3.2) 2729 2730 Interact with the IV/WRS to: 2731 • Complete withdrawal session, if applicable 2732 • Complete trial product dispensing session (see section 9.3) 2733 • Interact with Drug Accountability module (see section 10.3) 2734 2735 Reminders: 2736 • An appointment for Visit 12 (36 weeks ± 5 days after Visit 2) should be made 2737 • Subjects should be reminded to: 2738 − Measure FPG on a regular basis, at the Investigator’s discretion (see section 8.2.4) 2739 − Complete their diabetes diary and return it at Visit 12 (see section 8.4.2 and 14) 2740 − Bring their glucose meter at Visit 12 2741 − Avoid caffeine, smoking and physical activity within 30 minutes prior to the blood pressure 2742 measurement at Visit 12 2743 − Return all used, partly used and unused trial products, including empty packing, for drug 2744 accountability at Visit 12 2745 • Subjects should be reminded to record the following in their diabetes diary: 2746 − Changes in concomitant medication (see section 11) 2747 − Measurements of plasma glucose in any event(s) of hypoglycaemia or hyperglycaemia, including 2748 details about hypoglycaemia (see section 8.3.2) 2749 2750 8.1.14 Visit 12, maintenance visit 2751 Visit 12 will take place 36 weeks ± 5 days after Visit 2. 2752 2753 The following will be performed and/or recorded in the eCRF: 2754 • Rescue criteria (see section 6.5) 2755 • Withdrawal criteria (see section 6.6) 2756 • Subject compliance (see section 8.5) 2757 • Concomitant medication (see section 11) 2758 • Body measurements (see section 8.2.1) 2759 • Vital signs (see section 8.2.6) 2760 • Mental Health questionnaires (see section 8.3.10) 2761 • AEs since last visit (see section 12) 2762 • For females of childbearing potential: urine pregnancy test as applicable (see section 8.3.6) 2763 • Collect and review diabetes diary and dispense new diabetes diary (see section 8.4.2 and 14) 2764 • Dispense 3-day food diary and instruct the subject in the completion hereof (see section 5.3.3 and 8.4.3) 2765 • Diet and physical activity counselling (see section 5.3.3)

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2766 Liraglutide 2771 2774 Date: 06 March 2012 Novo Nordisk 2767 Trial ID: NN8022-1922 2772 CONFIDENTIAL 2775 Version: 6.0 2768 Protocol - Revised edition 2773 2776 Status: Final 2769 EudraCT No.: 2008-002199-88 2777 Page: 61 of 133 27782770 2779 Transcription from the diabetes diary: 2780 • Any change in concomitant medication (see section 11) 2781 • Hypoglycaemic episodes since last visit (see section 8.3.2) 2782 2783 Interact with the IV/WRS to: 2784 • Complete withdrawal session, if applicable 2785 • Complete trial product dispensing session (see section 9.3) 2786 • Interact with Drug Accountability module (see section 10.3) 2787 2788 Reminders: 2789 • An appointment for Visit 13 (40 weeks ± 5 days after Visit 2) should be made 2790 • Subjects should be reminded to: 2791 − Measure FPG on a regular basis, at the Investigator’s discretion (see section 8.2.4) 2792 − Complete their diabetes diary and return it at Visit 13 (see section 8.4.2 and 14) 2793 − Bring their glucose meter at Visit 13 2794 − Complete their 3-day food diary and return it at Visit 13 (see section 5.3.3 and 8.4.3) 2795 − Attend Visit 13 fasting (i.e., at least eight hours overnight fast without food and/or drink intake, 2796 except for water) 2797 − To withhold treatment with background medication and trial product on the day of Visit 13 until 2798 blood sampling has been done 2799 − Avoid caffeine, smoking and physical activity within 30 minutes prior to the blood pressure 2800 measurement at Visit 13 2801 − return all used, partly used and unused trial products, including empty packing, for drug 2802 accountability at Visit 13 2803 • Subjects should be reminded to record the following in their diabetes diary: 2804 − Changes in concomitant medication (see section 11) 2805 − Measurements of plasma glucose in any event(s) of hypoglycaemia or hyperglycaemia, including 2806 details about hypoglycaemia (see section 8.3.2) 2807 2808 8.1.15 Visit 13, maintenance visit 2809 Visit 13 will take place 40 weeks ± 5 days after Visit 2. 2810 2811 The subject should attend the visit fasting (i.e., at least eight hours overnight fast without food and/or drink 2812 intake, except for water). If the subjects attend the visit without being fasting, a new appointment for blood 2813 sampling and body measurements should be made within the visit window. 2814 2815 The following will be performed and/or recorded in the eCRF: 2816 • Rescue criteria (see section 6.5) 2817 • Withdrawal criteria (see section 6.6) 2818 • Subject compliance (see section 8.5) 2819 • Concomitant medication (see section 11) 2820 • Body measurements (see section 8.2.1)

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2821 Liraglutide 2826 2829 Date: 06 March 2012 Novo Nordisk 2822 Trial ID: NN8022-1922 2827 CONFIDENTIAL 2830 Version: 6.0 2823 Protocol - Revised edition 2828 2831 Status: Final 2824 EudraCT No.: 2008-002199-88 2832 Page: 62 of 133 28332825 2834 • Vital signs (see section 8.2.6) 2835 • Mental Health questionnaires (see section 8.3.10) 2836 • AEs since last visit (see section 12) 2837 • For females of childbearing potential: urine pregnancy test as applicable (see section 8.3.6) 2838 • Collect and review diabetes diary and dispense new diabetes diary (see section 8.4.2 and 14) 2839 • Collect and review 3-day food diary (see section 5.3.3 and 8.4.3) 2840 • Diet and physical activity counselling (based on the 3-day food diary) (see section 5.3.3) 2841 • Record the subject’s dietary compliance and physical activity (see section 5.3.3) 2842 2843 Transcription from the diabetes diary: 2844 • Any change in concomitant medication (see section 11) 2845 • Hypoglycaemic episodes since last visit (see section 8.3.2) 2846 2847 Blood sampling for measurements of:

2848 • HbA1c (see section 8.2.2) 2849 • FPG (see section 8.2.3) 2850 • Haematology and biochemistry (see section 8.3.5) 2851 2852 Interact with the IV/WRS to: 2853 • Complete withdrawal session, if applicable 2854 • Complete trial product dispensing session (see section 9.3) 2855 • Interact with Drug Accountability module (see section 10.3) 2856 2857 Reminders: 2858 • An appointment for Visit 14 (44 weeks ± 5 days after Visit 2) should be made 2859 • Subjects should be reminded to: 2860 − Measure FPG on a regular basis, at the Investigator’s discretion (see section 8.2.4) 2861 − Complete their diabetes diary and return it at Visit 14 (see section 8.4.2 and 14) 2862 − Bring their glucose meter at Visit 14 2863 − Avoid caffeine, smoking and physical activity within 30 minutes prior to the blood pressure 2864 measurement at Visit 14 2865 − return all used, partly used and unused trial products, including empty packing, for drug 2866 accountability at Visit 14 2867 • Subjects should be reminded to record the following in their diabetes diary: 2868 − Changes in concomitant medication (see section 11) 2869 − Measurements of plasma glucose in any event(s) of hypoglycaemia or hyperglycaemia, including 2870 details about hypoglycaemia (see section 8.3.2) 2871 2872 8.1.16 Visit 14, maintenance visit 2873 Visit 14 will take place 44 weeks ± 5 days after Visit 2.

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2874 Liraglutide 2879 2882 Date: 06 March 2012 Novo Nordisk 2875 Trial ID: NN8022-1922 2880 CONFIDENTIAL 2883 Version: 6.0 2876 Protocol - Revised edition 2881 2884 Status: Final 2877 EudraCT No.: 2008-002199-88 2885 Page: 63 of 133 28862878 2887 The following will be performed and/or recorded in the eCRF: 2888 • Rescue criteria (see section 6.5) 2889 • Withdrawal criteria (see section 6.6) 2890 • Subject compliance (see section 8.5) 2891 • Concomitant medication (see section 11) 2892 • Body measurements (see section 8.2.1) 2893 • Vital signs (see section 8.2.6) 2894 • Mental Health questionnaires (see section 8.3.10) 2895 • AEs since last visit (see section 12) 2896 • For females of childbearing potential: urine pregnancy test as applicable (see section 8.3.6) 2897 • Collect and review diabetes diary and dispense new diabetes diary (see section 8.4.2 and 14) 2898 • Diet and physical activity counselling (see section 5.3.3) 2899 2900 Transcription from the diabetes diary: 2901 • Any change in concomitant medication (see section 11) 2902 • Hypoglycaemic episodes since last visit (see section 8.3.2) 2903 2904 Interact with the IV/WRS to: 2905 • Complete withdrawal session, if applicable 2906 • Complete trial product dispensing session (see section 9.3) 2907 • Interact with Drug Accountability module (see section 10.3) 2908 2909 Reminders: 2910 • An appointment for Visit 15 (50 weeks ± 5 days after Visit 2) should be made 2911 • Subjects should be reminded to: 2912 − Measure FPG on a regular basis, at the Investigator’s discretion (see section 8.2.3) 2913 − Complete their diabetes diary and return it at Visit 15 (see section 8.4.2 and 14) 2914 − Bring their glucose meter at Visit 15 2915 − Attend Visit 15 fasting (i.e., at least eight hours overnight fast without food and/or drink intake, 2916 except for water) 2917 − Avoid caffeine, smoking and physical activity within 30 minutes prior to the blood pressure 2918 measurement at Visit 15 2919 − To withhold treatment with background medication and trial product on the day of Visit 15 until 2920 blood sampling has been done 2921 − Return all used, partly used and unused trial products, including empty packing, for drug 2922 accountability at Visit 15 2923 • Subjects should be reminded to record the following in their diabetes diary: 2924 − Changes in concomitant medication (see section 11) 2925 − Measurements of plasma glucose in any event(s) of hypoglycaemia or hyperglycaemia, including 2926 details about hypoglycaemia (see section 8.3.2)

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2927 Liraglutide 2932 2935 Date: 06 March 2012 Novo Nordisk 2928 Trial ID: NN8022-1922 2933 CONFIDENTIAL 2936 Version: 6.0 2929 Protocol - Revised edition 2934 2937 Status: Final 2930 EudraCT No.: 2008-002199-88 2938 Page: 64 of 133 29392931 2940 8.1.17 Visit 15, maintenance visit 2941 Visit 15 will take place 50 weeks ± 5 days after Visit 2. 2942 2943 The subject should attend the visit fasting (i.e., at least eight hours overnight fast without food and/or drink 2944 intake, except for water). If the subjects attend the visit without being fasting, a new appointment for blood 2945 sampling and body measurements should be made within the visit window. 2946 2947 The following will be performed and/or recorded in the eCRF: 2948 • Rescue criteria (see section 6.5) 2949 • Withdrawal criteria (see section 6.6) 2950 • Subject compliance (see section 8.5) 2951 • Concomitant medication (see section 11) 2952 • Body measurements (see section 8.2.1) 2953 • Vital signs (see section 8.2.6) 2954 • AEs since last visit (see section 12) 2955 • For females of childbearing potential: urine pregnancy test as applicable (see section 8.3.6) 2956 • Mental Health questionnaires (see section 8.3.10) 2957 • Collect and review diabetes diary and dispense new diabetes diary (see section 8.4.2 and 14) 2958 • Dispense 3-day food diary and instruct the subject in the completion hereof (see section 5.3.3 and 8.4.3) 2959 • Diet and physical activity counselling (see section 5.3.3) 2960 • Provide collection cup for urine sample 2961 2962 Transcription from the diabetes diary: 2963 • Any change in concomitant medication (see section 11) 2964 • Hypoglycaemic episodes since last visit (see section 8.3.2) 2965 2966 Blood sampling for measurement of: 2967 • FPG (see section 8.2.3) 2968 2969 Interact with the IV/WRS to: 2970 • Complete withdrawal session, if applicable 2971 • Complete trial product dispensing session (see section 9.3) 2972 • Interact with Drug Accountability module (see section 10.3) 2973 2974 Reminders: 2975 • An appointment for Visit 16 (56 weeks ± 3 days after Visit 2) should be made 2976 • Subjects should be reminded to: 2977 − Measure FPG on a regular basis, at the Investigator’s discretion (see section 8.2.4) 2978 − Complete their diabetes diary and return it at Visit 16 (see section 8.4.2 and 14) 2979 − Complete their 3-day food diary and return it at Visit 16 (see section 5.3.3) 2980 − Bring their glucose meter at Visit 16 2981 − Bring the urine sample at Visit 16

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2982 Liraglutide 2987 2990 Date: 06 March 2012 Novo Nordisk 2983 Trial ID: NN8022-1922 2988 CONFIDENTIAL 2991 Version: 6.0 2984 Protocol - Revised edition 2989 2992 Status: Final 2985 EudraCT No.: 2008-002199-88 2993 Page: 65 of 133 29942986 2995 − Attend Visit 16 fasting (i.e., at least eight hours overnight fast without food and/or drink intake, 2996 except for water) 2997 − To withhold treatment with background medication and trial product on the day of Visit 16 until 2998 blood sampling has been done 2999 − Avoid caffeine, smoking and physical activity within 30 minutes prior to the blood pressure 3000 measurement at Visit 16 3001 − return all used, partly used and unused trial products, including empty packing, for drug 3002 accountability at Visit 16 3003 • Subjects should be reminded to record the following in their diabetes diary: 3004 − Changes in concomitant medication (see section 11) 3005 − A 7-point plasma glucose profile on a normal representative day within a week prior to Visit 16 (see 3006 section 8.2.4) 3007 − Measurements of plasma glucose in any event(s) of hypoglycaemia or hyperglycaemia, including 3008 details about hypoglycaemia (see section 8.3.2) 3009 3010 8.1.18 Visit 16, End of treatment/premature discontinuation before Visit 16 3011 Visit 16 will take place 56 weeks ± 3 days after Visit 2. 3012 3013 Subjects discontinuing (leaving/being withdrawn from) the trial prematurely before or at Visit 16 should 3014 have procedures according to Visit 16 performed at their last visit, if possible. 3015 3016 The subject should attend the visit fasting (i.e., at least eight hours overnight fast without food and/or drink 3017 intake, except for water). If the subjects attend the visit without being fasting, a new appointment for blood 3018 sampling and body measurements should be made within the visit window. 3019 3020 The following will be performed and/or recorded in the eCRF: 3021 • Subject compliance (see section 8.5) 3022 • Subject main trial completer (Y/N) 3023 • Concomitant medication (see section 11) 3024 • Body measurements (see section 8.2.1) 3025 • Vital signs (see section 8.2.6) 3026 • Mental Health questionnaires (see section 8.3.10) 3027 • Physical examination (see section 8.3.1) 3028 • ECG (see section 8.3.3) 3029 • AEs since last visit (see section 12) 3030 • Collect and review diabetes diary and dispense new diabetes diary (see section 8.4.2 and 14) 3031 • Collect and review 3-day food diary (see section 5.3.3 and 8.4.3) 3032 • Diet and physical activity counselling (based on the 3-day food diary). 3033 • Provide counselling on the management of weight control and advise the subject to continue on their 3034 treatment with background OAD therapy or other treatment modalities (treatments listed in withdrawal 3035 criterion no.4 may not be used in the follow-up period, see section 6.6) at the discretion of the 3036 Investigator (see section 5.3.3) 3037 • Record the subject’s dietary compliance and physical activity (see section 5.3.3)

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3038 Liraglutide 3043 3046 Date: 06 March 2012 Novo Nordisk 3039 Trial ID: NN8022-1922 3044 CONFIDENTIAL 3047 Version: 6.0 3040 Protocol - Revised edition 3045 3048 Status: Final 3041 EudraCT No.: 2008-002199-88 3049 Page: 66 of 133 30503042 3051 • Provide collection cup for urine sample 3052 • For subjects in France, Germany, Spain, Sweden, United Kingdom and USA: PRO questionnaires 3053 (see section 8.2.9 and 8.3.15). 3054 • For subjects discontinuing the trial prematurely before Visit 16: Complete PRO questionnaires 3055 • For subjects discontinuing the trial prematurely before Visit 16: Complete Mental Health questionnaires 3056 • For subjects who discontinue the trial prematurely before Visit 16: Complete EOT form 3057 3058 Transcription from the diabetes diary: 3059 • Any change in concomitant medication (see section 11) 3060 • Self-measured 7-point plasma glucose profile (see section 8.2.4) 3061 • Hypoglycaemic episodes since last visit (see section 8.3.2) 3062 3063 Blood sampling for measurements of:

3064 • HbA1c (see section 8.2.2) 3065 • FPG (see section 8.2.3) 3066 • Glucose metabolism (see section 8.2.5) 3067 • Lipids (see section 8.2.6) 3068 • Cardiovascular biomarkers (see section 8.2.8) 3069 • Haematology and biochemistry (see section 8.3.5) 3070 • For females of childbearing potential: serum pregnancy test (see section 8.3.6) 3071 • For subjects who discontinue the trial prematurely before Visit 16: liraglutide antibodies (see section 3072 8.3.7) 3073 3074 Urine sampling for measurements of: 3075 • Urinary Albumin-to-Creatinine ratio (see section 8.2.10) 3076 3077 Interact with the IV/WRS to: 3078 • Complete withdrawal session, if applicable 3079 • Interact with Drug Accountability module (see section 10.3) 3080 3081 Reminders: 3082 • An appointment for Visit 17 should be made 58 weeks ± 3 days after Visit 2 3083 • Subjects should be reminded to: 3084 - Measure FPG on a regular basis, at the Investigator’s discretion (see section 8.2.4) 3085 - Complete their diabetes diary and return it at Visit 17 (see section 8.4.2 and 14) 3086 - Bring their glucose meter at Visit 17 3087 - Bring the urine sample at Visit 17 3088 - Attend Visit 17 fasting (i.e., at least eight hours overnight fast without food and/or drink intake, 3089 except for water) 3090 - To withhold treatment with background medication and trial product on the day of Visit 17 until 3091 blood sampling has been done

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3092 Liraglutide 3097 3100 Date: 06 March 2012 Novo Nordisk 3093 Trial ID: NN8022-1922 3098 CONFIDENTIAL 3101 Version: 6.0 3094 Protocol - Revised edition 3099 3102 Status: Final 3095 EudraCT No.: 2008-002199-88 3103 Page: 67 of 133 31043096 3105 - Avoid caffeine, smoking and physical activity within 30 minutes prior to the blood pressure 3106 measurement at Visit 17 3107 • Subjects should be reminded to record the following in their diabetes diary: 3108 − Changes in concomitant medication (see section 11) 3109 − Measurements of plasma glucose in any event(s) of hypoglycaemia or hyperglycaemia, including 3110 details about hypoglycaemia (see section 8.3.2) 3111 • Subjects that have discontinued the trial prematurely before Visit 16 should be reminded that a body 3112 weight recording visit will be performed 56 weeks after the randomisation date. 3113 3114 8.1.19 Visit 16x, Body weight/MESI recording visit 3115 Visit 16x will take place 56 weeks ± 5 days after Visit 2. 3116 3117 The body weight recording visit is only applicable for subjects who have discontinued the trial prematurely 3118 before Visit 16 and accept that they can be contacted 56 weeks after their randomisation date. 3119 3120 Subjects will be asked to attend this visit 56 weeks after their randomisation date for the purpose of body 3121 weight recording and assessment of MESI. The assessment will be done by asking the subject if he/she has 3122 experienced any MESI (see section 12.2.1 and appendix H) since the last contact. The subjects should attend 3123 Visit 16x fasting (i.e., at least eight hours overnight fast without food and/or drink intake, except for water). 3124 3125 If the subject is not willing to attend Visit 16x, it should be documented in the patient medical record that the 3126 subject has refused to attend the visit. 3127 3128 The following will be performed and/or recorded in the eCRF: 3129 • Body weight (see section 8.2.1) 3130 • MESI, if any (see section 12.2.1) 3131 • Fasting state 3132 3133 8.1.20 Visit 17, follow-up visit/premature discontinuation at Visit 17 3134 Visit 17 will take place 58 weeks ± 3 days after Visit 2. 3135 3136 Subjects discontinuing (leaving/being withdrawn from) the trial prematurely after visit 16 or at Visit 17 3137 should have procedures according to Visit 17 performed, if possible. 3138 3139 The subject should attend the visit fasting (i.e., at least eight hours overnight fast without food and/or drink 3140 intake, except for water). If the subjects attend the visit without being fasting, a new appointment for blood 3141 sampling and body measurements should be made within the visit window. 3142 3143 The following will be performed and/or recorded in the eCRF: 3144 • Withdrawal criteria (see section 6.6) 3145 • Concomitant medication (see section 11) 3146 • Body measurements (see section 8.2.1) 3147 • Vital signs (see section 8.2.6)

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3148 Liraglutide 3153 3156 Date: 06 March 2012 Novo Nordisk 3149 Trial ID: NN8022-1922 3154 CONFIDENTIAL 3157 Version: 6.0 3150 Protocol - Revised edition 3155 3158 Status: Final 3151 EudraCT No.: 2008-002199-88 3159 Page: 68 of 133 31603152 3161 • Mental health questionnaires (see section 8.3.8) 3162 • AEs since last visit (see section 12) 3163 • Collect and review diabetes diary and dispense new diabetes diary (see section 8.4.2 and 14) 3164 • For subjects who discontinue the trial prematurely after visit 16 or at Visit 17: Complete EOT form 3165 • For subjects in France, Germany, Spain, Sweden, United Kingdom and USA: PRO questionnaires 3166 (only Binge Eating Scale questionnaire [see section 8.3.15]) 3167 3168 Transcription from the diabetes diary: 3169 • Any change in concomitant medication (see section 11) 3170 • Hypoglycaemic episodes since last visit (see section 8.3.2) 3171 3172 Blood sampling for measurements of: 3173 • FPG (see section 8.2.3) 3174 • Haematology and biochemistry (see section 8.3.5) 3175 • Liraglutide antibodies (see section 8.3.7) 3176 3177 Urine sampling for measurements of: 3178 • Albumin/creatine ratio (see section 8.2.10) 3179 3180 3181 Interact with the IV/WRS to: 3182 • Complete withdrawal session, if applicable 3183 3184 Reminders 3185 • An appointment for Visit 18 should be made 60 weeks ± 5 days after Visit 2 3186 • Subjects should be advised to adjust their background type 2 diabetes treatment, at the discretion of the 3187 investigator 3188 • Subjects should be reminded to: 3189 - Measure FPG on a regular basis, at the Investigator’s discretion (see section 8.2.4) 3190 - Complete their diabetes diary and return it at Visit 18 (see section 8.4.2 and 14) 3191 - Bring their glucose meter at Visit 18 3192 - Avoid caffeine, smoking and physical activity within 30 minutes prior to the blood pressure 3193 measurement at Visit 18 3194 • Subjects should be reminded to record the following in their diabetes diary: 3195 − Changes in concomitant medication (see section 11) 3196 − Measurements of plasma glucose in any event(s) of hypoglycaemia or hyperglycaemia, including 3197 details about hypoglycaemia (see section 8.3.2) 3198 3199 8.1.21 Visit 18, follow-up 3200 Visit 18 will take place 60 weeks ± 5 days after Visit 2.

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3201 Liraglutide 3206 3209 Date: 06 March 2012 Novo Nordisk 3202 Trial ID: NN8022-1922 3207 CONFIDENTIAL 3210 Version: 6.0 3203 Protocol - Revised edition 3208 3211 Status: Final 3204 EudraCT No.: 2008-002199-88 3212 Page: 69 of 133 32133205 3214 The following will be performed and/or recorded in the eCRF: 3215 • Withdrawal criteria (see section 6.6) 3216 • Concomitant medication (see section 11) 3217 • Body measurements (see section 8.2.1) 3218 • Vital signs (see section 8.2.6) 3219 • Mental Health questionnaires (see section 8.3.10) 3220 • AEs since last visit (see section 12) 3221 • Collect and review diabetes diary and dispense new diabetes diary (see section 8.4.2 and 14) 3222 • Dispense 3-day food diary and instruct the subject in the completion hereof (see section 5.3.3 and 8.4.3) 3223 • Diet and physical activity counselling (see section 5.3.3) 3224 3225 Transcription from the diabetes diary: 3226 • Any change in concomitant medication (see section 11) 3227 • Hypoglycaemic episodes since last visit (see section 8.3.2) 3228 3229 Interact with the IV/WRS to: 3230 • Complete withdrawal session, if applicable 3231 3232 Reminders 3233 • An appointment for Visit 19 should be made 64 weeks ± 5 days after Visit 2 3234 • Subjects should be advised to adjust their background type 2 diabetes treatment, at the discretion of the 3235 investigator 3236 • Subjects should be reminded to: 3237 - Measure FPG on a regular basis, at the Investigator’s discretion (see section 8.2.4) 3238 - Complete their diabetes diary and return it at Visit 19 (see section 8.4.2 and 14) 3239 - Bring their glucose meter at Visit 19 3240 - Avoid caffeine, smoking and physical activity within 30 minutes prior to the blood pressure 3241 measurement at Visit 19 3242 • Subjects should be reminded to record the following in their diabetes diary: 3243 − Changes in concomitant medication (see section 11) 3244 − Measurements of plasma glucose in any event(s) of hypoglycaemia or hyperglycaemia, including 3245 details about hypoglycaemia (see section 8.3.2) 3246 3247 8.1.22 Visit 19, follow-up 3248 Visit 19 will take place 64 weeks ± 5 days after Visit 2. 3249 3250 The following will be performed and/or recorded in the eCRF: 3251 • Withdrawal criteria (see section 6.6) 3252 • Concomitant medication (see section 11) 3253 • Body measurements (see section 8.2.1) 3254 • Vital signs (see section 8.2.6) 3255 • Mental Health questionnaires (see section 8.3.10)

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3256 Liraglutide 3261 3264 Date: 06 March 2012 Novo Nordisk 3257 Trial ID: NN8022-1922 3262 CONFIDENTIAL 3265 Version: 6.0 3258 Protocol - Revised edition 3263 3266 Status: Final 3259 EudraCT No.: 2008-002199-88 3267 Page: 70 of 133 32683260 3269 • AEs since last visit (see section 12) 3270 • Collect and review diabetes diary and dispense new diabetes diary (see section 8.4.2 and 14) 3271 • Collect and review 3-day food diary (see section 5.3.3 and 8.4.3) 3272 • Diet and physical activity counselling (based on the 3-day food diary) 3273 • Provide collection cup for urine sample 3274 3275 Transcription from the diabetes diary: 3276 • Any change in concomitant medication (see section 11) 3277 • Hypoglycaemic episodes since last visit (see section 8.3.2) 3278 3279 Interact with the IV/WRS to: 3280 • Complete withdrawal session, if applicable 3281 3282 Reminders 3283 • An appointment for Visit 20 should be made 68 weeks ± 5 days after Visit 2 3284 • Subjects should be advised to adjust their background type 2 diabetes treatment, at the discretion of the 3285 investigator 3286 • Subjects should be reminded to: 3287 - Measure FPG on a regular basis, at the Investigator’s discretion (see section 8.2.4) 3288 - Complete their diabetes diary and return it at Visit 20 (see section 8.4.2 and 14) 3289 - Bring their glucose meter at Visit 20 3290 - Bring the urine sample at Visit 20 3291 - Attend Visit 20 fasting (i.e., at least eight hours overnight fast without food and/or drink intake, 3292 except for water) 3293 - To withhold treatment with background medication on the day of Visit 20 until blood sampling has 3294 been done 3295 - Avoid caffeine, smoking and physical activity within 30 minutes prior to the blood pressure 3296 measurement at Visit 20 3297 • Subjects should be reminded to record the following in their diabetes diary: 3298 − Changes in concomitant medication (see section 11) 3299 − Measurements of plasma glucose in any event(s) of hypoglycaemia or hyperglycaemia, including 3300 details about hypoglycaemia (see section 8.3.2) 3301 3302 8.1.23 Visit 20, follow-up/premature discontinuation after Visit 17 3303 Visit 20 will take place 68 weeks ± 5 days after Visit 2. 3304 3305 Subjects discontinuing (leaving/being withdrawn from) the trial prematurely after Visit 17 should have 3306 procedures according to Visit 20 performed at their last visit, if possible. 3307 3308 The subject should attend the visit fasting (i.e., at least eight hours overnight fast without food and/or drink 3309 intake, except for water). If the subjects attend the visit without being fasting, a new appointment for blood 3310 sampling and body measurements should be made within the visit window.

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3311 Liraglutide 3316 3319 Date: 06 March 2012 Novo Nordisk 3312 Trial ID: NN8022-1922 3317 CONFIDENTIAL 3320 Version: 6.0 3313 Protocol - Revised edition 3318 3321 Status: Final 3314 EudraCT No.: 2008-002199-88 3322 Page: 71 of 133 33233315 3324 The following will be performed and/or recorded in the eCRF: 3325 • Concomitant medication (see section 11) 3326 • Body measurements (see section 8.2.1) 3327 • Vital signs (see section 8.2.6) 3328 • Mental Health questionnaires (see section 8.3.10) 3329 • AEs since last visit (see section 12) 3330 • Collect and review diabetes diary (see section 8.4.2 and 14) 3331 • Complete the EOT form 3332 3333 Transcription from the diabetes diary: 3334 • Any change in concomitant medication (see section 11) 3335 • Hypoglycaemic episodes since last visit (see section 8.3.2) 3336 3337 Blood sampling for measurements of: 3338 • FPG (see section 8.2.3) 3339 • Haematology and biochemistry (see section 8.3.5) 3340 3341 Urine sampling for measurements of: 3342 • Urinary Albumin-to-Creatinine ratio (see section 8.2.10) 3343 3344 Interact with the IV/WRS to: 3345 • Complete withdrawal session, if applicable 3346 • Make completion call for subjects completing the trial 3347 3348 Reminders 3349 • Subjects should be advised to adjust their background type 2 diabetes treatment, at the discretion of the 3350 investigator 3351 3352 3353 8.2 Assessments for efficacy 3354 The laboratory analyses for efficacy and safety will be outsourced to a Central Laboratory unless otherwise 3355 specified. Descriptions of assay methods, instrumentation and procedures for obtaining samples, handling 3356 and storage of samples will be described in a trial specific laboratory manual provided by the Central 3357 Laboratory. 3358 3359 Blood samples that are not drawn on the day of the scheduled visit may be drawn on another day at an 3360 additional visit (e.g. if the subject is not fasting), preferably within the visit window. 3361 3362 Samples will be coded with the intention that the subject’s identity will remain encrypted but information 3363 such as age, sex, race, health information and response to liraglutide will be correlated. The samples will 3364 only be used in relation to the present trial. Novo Nordisk and its representatives and/or regulatory 3365 authorities, may have access to this information. However, the subject’s identity will not be revealed.

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3366 Liraglutide 3371 3374 Date: 06 March 2012 Novo Nordisk 3367 Trial ID: NN8022-1922 3372 CONFIDENTIAL 3375 Version: 6.0 3368 Protocol - Revised edition 3373 3376 Status: Final 3369 EudraCT No.: 2008-002199-88 3377 Page: 72 of 133 33783370 3379 Laboratory analysis results will be sent to the Investigator on an ongoing basis except for the results of 3380 liraglutide antibody analyses and liraglutide plasma concentration. All laboratory reports must be dated and 3381 signed by the Investigator on the day of evaluation. If a result is outside the normal range, the Investigator has 3382 to judge whether the abnormality is clinically significant or not (see section 12.1 ). The signed laboratory 3383 report is retained at the Investigator site as source documentation. 3384 3385 Any abnormal, clinically significant result identified at screening visit 1 will be recorded as concomitant 3386 illnesses. 3387 3388 8.2.1 Body measurements 3389 Body measurements include weight, height and waist circumference. 3390 3391 8.2.1.1 Weight and height 3392 Weight will be recorded to the nearest 0.1 kg. Weight should be measured at all visits to the clinic using 3393 calibrated scales. At Visit 2, 3, 4, 5b, 7, 8, 10, 13, 15, 16, 16x, 17 and 20 the weight should be measured in 3394 the fasting state. If the weight is not measured fasting, the subject should be called in for a new visit within 3395 the visit window to have the fasting weight measured (see section 8.1). At the remaining visits the 3396 measurement will be performed in a non-fasting state. 3397 3398 The same pair of scales should be used throughout the trial. Weight should be measured with an empty 3399 bladder, without shoes and only wearing light clothing. Weight measured at Visit 1 will only be used for the 3400 Investigator’s calculation of BMI, whereas weight measured at Visit 2 will be used as baseline for 3401 assessment of change in body weight. 3402 3403 Height without shoes will be recorded at Visit 1. 3404 3405 BMI will be calculated as follows: BMI = weight (kg)/height2 (m2) 3406 3407 8.2.1.2 Waist circumference 3408 Waist circumference will be determined in a fasting state at Visit 2, 3, 4, 5b, 7, 8, 10, 13, 15, 16, 17 and 20 3409 and in a non-fasting state at the remaining visits according to the procedure below. 3410 3411 Three consecutive measurements will be performed at each visit and will be recorded in the eCRF. The waist 3412 circumference will be measured in the horizontal plane to the nearest 0.5 cm using a non-stretchable 3413 measuring tape. 3414 3415 Subjects should be measured in the standing position, with an empty bladder and wearing only light clothing. 3416 The measuring tape should lie flat against the skin without compressing the soft tissue and need to be 3417 removed between each measurement. 3418 3419 The observer should be sitting in front of the subject during the measurement. The subject should be standing 3420 with arms at their side and feet together. Subjects should be asked to breathe normally and the measurement 3421 should be performed when the subject is breathing out gently.

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3422 Liraglutide 3427 3430 Date: 06 March 2012 Novo Nordisk 3423 Trial ID: NN8022-1922 3428 CONFIDENTIAL 3431 Version: 6.0 3424 Protocol - Revised edition 3429 3432 Status: Final 3425 EudraCT No.: 2008-002199-88 3433 Page: 73 of 133 34343426 3435 The waist circumference is defined as the abdominal circumference located midway between the lower rib 3436 margin and the iliac crest. 3437 3438 8.2.2 HbA1c

3439 Samples will be drawn at Visit 1, 2, 4, 7, 10, 13 and 16 for measurement of HbA1c. The assay method used 3440 will be a National Glycohemoglobin Standardisation Program (NGSP) certified method. 3441 3442 8.2.3 Fasting plasma glucose 3443 FPG will be determined from central laboratory analyses of blood samples drawn at Visits 2, 3, 4, 5b, 7, 8, 3444 10, 13, 15, 16, 17 and 20. 3445 3446 8.2.4 Self-monitored fasting plasma glucose 3447 Self-monitoring of PG will be performed using a glucose meter, supplied by Novo Nordisk. A sufficient 3448 amount of test strips and calibration solutions will be supplied together with the glucose meter. 3449 3450 The subjects will be instructed in the use of the device, and will also be provided with written instructions. 3451 The Investigator must ensure that the subject uses the glucose meter correctly. The instructions should 3452 include: 3453 • Advice on regular calibration according to the manufacturer’s instructions 3454 • Instruction in performing self-measurement of PG concentration 3455 3456 The glucose meters use test strips calibrated to plasma values. This means that all capillary blood glucose 3457 measurements performed with these glucose meters are automatically converted into plasma equivalent 3458 glucose values, which will be shown in the display. These values are to be used for evaluation purposes. 3459 3460 All subjects are encouraged to measure their FPG concentrations on a regular basis as agreed with the 3461 Investigator. Also subjects should measure their PG at least every time the subject has symptoms of 3462 hypoglycaemia or hyperglycaemia. Hypoglycaemic episodes should be recorded in the diary (see section 3463 8.3.2). The Investigator may ask the subject to perform additional PG self-measurements if needed for any 3464 safety reason. 3465 3466 If self-measured FPG falls below 6.1 mmol/L (110 mg/dL), or from baseline to 6 weeks, increases above 3467 15 mmol/L (270 mg/dL) or from 7 weeks to 12 weeks, increases above 13.3 mmol/L (240 mg/dL) or from 3468 13 weeks to 56 weeks, increases above 11.1 mmol/L (200 mg/dL) on three consecutive days/occasions, the 3469 subject should contact the Investigator. The outcome of the contact will be recorded on an Unscheduled Visit 3470 Form in the eCRF. 3471 3472 8.2.4.1 7-Point plasma glucose profiles 3473 Subjects will be instructed on how to perform a 7-point plasma glucose profile on a normal representative day 3474 (not on a day when they anticipate unusual strenuous physical activity) within a week prior to Visit 2, 10 3475 and 16. The 7-point profile includes plasma glucose measurements at the following time points: 3476 3477 • Before each main meal (breakfast, lunch and dinner)

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3478 Liraglutide 3483 3486 Date: 06 March 2012 Novo Nordisk 3479 Trial ID: NN8022-1922 3484 CONFIDENTIAL 3487 Version: 6.0 3480 Protocol - Revised edition 3485 3488 Status: Final 3481 EudraCT No.: 2008-002199-88 3489 Page: 74 of 133 34903482 3491 • 90 minutes after start of each main meal (breakfast, lunch and dinner) 3492 • At bedtime 3493 3494 Subjects will be instructed how to record the results in the diabetes diaries provided. The record of each 3495 measurement should always include the date, actual time and plasma glucose value. The results entered into 3496 the diary will be transcribed to the eCRF at the following visit. 3497 3498 8.2.5 Glucose metabolism 3499 Blood samples for determination of glucose metabolism will be taken at Visit 2, 10 and 16. 3500 3501 • Fasting glucagon 3502 • Fasting insulin 3503 • Fasting C-peptide 3504 • Fasting pro-insulin 3505 3506 β-cell function (and insulin resistance) will be derived from FPG and fasting insulin data using the 3507 HOMA(16). 3508 3509 8.2.6 Vital signs 3510 3511 8.2.6.1 Blood pressure 3512 Systolic and diastolic blood pressure will be measured at all visits to the clinic except for Visit 3 according to 3513 the procedure described in Appendix D. 3514 3515 8.2.6.2 Pulse 3516 Pulse will be recorded after resting for five minutes in a sitting position at all visits to the clinic except for 3517 Visit 3. 3518 3519 8.2.7 Lipids 3520 Blood samples for determination of cholesterol, LDL cholesterol, HDL cholesterol, VLDL cholesterol, TG 3521 and FFA will be drawn in a non-fasting state at Visit 1 and in a fasting state at Visit 2, 10 and 16. When the 3522 blood sample is taken in a fasting state it is important that the subject has consumed only water at least 8 3523 hours overnight prior to blood sampling. 3524 3525 8.2.8 Cardiovascular biomarkers 3526 Samples for determination of selected cardiovascular biomarkers will be drawn in a fasting state at Visit 2, 3527 10 and 16: 3528 3529 • hsCRP 3530 • Adiponectin 3531 • Fibrinogen 3532 • PAI-1

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3533 Liraglutide 3538 3541 Date: 06 March 2012 Novo Nordisk 3534 Trial ID: NN8022-1922 3539 CONFIDENTIAL 3542 Version: 6.0 3535 Protocol - Revised edition 3540 3543 Status: Final 3536 EudraCT No.: 2008-002199-88 3544 Page: 75 of 133 35453537 3546 8.2.9 Patient reported outcomes (PRO) questionnaires 3547 PRO will be performed in France, Germany, Spain, Sweden, United Kingdom and USA. It will be assessed 3548 at Visit 2, 10 and 16 with the IWQoL-Lite and by the use of the DTSQs. The Binge Eating Scale 3549 questionnaire will be completed at Visit 2, 16 and 17 (see section 8.3.15) 3550 3551 Subjects discontinuing the trial prematurely before Visit 16 should complete the questionnaires at the end of 3552 treatment visit (Visit 16). 3553 3554 The questionnaires are validated and will be translated into local language before being handed out to the 3555 subjects participating in the trial. The questionnaires should preferably be completed before any trial related 3556 procedures and subjects should be given the opportunity to complete the questionnaires by themselves 3557 without interruption. The investigator or his delegate must review patient reported outcome(s) for 3558 completeness and AEs immediately following administration. 3559 3560 8.2.9.1 IWOoL-Lite 3561 IWQoL-Lite provides an individual perception of impact of weight on physical function, self-esteem, sexual 3562 life, public distress, and work(21). The questionnaire contains 31 items and it takes approximately 10 3563 minutes to complete. 3564 3565 8.2.9.2 Diabetes treatment satisfaction questionnaire 3566 DTSQs is designed to assess the impact of treatment on subjects’ treatment satisfaction. Treatment 3567 satisfaction includes assessments of perceived frequency of hyperglycaemia, perceived frequency of 3568 hypoglycaemia, and satisfaction with treatment(22). It will take approximately 10 minutes to complete. 3569 3570 8.2.10 Urinary Albumin-to-Creatinine ratio 3571 A urine sample will be taken at site visits 2, 10, 16, 17 and 20 for assessment of Urinary Albumin-to- 3572 Creatinine ratio. The subjects will receive materials to collect a sample of their morning urine on the visit 3573 prior to the above listed visits and will be asked to bring the sample to the site for central laboratory 3574 assessment. 3575 3576 3577 8.3 Assessments for safety 3578 3579 8.3.1 Physical examination 3580 Physical examination will be performed at Visit 1 and 16 according to local procedure. Physical examination 3581 should include the cardiovascular system, respiratory system, abdomen, central and peripheral nervous 3582 system, musculo-skeletal system and the thyroid gland. 3583 3584 Any abnormal, clinical significant findings at Visit 1 must be recorded as a concomitant illness (see section 3585 11 ). 3586 3587 Any changes in subsequent visits as compared to Visit 1 which fulfil the criteria for an AE must be recorded 3588 as an AE (see section 12).

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3589 Liraglutide 3594 3597 Date: 06 March 2012 Novo Nordisk 3590 Trial ID: NN8022-1922 3595 CONFIDENTIAL 3598 Version: 6.0 3591 Protocol - Revised edition 3596 3599 Status: Final 3592 EudraCT No.: 2008-002199-88 3600 Page: 76 of 133 36013593 3602 8.3.2 Hypoglycaemic episodes 3603 Plasma glucose should always be measured when there is the suspicion of a hypoglycaemic episode. All 3604 plasma glucose (PG) values ≤ 3.9 mmol/L (70 mg/dL), as well as values > 3.9 mmol/L (70 mg/dL) when 3605 hypoglycaemic symptoms have occurred, should be recorded by the subjects in the diaries. Hypoglycaemic 3606 episodes will be recorded by the subject in his/her diary throughout the trial and must be transcribed into the 3607 eCRF by the Investigator at each site visit throughout the trial from randomisation (site visit 2) to follow-up 3608 (site visit 20). The recording should include: 3609 • date of hypoglycaemic episode 3610 • time of hypoglycaemic episode 3611 • time of last trial drug prior to episode trial drug 3612 • date and time of diabetes background treatment prior to episode 3613 • time of last main meal prior to episode 3614 • whether the episode was symptomatic 3615 • whether the episode was in relation to exercise 3616 • whether the subject was able to treat him-herself (if not answered, the Investigator must provide an 3617 explanation in the eCRF) 3618 • if the subject was not able to treat him-herself, whether he-she recovered with oral administration of 3619 carbohydrates 3620 • the plasma glucose level before treating the episode (if available) 3621 3622 The answer to the question: “Was subject able to treat him/herself?” should be answered “No” if oral 3623 carbohydrates, glucagon or intravenous glucose had to be administered to the subject by another person 3624 because of severe central nervous system (CNS) dysfunction associated with the hypoglycaemic episode. 3625 Oral carbohydrates should not be given in case the subject is unconscious. 3626 3627 A hypoglycaemic episode will be defined as treatment emergent if the onset of the episode is on or after the 3628 first day of trial product, and no later than 14 days after the last day of randomised treatment. 3629 Hypoglycaemic episodes will be defined as nocturnal if the time of onset is between 00:01 and 05.59 (both 3630 included). 3631 3632 A hypoglycaemic episode form and an AE form must be filled in for all hypoglycaemic episodes. If the 3633 hypoglycaemic episode fulfils the criteria for a serious AE and/or a MESI, a hypoglycaemic episode form, an 3634 AE form and a safety information form must be filled in according to section 12. Severe hypoglycaemic 3635 episodes will be recorded as MESIs. 3636 3637 Hypoglycaemic episodes will be summarised based on the ADA classification (23), and also according to an 3638 additional definition. Both ADA classification and the additional definition will be applicable to the 3639 statistical analysis of the confirmatory endpoints. 3640 3641 ADA hypoglycaemia classification 3642 3643 According to the ADA the definition of a hypoglycaemic episode (Figure 8–1) is categorised as:

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3644 Liraglutide 3649 3652 Date: 06 March 2012 Novo Nordisk 3645 Trial ID: NN8022-1922 3650 CONFIDENTIAL 3653 Version: 6.0 3646 Protocol - Revised edition 3651 3654 Status: Final 3647 EudraCT No.: 2008-002199-88 3655 Page: 77 of 133 36563648 3657 Severe hypoglycaemia: An episode requiring assistance of another person to actively administer 3658 carbohydrate, glucagon, or other resuscitative actions. 3659 3660 Documented symptomatic hypoglycaemia: An episode during which typical symptoms of hypoglycaemia 3661 are accompanied by a measured plasma glucose concentration ≤ 3.9 mmol/L (70 mg/dL). 3662 3663 Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of hypoglycamia, but 3664 with a measured plasma glucose concentration ≤ 3.9 mmol/L (70 mg/dL). 3665 3666 Probable symptomatic hypoglycaemia: An episode during which symptoms of hypoglycaemia are not 3667 accompanied by a plasma glucose determination (but that was presumably caused by a plasma glucose 3668 concentration ≤ 3.9 mmol/L (70 mg/dL)). 3669 3670 Relative hypoglycaemia: An episode during which the person with diabetes reports any of the typical 3671 symptoms of hypoglycaemia, and interprets those as indicative of hypoglycaemia, but with a measured 3672 plasma glucose concentration > 3.9 mmol/L (70 mg/dL). 3673

3674 3675 3676 Figure 8–1 Classification of hypoglycaemia 3677 3678 Additional definition 3679 3680 In normal physiology, hypoglycaemia symptoms occur at a blood glucose level of approximately < 2.8 3681 mmol/L (50 mg/dL)/plasma glucose level < 3.1 mmol/L (56 mg/dL). Therefore, Novo Nordisk has used this 3682 cut-off value to define minor hypoglycaemia. 3683 3684 Minor hypoglycaemic episode is defined as:

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3685 Liraglutide 3690 3693 Date: 06 March 2012 Novo Nordisk 3686 Trial ID: NN8022-1922 3691 CONFIDENTIAL 3694 Version: 6.0 3687 Protocol - Revised edition 3692 3695 Status: Final 3688 EudraCT No.: 2008-002199-88 3696 Page: 78 of 133 36973689 3698 • An episode with symptoms consistent with hypoglycaemia with confirmation by plasma glucose < 3.1 3699 mmol/L (56 mg/dL), or full blood glucose < 2.8 mmol/L (50 mg/dL) and which is handled by the subject 3700 himself/herself 3701 • Or any asymptomatic plasma glucose value < 3.1 mmol/L (56 mg/dL) or full blood glucose value < 2.8 3702 mmol/L (50 mg/dL) 3703 Minor hypoglycaemic episodes will be summarised according to this definition, and can be subject to 3704 additional analysis. 3705 3706 3707 8.3.3 ECG 12 lead 3708 ECG will be performed at visits 1, 10, 16 and 20. The ECG will be interpreted, signed and dated by the 3709 Investigator. 3710 3711 The interpretation must follow the categories: 3712 3713 − Normal 3714 − Abnormal, not clinically significant 3715 − Abnormal, clinically significant 3716 3717 In case of an abnormal ECG, the Investigator must evaluate if the abnormal ECG fulfils the criteria of an AE 3718 or a SAE, and if so, should be reported as an AE or a SAE, respectively (see section 12). 3719 3720 An ECG taken within the period starting at Visit 1 and ending at the date of Visit 2 is acceptable. In 3721 addition, all ECG will undergo central assessment. 3722 3723 Sites will be informed of the central ECG evaluation in case this evaluation reveals an abnormal ECG 3724 reading. If the abnormality represents an unreported AE or SAE it must be reported by the Investigator. 3725 3726 8.3.4 Adverse events (AEs) 3727 All AEs will be recorded at each visit after Visit 1 according to procedures described in section 12. 3728 3729 8.3.5 Haematology and biochemistry 3730 Samples will be drawn in a non-fasting state at Visit 1 and in a fasting state at Visit 2, 4, 7, 10, 13, 16, 17 and 3731 20 and will be analysed by the Central Laboratory. Calcitonin assessments will be made at Visit 1, 2, 4, 7, 3732 10, 13, 16, 17 and 20. 3733 3734 The central laboratory equipment may provide analyses not requested in the protocol but produced 3735 automatically in connection with the requested analyses. Such data will not be transferred to the trial 3736 database, but may be reported to the investigator according to specifications in the laboratory standard 3737 operating procedures and requirements. The additional data is specified in the trial specific laboratory 3738 manual. The investigator must review all laboratory results for concomitant illnesses and adverse events and 3739 report these according to this protocol.

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3740 Liraglutide 3745 3748 Date: 06 March 2012 Novo Nordisk 3741 Trial ID: NN8022-1922 3746 CONFIDENTIAL 3749 Version: 6.0 3742 Protocol - Revised edition 3747 3750 Status: Final 3743 EudraCT No.: 2008-002199-88 3751 Page: 79 of 133 37523744 3753 Haematology 3754 • Haemoglobin 3755 • Haematocrit 3756 • Thrombocytes 3757 • Erythrocytes 3758 • Leucocytes 3759 • Differential count 3760 − Eosinophils 3761 − Neutrophils 3762 − Basophils 3763 − Monocytes 3764 − Lymphocytes 3765 3766 Biochemistry 3767 • Creatinine 3768 • Creatine kinase 3769 • Urea 3770 • Albumin 3771 • Bilirubins, total 3772 • ALAT 3773 • ASAT 3774 • Alkaline phosphatase 3775 • Sodium 3776 • Potassium 3777 • Calcium, total 3778 • Amylase 3779 • Lipase 3780 • Calcitonin 3781 • TSH 3782 3783 3784 For subjects with calcitonin ≥ 20 ng/L (from visit 2 onwards) a repeat measurement of calcitonin must be 3785 performed preferably within four weeks and if confirmed, the event “elevated calcitonin” should be reported 3786 as a MESI (i.e., any confirmed episode of calcitonin concentration value ≥ 20 ng/L, if not already reported as 3787 a MESI, see section 12.2.1). 3788 3789 8.3.6 Pregnancy test 3790 Females of childbearing potential will have a serum pregnancy test (hCG) performed in connection with Visit 3791 1 (screening visit), Visit 16 (the end of treatment visit) and Visit 20 (the end of trial visit). Blood drawn 3792 for biochemistry will be used (see section 8.3.5).

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3793 Liraglutide 3798 3801 Date: 06 March 2012 Novo Nordisk 3794 Trial ID: NN8022-1922 3799 CONFIDENTIAL 3802 Version: 6.0 3795 Protocol - Revised edition 3800 3803 Status: Final 3796 EudraCT No.: 2008-002199-88 3804 Page: 80 of 133 38053797 3806 Urine pregnancy tests will be performed for females of childbearing potential at any time during the trial if a 3807 menstrual period is missed or as required by local law. Urine pregnancy kits will be supplied by the Central 3808 Laboratory. The test will be performed at the site. 3809 3810 Pregnancy testing will not be required for women who have undergone a hysterectomy or bilateral tubal 3811 ligation, or for women above the age of 50, who have been without menses for at least 1 year. 3812 3813 8.3.7 Liraglutide antibodies 3814 Blood samples for serum antibody against liraglutide will be drawn at Visit 2 and 17. For subjects 3815 discontinuing (leaving/being withdrawn from) the trial prematurely before Visit 16, the samples will be 3816 drawn at Visit 16 instead of Visit 17. 3817 3818 The sample drawn at baseline (Visit 2) will be analysed ongoing with the sample drawn at Visit 16 (only for 3819 subjects discontinuing)/Visit 17. Antibody analyses are done by use of a radioimmunoassay. All antibody 3820 positive samples will be further characterised for neutralising effect and cross reactivity to native GLP-1 and 3821 liraglutide. The neutralising effect of anti-drug antibodies is measured using a cell based assay. 3822 3823 8.3.8 Suspicion of Acute Hypersensitivity (allergic reaction) to Trial Product 3824 If acute hypersensitivity to trial product is suspected, local testing for blood tryptase concentration (total 3825 and/or mature tryptase) is recommended. 3826 3827 If trial product is discontinued as a consequence of suspicion of acute hypersensitivity, blood sampling for 3828 central assessment of liraglutide antibodies and IgE-isotype of liraglutide antibodies should be conducted, at 3829 least 14 days after trial product discontinuation. 3830 3831 Tryptase concentrations (if measured) as well as results of liraglutide antibody and IgE-isotype liraglutide 3832 antibodies will be sent to Novo Nordisk and will be included in the final MESI report. 3833 3834 8.3.9 Suspicion of Immune-complex Disease 3835 If immune-complex disease is suspected, blood sampling for central assessment of complement levels (C3 3836 and C4) should be conducted. Results should be included when reporting a MESI. 3837 3838 8.3.10 Mental Health questionnaires 3839 In recent years there has been increasing attention on the influence of seemingly innocuous changes in body 3840 chemistry on mental health, and even drugs thought to be largely free of mental effects are now seen as 3841 having the potential to affect mental health. Makers of drugs to treat obesity, urinary incontinence, epilepsy, 3842 smoking cessation, depression and many other conditions are being asked by regulators to put comprehensive 3843 mental health assessments into clinical trials. Therefore, even though liraglutide has not been associated 3844 with causing depression or suicidality two mental health questionnaires have been included in the present 3845 trial.

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3846 Liraglutide 3851 3854 Date: 06 March 2012 Novo Nordisk 3847 Trial ID: NN8022-1922 3852 CONFIDENTIAL 3855 Version: 6.0 3848 Protocol - Revised edition 3853 3856 Status: Final 3849 EudraCT No.: 2008-002199-88 3857 Page: 81 of 133 38583850 3859 Mental Health will be assessed at all site visits by the use of C-SSRS and PHQ-9. Subjects discontinuing the 3860 trial prematurely before Visit 16 will complete the mental health questionnaires at Visit 16 (end of treatment 3861 visit). 3862 3863 The subject should be given the opportunity to complete the PHQ-9 questionnaire by themselves without 3864 interruption. 3865 3866 The investigator or his delegate must review the C-SSRS and PHQ-9 questionnaires for completeness and 3867 AEs immediately following administration. 3868 3869 8.3.10.1C-SSRS 3870 The C-SSRS is a detailed questionnaire assessing both suicidal behaviour and suicidal ideation. The 3871 questionnaire will be administered as an interview by the Investigator or a sufficiently trained and medically 3872 qualified delegate according to local law (14). 3873 3874 The Investigator must assess the C-SSRS score at Visit 1 (screening visit) and Visit 2 (randomisation visit) to 3875 exclude subjects with any suicidal ideation of type 4 (active suicidal ideation with some intent to act, without 3876 specific plan) or type 5 (active suicidal ideation with specific plan and intent) (see section 6.3). 3877 3878 8.3.10.2 PHQ-9 3879 The PHQ-9 is a 9-item self-reported depression screening tool (24). The questionnaire takes approximately 3880 10 minutes to complete. 3881 3882 The Investigator must assess the PHQ-9 score at Visit 1 (screening visit) and Visit 2 (randomisation visit) to 3883 exclude subjects with a major depression (PHQ-9 score ≥ 15) (see section 6.3). 3884 3885 The investigator or his delegate must review the PHQ-9 questionnaire for completeness and AEs 3886 immediately following administration. 3887 3888 8.3.11 Thyroidectomy Pathology Slides 3889 In case a subject undergoes a thyroidectomy (partial or total) for any reason during the trial, pathology slides 3890 of the thyroid tissue will be centrally reviewed in addition to the routine examination at the site level. Both 3891 the site pathology report and the central pathology report will be reviewed by an independent Event 3892 Adjudication Committee (EAC), see section 12.2.2. A set of pathology slides routinely made after 3893 thyroidectomies by the pathology laboratory of the hospital where the operation was performed will be sent 3894 centrally for a second reading by a pathologist with expertise in thyroid and C-cell pathology, who will be 3895 blinded to both trial treatment and site diagnosis. Once the samples are re-examined they will be sent back to 3896 the site laboratory. 3897 3898 The investigator will be informed of the second pathology report, in order to take appropriate action (e.g. in 3899 case of a difference to the diagnosis of the site pathology)

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3900 Liraglutide 3905 3908 Date: 06 March 2012 Novo Nordisk 3901 Trial ID: NN8022-1922 3906 CONFIDENTIAL 3909 Version: 6.0 3902 Protocol - Revised edition 3907 3910 Status: Final 3903 EudraCT No.: 2008-002199-88 3911 Page: 82 of 133 39123904 3913 8.3.12 Thyroid Tissue Sample Collection in Case of Thyroidectomy 3914 Subjects scheduled for thyroidectomy will be asked to inform the Investigator prior to their operation. These 3915 subjects will be asked to consent to have a small sample of the removed thyroid tissue collected for testing of 3916 RET Y1062 phosphorylation in the thyroid C-cells. This is only applicable if C-cell pathology is confirmed 3917 (i.e., hyperplastic or neoplastic thyroid C-cells), and only if allowed by local law. The tissue sample will be 3918 destroyed after examination. 3919 3920 8.3.13 Genetic Testing in case of Confirmed C-cell Pathology 3921 Subjects scheduled for thyroidectomy will be asked to consent to be tested (blood sample) to identify 3922 germline RET gene mutations associated with MEN 2 syndrome. This RET gene mutation detection will be 3923 conducted in subjects with pathology reports confirming C-cell abnormality (medullary carcinoma or C-cell 3924 hyperplasia). Genetic testing will only be performed if allowed by local law and if the subject chooses to 3925 consent to it. 3926 3927 8.3.14 Eye examination 3928 Fundoscopy/fundusphotography will be performed preferably at Visit 1 but at the latest before Visit 2 by the 3929 Investigator, a local Ophthalmologist or an Optometrist according to local practice. Result of the 3930 fundoscopy/fundusphotography will be interpreted locally by the Investigator in relation to the trial. To 3931 document this, the Investigator must sign and date the result page. The interpretation must follow the 3932 categories: 3933 3934 • “Normal” 3935 • “Abnormal, not clinically significant” 3936 • “Abnormal, clinically significant” 3937 3938 In case of an “abnormal, clinically significant” fundoscopy/fundusphotography, the Investigator must 3939 comment in the subject notes and withdraw the subject if exclusion criterion no. 6 (known proliferative 3940 retinopathy) is fulfilled. 3941 3942 If a fundoscopy/fundusphotography has been performed within eight weeks before the screening visit (Visit 3943 1) and if the results are available, the procedure does not need to be repeated. The Investigator must still 3944 interpret, sign and date the fundoscopy/fundusphotography. If the fundoscopy/fundusphotography is 3945 performed before the subject has signed the informed consent form, it must be documented in the subject 3946 notes that the reason for performing the procedure was not related to this trial. 3947 3948 The date of Fundoscopy/fundusphotography must be recorded in the eCRF and be source data verifiable. 3949 3950 8.3.15 Binge Eating Scale questionnaire 3951 The binge eating scale questionnaire is a 16-item self-report diagnostic tool designed to capture both the 3952 behavioural and emotional characteristics of binge eating (16-18). It takes approximately 10 minutes to 3953 complete the questionnaire.

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3954 Liraglutide 3959 3962 Date: 06 March 2012 Novo Nordisk 3955 Trial ID: NN8022-1922 3960 CONFIDENTIAL 3963 Version: 6.0 3956 Protocol - Revised edition 3961 3964 Status: Final 3957 EudraCT No.: 2008-002199-88 3965 Page: 83 of 133 39663958 3967 Subjects discontinuing the trial prematurely before Visit 16 should complete the questionnaires at the end of 3968 treatment visit (Visit 16). 3969 3970 The investigator or his delegate must review patient reported outcome(s) for completeness and AEs 3971 immediately following administration. 3972 3973 3974 8.4 Other assessments 3975 3976 8.4.1 Smoking habits 3977 At the screening visit (Visit 1) it should be recorded whether the subject is a smoker. 3978 3979 8.4.2 Diabetes diary 3980 A diabetes diary will be handed out to the subjects at Visit 1 to 19. From Visit 2 to Visit 20 the Investigator 3981 should collect and review the diaries. 3982 3983 The Investigator should ask the subjects to report the following in the diabetes diary: 3984 • Date of first dose of randomised treatment 3985 • Concomitant medication (dosage changes and new medications) (see section 11) 3986 • Hypoglycaemic episodes (see section 8.3.2) 3987 • 7-point plasma glucose profile (only before Visit 2, 10 and 16) (see section 8.2.4) 3988 3989 8.4.3 3-day food diary 3990 A 3-day food diary will be handed out to the subjects at Visit 1, 4, 6, 8, 10, 12, 15 and 18. Subjects will be 3991 instructed by the dietician to register food intake. The dietician should collect and review the diaries. The 3992 diary will be used for diet counselling at Visit 2, 5b, 7, 9, 11, 13, 16 and 19. 3993 3994 8.4.4 Dietary compliance and physical activity 3995 The subject’s dietary compliance and the average daily level of physical activity will be recorded every 3996 second month at Visit 2 (only average daily level of physical activity), 5b, 7, 9, 11, 13, 16 and 19. The 3997 subject will be questioned whether they performed less than half an hour, between half an hour and one hour 3998 or more than 1 hour of physical activity per day. An increase in physical activity (recommended minimum 3999 150 minutes/week) will be encouraged and re-enforced by use of pedometers. 4000 4001 Whether or not the subject is in compliance with the prescribed diet is at the discretion of the dietician after 4002 review of the 3-day food diaries. 4003 4004 4005 8.4.5 Liraglutide concentration (population PK) 4006 A single blood sample for measurement of plasma liraglutide concentration will be drawn at Visit 3 (dose 4007 escalation period), Visit 6 and 10 (maintenance period). The PK assessments will be performed in a fasting 4008 state at Visit 3 and Visit 10 and in a non-fasting state at Visit 6. Subjects will be instructed to note the exact 4009 date and time of administration, injection site and the dose of liraglutide/liraglutide placebo of the 3 doses

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4010 Liraglutide 4015 4018 Date: 06 March 2012 Novo Nordisk 4011 Trial ID: NN8022-1922 4016 CONFIDENTIAL 4019 Version: 6.0 4012 Protocol - Revised edition 4017 4020 Status: Final 4013 EudraCT No.: 2008-002199-88 4021 Page: 84 of 133 40224014 4023 immediately prior to Visit 3, 6 and 10. Injection site, date and time of administration and the dose will be 4024 recorded in the eCRF. Diaries will be used to capture information on the injection date and time, dose as well 4025 as injection site. Exact date, time and injection site of liraglutide/ liraglutide placebo will be transcribed from 4026 the diaries into the eCRF. The date and actual time of blood sampling for the measurement of the liraglutide 4027 plasma concentration should also be recorded in the eCRF at each visit (Visit 3, Visit 6 and Visit 10). 4028 4029 A special laboratory will be responsible for the analysis of the liraglutide plasma concentration. Blood 4030 samples for liraglutide plasma concentration are collected, treated and shipped according to the description in 4031 the laboratory manual supplied by the special laboratory. Samples will be analysed on an ongoing basis 4032 during the trial. Codes with the randomisation number containing information about treatment for the 4033 particular subject will be available to the special laboratory. Novo Nordisk, Investigator and subject will 4034 remain blinded to the treatment until after database lock. 4035 4036 8.4.6 History of diabetes complications 4037 Information related to microvascular complications of diabetes, (i.e. Diabetic retinopathy, Diabetic 4038 neuropathy, Diabetic nephropatly (including Microalbuminia), Diabetic Macroangiopathy, Foot ulcer) will 4039 be recorded in the eCRF at Visit 1. 4040 4041 8.4.7 History of Concomitant Cardiovascular Disease 4042 Information related to concomitant cardiovascular disease (i.e., myocardial infarction, disorders of rhythm or 4043 conduction, heart failure incl. NYHA class, ischemic heart disease incl. type, PCI and CABG, left ventricular 4044 systolic dysfunction, left ventricular diastolic dysfunction, hypertension, ischemic stroke, transient ischemic 4045 attack, hemorrhagic stroke, intracranial artery stenosis, carotid artery stenosis, peripheral arterial disease incl. 4046 > 50% stenosis on angiography or other imaging) will be recorded in the eCRF at Visit 1. 4047 4048 8.4.8 History of Gallbladder Disease 4049 Information related to gallbladder disease will be recorded in the eCRF at Visit 1. 4050 4051 8.4.9 History of Psychiatric Disorders 4052 Information related to psychiatric disorders (specifically history of depression, suicidal behaviour, anxiety, 4053 mood disorders, insomnia, or other sleep disorders) will be recorded in the eCRF at Visit 1. 4054 4055 4056 8.5 Subject compliance 4057 The Investigator will at each visit remind the subject to follow protocol procedures. 4058 4059 At Visit 4 and 5b-16 (including the end of treatment visit, early discontinuation visit or any unscheduled visit 4060 when drug accountability is performed) the subject will return their partly used or unused trial products 4061 including all empty packaging material. The Investigator will assess the amount of trial product returned 4062 compared to what was dispensed at the last dispensing visit, and ask the subject if the trial product has been 4063 used as prescribed.

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4064 Liraglutide 4069 4072 Date: 06 March 2012 Novo Nordisk 4065 Trial ID: NN8022-1922 4070 CONFIDENTIAL 4073 Version: 6.0 4066 Protocol - Revised edition 4071 4074 Status: Final 4067 EudraCT No.: 2008-002199-88 4075 Page: 85 of 133 40764068 4077 If a subject is discovered to be non-compliant, the Investigator should counsel the subject on the importance 4078 of taking trial products as directed. Failure to comply can ultimately lead to withdrawal from the trial. This 4079 must always be preceded by discussions with and approval by Novo Nordisk.

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4080 Liraglutide 4087 4090 Date: 06 March 2012 Novo Nordisk 4081 Trial ID: NN8022-1922 4088 CONFIDENTIAL 4091 Version: 6.0 4082 Protocol - Revised edition 4089 4092 Status: Final 4083 EudraCT No.: 2008-002199-88 4093 Page: 86 of 133 4084 4085 9 Trial supplies 40944086 4095 Procedures for supply, handling and storage of trial materials will be described in a separate Trial Materials 4096 Manual (TMM) provided by Novo Nordisk. 4097 4098 The trial products will be dispensed to each subject as required according to treatment group. The IV/WRS 4099 will allocate trial product DUN to the subject at each dispensing or randomisation visit. The correct DUN 4100 must be dispensed to the subject. 4101 4102 4103 9.1 Trial product(s) 4104 The administration of liraglutide/liraglutide placebo will be as outlined in section 5.3.

4105 The following trial products will be supplied by Novo Nordisk, Denmark.

4106 • Liraglutide 6.0 mg/mL, 3 mL FlexPen® for subcutaneous (s.c.) injection 4107 • Liraglutide placebo 3 mL FlexPen® for subcutaneous (s.c.) injection 4108

4109 9.2 Packaging and labelling of trial product(s) 4110 All trial products will be packed and labelled by Novo Nordisk and provided in non subject specific boxes.

4111 Labelling will be in accordance with Annex 13, local law and trial requirements.

4112 Each investigator site will be supplied with sufficient trial products for the trial on an ongoing basis 4113 controlled by the IV/WRS. 4114 4115 Dispensing units will be prepared and distributed to the sites according to enrolment. Please refer to the 4116 TMM provided by Novo Nordisk for details regarding trial products standard packages. 4117 4118 The Investigator will provide each subject with a direction for use for liraglutide FlexPen® at each drug 4119 dispensing visit. 4120 4121 4122 9.3 Storage and drug accountability of trial product(s) 4123 The Investigator must keep track of all received, used, partly used and unused trial products by the use of the 4124 drug accountability module in the IV/WRS. 4125 4126 Store in a refrigerator (2°C to 8°C). Do not store in the freezer or directly adjacent to the refrigerator cooling 4127 element. Do not freeze liraglutide/liraglutide placebo and do not use liraglutide/liraglutide placebo if it has 4128 been frozen. 4129 4130 Liraglutide/liraglutide placebo should not be used if it does not appear clear and colourless.

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4131 Liraglutide 4136 4139 Date: 06 March 2012 Novo Nordisk 4132 Trial ID: NN8022-1922 4137 CONFIDENTIAL 4140 Version: 6.0 4133 Protocol - Revised edition 4138 4141 Status: Final 4134 EudraCT No.: 2008-002199-88 4142 Page: 87 of 133 41434135 4144 After first use of the liraglutide/liraglutide placebo pen, the product can be stored for 1 month at room 4145 temperature (below 30°C) or in a refrigerator (2°C to 8°C). 4146 4147 US: 30 days at room temperature (+15°C to +30°C)/(59°F to 86°F) or in a refrigerator (+2°C to 4148 +8°C)/(+36°F to +46°F) 4149 4150 Keep the pen cap on when liraglutide/liraglutide placebo pen is not in use in order to protect from light. 4151 Liraglutide/liraglutide placebo should be protected from excessive heat and sunlight. 4152 4153 Always remove the injection needle after each injection and store the liraglutide/liraglutide placebo pen 4154 without an injection needle attached. This prevents contamination, infection, and leakage. It also ensures that 4155 the dosing is accurate. 4156 4157 No trial product which has exceeded the expiry date must be used. 4158 4159 The Investigator must ensure the availability of proper storage conditions and record and evaluate the 4160 temperature. The temperature must be recorded and evaluated on a daily basis (working days) using as a 4161 minimum a calibrated min/max thermometer. A log to document the temperature must be kept. For sites 4162 using Elpro Libero storage device a weekly (work week) manual handwritten log must be maintained to 4163 confirm by signature and date that the storage temperature is within the acceptable ranges, plus a monthly 4164 print out of the loggings (graph/data) must be reviewed, signed and dated. 4165 4166 Storage facilities should be checked frequently (at least once every working day). 4167 4168 In case of incorrect storage the Investigator or site staff must contact the monitor without delay. Trial 4169 product must be set on-hold and not dispensed to subjects until notified by the monitor. 4170 4171 No trial product(s) should be dispensed to any person not enrolled in the trial and the IV/WRS should always 4172 be contacted when dispensing trial product(s). 4173 4174 Returned trial product(s) (partly used or unused including empty packaging material) must be stored 4175 separately from non-allocated trial product(s) until the monitor has performed drug accountability. The 4176 monitor will be responsible for retrieval of trial products from the site. Destruction of trial products will be 4177 done according to local laws and will be recorded on a Destruction Form, which must be signed by the 4178 person responsible for destruction, as agreed with the monitor. 4179 4180 4181 9.4 Auxiliary supply 4182 Novo Nordisk will provide the following auxiliary supplies: NovoFine® needles, blood glucose meters 4183 (Abbott Diabetes Care), lancets, test strips control solution and pedometers. 4184 4185 For further details please refer to the TMM.

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4186 Liraglutide 4191 4194 Date: 06 March 2012 Novo Nordisk 4187 Trial ID: NN8022-1922 4192 CONFIDENTIAL 4195 Version: 6.0 4188 Protocol - Revised edition 4193 4196 Status: Final 4189 EudraCT No.: 2008-002199-88 4197 Page: 88 of 133 41984190 4199 10 Randomisation, breaking of blinded codes and interactive 4200 voice/web response system (IV/WRS) 4201 4202 10.1 Randomisation 4203 Randomisation to the liraglutide 3.0 mg arm, the liraglutide 1.8 mg arm and the liraglutide placebo arm will 4204 be carried out in a 2:1:1 manner, respectively. The placebo arm will be further subdivided into two arms with 4205 different injection volumes corresponding to the different dose levels of liraglutide i.e. subjects will be 4206 randomised to four treatment groups. The trial is a double-blinded trial. 4207 4208 The treatment will be allocated in a centralised manner via the IV/WRS system and will be stratified 4209 according to background treatment (see section 5.1) and baseline HbA1c (see section 5.1). 4210 4211 Subjects randomised in the trial will continue with the subject number allocated at screening. 4212 4213 4214 10.2 Breaking of blinded codes 4215 The code for a particular subject may be broken in a medical emergency if knowing the identity of the 4216 treatment allocation would influence the treatment of the subject. Whenever a code is broken, the person 4217 breaking the code must print the Code Break Confirmation generated by the IV/WRS, record the reason, and 4218 sign and date the document. 4219 4220 If the trial site needs to break the code, Novo Nordisk should, if possible, be contacted prior to breaking the 4221 code. Novo Nordisk (Monitor and department responsible for global product safety) will be notified 4222 immediately after the code break by the IV/WRS. 4223 4224 If the subject should be withdrawn following a code break, a withdrawal session should be completed in 4225 IV/WRS. 4226 4227 When code is broken the treatment allocation will be accessible to the Investigator and the department 4228 responsible for global product safety, Novo Nordisk. 4229 4230 In case IV/WRS is not accessible at the time of code break the IV/WRS vendor helpdesk should be 4231 contacted. 4232 4233 4234 10.3 Interactive voice/web response system (IV/WRS) 4235 A trial specific IV/WRS will be set-up, and can be accessed at any time by the internet. Some sessions may 4236 be available through a toll-free telephone number. Accessibility to the IV/WRS must be restricted to and 4237 controlled by authorised persons. 4238 4239 IV/WRS is used for: 4240 • screening 4241 • screening failure

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4242 Liraglutide 4247 4250 Date: 06 March 2012 Novo Nordisk 4243 Trial ID: NN8022-1922 4248 CONFIDENTIAL 4251 Version: 6.0 4244 Protocol - Revised edition 4249 4252 Status: Final 4245 EudraCT No.: 2008-002199-88 4253 Page: 89 of 133 42544246 4255 • randomisation 4256 • dispensing 4257 • medication arrival 4258 • withdrawal 4259 • completion 4260 • code break 4261 • drug accountability 4262 • live data change 4263 4264 4265 An IV/WRS user manual will be provided to the trial site.

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4266 Liraglutide 4271 4274 Date: 06 March 2012 Novo Nordisk 4267 Trial ID: NN8022-1922 4272 CONFIDENTIAL 4275 Version: 6.0 4268 Protocol - Revised edition 4273 4276 Status: Final 4269 EudraCT No.: 2008-002199-88 4277 Page: 90 of 133 42784270 4279 11 Concomitant illnesses/Medical history and concomitant 4280 medication

4281 Definitions: 4282 Concomitant illness: any illness that is present at the start of the trial (i.e. at the first 4283 visit). 4284 4285 Medical history: any relevant medical history which is not present at the start of 4286 the trial as judged by the Investigator. 4287 4288 Concomitant medication: any medication other than the trial product(s) that is taken 4289 during the trial, including the screening period. 4290 4291 Details of all concomitant illnesses and medication must be recorded at trial entry (i.e. at the first visit). Any 4292 changes in concomitant medication must be recorded at each visit. If a change is due to an AE then this must 4293 be recorded and reported according to section 12. If the change influences the subject’s eligibility to continue 4294 in the trial then the Monitor must be informed. 4295 4296 The information collected for each concomitant medication includes, at a minimum, start date, stop date or 4297 continuing and indication. 4298 4299 Proportion of subjects with change in concomitant medication from baseline to Week 56 in: 4300 • Anti-hypertensitive agents 4301 • Lipid-lowering agents 4302 • Oral- antidiabetic drugs

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4303 Liraglutide 4308 4311 Date: 06 March 2012 Novo Nordisk 4304 Trial ID: NN8022-1922 4309 CONFIDENTIAL 4312 Version: 6.0 4305 Protocol - Revised edition 4310 4313 Status: Final 4306 EudraCT No.: 2008-002199-88 4314 Page: 91 of 133 43154307 4316 12 Adverse events and Pregnancies 4317 4318 12.1 Definitions 4319 Adverse event (AE): 4320 4321 Any untoward medical occurrence in a subject or clinical investigation subject administered a 4322 pharmaceutical product and which does not necessarily have to have a causal relationship with this 4323 treatment. 4324 4325 An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory 4326 finding, for example), symptom, or disease temporally associated with the use of a medicinal product, 4327 whether or not considered related to the medicinal product. 4328 4329 Note: This includes events from the first trial related activity after the subject has signed the informed 4330 consent and until post treatment follow-up period as defined in the protocol (the period from Visit 16 – End 4331 of treatment to Visit 20 – End of trial). 4332 4333 The following should not be recorded as AEs: 4334 4335 • Pre-planned procedures unless the condition for which the procedure was planned has worsened from the 4336 first trial related activity after the subject has signed the informed consent. 4337 • Pre-existing conditions found as a result of screening procedures. These should be recorded as medical 4338 history/concomitant illness. 4339 4340 An AE can also be a clinical laboratory abnormality regarded as clinically significant i.e. an abnormality that 4341 suggests a disease and/or organ toxicity and is of a severity which requires active management (i.e. change of 4342 dose, discontinuation of trial product, more frequent follow-up or diagnostic investigation). 4343 4344 A worsening in concomitant illness must be recorded as an AE. A worsening of an ongoing AE should be 4345 reported on a new AE form by making a new assessment for seriousness and/or severity. 4346 4347 Serious adverse event (SAE): 4348 A Serious AE is an experience that at any dose results in any of the following: 4349 4350 • Death 4351 • A life-threatening* experience 4352 • In-subject hospitalisation* or prolongation of existing hospitalisation 4353 • A persistent or significant disability/incapacity* 4354 • A congenital anomaly/birth defect 4355 • Important medical events* that may not result in death, be life-threatening*, or require 4356 hospitalisation may be considered an SAE when, based upon appropriate medical judgement, they may 4357 jeopardise the subject and may require medical or surgical intervention to prevent one of the outcomes 4358 listed in this definition.

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4359 Liraglutide 4364 4367 Date: 06 March 2012 Novo Nordisk 4360 Trial ID: NN8022-1922 4365 CONFIDENTIAL 4368 Version: 6.0 4361 Protocol - Revised edition 4366 4369 Status: Final 4362 EudraCT No.: 2008-002199-88 4370 Page: 92 of 133 43714363 4372 * The term “life-threatening” in the definition of SAE refers to an event in which the subject was at 4373 risk of death at the time of the event. It does not refer to an event which hypothetically might have 4374 caused death if it were more severe. 4375 4376 * The term “hospitalisation” is the definition of a subject admitted to a hospital/inpatient (irrespective 4377 of the duration of physical stay), or not admitted to a hospital/not inpatient, but stays at the hospital 4378 for treatment or observation for more than 24 hours. Medical judgement must always be exercised, 4379 and when in doubt, the hospital contact should be regarded as a hospitalisation. Hospitalisations for 4380 administrative, trial related and social purposes do not constitute AEs and should therefore neither be 4381 reported as AEs or SAEs. Likewise, hospital admissions for surgical procedures planned prior to trial 4382 inclusion are not considered AEs or SAEs. 4383 4384 * The term “disability/incapacity” means that following the event the subject or clinical investigation 4385 subject has significant, persistent or permanent change, impairment, damage or disruption in his body 4386 function or structure, physical activity and/or quality of life. 4387 4388 * The term “important medical events” means events which may jeopardise the subject or require 4389 intervention to prevent a seriousness criterion. It can be adverse events which suggest a significant 4390 hazard or put the subject or clinical investigation subject at risk, such as drug- interactions, contra- 4391 indications or precautions, occurrence of malignancies or development of drug dependency or drug 4392 abuse. 4393 4394 Non-serious adverse event: 4395 A non-serious AE is any AE which does not fulfil the definition of a serious AE. 4396 4397 Severity assessment definitions: 4398 • Mild – No or transient symptoms, no interference with the subject’s daily activities 4399 • Moderate - Marked symptoms, moderate interference with the subject’s daily activities 4400 • Severe - Considerable interference with the subject’s daily activities, unacceptable 4401 4402 Relationship to trial product (liraglutide and liraglutide placebo) assessment definitions: 4403 • Probable: good reasons and sufficient documentation to assume a causal relationship 4404 • Possible: a causal relationship is conceivable and cannot be dismissed 4405 • Unlikely: the event is most likely related to an aetiology other than the trial product 4406 4407 Outcome categories and definitions: 4408 • Recovered - Fully recovered, or by medical or surgical treatment the condition has returned to the level 4409 observed at the first trial related activity after the subject signed the informed consent 4410 • Recovering - The condition is improving and the subject is expected to recover from the event. This term 4411 should only be used when the subject has completed the trial 4412 • Recovered with sequelae - As a result of the AE the subject suffered persistent and significant 4413 disability/incapacity (e.g. became blind, deaf, paralysed). If the sequelae meet seriousness criteria, the 4414 AE must be reported as an SAE.

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4415 Liraglutide 4420 4423 Date: 06 March 2012 Novo Nordisk 4416 Trial ID: NN8022-1922 4421 CONFIDENTIAL 4424 Version: 6.0 4417 Protocol - Revised edition 4422 4425 Status: Final 4418 EudraCT No.: 2008-002199-88 4426 Page: 93 of 133 44274419 4428 • Not recovered 4429 • Fatal 4430 • Unknown - This term should only be used in cases where the subject is lost to follow-up 4431 4432 12.1.1 Technical complaints 4433 A technical complaint is any written, electronic, or oral communication that alleges defects on trial products 4434 - listed as trial products in this protocol (9.1). The technical complaint may be associated with an AE, but 4435 does not concern the AE itself. 4436 4437 A technical complaint may for example concern: 4438 4439 • the physical or chemical appearance of trial products (e.g. discoloration, particles or contamination) 4440 • the packaging material (e.g. leakage, cracks, problems with rubber membrane in the cartridge or errors in 4441 labelling text) 4442 • problems related to devices (e.g. to the injection mechanism, dose setting mechanism, glucose 4443 measurement, push button or interface between the pen and the needle) 4444 4445 4446 12.2 Collection, recording and reporting of adverse events 4447 All events meeting the definition of an AE must be collected and reported. At each contact with the trial site 4448 (visit or telephone, excluding safety visits, where the subject is not seeing the Investigator or his staff [e.g. 4449 visits to the laboratory]), the subject must be asked about adverse events. The subject will be asked about 4450 AEs in the following manner: “Have you experienced any problems since the last contact?”. All AEs, either 4451 observed by the Investigator or reported by the subject, must be recorded by the Investigator and evaluated. 4452 4453 Novo Nordisk's assessment of expectedness is done according to the reference documents: 4454 4455 • Liraglutide obesity: IB, 3rd edition, 2010 or any updates hereof 4456 4457 The Investigator should record the diagnosis, if available. If no diagnosis is available the Investigator should 4458 record each sign and symptom as individual adverse events. 4459 4460 All AEs, SAEs and MESIs must be recorded by the Investigator on the AE Form in EDC. If more than one 4461 sign or symptom is to be reported, create a separate adverse event form for each sign and symptom. 4462 4463 For SAEs and MESIs, the SIF pages also have to be completed for each event in the eCRF. However if 4464 several symptoms or diagnosis occur as part of the same clinical picture, only one set of SIF can be used to 4465 describe all the SAEs. All concerned AE numbers must be included in the AE number field in the header of 4466 the SIF. 4467 4468 For MESIs, the specific MESI follow-up questions have also to be completed in the eCRF. For MESIs 4469 qualifying for adjudication, the Source Data Collection Tool has also to be completed in the eCRF.

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4470 Liraglutide 4475 4478 Date: 06 March 2012 Novo Nordisk 4471 Trial ID: NN8022-1922 4476 CONFIDENTIAL 4479 Version: 6.0 4472 Protocol - Revised edition 4477 4480 Status: Final 4473 EudraCT No.: 2008-002199-88 4481 Page: 94 of 133 44824474 4483 The Investigator must report initial information on all SAEs and MESIs to Novo Nordisk within 24 hours of 4484 obtaining knowledge about the event by completing the following in EDC: 4485 4486 • AE form 4487 • SIF 4488 The investigator must sign the relevant AE form and SIF within 7 calendar days after entering/updating the 4489 AE form and SIF for SAEs and MESIs 4490 4491 The specific MESI follow-up questions and source data collection tool also have to be completed if 4492 applicable. 4493 4494 If for any reason the EDC application is unavailable, complete the AE form, SIF and if applicable the 4495 specific MESI follow-up questions and Source Data Collection Tool on paper CRFs and forward a copy 4496 electronically in PDF format by e-mail, or by fax or courier to Novo Nordisk within the same timelines. 4497 4498 The Investigator/Novo Nordisk must inform the regulatory authorities and independent ethics committee 4499 (IEC)/institutional review boards (IRB) in accordance with the local requirements in force and International 4500 Conference on Harmonisation Good Clinical Practice (ICH GCP) (25). 4501 4502 Novo Nordisk will notify the Investigator of trial product related suspected unexpected serious adverse 4503 reactions in accordance with the local requirements (e.g. European Directive 2001/20/EC and International 4504 Conference on Harmonisation/Good Clinical Practice [ICH GCP (25)]). In addition, the Investigator will be 4505 informed of any trial related procedure SAE which may warrant a change of any trial procedure. 4506 4507 Investigators will be notified of trial-related SAEs in accordance with the local requirements in force and 4508 ICH GCP (25). 4509 4510 The monitor must be informed accordingly. 4511 4512 12.2.1 Medical events of special interest 4513 A medical event of special interest (MESI) (serious or non-serious) is a noteworthy event of scientific and 4514 medical concern that Novo Nordisk continues to monitor. 4515 4516 A MESI does not necessarily have a causal relationship with the Investigational Medicinal Product (IMP). 4517 4518 A MESI should be reported following the same reporting requirements and timelines as for SAEs (see 4519 section 12.1), irrespective of the MESI fulfils a SAE criterion. 4520 4521 The following are defined as MESIs in this trial (see Appendix H for further definitions) 4522 4523 • Medication errors concerning trial products 4524 − administration of wrong drug or use of wrong device 4525 − wrong route of administration, such as intramuscular instead of subcutaneous 4526 − administration of a high dose with the intention to cause harm, e.g. suicide attempt

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4527 Liraglutide 4532 4535 Date: 06 March 2012 Novo Nordisk 4528 Trial ID: NN8022-1922 4533 CONFIDENTIAL 4536 Version: 6.0 4529 Protocol - Revised edition 4534 4537 Status: Final 4530 EudraCT No.: 2008-002199-88 4538 Page: 95 of 133 45394531 4540 − administration of an accidental overdose, i.e. dose which may lead to significant health 4541 consequences, as judged by the Investigator, irrespective of whether the SAE criteria are fulfilled or 4542 not 4543 • Suspected transmission of an infectious agent via a trial product 4544 • Death (if not already reported as a cardiovascular MESI) 4545 • Acute coronary syndrome (myocardial infarction or hospitalisation for unstable angina) 4546 • Cerebrovascular event (stroke or transient ischemic attack) 4547 • Heart failure 4548 • Stent trombosis 4549 • Revascularisation procedure 4550 • Hospitalisation for cardiac arrhythmia 4551 • Pancreatitis or acute, severe, persistent abdominal pain leading to a suspicion of pancreatitis 4552 • Acute gallstone disease (biliary colic or acute cholecystitis) 4553 • Elevated lipase or amylase ≥ 3 xUNR reported as result of protocol-scheduled visits: Should always be 4554 reported as separate MESI, even if followed by diagnosis of pancreatitis (i.e. event/diagnosis not to be 4555 updated, new event to be filed) 4556 • Neoplasms (if thyroid neoplasm select Thyroid disease MESI) 4557 • Thyroid disease 4558 • Any confirmed episode of calcitonin value ≥ 20 ng/L (from Visit 2 and onwards) 4559 • Acute renal failure 4560 • Severe hypoglycaemic events 4561 • Immunogenisity event ( allergic reactions including allergic reactions at injection sites, or immune- 4562 complex disease) 4563 • AEs leading to withdrawal (if not already reported as any of the listed MESIs) 4564 • Psychiatric Disorders (including psychiatric disorders diagnosed by C-SSRS and PHQ-9 questionnaires) 4565 4566 All events confirmed or suspected to be a MESI must be reported. Additionally, in case the sponsor identifies 4567 potentially missed MESIs through predefined review of available data, the Investigator will be asked to 4568 reconsider if this is a MESI. 4569 4570 Some events might apply to more than one MESI category. Medical judgement should be exercised when 4571 choosing which MESI form to fill out. 4572 4573 For subjects with calcitonin ≥ 20 ng/L (from visit 2 and onwards) a repeat measurement of calcitonin must 4574 be performed preferably within four weeks and if confirmed, the event “elevated calcitonin” should be 4575 reported as a MESI (i.e., any confirmed episode of calcitonin concentration value ≥ 20 ng/L, if not already 4576 reported as a MESI). 4577 4578 For details on how increased calcitonin levels at follow-up visits should be reported and followed up, please 4579 refer to Appendix H for reporting of MESIs and Appendix I describing how the Calcitonin Monitoring 4580 Committee works.

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4581 Liraglutide 4586 4589 Date: 06 March 2012 Novo Nordisk 4582 Trial ID: NN8022-1922 4587 CONFIDENTIAL 4590 Version: 6.0 4583 Protocol - Revised edition 4588 4591 Status: Final 4584 EudraCT No.: 2008-002199-88 4592 Page: 96 of 133 45934585 4594 In addition the following rules for increased lipase and /or amylase apply: 4595 If the amylase or lipase baseline (at screening) value is > 3xUNR this information will be recorded as 4596 medical history for that subject. If at any post baseline visit the amylase or lipase value is > 3xUNR a MESI 4597 should be reported. 4598 4599 If the patient is diagnosed with a thyroid neoplasm only the “Thyroid disease” MESI form has to be filled out 4600 and not the “Neoplasm” MESI form. 4601 4602 Revascularisation procedures and stent thrombosis’ should always be reported as separate AEs and captured 4603 separately on the respective MESI forms. 4604 4605 For all SAE(s)/MESI(s) with a fatal outcome the MESI form “Death” should be filled out unless the death is 4606 caused by a cardiovascular MESI. In this case only the cardiovascular MESI should be filled out. If death is a 4607 consequence of a cardiovascular MESI previously reported this MESI should be updated with the outcome 4608 death. 4609 4610 Certain MESIs will be adjudicated by an external independent event adjudication committee as described in 4611 section (12.2.2). For further information regarding definitions of MESIs and an overview of which events 4612 that should undergo adjudication, please refer to Appendix H. 4613 4614 Complete the AE form, Safety Information Form (SIF), specific MESI follow-up questions and if applicable 4615 Source Data Collection Tool in the eCRF within 7 calendar days. 4616 4617 If for any reason the electronic data capture (EDC) application is unavailable, complete the AE form, SIF, 4618 specific MESI follow-up question and if applicable Source Data Collection Tool on paper CRFs and forward 4619 a copy electronically in PDF format by e-mail, or by fax or courier to Novo Nordisk within 7 calendar days. 4620 4621 4622 12.2.2 External independent event adjudication committee 4623 An external independent Event Adjudication Committee (EAC) is constituted for this trial to perform 4624 ongoing adjudication, standardisation and assessment of events listed in Appendix H. 4625 4626 The following events, except for screening failures, (also described in 12.2.1 under MESIs) will be 4627 adjudicated and evaluated by the EAC in an independent and blinded manner: 4628 4629 • Death 4630 • Acute coronary syndrome (myocardial infarction or hospitalisation for unstable angina) 4631 • Cerebrovascular event (stroke or transient ischemic attack) 4632 • Heart failure requiring hospitalisation 4633 • Stent thrombosis 4634 • Coronary revascularisation procedure 4635 • Pancreatitis or acute, severe, persistent abdominal pain leading to a suspicion of pancreatitis 4636 • Neoplasms 4637 • Thyroid disorders requiring thyroidectomy

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4638 Liraglutide 4643 4646 Date: 06 March 2012 Novo Nordisk 4639 Trial ID: NN8022-1922 4644 CONFIDENTIAL 4647 Version: 6.0 4640 Protocol - Revised edition 4645 4648 Status: Final 4641 EudraCT No.: 2008-002199-88 4649 Page: 97 of 133 46504642 4651 4652 The EAC is composed of permanent members who cover required medical specialties. The EAC members 4653 must disclose any potential conflicts of interest and must be independent of Novo Nordisk. 4654 4655 The EAC works in accordance with written guidelines included in the EAC Charter that describes in detail 4656 the composition, tasks, responsibilities, and work processes of the committee. The charter will be finalised 4657 prior to first patient first visit. 4658 4659 The EAC will perform adjudication based on the criteria and definitions described in the EAC Charter. The 4660 cardiovascular events will be classified according to FDA requirements (26). 4661 4662 The EAC will review translated copies in English of medical documentation received in the adjudication 4663 packages (for example X-ray, ECGs, ultrasound images, discharge summaries, pathology reports, and death 4664 certificates). The Investigator will provide them as soon as possible, when they receive the request from 4665 Novo Nordisk. 4666 4667 The role of the EAC is solely to adjudicate events in a blinded manner. The EACs will have no authorisation 4668 to impact on trial conduct, trial protocol and amendments. 4669 4670 The assessments made by the EAC will be included in the CTR as well as assessments made by the 4671 Investigator. However, the adjudication made by an EAC, given its independence and in-depth analysis of 4672 each event, will be attributed with greater importance of the two. The outcomes of adjudication will be kept 4673 in the Global Safety database as well as in the clinical trial database. 4674 4675 4676 12.3 Follow-up of adverse events 4677 During and following a subject’s participation in a clinical trial, the Investigator/institution should ensure 4678 that adequate medical care is provided to the subject for any adverse events, including clinically significant 4679 laboratory values related to the trial. The Investigator/institution should inform the subject when medical 4680 care is needed for adverse event(s) of which the Investigator becomes aware. 4681 4682 The follow up information should only include new (updated and/or additional) information that reflects the 4683 situation at the time of the Investigator’s signature. 4684 4685 Follow-up information (corrections, new or additional information) should be reported within 24 hours of 4686 obtaining knowledge of the information for SAEs and MESIs, and if previously non-serious AEs become 4687 SAEs by updating the AE form and/or SIF in the eCRF. 4688 4689 All non-serious AEs classified as severe or possibly/probably related to the trial product must be followed 4690 until the subject has “recovered” or “recovered with sequelae” and all queries have been resolved. Cases of 4691 chronic conditions or cancer or AEs ongoing at time of death (i.e., subject dies from another AE) can be 4692 closed with an outcome of “recovering” or “not recovered”. Cases can be closed with an outcome of 4693 “recovering” when the subject has completed the post-trial follow-up period and is expected by the 4694 Investigator to recover.

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4695 Liraglutide 4700 4703 Date: 06 March 2012 Novo Nordisk 4696 Trial ID: NN8022-1922 4701 CONFIDENTIAL 4704 Version: 6.0 4697 Protocol - Revised edition 4702 4705 Status: Final 4698 EudraCT No.: 2008-002199-88 4706 Page: 98 of 133 47074699 4708 All other non-serious AEs must be followed until the outcome of the event is “recovering”, “recovered” or 4709 “recovered with sequelae” or until the end of the post-treatment follow-up stated in the protocol, whichever 4710 comes first, and until all queries related to these AEs have been resolved. AEs ongoing at time of death (i.e. 4711 subjects dies from another AE) can be closed with an outcome of “recovering” or “not recovered”. 4712 4713 The Investigator must ensure that the worst case severity and seriousness is kept consistent. 4714 4715 The Investigator must record follow-up information on non-serious adverse events by updating the adverse 4716 event form in the eCRF. The follow-up information should only include new (updated and/or additional) 4717 information that reflects the situation at the time of the Investigator´s signature. 4718 4719 Queries or follow-up requests from Novo Nordisk should be responded to within 7 calendar days, unless 4720 otherwise specified. This must be done by updating the AE form and/or SIF in the eCRF. If for any reason 4721 EDC/eCRF application is unavailable, then the relevant paper forms have to be filled in, marked as follow- 4722 up and forwarded by fax or e-mail to Novo Nordisk within the same timelines. 4723 4724 When a MESI of a specific category occurs for the first time in the subject and is selected on the AE form, 4725 the predefined follow-up section for that MESI category is automatically activated in the EDC. Each of these 4726 sections have follow-up forms related to the reported MESI, and the forms should be considered as a follow- 4727 up request from Novo Nordisk, and should therefore also be responded to within 7 calendar days from the 4728 date of awareness of the MESI. 4729 4730 For MESIs qualifying for adjudication, the Source Data Collection Tool has to be completed in the eCRF 4731 within 7 calendar days. 4732 4733 All SAEs and MESIs must be followed up until the outcome of the event is “recovered”, “recovered with 4734 sequelae” or “fatal” and until all queries have been resolved. Cases of chronic conditions or cancer or AEs 4735 ongoing at time of death (ie the subject dies form another AE) can be closed with the outcome of 4736 “recovered” or “not recovered”. Cases can be closed with an outcome of “recovering” when the subject has 4737 completed the trial and is expected by the Investigator to recover. 4738 4739 After access to update the AE form and SIF in EDC is removed the Investigator must record any SAE and 4740 MESI follow-up information, if required, on the paper CRFs provided at trial closure. 4741 4742 12.3.1 Collection and reporting of technical complaints 4743 All technical complaints as defined in section 12.1.1 - occurring from the time of first and until the last usage 4744 of trial product - must be collected and reported to Novo Nordisk. 4745 4746 The subject must be asked about technical complaints during each contact (site visit or telephone contact) 4747 with the Investigator or trial site staff. This may be done by posing a simple question such as “have you 4748 experienced any problems since the last contact?”. 4749 4750 The Investigator must assess whether the technical complaint is related to: 4751 − AE(s), SAE(s) and/or MESI(s)

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4752 Liraglutide 4757 4760 Date: 06 March 2012 Novo Nordisk 4753 Trial ID: NN8022-1922 4758 CONFIDENTIAL 4761 Version: 6.0 4754 Protocol - Revised edition 4759 4762 Status: Final 4755 EudraCT No.: 2008-002199-88 4763 Page: 99 of 133 47644756 4765 4766 The AE(s), SAE(s) and MESI(s) related to technical complaint(s) must be reported by the Investigator 4767 following the same reporting requirements and timelines as for other AEs, SAEs and MESIs (see section 4768 12.1). 4769 4770 Technical complaints must be reported on the technical complaint form by the Investigator, as described in 4771 the following: 4772 • One technical complaint form must be completed for each trial product, non-investigational medicinal 4773 product (NIMP) or auxiliary supply. If the technical complaint involves more than one batch number, a 4774 technical complaint form for each batch number must be completed. 4775 4776 The Investigator must complete the technical complaint form in the eCRF within the following timelines of 4777 the trial site obtaining knowledge of the technical complaint: 4778 • technical complaint assessed as related to a SAE and/or MESI within 24 hours 4779 • all other technical complaints within 5 calendar days 4780 If the eCRF is unavailable, the paper technical complaint form should be completed and faxed to Customer 4781 Complaint Center, Novo Nordisk, fax: +45 44 42 13 70, within the same timelines as for eCRF. 4782 4783 4784 12.3.2 Collection, storage and shipment of technical complaint samples 4785 The Investigator must collect the technical complaint sample from the subject. If the technical complaint 4786 sample is unobtainable, the Investigator must specify on the technical complaint form why it is unobtainable. 4787 4788 The technical complaint sample and a paper copy of the technical complaint form must be sent to Novo 4789 Nordisk within 5 calendar days of receiving the technical complaint sample at trial site by using the 4790 following address: 4791 4792 Novo Nordisk, Att.: Customer Complaint Center, Nybrovej 80, 2820 Gentofte, Denmark. 4793 4794 The Investigator must ensure that the techincal complaint sample is labelled with the batch number and, if 4795 available, the DUN number. 4796 4797 Storage and shipment of the technical complaint sample should be done in accordance with the conditions 4798 prescribed for the product (see section 9). 4799 4800 4801 12.4 Pregnancy 4802 Subjects must be instructed to notify the Investigator immediately if they (Only applicable to US: or their 4803 partner) become pregnant during the trial. 4804 4805 The Investigator must report any pregnancy reported during the trial to Novo Nordisk except for pregnancies 4806 occurring in the screening period. Trial subjects will give consent on enrolment that the Investigator will 4807 report any pregnancy during the trial to Novo Nordisk and they will be asked to provide information about 4808 the pregnancy, delivery and the health of her infant until one month of age. The Investigator must report

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4809 Liraglutide 4814 4817 Date: 06 March 2012 Novo Nordisk 4810 Trial ID: NN8022-1922 4815 CONFIDENTIAL 4818 Version: 6.0 4811 Protocol - Revised edition 4816 4819 Status: Final 4812 EudraCT No.: 2008-002199-88 4820 Page: 100 of 133 48214813 4822 information on pregnancy and follow-up within 14 calendar days of obtaining the information using the 4823 pregnancy form part A and the pregnancy form part B respectively. Prior to asking for any data on the female 4824 subject’s male partner a ‘male partner consent’ must be obtained. If the pregnancy results in an abnormal 4825 outcome, such as congenital anomalities, foetal death, spontaneous abortion, or SAE in the neonate, 4826 this should be regarded as an SAE with the same reporting requirements and timelines as for SAEs. 4827 4828 If an SAE occurs in relation to a pregnancy, either to the mother or the newborn, then follow the same 4829 reporting requirements and timelines as for SAEs. 4830 4831 Complete the AE form and SIF in the eCRF. 4832 4833 If for any reason the EDC/eCRF application is unavailable, then the relevant paper forms have to be 4834 completed and forwarded by fax or email to Novo Nordisk. 4835 4836 (Only applicable to US: 12.4.1 Pregnancies in Partners of Trial Subjects. 4837 In case of an SAE (with a causal relationship evaluated as possible or probable by the Investigator) in the 4838 foetus, newborn infant(s) or infant(s)/toddler(s) of a trial subject´s partner, who is potentially exposed to the 4839 trial product via the trial subject, the pregnancy and the SAE should be reported on the same forms and 4840 within the same timelines as for a subject in the trial. Prior to obtaining any data on the pregnancy, a 4841 “pregnant partner consent” must be completed by the male subject´s partner.) 4842 4843 4844 12.5 Precautions/over-dosage 4845 There is one overdose report for liraglutide. A male subject accidentally administered 17.4 mg of liraglutide 4846 instead of the prescribed 0.6 mg. The subject recovered with no intervention and no lasting sequelae was 4847 seen. Please refer to liraglutide obesity IB, 3rd edition 2010 or any updates hereof. 4848 4849 When initiating treatment with liraglutide, the subject may in some cases experience loss of 4850 fluids/dehydration, eg in cases of vomiting, nausea or diarrhoea. It is important to avoid dehydration by 4851 drinking plenty of fluids. 4852 4853 4854 12.6 Safety committee 4855 4856 12.6.1 Internal Novo Nordisk safety committee 4857 Novo Nordisk will constitute an internal safety committee to perform ongoing safety surveillance. 4858 4859 The safety committee will conduct ongoing monitoring of blinded safety data (all haematology and 4860 biochemistry results including calcitonin, amylase and lipase). 4861 4862 The safety committee may recommend unblinding of any data for further analysis. If so, an independent ad 4863 hoc group will be established to maintain the blinding.

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4864 Liraglutide 4869 4872 Date: 06 March 2012 Novo Nordisk 4865 Trial ID: NN8022-1922 4870 CONFIDENTIAL 4873 Version: 6.0 4866 Protocol - Revised edition 4871 4874 Status: Final 4867 EudraCT No.: 2008-002199-88 4875 Page: 101 of 133 48764868 4877 12.6.2 Calcitonin Monitoring Committee 4878 Monitoring of calcitonin in regular intervals will be implemented in the trial. Algorithm of further clinical 4879 and laboratory evaluation, supervised by an independent committee of thyroid experts (Calcitonin 4880 Monitoring Committee) will be recommended to be followed in all subjects with clinically relevant abnormal 4881 calcitonin values. This algorithm has been developed in collaboration with leading independent experts in 4882 thyroid/C-cell disease. In cases where the follow-up action recommended by the CMC, based on the elevated 4883 calcitonin levels results in establishing the presence of a thyroid disease, the thyroid disease should be 4884 reported as a new MESI. If the thyroid disease is a neoplasm or result in a thyroidectomy, the event will 4885 undergo adjudication by the neoplasm EAC.

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4886 Liraglutide 4893 4896 Date: 06 March 2012 Novo Nordisk 4887 Trial ID: NN8022-1922 4894 CONFIDENTIAL 4897 Version: 6.0 4888 Protocol - Revised edition 4895 4898 Status: Final 4889 EudraCT No.: 2008-002199-88 4899 Page: 102 of 133 4890 4891 13 Case report forms 49004892 4901 Novo Nordisk will provide a system for electronic data capture (EDC). This system and support services to 4902 the system will be supplied by a clinical services vendor Phase Forward. The activities of this vendor will be 4903 under the direction and supervision of Novo Nordisk. 4904 4905 4906 13.1 Rules for completing eCRFs 4907 Ensure that all relevant questions are answered and that no empty data blocks exist. 4908 4909 If a test/assessment has not been done and will not be available, or if the question is irrelevant (e.g. is not 4910 applicable) indicate this according to the data entry instructions. 4911 4912 The Investigator or Investigator’s authorised staff must ensure that all information derived from source 4913 documentation is consistent with the source information. By signing the Case Book sign off electronically, 4914 the Investigator confirms that the information is complete and correct. 4915 4916 4917 13.2 Corrections to eCRFs 4918 Corrections to the eCRF data will be made by the Investigator or the Investigator’s authorised staff. An audit 4919 trail will be maintained in the EDC application containing as a minimum: identification of the person 4920 entering the data, date and time of the entry and reason for the correction. 4921 4922 If corrections are made by the Investigator’s authorised staff after the date of the Investigator’s signature on 4923 the Case Book sign off, the form must be signed again by the Investigator. 4924 4925 4926 13.3 eCRF flow 4927 The Investigator must ensure that data is recorded in the eCRFs as soon as possible after the visit, preferably 4928 within 3 business days. When data is entered it will be available to Novo Nordisk for data verification 4929 activities. 4930 4931 The Investigator will receive the laboratory results directly from the central laboratory. The Investigator must 4932 review, sign and date the laboratory report on the day of evaluation. The signed laboratory report is retained 4933 by the site as source documentation. 4934 4935 At the end of trial the Investigator must ensure that all remaining data have been entered into the eCRF no 4936 later than 3 days after the last subject’s last visit at the site in order to ensure the planned lock of the 4937 database 4938 4939 Site specific eCRF data (in an electronic readable format) will be provided to the Investigator site after the 4940 trial database is released and access to update the trial data on the EDC application is removed. This data will 4941 be retained by the site.

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4942 Liraglutide 4947 4950 Date: 06 March 2012 Novo Nordisk 4943 Trial ID: NN8022-1922 4948 CONFIDENTIAL 4951 Version: 6.0 4944 Protocol - Revised edition 4949 4952 Status: Final 4945 EudraCT No.: 2008-002199-88 4953 Page: 103 of 133 49544946 4955 When the final clinical trial report is available the data will be archived by Novo Nordisk. 4956 4957

4958 14 Monitoring procedures

4959 During the course of the trial the Monitor will visit the trial site to ensure that the protocol is adhered to, that 4960 all issues have been recorded, to perform source data verification and to monitor drug accountability. The 4961 visit intervals will depend on the outcome of the remote monitoring of the eCRFs, the trial site's recruitment 4962 rate and the compliance of the trial site to the protocol and GCP. Factors to be considered in this 4963 determination may include objective, purpose, design, complexity, blinding, size, and endpoint for the trial. 4964 The intervals between visits should not exceed 12 weeks. The Monitor must visit the site shortly after the 4965 first subject has attended Screening visit 1 to ensure that mistakes are caught early. Hereafter the intervals 4966 between visits should not exceed 12 weeks However, more frequent monitoring visits are required during 4967 peak periods such as recruitment period and finalisation of the trial. 4968 4969 4970 The monitor must be given direct access to source documents (original documents, data and records). Direct 4971 access includes permission to examine, analyse, verify and reproduce any record(s) and report(s) that are 4972 important to evaluation of the clinical trial. In addition, the monitor should be available for discussions by 4973 telephone. 4974 4975 The Monitor must ensure that all required eCRF forms for screening failures are completed, (eg screening 4976 failure form and that the case book sign off (affirmation statement) is electronically signed by the 4977 Investigator). 4978 4979 As a minimum requirement the following data must be source data verifiable in source documentation other 4980 than the eCRF: 4981 4982 • Existence of subject (subject identifier; subject number and date of birth) 4983 • Confirmation of participation in the trial (subject identification number [ID], trial ID and signed and 4984 dated informed consent form) 4985 • Date of diagnosis of type 2 diabetes 4986 • Visit dates 4987 • Data from: 4988 − Adverse event form(s) 4989 − Safety information form(s) 4990 − Pregnancy form(s) 4991 • Relevant medical history, concomitant illness 4992 • Diabetes treatment including trial product 4993 • Reason for exclusion or withdrawal 4994 • Body weight 4995 4996 For all data recorded the source document must be defined in a source document agreement at each site.

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4997 Liraglutide 5002 5005 Date: 06 March 2012 Novo Nordisk 4998 Trial ID: NN8022-1922 5003 CONFIDENTIAL 5006 Version: 6.0 4999 Protocol - Revised edition 5004 5007 Status: Final 5000 EudraCT No.: 2008-002199-88 5008 Page: 104 of 133 50095001 5010 The source data must reflect/document the dose regimen, but not the full drug accountability. 5011 5012 The following data can be recorded directly on the CRFs and will be considered source data: 5013 • PRO questionnaires (IWQoL, DTSQs, BES) 5014 • Mental health questionnaires (PHQ-9, C-SSRS) 5015 For all other data in the eCRFs, it must be possible to verify these against source documents. The monitor 5016 will ensure that the eCRFs are completed. 5017 5018 The subjects’ diaries will be collected after each visit and must be kept as source data by the 5019 Investigator for verification of the following items: 5020 5021 • The date of first and last dose of administration of liraglutide/liraglutide placebo 5022 • Concomitant medication 5023 • 7-point plasma glucose profiles 5024 • Hypoglycaemic episodes

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5025 Liraglutide 5032 5035 Date: 06 March 2012 Novo Nordisk 5026 Trial ID: NN8022-1922 5033 CONFIDENTIAL 5036 Version: 6.0 5027 Protocol - Revised edition 5034 5037 Status: Final 5028 EudraCT No.: 2008-002199-88 5038 Page: 105 of 133 5029 5030 15 Data management 50395031 5040 Data management is the responsibility of Data Management, Novo Nordisk Headquarters. Data management 5041 may be delegated under an agreement of transfer of responsibilities to another data management unit within 5042 Novo Nordisk. 5043 5044 The subject and the biological material obtained from the subject will be identified by subject number, trial 5045 site and trial identification number. Appropriate measures such as encryption or deletion will be enforced to 5046 protect the identity of human subjects in all presentations and publications as required by 5047 local/regional/national requirements. 5048 5049 Appropriate measures such as encryption of data files will be used to assure confidentiality of subject data 5050 when it is transmitted over open networks. 5051 5052 Laboratory data will be transferred electronically from the central laboratory performing clinical analyses. 5053 The electronic laboratory data will be considered source data. In cases where laboratory data is transferred 5054 via non-secure electronic networks, data will be encrypted during transfer.

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5055 Liraglutide 5060 5063 Date: 06 March 2012 Novo Nordisk 5056 Trial ID: NN8022-1922 5061 CONFIDENTIAL 5064 Version: 6.0 5057 Protocol - Revised edition 5062 5065 Status: Final 5058 EudraCT No.: 2008-002199-88 5066 Page: 106 of 133 50675059 5068 16 Computerised systems

5069 Novo Nordisk will capture and process clinical data using computerised systems which are described in 5070 Novo Nordisk Standard Operating Procedures and IT architecture documentation. The use and control of 5071 these systems are documented. 5072 5073 Investigators working on the trial may use their own electronic systems to capture source data. Novo Nordisk 5074 will collect information on the practical use of these systems within the conduct of this clinical trial.

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5075 Liraglutide 5080 5083 Date: 06 March 2012 Novo Nordisk 5076 Trial ID: NN8022-1922 5081 CONFIDENTIAL 5084 Version: 6.0 5077 Protocol - Revised edition 5082 5085 Status: Final 5078 EudraCT No.: 2008-002199-88 5086 Page: 107 of 133 50875079 5088 17 Evaluability of subjects for analysis

5089 The following analysis sets are defined: 5090 5091 Full analysis set (FAS) 5092 All randomised subjects exposed to at least one dose of the trial product and with at least one post-baseline 5093 assessment of any efficacy endpoint will be included. Subjects in the FAS will be analysed according to 5094 randomised treatment. 5095 5096 The requirement of a post-baseline observation is in alignment with the FDA recommendations(27) 5097 5098 Safety analysis set 5099 All randomised subjects who have been exposed to at least one dose of trial product. Subjects in the safety 5100 analysis set will be analysed “as treated”.

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5101 Liraglutide 5106 5109 Date: 06 March 2012 Novo Nordisk 5102 Trial ID: NN8022-1922 5107 CONFIDENTIAL 5110 Version: 6.0 5103 Protocol - Revised edition 5108 5111 Status: Final 5104 EudraCT No.: 2008-002199-88 5112 Page: 108 of 133 51135105 5114 18 Statistical considerations

5115 Biostatistics Novo Nordisk will be responsible for the statistical analysis. 5116 5117 5118 18.1 Sample size calculation 5119 A sample size of 400 subjects randomised to 3.0 mg liraglutide treatment, 200 subjects randomised to 1.8 mg 5120 liraglutide treatment and 200 subjects randomised to placebo was chosen. In order to ensure the blinding of 5121 the subjects, 150 subjects will be randomised to 3.0 mg liraglutide placebo, whereas 50 will be randomised 5122 to 1.8 mg liraglutide placebo. In the statistical analysis the placebo treated subjects will be treated as one 5123 group. 5124 5125 These numbers are considered to provide a reasonable estimation of the safety of liraglutide as a weight- 5126 management product in diabetic subjects. The number of subjects exposed to 3.0 mg liraglutide was chosen 5127 to be larger than the number of subjects exposed to 1.8 mg liraglutide since the safety of the latter dose is 5128 well known from the extensive LEAD programme. 5129 5130 The sample size furthermore provides sufficient power for the primary efficacy endpoints weight change, the 5131 proportion of subjects with a weight loss of at least 5% and the proportion of subjects with a weight loss 5132 larger than 10%. The hypothesis of equality of 3.0 mg liraglutide versus placebo for each of the three 5133 endpoints will be tested in a hierarchical manner in the order in which they are mentioned. If superiority is 5134 demonstrated for liraglutide 3.0 mg compared to placebo for all three endpoints, the hypotheses of equality 5135 between liraglutide 1.8 mg and placebo will be tested in the same hierarchical manner. 5136 5137 The power for the primary endpoint weight change is calculated based on a two sided t-test with a 5138 significance level of 5%. The power with regard to the co-primary dichotomous endpoints is calculated 5139 based on a two-sided chi-square test. 5140 5141 With a sample size of 400 subjects treated with 3.0 mg liraglutide and 200 subjects treated with placebo, the 5142 trial will have 89% power to detect a difference between liraglutide and placebo in the proportion of subjects 5143 with a weight loss greater than 10%, given that the probabilities to achieve this weight loss is 10% for 5144 placebo and 20% for liraglutide. The trial will have 90% power to detect a difference in mean weight change 5145 between liraglutide and placebo, given that the true difference is 1.7 kg and the standard deviation is 5.9 kg. 5146 5147 Similarly, with a sample size of 200 subjects treated with 1.8 mg liraglutide and 200 subjects treated with 5148 placebo, the trial will have 90% power to detect a difference between 1.8 mg liraglutide and placebo in the 5149 proportion of subjects with a weight loss greater than 10%, given that the probabilities to achieve this weight 5150 loss is 10% for placebo and 22% for 1.8 mg liraglutide. Furthermore the trial will have more than 90% power 5151 to detect a difference in mean weight change between 1.8 mg liraglutide and placebo, given that the true 5152 difference is 2 kg and the standard deviation is 5.9 kg. 5153 5154 5155 18.2 Statistical methods 5156 All statistical tests are two-sided at a 5% significance level.

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5157 Liraglutide 5162 5165 Date: 06 March 2012 Novo Nordisk 5158 Trial ID: NN8022-1922 5163 CONFIDENTIAL 5166 Version: 6.0 5159 Protocol - Revised edition 5164 5167 Status: Final 5160 EudraCT No.: 2008-002199-88 5168 Page: 109 of 133 51695161 5170 5171 For all efficacy evaluations, only observations on drug (defined as last injection taken the day before or on 5172 the day of the visit) will be included in the statistical analyses and summaries. For all weight and glycaemic 5173 efficacy endpoints, only observations prior to rescue medication will be included in the statistical analyses 5174 and summaries, as rescue medication will confound the subsequent measurement of these parameters. 5175 Excluded observations will be listed. 5176 5177 18.2.1 Primary efficacy endpoints 5178 The three co-primary endpoints are defined as: 5179 5180 • Change from baseline in fasting body weight at 56 weeks 5181 • The proportion of subjects losing at least 5% of baseline fasting weight (measured at Week 0) 5182 • The proportion of subjects losing more than 10% of baseline fasting weight (measured at Week 0) 5183 The first primary endpoint is suggested as a primary endpoint in the FDA guidance(28) as well as the EMEA 5184 guidance(29). The second primary endpoint is suggested by FDA, whereas EMEA instead focus on the third 5185 of the endpoints. 5186 5187 18.2.1.1 Primary analysis of the co-primary endpoints 5188 5189 5190 Description of the applied LOCF approach 5191 In the primary analyses of all three endpoints, the last observation carried forward on treatment will be 5192 applied (LOCF). Only fasting weight measurements will be used and only measurements performed after 5193 randomization will be carried forward. The follow-up weight measurements at 56 weeks (Visit 16x) after 5194 randomisation will not be applied in the primary analyses. 5195 5196 Primary analysis of Change from baseline in fasting Body weight at 56 weeks 5197 The continuous primary endpoint, fasting body weight loss, analysed as change in fasting body weight from 5198 Week 0 to Week 56 will be compared between liraglutide and placebo using an ANCOVA (Analysis of 5199 Covariance) model with treatment (3.0 mg liraglutide, 1.8 mg liraglutide, placebo), country, Hba1c 5200 stratification factor, back ground treatment stratification factor, interaction between stratification factors and 5201 gender as fixed effects and with baseline body weight (at Week 0) as a covariate. The analysis will be 5202 performed for the FAS. From this model the expected differences in weight change between 3.0 mg 5203 liraglutide treatment and placebo, as well as the expected differences in weight change between 1.8 mg 5204 liraglutide treatment and placebo will be estimated together with the associated 95% confidence intervals and 5205 p-values corresponding to the test of the hypotheses of no difference between treatments. 5206 5207 Primary analysis of the proportion of subjects losing at least 5% of baseline fasting weight 5208 (measured at Week 0) 5209 For this categorical primary endpoint, a logistic regression model with treatment (3.0 mg liraglutide, 1.8 mg 5210 liraglutide, placebo), country, Hba1c stratification factor, back ground treatment stratification factor, 5211 interaction between stratification factors and gender as fixed effects and with baseline fasting body weight 5212 (at Week 0) as a covariate, will be used to compare the proportion that after 56 weeks of treatment at least

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5213 Liraglutide 5218 5221 Date: 06 March 2012 Novo Nordisk 5214 Trial ID: NN8022-1922 5219 CONFIDENTIAL 5222 Version: 6.0 5215 Protocol - Revised edition 5220 5223 Status: Final 5216 EudraCT No.: 2008-002199-88 5224 Page: 110 of 133 52255217 5226 5% of their baseline fasting bodyweight in the three groups. The analysis will be performed for the FAS 5227 using the LOCF approach described above. From this model the odds ratios between the 3.0 mg liraglutide 5228 treatment and placebo, as well as the odds ratios between the 1.8 mg liraglutide treatment and placebo will 5229 be estimated together with the associated 95% confidence intervals and p-values corresponding to the tests of 5230 the hypotheses of no difference between treatments. 5231 5232 Primary analysis of the proportion of subjects losing more than 10% of baseline fasting 5233 weight (measured at Week 0) 5234 This endpoint will be analysed in the same manner as the proportion of subjects losing at least 5% of 5235 baseline fasting weight. 5236 5237 Description of the testing procedure 5238 The tests of equality between 3.0 mg liraglutide and placebo for each of the endpoints are tested in a 5239 hierarchical manner in the order in which the endpoints are presented. If superiority of the 3.0 mg liraglutide 5240 dose is demonstrated for all three co-primary endpoints, the tests of equality between 1.8 mg liraglutide and 5241 placebo will be performed in a similar hierarchical manner. 5242 5243 • 3.0 mg liraglutide will be considered statistically significantly better than placebo with respect to the first 5244 co-primary endpoint if the hypothesis of equality between 3.0 mg liraglutide and placebo is rejected and if 5245 the estimated effects of treatment are better in the 3.0 mg liraglutide group than in the placebo group for 5246 the first co-primary endpoint. 5247 • 3.0 mg liraglutide will only be considered statistically significantly better than placebo with respect to 5248 the second co-primary endpoint if it is considered statistically significantly better with respect to the first 5249 of the co-primary endpoints, if the hypothesis of equality between 3.0 mg liraglutide and placebo is 5250 rejected for the secondary co-primary endpoint, and if the estimated effects of treatment are better in the 5251 3.0 mg liraglutide group than in the placebo group for the second co-primary endpoint. 5252 • 3.0 mg liraglutide will only be considered statistically significantly better than placebo with respect to 5253 the third co-primary endpoint if it is considered statistically significantly better with respect to the first 5254 and the second of the co-primary endpoints, if the hypothesis of equality between 3.0 mg liraglutide and 5255 placebo is rejected for the third co-primary endpoint, and if the estimated effects of treatment are better 5256 in the 3.0 mg liraglutide group than in the placebo group for the third co-primary endpoint. 5257 • 1.8 mg liraglutide will only be considered statistically significantly better than placebo with respect to 5258 the first of the co-primary endpoints if the 3.0 mg liraglutide is considered statistically significantly 5259 better than placebo for all three co-primary endpoints, if the test of equality between the 1.8 mg 5260 liraglutide group and placebo is rejected for the first co-primary endpoint and if the estimated effect of 5261 treatment with respect to the first endpoint is better in the 1.8 mg liraglutide group than in the placebo 5262 group. 5263 • 1.8 mg liraglutide will only be considered statistically significantly better than placebo with respect to 5264 the second of the co-primary endpoints if 3.0 mg liraglutide is considered statistically significantly better 5265 than placebo for all three co-primary endpoints, if 1.8 mg liraglutide is considered statistically 5266 significantly better than placebo for the first co-primary endpoint, if the test of equality between the 1.8 5267 mg liraglutide group and placebo is rejected for the second co-primary endpoint and if the estimated

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5268 Liraglutide 5273 5276 Date: 06 March 2012 Novo Nordisk 5269 Trial ID: NN8022-1922 5274 CONFIDENTIAL 5277 Version: 6.0 5270 Protocol - Revised edition 5275 5278 Status: Final 5271 EudraCT No.: 2008-002199-88 5279 Page: 111 of 133 52805272 5281 effect of treatment with respect to the second co-primary endpoint is better in the 1.8 mg liraglutide 5282 group than in the placebo group. 5283 • 1.8 mg liraglutide will only be considered statistically significantly better than placebo with respect to 5284 the third of the co-primary endpoints if 3.0 mg liraglutide is considered statistically significantly better 5285 than placebo for all three co-primary endpoints, if 1.8 mg liraglutide is considered statistically 5286 significantly better than placebo for the first and the second co-primary endpoint, if the test of equality 5287 between the 1.8 mg liraglutide group and placebo is rejected for the third co-primary endpoint and if the 5288 estimated effect of treatment with respect to the third co-primary endpoint is better in the 1.8 mg 5289 liraglutide group than in the placebo group. 5290 5291 18.2.1.2 Sensitivity analyses of the co-primary endpoints 5292 Sensitivity analyses of change from baseline in fasting Body weight at 56 weeks 5293 5294 For supporting evidence, the following sensitivity analyses will be carried out: 5295 5296 • The same analysis as above will be applied to the completers (week 56) 5297 • The same analysis as above, applied to all randomised subjects allowing for baseline carried forward for 5298 subjects without a post baseline measurements 5299 • The same analysis as above, applied to the FAS including the fasting and non-fasting weight 5300 measurements, off drug weight measurements and the follow-up weight measurements 56 weeks after 5301 randomisation (Visit 16x) 5302 • The same analysis as above, applied to the FAS including the fasting and non-fasting weight 5303 measurements, off drug weight measurements, and the follow-up weight measurements 56 weeks after 5304 randomisation (Visit 16x) and weight measurements following rescue medication 5305 • The same analysis as above, applied to the FAS, but imputing missing observations with the regression 5306 method (30). Five sets of imputations and subsequent analyses will be done. 5307 • The following repeated measures analysis (linear mixed effect model) using all longitudinal fasting 5308 weight measurements taken prior to glycaemic rescue medication available for the FAS will be applied. 5309 The response variable is the change of body weight from baseline, and the model includes visit, 5310 treatment, country, HbA1c stratification factor, back ground treatment stratification factor, interaction 5311 between stratification factors and gender and the interaction between treatment and visit and baseline 5312 body weight and visit as fixed effects and with baseline body weight (at Week 0) as a covariate. Subject 5313 will be included as a random factor. The model will be used to compare liraglutide and placebo at Week 5314 56 5315 5316 Sensitivity analyses of the proportion of subjects losing at least 5% of baseline fasting weight 5317 (measured at Week 0) 5318 For supporting evidence the following sensitivity analyses will be carried out: 5319 • The same analysis as above will be applied to the completers (week 56) 5320 • The same analysis as above, applied to all randomised subjects allowing for baseline carried forward for 5321 subjects without a post baseline measurements

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5322 Liraglutide 5327 5330 Date: 06 March 2012 Novo Nordisk 5323 Trial ID: NN8022-1922 5328 CONFIDENTIAL 5331 Version: 6.0 5324 Protocol - Revised edition 5329 5332 Status: Final 5325 EudraCT No.: 2008-002199-88 5333 Page: 112 of 133 53345326 5335 • The same analysis as above, applied to the FAS, including the fasting and non-fasting weight 5336 measurements , off drug weight measurements and the follow-up weight measurement 56 weeks after 5337 randomisation (Visit 16x) 5338 • The same analysis as above, applied to the FAS including the fasting and non-fasting weight 5339 measurements, off drug weight measurements and the follow-up weight measurements56 weeks after 5340 randomisation (Visit 16x) and weight measurements following rescue medication 5341 • The same analysis as above, applied to the FAS, but regarding subjects without a valid assessment of 5342 weight at 56 weeks as non-responders, i.e. as not having lost 5% of their body weight. (For subjects 5343 withdrawing prematurely from the trial, their follow-up weights at 52 weeks after randomisation, if 5344 available, will be used) 5345 • The same analysis as above, applied to the FAS, but imputing missing observations with the regression 5346 method (30). Five sets of imputations and subsequent analyses will be done. 5347 5348 Sensitivity analyses of the proportion of subjects losing more than 10% of baseline fasting 5349 weight (measured at Week 0) 5350 The sensitivity analyses for this endpoint will be analysed in the same manner as the proportion of subjects 5351 losing at least 5% of baseline fasting weight. 5352 5353 18.2.2 Analysis of secondary efficacy endpoints 5354 All secondary efficacy endpoints will be based on the FAS. 5355 5356 All endpoints will be summarized descriptively by visit using observed data. At end of treatment (week 56) 5357 and follow-up (week 68) summaries will be presented for both observed and LOCF imputed data. Week 56 5358 will only be imputed with observations on treatment (post baseline observations up to end of treatment) and 5359 week 68 will only be imputed with observations off treatment (visits in the follow-up period). 5360 5361 Summary statistics for continuous endpoints include number of observations, arithmetic mean, median, 5362 standard deviation, minimum and maximum. Summary statistics for categorical endpoints include number of 5363 observations, number and percentage of subjects fulfilling the criteria. 5364 5365 Table 18.1 and 18.2 give an overview of the statistical analysis for the secondary endpoints at week 56 and 5366 68 5367 5368 Continuous secondary endpoints will be analysed and presented similarly to the primary analysis of weight 5369 change. Baseline values will be included as covariates in the analyses of the corresponding response 5370 variables. This analysis is referred to as ANCOVA in table 18.1 and 18.2. 5371 5372 Categorical secondary endpoints will be analysed and presented similarly to the primary analysis of 5373 proportion of subjects losing at least 5% of baseline body weight. Continuous baseline values will be 5374 included as covariates in the analyses of the corresponding response variables unless otherwise specified. 5375 This analysis is referred to as LR in table 18.1 and 18.2.

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5376 Liraglutide 5381 5384 Date: 06 March 2012 Novo Nordisk 5377 Trial ID: NN8022-1922 5382 CONFIDENTIAL 5385 Version: 6.0 5378 Protocol - Revised edition 5383 5386 Status: Final 5379 EudraCT No.: 2008-002199-88 5387 Page: 113 of 133 53885380 5389 Table 18.1: Overview of statistical analysis of secondary efficacy endpoints at week 56 5390 Endpoint Endpoint type Statistical analysis Change from baseline (week 0) to week 56 in body weight (kg) Continuous ANCOVA Change from baseline (week 0) to week 56 in HbA1c Continuous ANCOVA Change from baseline (week 0) to week 56 in FPG Continuous ANCOVA 7-point plasma glucose profile (self-measured) Continuous N/A Change from baseline (week 0) to week 56 in beta cell function (HOMA) Continuous ANCOVA Change from baseline (week 0) to week 56 in insulin resistance (HOMA) Continuous ANCOVA Change from baseline (week 0) to week 56 in fasting glucagon Continuous ANCOVA Change from baseline (week 0) to week 56 in fasting insulin Continuous ANCOVA Change from baseline (week 0) to week 56 in fasting c-peptide Continuous ANCOVA Change from baseline (week 0) to week 56 in pro-insulin to insulin ratio Continuous ANCOVA Proportion of subjects reaching target HbA1c < 7% at week 56 Categorical LR Proportion of subjects reaching target HbA1c ≤ 6.5% at week 56 Categorical LR Change from baseline (week 0) to week 56 in waist circumference Continuous ANCOVA Change from baseline (week 0) to week 56 in systolic blood pressure Continuous ANCOVA Change from baseline (week 0) to week 56 in diastolic blood pressure Continuous ANCOVA Change from baseline (week 0) to week 56 in total cholesterol Continuous ANCOVA Change from baseline (week 0) to week 56 in LDL cholesterol Continuous ANCOVA Change from baseline (week 0) to week 56 in HDL cholesterol Continuous ANCOVA Change from baseline (week 0) to week 56 in vLDL cholesterol Continuous ANCOVA Change from baseline (week 0) to week 56 in triglycerides Continuous ANCOVA Change from baseline (week 0) to week 56 in free fatty acids Continuous ANCOVA Change from baseline (week 0) to week 56 in hsCRP Continuous ANCOVA Change from baseline (week 0) to week 56 in adiponectin Continuous ANCOVA Change from baseline (week 0) to week 56 in fibrinogen Continuous ANCOVA Change from baseline (week 0) to week 56 PAI-1 Continuous ANCOVA Change from baseline (week 0) to week 56 in urinary albumin to creatinine ratio Continuous ANCOVA Proportion of subjects reaching American Diabetes Association (ADA) treatment Categorical LR targets for LDL cholesterol (< 100 mg/dL) and triglycerides (< 150 mg/dL) at week 56 (yes/ no) Proportion of subjects who attain ADA treatment targets for blood pressure (< Categorical LR 130/80 mmHg) at week 56 Scores from PRO questionnaire IWQoL-Lite at week 56 Continuous ANCOVA Scores from PRO questionnaire DTSQs at week 56 Continuous ANCOVA Proportion of subjects with change from baseline (week 0) to week 56 in anti- Categorical LR 1 hypertensives (lowering/ increase or no change) Proportion of subjects with change from baseline (week 0) to week 56 in lipid Categorical LR 1 lowering agents (lowering/ increase or no change) Proportion of subjects with change from baseline (week 0) to week 56 in oral Categorical LR 1 antidiabetic drugs (lowering/ increase or no change) 5391 N/A Not available

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5392 Liraglutide 5397 5400 Date: 06 March 2012 Novo Nordisk 5393 Trial ID: NN8022-1922 5398 CONFIDENTIAL 5401 Version: 6.0 5394 Protocol - Revised edition 5399 5402 Status: Final 5395 EudraCT No.: 2008-002199-88 5403 Page: 114 of 133 54045396 5405 1 Relevant concomitant medication status (present/absent) will be included as covariate 5406 5407 For assessments in the follow-up period statistical analysis and summaries will be done for subjects in the 5408 FAS, who complete the 56 week treatment period and who have a valid assessment in the follow-up period. 5409 Statistical analysis models are similar to the main treatment period. 5410 5411 Table 18.2: Overview of statistical analysis of secondary efficacy endpoints at week 68 5412 Endpoint Endpoint type Statistical analysis Change from baseline (week 0) to week 68 in fasting body weight (kg and %) Continuous ANCOVA Change from baseline (week 0) 56 week 68 in fasting body weight (kg and %) Continuous N/A Change from baseline (week 0) to week 68 in waist circumference Continuous ANCOVA Change from week 56 to 68 in waist circumference Continuous N/A Change from baseline (week 0) to week 68 in FPG Continuous ANCOVA Change from baseline (week 0) to week 68 in systolic blood pressure Continuous ANCOVA Change from week 56 to 68 in systolic blood pressure Continuous N/A Change from baseline (week 0) to week 68 in diastolic blood pressure Continuous ANCOVA Change from week 56 to 68 in diastolic blood pressure Continuous N/A Change from week 56 to 68 in pulse Continuous N/A Change from baseline (week 0) to week 56 in urinary albumin to creatinine ratio Continuous ANCOVA Change from week 56 to 68 in urinary albumin to creatinine ratio Continuous N/A 5413 N/A Not available 5414 5415 5416 18.2.3 Analysis of safety endpoints 5417 All conducted analyses will be done with the aim to compare the liraglutide group to the liraglutide placebo 5418 group. All analyses and tabulations regarding safety endpoints will be done using the safety analysis set. 5419 5420 Physical examination 5421 5422 Physical examinations are recorded at screening and at end of treatment. Physical examination at screening 5423 as well as changes in physical examination will be summarised. 5424 5425 Hypoglycaemic episodes 5426 5427 Hypoglycaemic episodes follow the same definition as AEs for treatment emergence. 5428 5429 All episodes will be summarized by both the ADA definition and the Novo Nordisk definition. The 5430 categorisations are severe, asymptomatic, probable symptomatic, relative, documented symptomatic (ADA 5431 definitions) and major, minor, or symptoms only (Novo Nordisk definition). Frequencies of subjects 5432 experiencing treatment emergent hypoglycaemic episodes will be summarised by severity and treatment. 5433 Hypoglycaemic episodes not defined as treatment emergent will be presented in a listing.

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5434 Liraglutide 5439 5442 Date: 06 March 2012 Novo Nordisk 5435 Trial ID: NN8022-1922 5440 CONFIDENTIAL 5443 Version: 6.0 5436 Protocol - Revised edition 5441 5444 Status: Final 5437 EudraCT No.: 2008-002199-88 5445 Page: 115 of 133 54465438 5447 ECG 5448 5449 Summary statistics and the frequencies of shifts from baseline to end of trial will be tabulated for each 5450 treatment group. 5451 5452 Adverse events 5453 5454 Adverse events will be coded using the current version of MedDRA. A treatment emergent adverse event 5455 (TEAE) is defined as an event that either: 5456 • Occurs before randomisation and increases in severity during the treatment period 5457 • Has onset date on or after the first day of randomised treatment and no later than 14 days after the last 5458 day of randomised treatment 5459 5460 Treatment emergent adverse events, TEAEs, are summarised descriptively, whereas non-treatment emergent 5461 AE’s are presented in listings. TEAE data will be displayed in terms of the number of subjects with at least 5462 one event (N), the percentage of subjects with at least one event (%), the number of events (E) and the event 5463 rate per 100 years (R). Furthermore, TEAE data are summarized by seriousness, severity, relation to trial 5464 drug, MESI, withdrawal due to AEs and outcome. 5465 5466 Summary tables by system organ class and preferred term are made for all TEAEs, serious TEAEs, possible 5467 or probably related to trial drug, severe TEAE, treatment emergent MESI, and TEAE occurring in at least 5468 5% of the subjects in any treatment arm. Corresponding tables will be done for TEAEs together with non- 5469 TEAEs starting after first drug date (including non-TEAEs in the observational period and MESI’s collected 5470 after withdrawal). 5471 5472 Mental health questionnaires and Binge eating scale 5473 5474 Results from the questionnaires will be summarised by treatment and visit. 5475 5476 Pulse 5477 Pulse will be summarised and analysed similar to blood pressure. 5478 5479 5480 Analysis of laboratory safety parameters 5481 5482 Laboratory safety parameters are measured throughout the trials and comprise haematology and 5483 biochemistry as defined in the flowchart. 5484 5485 No formal statistical analyses are planned for the laboratory safety parameters. 5486 5487 The distribution of each continuous laboratory parameter will be presented using box plots by treatment and 5488 week. Continuous laboratory values will be compared to the relevant references ranges and results will be 5489 presented as follows:

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5490 Liraglutide 5495 5498 Date: 06 March 2012 Novo Nordisk 5491 Trial ID: NN8022-1922 5496 CONFIDENTIAL 5499 Version: 6.0 5492 Protocol - Revised edition 5497 5500 Status: Final 5493 EudraCT No.: 2008-002199-88 5501 Page: 116 of 133 55025494 5503 • Shift tables for each laboratory parameter will be provided by treatment group. The shift tables will 5504 include the number of subjects below, within and above the reference ranges at baseline (Week 0) and 5505 after end of treatment 5506 • For each laboratory parameter the proportion of subjects with laboratory values outside the normal 5507 ranges will be tabulated per visit and treatment group 5508 • For each laboratory parameter individual values outside the reference ranges (abnormal values) will be 5509 listed by treatment and subject 5510 5511 Categorical laboratory parameters will be summarised with shift tables. 5512 5513 Amylase and lipase 5514 5515 Tables showing shifts from baseline to highest value in treatment period to UNR, 2UNR or 3UNR will be 5516 presented. 5517 5518 Mean plots by visit will be presented. At end of treatment (week 56) and follow-up (week 68) summaries 5519 will be presented for both observed and LOCF imputed data. Week 56 will only be imputed with 5520 observations in the treatment period (post baseline observations up to week 56) and week 68 will only be 5521 imputed with observations off treatment (visits in the follow-up period). 5522 5523 Number and percentage of subjects with amylase and lipase levels ≥UNR, ≥2UNR and ≥3UNR by 5524 treatment and visit will be tabulated. At end of treatment (week 56) and follow-up (week 68) summaries will 5525 be presented for both observed and LOCF imputed data. 5526 5527 Subjects with values ≥2UNR will be presented with spaghetti plots and listings showing medical history of 5528 GI AEs, GI AEs and liver lab parameters. 5529 5530 Calcitonin 5531 5532 Number, percentage and incidence of subjects with persistent (all post baseline measurements) and incidental 5533 (at least one post baseline measurement) increases in calcitonin for the criteria below will be tabulated for all 5534 subjects, males and females. 5535 5536 • From baseline

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5546 Liraglutide 5551 5554 Date: 06 March 2012 Novo Nordisk 5547 Trial ID: NN8022-1922 5552 CONFIDENTIAL 5555 Version: 6.0 5548 Protocol - Revised edition 5553 5556 Status: Final 5549 EudraCT No.: 2008-002199-88 5557 Page: 117 of 133 55585550 5559 The distribution of all calcitonin measurements across treatment groups and time will be shown with 5560 histograms and corresponding cumulative plots by gender and total for actual levels. Sum curves will be 5561 done for baseline (pooled) and week 56 (LOCF) by treatment. Histograms will be shown for baseline 5562 (pooled) and by treatment for week 56 and 68 (both using LOCF). 5563 5564 A summary table showing number and percentage of observations < and ≥ LLOQ, minimum, Q25, median, 5565 Q75, maximum and geometric mean will be done by treatment group, gender and week. 5566 5567 Geometric means will be plotted by treatment and visit in order to assess the pattern of the longitudinal 5568 changes. 5569 5570 In addition, a scatter plot of baseline vs. maximum post baseline calcitonin measurement will be done by 5571 treatment. 5572 5573 Longitudinal changes for subjects with calcitonin ≥ 20ng/L will be evaluated with spaghetti plots. The 5574 spaghetti plots will follow the above by treatment group and gender. 5575 5576 Selected listings of subjects with at least one post baseline calcitonin measurement above 20ng/L will be 5577 done. The listings will include treatment, age, gender, smoking habits at baseline, risk factor information (use 5578 of relevant concomitant medication at time of assessment (proton pump inhibitors and H2 blockers) and 5579 medical history of thyroid disorder) and calcitonin measurements. 5580 5581 Liraglutide antibodies 5582 5583 Frequencies of subjects with liraglutide antibodies will be tabulated by week and treatment. Frequencies of 5584 subjects with liraglutide antibodies with neutralising effect and with cross-reacting liraglutide will be 5585 tabulated similarly. 5586 5587 5588 18.3 Interim analysis 5589 Not applicable. 5590 5591 5592 18.4 Sequential safety analysis/safety monitoring 5593 Sequential safety analysis for medical events of special interest is planned to be monitored by an internal 5594 Data Monitoring group. No formal statistical analyses are planned, blinded summary statistics and graphical 5595 presentation of data will be the basis of the safety group’s decisions. 5596 5597 5598 18.5 Explorative statistical analysis for pharmacogenetics and biomarkers 5599 Not applicable.

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5600 Liraglutide 5605 5608 Date: 06 March 2012 Novo Nordisk 5601 Trial ID: NN8022-1922 5606 CONFIDENTIAL 5609 Version: 6.0 5602 Protocol - Revised edition 5607 5610 Status: Final 5603 EudraCT No.: 2008-002199-88 5611 Page: 118 of 133 56125604 5613 18.6 Health economics and/or subject reported outcome 5614 Please refer to Analysis of secondary efficacy endpoints, section 18.2.2 5615 5616 5617 18.7 PK and/or PD modelling 5618 The pharmacokinetics of liraglutide will be evaluated using population PK analysis methods. The analyses 5619 will be based on plasma samples taken from all subjects, using a sparse sampling scheme. 5620 5621 A separate modelling plan will be prepared before Database Lock outlining details of the analysis

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5622 Liraglutide 5629 5632 Date: 06 March 2012 Novo Nordisk 5623 Trial ID: NN8022-1922 5630 CONFIDENTIAL 5633 Version: 6.0 5624 Protocol - Revised edition 5631 5634 Status: Final 5625 EudraCT No.: 2008-002199-88 5635 Page: 119 of 133 5626 5627 19 Ethics 56365628 5637 The trial will be conducted in compliance with ICH GCP (25) and applicable regulatory requirements, and in 5638 accordance with the Declaration of Helsinki(31). 5639 5640 All subjects participating in the trial will receive instruction in a hypocaloric diet calculated to induce a 5641 moderate weight loss during the trial, and all subjects will receive instruction and encouragement on regular 5642 physical activity to aid in weight management and improvement of risk factors. A standard panel of safety 5643 laboratory evaluations will be performed regularly during the trial (including vital signs, haematology, and 5644 biochemistry) and side effects will be monitored closely. 5645 5646 In this trial all subjects will be instructed in symptom recognition and handling of hypoglycaemia as well as 5647 regular clinic measurement of fasting plasma glucose as precautionary measures. 5648 5649 The trial drugs may be associated with AEs, but relevant precautions have been implemented in the design 5650 and planned conduct of the trial, in order to minimise the risks and inconveniences of participating in the 5651 trial. These precautions include thorough information regarding the correct administration of the trial drugs 5652 and gradual dose escalation. Furthermore, subjects are fully informed about possible AEs and 5653 inconveniences, and will be instructed to contact the Investigator in case of any concerns regarding the trial 5654 participation. 5655 5656 Treatment with liraglutide was generally well-tolerated, with high completion rates in groups (75% in 5657 liraglutide group, 70% in placebo group). The number of withdrawals due to adverse events was evenly 5658 distributed between groups (8.5% in the liraglutide group vs. 8.6% in placebo group). Serious adverse events 5659 were relatively uncommon, but were more frequent in liraglutide-treated subjects (4.2%) compared to 5660 placebo (2.4%). There were no events of pancreatitis or medullary thyroid cancer, and no treatment-related 5661 increases in blood calcitonin levels. Consistent with previous trials with liraglutide, the most commonly 5662 reported adverse events were from the gastrointestinal system, with nausea reported by 47% of subjects in the 5663 liraglutide group compared to 17% in the placebo groups, and vomiting by 17% vs. 2%, respectively. As 5664 in previous trials, the majority of events were reported in the first 6-8 weeks, were mild or moderate in 5665 severity and transient in nature. Please refer to liraglutide obesity Investigators Brochure, 3rd Edition, 2010, 5666 or any updates hereof. Patients treated with liraglutide should be advised of the potential risk of dehydration 5667 in relation to gastrointestinal side effects and take precautions to avoid fluid depletion. 5668 5669 In order to reduce the level of side effects, liraglutide is gradually escalated up to maximum dose (3.0 or 5670 1.8 mg). If subjects do not tolerate an increase in dose during dose-escalation, the Investigator has the option 5671 to individualise the dose escalation with a total delay of up to 7 days. All subjects must be at the target dose 5672 of 3.0 mg 35 days after randomisation or 1.8 mg 21 days after randomisation. 5673 5674 All subjects will continue their fixed pre-trial treatment with metformin, sulphonylurea or glitazone as single 5675 agent therapy or a combination throughout the trial. Subjects treated with sulphonylureas will however be 5676 asked to reduce the dose with 50% to prevent SU-induced hypoglycaemia. Even though this may worsen 5677 glycaemic control initially, reinforcement of rescue criteria to reinstate pre-trial dose levels and addition of

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5678 Liraglutide 5683 5686 Date: 06 March 2012 Novo Nordisk 5679 Trial ID: NN8022-1922 5684 CONFIDENTIAL 5687 Version: 6.0 5680 Protocol - Revised edition 5685 5688 Status: Final 5681 EudraCT No.: 2008-002199-88 5689 Page: 120 of 133 56905682 5691 rescue background medication should ensure adequate glycaemic control even for subjects on SUs 5692 randomised to liraglutide placebo. 5693 5694 Inclusion criteria have been defined in order to ensure that, at enrolment, subjects are eligible for treatment 5695 intensification and for trial participation. Furthermore, rescue criteria are defined to ensure that subjects are 5696 considered for glycaemic rescue if plasma glucose levels exceed acceptable limits during trial participation. 5697 5698 Liraglutide have shown to be effective in lowering blood glucose levels. It can therefore be expected that 5699 subjects receiving liraglutide and enters the trial with insufficiently controlled blood glucose will experience 5700 an improved glucose control during the trial. 5701 5702 Another potential benefit of participating in the trial is that the Investigator will obtain an additional 5703 knowledge of the subjects’ disease and will therefore be able to provide recommendations for the best 5704 treatment to be used following the trial participation. 5705 5706 Few cases of acute pancreatitis (inflammation of the pancreas) presenting with persistent severe abdominal 5707 pain (usually accompanied by vomiting) have been reported with liraglutide and exenatide. Post-marketing 5708 surveillance identified at least 30 cases of pancreatitis with exenatide(14). However, a health services 5709 registry-based study found no increased frequency of pancreatitis among exenatide users.(15) 5710 5711 If the investigator suspects acute pancreatitis, all suspected drugs should be discontinued until confirmatory 5712 tests have been conducted, and appropriate treatment should be initiated. Subjects diagnosed with acute 5713 pancreatitis (as a minimum 2 of 3: characteristic abdominal pain, amylase and/or lipase >3x UNR or 5714 characteristic findings on CT/MRI) should be withdrawn from the study. 5715 5716 Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically 5717 relevant exposures in both genders of rats and mice. It is unknown whether liraglutide causes thyroid C-cell 5718 tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be ruled 5719 out by clinical or nonclinical studies. Liraglutide is contraindicated in patients with a personal or family 5720 history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Based on the 5721 findings in rodents, monitoring with serum calcitonin or thyroid ultrasound was performed during clinical 5722 trials, but this may have increased the number of unnecessary thyroid surgeries. It is unknown whether 5723 monitoring with serum calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumors. 5724 5725 In a 2-year repeat subcutaneous dose carcinogenicity study of liraglutide injected once a day in CD-1 mice, a 5726 treatment-related increase in fibrosarcomas was seen on the dorsal skin and subcutis, the body surface used 5727 for drug injection, in males in the 3 mg/kg/day group. These fibrosarcomas were attributed to the high local 5728 concentration of drug near the injection site. The liraglutide concentration in the clinical formulation (6 5729 mg/mL) is 10 times higher than the concentration in the formulation used to administer 3 mg/kg/day 5730 liraglutide to mice in the carcinogenicity study (0.6 mg/mL). 5731 5732 The subjects will have the right to withdraw from the trial at any time, without giving a specific reason. 5733 Novo Nordisk will be entitled to keep the data collected until withdrawal of the subject.

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5734 Liraglutide 5739 5742 Date: 06 March 2012 Novo Nordisk 5735 Trial ID: NN8022-1922 5740 CONFIDENTIAL 5743 Version: 6.0 5736 Protocol - Revised edition 5741 5744 Status: Final 5737 EudraCT No.: 2008-002199-88 5745 Page: 121 of 133 57465738 5747 19.1 Informed consent form for trial subjects 5748 In seeking and documenting informed consent, the Investigator must comply with the applicable regulatory 5749 requirement(s) and adhere to the ICH GCP(25) and the requirements in the Declaration of Helsinki(31). 5750 5751 Prior to any trial-related activity, the Investigator must give the subject oral and written information about 5752 the trial in a form that the subject can read and understand. 5753 5754 A voluntary, signed and personally dated informed consent form will be obtained from the subject prior to 5755 any trial-related activity. 5756 5757 The responsibility for seeking informed consent must remain with the Investigator or an adequately 5758 medically qualified person delegated by the investigator. The written informed consent must be signed and 5759 personally dated by the person who seeks the informed consent. 5760 5761 If information becomes available that may be relevant to the subject’s willingness to continue participating in 5762 the trial, the Investigator must inform the subject in a timely manner, and a revised written informed consent 5763 must be obtained. 5764 5765 5766 19.2 Data Handling 5767 If the subject withdraws the previously given informed consent the subject’s data will be handled as follows: 5768 5769 • Data collected will be retained by Novo Nordisk and entered into the database 5770 • Safety events will be reported to the department responsible for global product safety, Novo 5771 Nordisk/regulatory authorities according to local/national requirements 5772 5773 If data is used, it will always be in accordance with local law and Institutional Review Board 5774 (IRB)/Independent Ethics Committee (IEC) procedures. 5775 5776 5777 19.3 Institutional review boards/independent ethics committee 5778 Prior to commencement of the trial, the protocol, any amendments, subject information/informed consent 5779 form, any other written information to be provided to the subject, subject recruitment procedures, if any, IB, 5780 information about payments and compensation available to subjects if not mentioned in the subject 5781 information, the Investigator’s current CV and/or other documentation evidencing qualifications, and other 5782 documents as required by the local IRB/IEC should be submitted. The submission letter should clearly 5783 identify (by trial identification number, including version, EudraCT no. where applicable, title and/or date of 5784 the document) which documents have been submitted to the IRB/IEC. Written approval/favourable opinion 5785 must be obtained from IRB/IEC prior to commencement of the trial. 5786 5787 During the trial, the Investigator must promptly in accordance with local requirements report the following to 5788 the IRB/IEC: updates to IB, unexpected SAEs where a causal relationship cannot be ruled out, substantial 5789 amendments to the protocol, non-substantial amendments according to local requirements, deviations to the 5790 protocol implemented to eliminate immediate hazards to the subjects, new information that may affect

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5791 Liraglutide 5796 5799 Date: 06 March 2012 Novo Nordisk 5792 Trial ID: NN8022-1922 5797 CONFIDENTIAL 5800 Version: 6.0 5793 Protocol - Revised edition 5798 5801 Status: Final 5794 EudraCT No.: 2008-002199-88 5802 Page: 122 of 133 58035795 5804 adversely the safety of the subjects or the conduct of the trial (including new risk/benefit analysis in case it 5805 will have an impact on the planned follow-up of the subjects), annually written summaries of the trial status 5806 and other documents as required by the local IRB/IEC. 5807 5808 Substantial amendments must not be implemented before approval/favourable opinion, unless necessary to 5809 eliminate hazards to the subjects. 5810 5811 The Investigator must maintain an accurate and complete record of all submissions made to the IRB/IEC. 5812 The records should be filed in the Investigator’s trial file and copies must be sent to Novo Nordisk. 5813 5814 5815 19.4 Regulatory authorities 5816 Regulatory authorities will receive the Clinical Trial Application (CTA), substantial/non-substantial 5817 amendments to the protocol, reports on SAEs, and the Clinical Trial Report (CTR) according to national 5818 requirements.

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5819 Liraglutide 5824 5827 Date: 06 March 2012 Novo Nordisk 5820 Trial ID: NN8022-1922 5825 CONFIDENTIAL 5828 Version: 6.0 5821 Protocol - Revised edition 5826 5829 Status: Final 5822 EudraCT No.: 2008-002199-88 5830 Page: 123 of 133 58315823 5832 20 Premature termination of the trial/ trial site

5833 Novo Nordisk, Investigator or a pertinent regulatory authority may decide to stop the trial or part of the trial 5834 at any time but agreement on procedures to be followed must be obtained. 5835 5836 If a trial is prematurely terminated or suspended, the Investigator should promptly inform the subjects and 5837 assure appropriate therapy and follow-up. Furthermore, the Investigator and/or Novo Nordisk should 5838 promptly inform the IRB/IEC and provide a detailed written explanation. The pertinent regulatory authorities 5839 should be informed according to national regulations. 5840 5841 If after the termination of the trial the risk/benefit analysis has changed, the new evaluation should be 5842 provided to the IRB/IEC in case it will have an impact on the planned follow-up of the subjects who have 5843 participated in the trial. If so, the actions needed to protect the subjects should be described.

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5844 Liraglutide 5851 5854 Date: 06 March 2012 Novo Nordisk 5845 Trial ID: NN8022-1922 5852 CONFIDENTIAL 5855 Version: 6.0 5846 Protocol - Revised edition 5853 5856 Status: Final 5847 EudraCT No.: 2008-002199-88 5857 Page: 124 of 133 5848 5849 21 Protocol compliance 58585850 5859 Deviations from the protocol should be avoided. 5860 5861 If deviations occur, the Investigator must inform the monitor and the implications of the deviation must be 5862 reviewed and discussed. 5863 5864 Protocol deviations must be documented stating the reason, date, the action(s) taken, and the impact for the 5865 subjects and/or the trial except for protocol deviations where no corrections are required as described in the 5866 trial specific validation checks in the approved Trial Validation Plan (TVP). The Investigator must approve 5867 these as outlined in the TVP. 5868 5869 The documentation for the protocol deviations must be kept in the Investigator’s trial file and the Novo 5870 Nordisk’s trial master file. 5871 5872 5873 21.1 Audits and inspections 5874 Any aspect of the clinical trial may be subject to audits conducted by Novo Nordisk internal Quality Audit 5875 System or an inspection from domestic or foreign regulatory authorities. The Investigator and the site staff as 5876 well as Novo Nordisk clinical staff have an obligation to cooperate and assist in such audits and inspections. 5877 This includes giving Auditors and Inspectors direct access to all source documents and other documents 5878 relevant to the conduct of the clinical trial at the site.

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5879 Liraglutide 5886 5889 Date: 06 March 2012 Novo Nordisk 5880 Trial ID: NN8022-1922 5887 CONFIDENTIAL 5890 Version: 6.0 5881 Protocol - Revised edition 5888 5891 Status: Final 5882 EudraCT No.: 2008-002199-88 5892 Page: 125 of 133 5883 5884 22 Critical documents 58935885 5894 Before the Investigator starts the trial (i.e. obtains informed consent from the first subject), the following 5895 documents must be available to Novo Nordisk: 5896 5897 • Regulatory approval and/or notification as required 5898 • Curricula vitae of Investigator and Sub-Investigator(s) (current, dated and signed and/or supported by an 5899 official regulatory document) 5900 • Signed and dated agreement on the final protocol 5901 • Signed and dated agreement on any substantial amendment(s), if applicable 5902 • Approval/favourable opinion from IEC/IRB clearly identifying the documents reviewed: the protocol, 5903 any substantial amendments, subject information/informed consent form and any other written 5904 information to be provided to the subject, subject recruitment procedures 5905 • Copy of IEC/IRB approved subject information/informed consent form/any other written 5906 information/advertisement 5907 • List of IEC/IRB members/constitution 5908 • Signed receipt of IB by Investigator 5909 • Other critical documents as required by local regulations 5910 • Financial agreement(s) 5911 − For US: Verification under disclosures per Code of Federal Regulations (CFR) of Financial 5912 Conflict of Interest (32) 5913 • FDA financial disclosure form or local equivalent as applicable. 5914 • Signed and dated FDA form 1572 for each US Investigator (listing individual US clinical trial staff if 5915 directly involved in the treatment or evaluation of research making a direct and significant contribution 5916 to the data). 5917 5918 Protocol NN8022-1922 (US sites): 5919 Intended for US sites 5920 − Conducted under the Investigational New Drug Application (IND) 5921 − All US Investigators will sign FDA Form 1572 5922 5923 Protocol NN8022-1922 (sites outside the US): 5924 Intended for participating sites outside the US 5925 − Not conducted under the IND 5926 − All Investigators outside the US will not sign FDA Form 1572 5927 As documented in writing by protocol signature, all Investigators will fully comply with ICH GCP (25), 5928 applicable regulatory requirements, and in accordance with the Declaration of Helsinki (31). 5929 5930 Novo Nordisk will analyse and report data from all sites together.

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5931 Liraglutide 5938 5941 Date: 06 March 2012 Novo Nordisk 5932 Trial ID: NN8022-1922 5939 CONFIDENTIAL 5942 Version: 6.0 5933 Protocol - Revised edition 5940 5943 Status: Final 5934 EudraCT No.: 2008-002199-88 5944 Page: 126 of 133 5935 5936 23 Responsibilities 59455937 5946 All staff Novo Nordisk, site, Central Laboratories, CRO etc must conduct the trial in compliance with ICH 5947 GCP (25), applicable regulatory requirements, and in accordance with the Declaration of Helsinki (31). 5948 5949 Novo Nordisk will be responsible for the preparation of the protocol, eCRF, supply of trial products and 5950 stated equipment, monitoring, data management, statistics, and the CTR as documented by Novo Nordisk 5951 procedures and internal specific agreements as well as the current GCP guidelines 5952 5953 Novo Nordisk will provide a system for EDC. This system and support services to the system will be 5954 supplied by a clinical services vendor. The activities of the clinical services vendor will be under the 5955 direction and supervision of Novo Nordisk. Furthermore, Novo Nordisk will be responsible for the IV/WRS. 5956 5957 A central laboratory will be responsible for providing all lab supplies for the analysis of all blood samples 5958 taken during the trial. All results are received as paper copies at the sites as well as electronic transfer to 5959 Novo Nordisk clinical database. 5960 5961 The name of the Central Laboratories will appear in the application to the authorities and in protocol 5962 Attachment I. 5963 5964 The Investigator is accountable for the conduct of the trial. If any tasks are delegated, the Investigator should 5965 maintain a list of appropriately qualified persons to whom he/she has delegated specified significant trial- 5966 related duties. 5967 5968 A qualified physician, who is an Investigator or a Sub-investigator for the trial, should be responsible for all 5969 trial-related medical decisions. 5970 5971 In case the Investigator is not able to fulfil the role as Investigator (eg retirement), a new Investigator must 5972 be appointed in collaboration with Novo Nordisk. 5973 5974 The Investigator will ensure that the last samples are shipped to the central laboratory within 24 hours after 5975 the last subject visit at the site. 5976 5977 The Investigator will follow the instructions from Novo Nordisk when processing data. 5978 5979 The Investigator will take all necessary technical and organisational safety measures to prevent accidental or 5980 wrongful destruction, loss or deterioration of data. The Investigator will prevent any unauthorised access to 5981 data or any other processing of data against applicable law. 5982 5983 Upon request from Novo Nordisk, the Investigator will provide Novo Nordisk with the necessary 5984 information to enable Novo Nordisk to ensure that such technical and organisational safety measures have 5985 been taken.

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5986 Liraglutide 5991 5994 Date: 06 March 2012 Novo Nordisk 5987 Trial ID: NN8022-1922 5992 CONFIDENTIAL 5995 Version: 6.0 5988 Protocol - Revised edition 5993 5996 Status: Final 5989 EudraCT No.: 2008-002199-88 5997 Page: 127 of 133 59985990 5999 24 Reports and publications

6000 The information obtained during the conduct of this trial is considered confidential and can be used by Novo 6001 Nordisk for regulatory purposes and for the general development of the trial product. All information 6002 supplied by Novo Nordisk in connection with this trial shall remain the sole property of Novo Nordisk and is 6003 to be considered confidential information. No confidential information shall be disclosed to others without 6004 prior written consent from Novo Nordisk. Such information shall not be used except in the performance of 6005 this trial. The information obtained during this trial may be made available to other physicians who are 6006 conducting other clinical trials with the trial product, if deemed necessary by Novo Nordisk. 6007 6008 The signatory Investigator, Professor Melanie Davies, United Kingdom will review and sign the CTR to 6009 confirm, to the best of her knowledge, that it accurately describes the conduct and results of the trial. 6010 6011 6012 24.1 Communication and publication 6013 No permission to publish shall be granted to any clinical research organisation involved in the trial described 6014 in this protocol. 6015 6016 Novo Nordisk commits to communicating or otherwise making available for public disclosure results of 6017 trials regardless of outcome. Public disclosure includes publication of a paper in a scientific journal, abstract 6018 submission with a poster or oral presentation at a scientific meeting, or by other means. 6019 6020 When the primary results are available, Novo Nordisk plans to discuss the interpretation of these with the 6021 principal Investigator, but reserves the right to release results that may impact Novo Nordisk financial 6022 expectations (e.g. a press release directly to the public or similar) without prior consultation with the 6023 remaining participating Investigators. Novo Nordisk reserves the right not to release data until specified 6024 milestones, e.g. a clinical trial report is available. This includes the right not to release interim results from 6025 clinical trials, because such results may lead to conclusions that are later shown to be incorrect. 6026 6027 At the end of the trial, one or more manuscripts for publication will be prepared in collaboration between 6028 Investigator(s) and Novo Nordisk. Novo Nordisk will not suppress or veto publications; however Novo 6029 Nordisk reserves the right to postpone publication and/or communication for a short time to protect 6030 intellectual property. 6031 6032 24.1.1 Authorship 6033 Authorship of publications should be in accordance with guidelines from The International Committee of 6034 Medical Journal Editors’ Uniform Requirements (sometimes referred to as the Vancouver Criteria(33)). 6035 6036 The signatory Investigator will together with Novo Nordisk establish and appoint members to a publication 6037 writing group consisting of minimum 3 Investigators that have been involved in the design of the trial or the 6038 interpretation of the results and minimum 3 Investigators considered contributing substantially to the 6039 acquisition of data. The remaining participating Investigators will be acknowledged as the NN8022-1922 6040 trial group in the author section of publications.

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6041 Liraglutide 6046 6049 Date: 06 March 2012 Novo Nordisk 6042 Trial ID: NN8022-1922 6047 CONFIDENTIAL 6050 Version: 6.0 6043 Protocol - Revised edition 6048 6051 Status: Final 6044 EudraCT No.: 2008-002199-88 6052 Page: 128 of 133 60536045 6054 24.1.2 Publication(s) 6055 The results of this trial will be subject to public disclosure at external web sites according to international 6056 regulations, which is reflected in Novo Nordisk Code of Conduct for Clinical Trial Disclosure 6057 6058 In all cases, the trial results shall be reported in an objective, accurate, balanced and complete manner, with a 6059 discussion of the strengths and limitations of the trial. All authors will be given the relevant statistical tables, 6060 figures, and reports needed to support the planned publication. In the event of any disagreement about the 6061 content of any publication, both the Investigators’ and Novo Nordisk’s opinions shall be fairly and 6062 sufficiently represented in the publication. 6063 6064 Novo Nordisk maintains the right to be informed of any Investigator plans for publication and to review any 6065 scientific paper, presentation, communication or other information concerning the investigation described in 6066 this protocol. Any such communication must be submitted in writing to the Novo Nordisk trial manager prior 6067 to submission for comments. Comments will be given within four weeks from receipt of the planned 6068 communication. 6069 6070 24.1.3 Site-specific publication(s) by Investigator(s) 6071 For a multi-centre clinical trial, analyses based on single-site data usually have significant statistical 6072 limitations and frequently do not provide meaningful information for healthcare professionals or subjects, 6073 and therefore may not be supported by Novo Nordisk. It is Novo Nordisk’s policy that such individual 6074 reports do not precede the primary manuscript and should always reference the primary manuscript of the 6075 trial. 6076 6077 Novo Nordisk reserves the right to prior review of such publication and to ask for deferment of publication 6078 of individual site results until after the primary manuscript is accepted for publication. 6079 6080 6081 24.2 Investigator access to data and review of results 6082 As owners of the trial database, Novo Nordisk has discretion to determine who will have access to the 6083 database. Generally, trial databases are only made available to regulatory authorities. 6084 6085 Individual Investigator(s) will have their own research participants' data and will be provided with the 6086 randomisation code after results are available.

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6087 Liraglutide 6092 6095 Date: 06 March 2012 Novo Nordisk 6088 Trial ID: NN8022-1922 6093 CONFIDENTIAL 6096 Version: 6.0 6089 Protocol - Revised edition 6094 6097 Status: Final 6090 EudraCT No.: 2008-002199-88 6098 Page: 129 of 133 60996091 6100 25 Retention of clinical trial documentation

6101 Subject notes must be kept for the maximum period permitted by the hospital, institution or private practice. 6102 6103 The Investigator must agree to archive the documentation (this includes both electronic and paperbased 6104 records) pertaining to the trial in an archive after completion or discontinuation of the trial if not otherwise 6105 notified. The Investigator should not destroy any documents without prior permission from Novo Nordisk. If 6106 the investigator cannot archive the documents at the trial site after trial completion, Novo Nordisk can refer 6107 the Investigator to an independent archiving provider who has a system in place that allows only the 6108 Investigator to access the files. 6109 6110 Clinical trial documentation must be retained until at least 2 years after the last approval of a marketing 6111 application in an ICH region and until there are no pending or contemplated marketing applications in an 6112 ICH region or at least 2 years have elapsed since the formal discontinuation of clinical development of the 6113 investigational product. 6114 6115 Novo Nordisk will maintain Novo Nordisk’s documentation pertaining to the trial as long as the product is 6116 on the market plus 15 years. The files from the Investigator site/institution will be retained 20 years after the 6117 completion of the trial, or longer if required by national regulations. 6118 6119 For Spain, the following applies: Any record of the participants will be kept confidential, in accordance with 6120 Organic Act. 15/1999 of 13 December of Personal Data/Records Protection.

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6121 Liraglutide 6128 6131 Date: 06 March 2012 Novo Nordisk 6122 Trial ID: NN8022-1922 6129 CONFIDENTIAL 6132 Version: 6.0 6123 Protocol - Revised edition 6130 6133 Status: Final 6124 EudraCT No.: 2008-002199-88 6134 Page: 130 of 133 6125 6126 26 Indemnity statement 61356127 6136 Novo Nordisk carries product liability for its products and liability assumed under the special laws, acts 6137 and/or guidelines for conducting clinical trials in any country, unless others have shown negligence. 6138 6139 Novo Nordisk assumes no liability in the event of negligence or any other liability by the clinics or doctors 6140 conducting experiments or by persons for whom the said clinic or doctors are responsible. 6141 6142 Novo Nordisk accepts liability in accordance with: 6143 6144 France: The French Public Health Code article L 1121-10 (law n° 2004-80 6 of 9 August 2004 art. 88 I, IX 6145 Journal Officiel of 11 August 2004). ‘Novo Nordisk is responsible for identification of the harmful 6146 consequences of the biomedical-cal research for the person lending himself thereto and for indemnification 6147 of his beneficiaries, except in case of proof, incumbent on it, that the prejudice is not attributable to his fault 6148 or to the fault of any intervening party, without the Novo Nordisk's being entitled to call on acts by a third 6149 party or the voluntary withdrawal of the person who had initially consented to cooperating in the research.’ 6150 6151 Germany: Drug law dated August 24, 1976, last amended per fifteenth law for amendment of the drug law 6152 dated July 17, 2009 6153 6154 Spain: Drug law dated August 24, 1976 last amended per fifteenth law for amendment of the drug law dated 6155 July 17, 2009

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6156 Liraglutide 6163 6166 Date: 06 March 2012 Novo Nordisk 6157 Trial ID: NN8022-1922 6164 CONFIDENTIAL 6167 Version: 6.0 6158 Protocol - Revised edition 6165 6168 Status: Final 6159 EudraCT No.: 2008-002199-88 6169 Page: 131 of 133 6160 6161 References 61706162 6171

6172 (1) Haslam DW, James WPT. Obesity. Lancet 2005;366(9492):1197-209. 6173 6174 (2) International O. Global Prevalence of Adult Obesity. 2009. 6175 http://www.iotf.org/database/documents/GlobalPrevalenceofAdultObesityFeb2009v2.pdf. 6176 Ref Type: Generic 6177 6178 (3) Wing RR. Weight loss in the management of type 2 diabetes. In: Gerstein HC, Haynes RB, 6179 editors. Evidence-based Diabetes Care.Ontario, Canada: B.C. Decker, Inc.; 2000. p. 252-76. 6180 6181 (4) Maggio CA, Pi-Sunyer FX. The prevention and treatment of obesity. Application to type 2 6182 diabetes. Diabetes Care 1997;20(11):1744-66. 6183 6184 (5) Pi-Sunyer FX. Weight loss and mortality in type 2 diabetes. Diabetes Care 6185 2000;23(10):1451-2. 6186 6187 (6) Buteau J, Roduit R, Susini S, Prentki M. Glucagon-like peptide-1 promotes DNA synthesis, 6188 activates phosphatidylinositol 3-kinase and increases transcription factor pancreatic and 6189 duodenal homeobox gene 1 (PDX-1) DNA binding activity in beta (INS-1)-cells. 6190 Diabetologia 1999;42(7):856-64. 6191 6192 (7) Edvell A, Lindström P. Initiation of increased pancreatic islet growth in young 6193 normoglycemic mice (Umeå +/?). Endocrinology 1999;140(2):778-83. 6194 6195 (8) Xu G, Stoffers DA, Habener JF, Bonner-Weir S. Exendin-4 stimulates both beta-cell 6196 replication and neogenesis, resulting in increased beta-cell mass and improved glucose 6197 tolerance in diabetic rats. Diabetes 1999;48(12):2270-6. 6198 6199 (9) Flint A, Raben A, Astrup A, Holst JJ. Glucagon-like peptide 1 promotes satiety and 6200 suppresses energy intake in humans. J Clin Invest 1998 Feb 1;101(3):515-20. 6201 6202 (10) Gutzwiller JP, Goke B, Drewe J, Hildebrand P, Ketterer S, Handschin D, et al. Glucagon- 6203 like peptide-1: a potent regulator of food intake in humans. Gut 1999;44(1):81-6. 6204 6205 (11) Naslund E, Barkeling B, King N, Gutniak M, Blundell JE, Holst JJ, et al. Energy intake and 6206 appetite are suppressed by glucagon-like peptide-1 (GLP-1) in obese men. Int J Obes Relat 6207 Metab Disord 1999 Mar;23(3):304-11. 6208 6209 (12) Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like 6210 peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: 6211 a parallel-group study. Lancet 2002 Mar 9;359(9309):824-30. 6212 6213 (13) Holst JJ. Enteroglucagon. Annu Rev Physiol 1997;59:257-71.

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6214 Liraglutide 6219 6222 Date: 06 March 2012 Novo Nordisk 6215 Trial ID: NN8022-1922 6220 CONFIDENTIAL 6223 Version: 6.0 6216 Protocol - Revised edition 6221 6224 Status: Final 6217 EudraCT No.: 2008-002199-88 6225 Page: 132 of 133 62266218 6227 (14) Ahmad SR, Swann J. Exenatide and rare adverse events. N Engl J Med 2008 May 6228 1;358(18):1970-1. 6229 6230 (15) Dore DD, Seeger JD, Chan KA. Use of a claims-based active drug safety surveillance 6231 system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared to 6232 metformin or glyburide. Current Medical Research and Opinion 2009 Apr;25(4):1019-27. 6233 6234 (16) Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. 6235 Homeostasis model assessment: insulin resistance and beta-cell function from fasting 6236 plasma glucose and insulin concentrations in man. Diabetologia 1985;28(7):412-9. 6237 6238 (17) ADA. Standard of Medical Care in Diabetes-2010. Diabetes Care 33, supp 1. 1-1-2010. 6239 Ref Type: Generic 6240 6241 (18) FAO/WHO/UNU. Human energy requirements. Report of a joint FAO/WHO/UNU expert 6242 consultation. FAO: food and nutrition technical report series 1. Rome: FAO/WHO/UNU; 6243 2004. 6244 6245 (19) De AC, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. Clinical trial registration: 6246 a statement from the International Committee of Medical Journal Editors. New Engl J Med 6247 2004;351(12):1250-1. 6248 6249 (20) Food and Drug Administration. Food and Drug Administration Amendments Act of 2007. 6250 http://www fda 6251 gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/Significa 6252 ntAmendmentstotheFDCAct/FoodandDrugAdministrationAmendmentsActof2007/default 6253 htm 2007Available from: URL: 6254 http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActF 6255 DCAct/SignificantAmendmentstotheFDCAct/FoodandDrugAdministrationAmendmentsAct 6256 of2007/default.htm 6257 6258 (21) Kolotkin RL, Crosby RD, Kosloski KD, Williams GR. Development of a brief measure to 6259 assess quality of life in obesity. Obes Res 2001;9(2):102-11. 6260 6261 (22) Bradley C. Diabetes treatment satisfaction questionnaire. Change version for use alongside 6262 status version provides appropriate solution where ceiling effects occur. Diabetes Care 1999 6263 Mar;22(3):530-2. 6264 6265 (23) ADA - American Diabetes Association. Defining and reporting hypoglycemia in diabetes: 6266 a report from the American Diabetes Association Workgroup on Hypoglycemia. Diabetes 6267 Care 2005 May;28(5):1245-9. 6268 6269 (24) Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity 6270 measure. J Gen Intern Med 2001 Sep;16(9):606-13.

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6271 Liraglutide 6276 6279 Date: 06 March 2012 Novo Nordisk 6272 Trial ID: NN8022-1922 6277 CONFIDENTIAL 6280 Version: 6.0 6273 Protocol - Revised edition 6278 6281 Status: Final 6274 EudraCT No.: 2008-002199-88 6282 Page: 133 of 133 62836275 6284 (25) International Conference on Harmonisation. ICH Harmonised Tripartite Guideline. Good 6285 Clinical Practice. 01 May 1996. 6286 Ref Type: Generic 6287 6288 (26) Food and Drug Administration. Standardized Definitions for Cardiovascular Outcomes 6289 Trials: Draft Recommendations. Division of Metabolism and Endocrinology Products, 6290 Center for Drug Evaluation and Research (CDER), 22-July-2009. Rockville, MD; 2009 Jul 6291 22. 22-7-2009. 6292 Ref Type: Generic 6293 6294 (27) Guidance for Industry. Developing products for weight management. Draft guidance. US 6295 Department of Health and Human Services. Food and Drug Administration, February 2007. 6296 Ref Type: Generic 6297 6298 (28) Food and Drug Administration. Guidance for Industry: Information Program on Clinical 6299 Trials for Serious or Life-Threatening Diseases and Conditions. 1-9. 2002. 6300 Ref Type: Generic 6301 6302 (29) EMEA, Committee for medicinal products for human use (CHMP). Guideline on clinical 6303 evaluation of medicinal products used in weight control. 2007 Nov 15. 6304 6305 (30) Rubin DB. Multiple Imputation for Nonresponse in Surveys, New York: John Wiley & 6306 Sons, Inc. 1987. 6307 Ref Type: Generic 6308 6309 (31) World Medical Association. Declaration of Helsinki. Ethical Principles for Medical 6310 Research Involving Human Subjects. Last amended by the 59th WMA Assembly, Seoul, 6311 October 2008. 6312 Ref Type: Generic 6313 6314 (32) Food and Drug Administration. Food and Drug Administration: Code of Federal 6315 Regulations, 21 CFR Part 54, Financial Disclosure by Clinical Investigators. http://www 6316 accessdata fda gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch cfm?CFRPart=54&showFR=1 6317 2006Available from: URL: 6318 http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRPart=54&sh 6319 owFR=1 6320 6321 (33) Uniform requirements for manuscripts submitted to biomedical journals. International 6322 Committee of Medical Journal Editors. N Engl J Med 1997;336(4):309-15.

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6323 Liraglutide 6328 6331 Date: 06 March 2012 Novo Nordisk 6324 Trial ID: NN8022-1922 6329 CONFIDENTIAL 6332 Version: 6.0 6325 Revised Protocol - Appendix B 6330 6333 Status: Final 6326 EudraCT No.: 2008-002199-88 6334 Page: 1 of 2 63356327 6336 Appendix B 6337 6338 6339 6340 6341 6342 6343 6344 6345 6346 Agreement on the final revised protocol 6347 6348 6349 6350 6351 6352 6353 6354 6355 6356 6357 6358 6359 6360 6361 6362 6363

6364 6365 This confidential document is the property of Novo Nordisk. No unpublished information contained herein 6366 may be disclosed without prior written approval from Novo Nordisk. Access to this document must be 6367 restricted to relevant parties.

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6368 Liraglutide 6373 6376 Date: 06 March 2012 Novo Nordisk 6369 Trial ID: NN8022-1922 6374 CONFIDENTIAL 6377 Version: 6.0 6370 Revised Protocol - Appendix B 6375 6378 Status: Final 6371 EudraCT No.: 2008-002199-88 6379 Page: 2 of 2 63806372 6381 Agreement on the final revised protocol 6382 6383 6384 Trial ID: NN8022-1922 6385 The Investigator and Novo Nordisk agree to conduct the trial as outlined in this protocol with 6386 reference to national/local regulations and in accordance with current Good Clinical Practice (GCP) 6387 guidelines. Any modification to the protocol must be agreed upon by both the Investigator and 6388 Novo Nordisk and documented in writing. By written agreement to this protocol, the Investigator 6389 agrees to allow direct access to all documentation, including source data, to authorised individuals 6390 representing Novo Nordisk (including monitoring staff and auditors), to institutional review 6391 boards/independent ethics committees (IEC/IRB) and/or to regulatory authorities. 6392 6393

6394 Investigator: 6395 6396 6397 6398 6399 Name (printed) Signature Date 6400 6401 6402 6403 Head of medical/clinical research or designee: 6404 6405 6406 6407 6408 Name (printed) Signature Date

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6409 Liraglutide 6414 6417 Date: 06 March 2012 Novo Nordisk 6410 Trial ID: NN8022-1922 6415 CONFIDENTIAL 6418 Version: 6.0 6411 Revised Protocol - Appendix C 6416 6419 Status: Final 6412 EudraCT No.: 2008-002199-88 6420 Page: 1 of 2 64216413 6422 6423 Appendix C 6424 6425 6426 6427 6428 6429 6430 6431 6432 6433 6434 New York Heart Association (NYHA) Criteria for 6435 Functional Capacity 6436 6437 6438 6439 6440 6441 6442 6443 6444 6445 6446 6447 6448 6449 6450

6451 This confidential document is the property of Novo Nordisk. No unpublished information contained herein 6452 may be disclosed without prior written approval from Novo Nordisk. Access to this document must be 6453 restricted to relevant parties.

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6454 Liraglutide 6459 6462 Date: 06 March 2012 Novo Nordisk 6455 Trial ID: NN8022-1922 6460 CONFIDENTIAL 6463 Version: 6.0 6456 Revised Protocol - Appendix C 6461 6464 Status: Final 6457 EudraCT No.: 2008-002199-88 6465 Page: 2 of 2 64666458 6467 Criteria for Functional Capacity* 6468 Functional Capacity Objective Assessment

Class I A Patients with cardiac disease but without resulting limitation of No objective evidence of physical activity. Ordinary physical activity does not cause undue cardiovascular disease. fatigue, palpitation, dyspnea, or anginal pain

Class II B Patients with cardiac disease resulting in slight limitation of physical Objective evidence of activity. They are comfortable at rest. Ordinary physical activity minimal cardiovascular results in fatigue, palpitation, dyspnea, or anginal pain disease.

Class III C Patients with cardiac disease resulting in marked limitation of physical Objective evidence of activity. They are comfortable at rest. Less than ordinary activity moderately severe causes fatigue, palpitation, dyspnea, or anginal pain cardiovascular disease.

Class IV D Patients with cardiac disease resulting in inability to carry on any Objective evidence of physical activity without discomfort. Symptoms of heart failure or the severe cardiovascular anginal syndrome may be present even at rest. If any physical activity disease. is undertaken, discomfort is increased

6469 *The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of 6470 the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994:253-256.

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6471 Liraglutide 6476 6483 Date: 06 March 2012 Novo Nordisk 6472 Trial ID: NN8022-1922 6477 CONFIDENTIAL 6484 Version: 6.0 6473 Revised Protocol - Appendix D 6478 6485 Status: Final 6474 EudraCT No.: 2008-002199-88 6479 6486 Page: 1 of 3 6475 6480 6481 Appendix D 6487 6482 6488 6489 6490 6491 6492 6493 6494 6495 6496 6497 6498

6499 Instruction for Blood Pressure Measurement 6500 6501 6502 6503 6504 6505 6506 6507 6508 6509 6510 6511 6512 6513 6514 6515 6516

6517 6518 This confidential document is the property of Novo Nordisk. No unpublished information contained herein 6519 may be disclosed without prior written approval from Novo Nordisk. Access to this document must be 6520 restricted to relevant parties.

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6521 Liraglutide 6526 6529 Date: 06 March 2012 Novo Nordisk 6522 Trial ID: NN8022-1922 6527 CONFIDENTIAL 6530 Version: 6.0 6523 Revised Protocol - Appendix D 6528 6531 Status: Final 6524 EudraCT No.: 2008-002199-88 6532 Page: 2 of 3 65336525 6534 6535

6536 Instructions for Blood Pressure Measurement

6537 For the purpose of standardisation, blood pressure measurements must be taken according to recent 6538 recommendations1,2:

6539 • The auscultatory method should be used to measure blood pressure 6540 6541 • Caffeine, smoking and physical activity should be avoided at least 30 minutes before 6542 measurement 6543 6544 • Before performing a blood pressure reading, the patient should be asked to remove all clothing 6545 that covers the location of cuff placement. The sleeve should not be rolled up such that it has a 6546 tourniquet effect above the blood pressure cuff 6547 6548 • The same type of sphygmomanometer should be used throughout the trial 6549 6550 • The measurement should be taken in a sitting position, with the legs uncrossed, the back and 6551 arm supported 6552 6553 • Subject should be sitting for at least 5 minutes before the first reading is taken 6554 6555 • Location for the measurement should be the upper arm, with the stethoscope at the elbow crease 6556 over the brachial artery. The middle of the cuff on the upper arm should be at the level of right 6557 atrium (the mid-point of the sternum) 6558 6559 • The same arm should be used for blood pressure measurements at all visits 6560 6561 • The size of the cuff should be selected so that the bladder of the cuff encircles at least 80% of 6562 the arm circumference, and the width of the cuff is at least 40% of the arm circumference 6563 6564 • Cuff placement must be preceded with palpation of the brachial artery in the antecubital fossa. 6565 The midline of the cuff bladder must be placed over the location of the arterial pulsation. The 6566 lower edge of the cuff should be 2-3 cm above the antecubital fossa to allow for stethoscope 6567 placement 6568 6569 • The cuff should be inflated to at least 30 mmHg above the point at which the radial pulse 6570 disappears. The pressure should then be reduced at 2 to 3 mm/second 6571 6572 • Korotkoff sounds should be used to measure blood pressure: the onset of phase I (appearance of 6573 clear tapping sound corresponding to the appearance of palpable pulse) should indicate the

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6574 Liraglutide 6579 6582 Date: 06 March 2012 Novo Nordisk 6575 Trial ID: NN8022-1922 6580 CONFIDENTIAL 6583 Version: 6.0 6576 Revised Protocol - Appendix D 6581 6584 Status: Final 6577 EudraCT No.: 2008-002199-88 6585 Page: 3 of 3 65866578 6587 systolic blood pressure, while phase V (the disappearance of sounds) should be used for 6588 recording diastolic pressure 6589 6590 • The measurement must be taken with the precision to the nearest 2 mmHg 6591 6592 • Neither the patient nor the observer should talk during the measurement 6593 6594 • Two reliable measurements at intervals of at least 2 minutes should be performed. In case of >5 6595 mmHg difference between the first and the second reading of diastolic blood pressure, one 6596 additional reading should be obtained 6597 6598 6599 6600 6601 6602 6603 6604 6605 6606 6607 6608 6609 6610 6611 6612 6613 6614 6615 6616

6617 References: 6618 1. Recommendations for Blood Pressure Measurement in Humans and Experimental Animals. Part 1: Blood Pressure 6619 Measurement in Humans. A Statement for Professionals From the Subcommittee of Professional and Public Education of the 6620 American Heart Association Council on High Blood Pressure Research. TG Pickering, JE Hall, LJ Appel, BE Falkner, J Graves, 6621 MN Hill, DW Jones, T Kurtz, SG Sheps, EJ Roccella. Hypertension 2005; 45: 142-161. 6622 6623 2. The Seventh Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. US 6624 Department of Health and Human Services, National Institutes of Health, National Heart, Lung, and Blood Institute. December 6625 2003.

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6626 Liraglutide 6631 6638 Date: 06 March 2012 Novo Nordisk 6627 Trial ID: NN8022-1922 6632 CONFIDENTIAL 6639 Version: 6.0 6628 Revised Protocol - Appendix E 6633 6640 Status: Final 6629 EudraCT No.: 2008-002199-88 6634 6641 Page: 1 of 8 6630 6635 6636 Appendix E 6642 6637 6643 6644 6645 6646 6647 6648 6649 6650 6651 6652 6653

6654 Extended Flowchart 6655 6656 6657 6658 6659 6660 6661 6662 6663 6664 6665 6666 6667 6668 6669 6670 6671

6672 6673 This confidential document is the property of Novo Nordisk. No unpublished information contained herein 6674 may be disclosed without prior written approval from Novo Nordisk. Access to this document must be 6675 restricted to relevant parties.

Downloaded From: https://jamanetwork.com/ on 09/26/2021 6676 Liraglutide Revised Protocol - Appendix E Date: 06 March 2012 Status: Final Novo Nordisk Trial ID: NN8022-1922 EudraCT No.: 2008-002199-88 Version: 6.0 Page: 2 of 8 6677 Dose End Rando- Screening escalation Maintenance period of Observational follow-up misation period treat 1 Visit Number 1 2 3 4 5a 5b 6 7 8 9 10 11 12 13 14 15 16 16x 17 18 19 20 Weeks in relation to Visit 2 -2 0 2 4 6 8 12 16 20 24 28 32 36 40 44 50 56 56 58 60 64 68 Visit Window, days ± 5 Baseline ± 3 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 3 ± 5 ± 3 ± 5 ± 5 ± 5 SUBJECTS Informed consent X In/exclusion criteria X X Randomisation criteria X Rescue criteria X X X X X X X X X X X X X X Withdrawal criteria X X X X X X X X X X X X X X X X X X Demography Date of birth X Sex X Race X Ethnicity X Date of diagnosis of X diabetes History of Diabetes X complications History of Concomitant X Cardiovascular Disease History of Gallbladder X Disease History of Psychiatric X Disorders Diabetes treatment history 6678 6679 6680 1 6681 Only subjects discontinuing the trial prematurely before Visit 16 will be asked to attend Visit 16x 56 weeks after their randomisation date for the assessment of body 6682 weight and MESI

Downloaded From: https://jamanetwork.com/ on 09/26/2021 6683 Liraglutide Revised Protocol - Appendix E Date: 06 March 2012 Status: Final Novo Nordisk Trial ID: NN8022-1922 EudraCT No.: 2008-002199-88 Version: 6.0 Page: 3 of 8 6684 Dose End Rando- Screening escalation Maintenance period of Observational follow-up misation period treat 1 Visit Number 1 2 3 4 5a 5b 6 7 8 9 10 11 12 13 14 15 16 16x 17 18 19 20 Weeks in relation to Visit 2 -2 0 2 4 6 8 12 16 20 24 28 32 36 40 44 50 56 56 58 60 64 68 Visit Window, days ± 5 Baseline ± 3 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 3 ± 5 ± 3 ± 5 ± 5 ± 5 Current diabetes X treatment Dose of current X diabetes treatment Concomitant X illness/Medical history Concomitant medication X X X X X X X X X X X X X X X X X X X X X Smoking habits X Attend visit fasting X X X X X X X X X X X X X EFFICACY Body measurements Body weight X X X X X X X X X X X X X X X X X X X X X X Height X Waist circumference X X X X X X X X X X X X X X X X X X X X X

HbA1c X X X X X X X Fasting plasma glucose X X X X X X X X X X X X 7-point plasma profile 2 X X X (self-measured) Glucose metabolism Fasting glucagon X X X Fasting insulin X X X Fasting C-peptide X X X Fasting pro-insulin X X X Urinary Albumin-to- X X X X X Creatinine ratio Vital signs 6685 6686 6687 2 On a normal representative day of the week (not on a day when they anticipate unusual strenuous exercise), preferably within one week prior to the visit

Downloaded From: https://jamanetwork.com/ on 09/26/2021 6688 Liraglutide Revised Protocol - Appendix E Date: 06 March 2012 Status: Final Novo Nordisk Trial ID: NN8022-1922 EudraCT No.: 2008-002199-88 Version: 6.0 Page: 4 of 8 6689 Dose End Rando- Screening escalation Maintenance period of Observational follow-up misation period treat 1 Visit Number 1 2 3 4 5a 5b 6 7 8 9 10 11 12 13 14 15 16 16x 17 18 19 20 Weeks in relation to Visit 2 -2 0 2 4 6 8 12 16 20 24 28 32 36 40 44 50 56 56 58 60 64 68 Visit Window, days ± 5 Baseline ± 3 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 3 ± 5 ± 3 ± 5 ± 5 ± 5 Systolic blood pressure, X X X X X X X X X X X X X X X X X X X X sitting Diastolic blood X X X X X X X X X X X X X X X X X X X X pressure, sitting Lipids Cholesterol X X X X LDL cholesterol X X X X HDL cholesterol X X X X VLDL cholesterol X X X X Triglycerides X X X X Free fatty acids X X X X Cardiovascular biomarkers hsCRP X X X Adiponectin X X X Fibrinogen X X X PAI-1 X X X 3,4 PRO questionnaires IWQoL-Lite X X X DTSQs X X X SAFETY Physical examination X X Pulse, sitting X X X X X X X X X X X X X X X X X X X X Hypoglycaemic episodes X X X X X X X X X X X X X X X X X X X X 6690 6691 6692 3 Applicable for subjects in France, Germany, Spain, Sweden, United Kingdom and USA 6693 4 The investigator or his delegate must review patient reported outcome(s) for completeness and AEs immediately following administration. For subjects discontinuing 6694 the trial prematurely before Visit 16 the questionnaire should be completed at the end of treatment visit (Visit 16).

Downloaded From: https://jamanetwork.com/ on 09/26/2021 6695 Liraglutide Revised Protocol - Appendix E Date: 06 March 2012 Status: Final Novo Nordisk Trial ID: NN8022-1922 EudraCT No.: 2008-002199-88 Version: 6.0 Page: 5 of 8 6696 Dose End Rando- Screening escalation Maintenance period of Observational follow-up misation period treat 1 Visit Number 1 2 3 4 5a 5b 6 7 8 9 10 11 12 13 14 15 16 16x 17 18 19 20 Weeks in relation to Visit 2 -2 0 2 4 6 8 12 16 20 24 28 32 36 40 44 50 56 56 58 60 64 68 Visit Window, days ± 5 Baseline ± 3 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 3 ± 5 ± 3 ± 5 ± 5 ± 5 ECG X X X X Eye examination X Adverse Events X X X X X X X X X X X X X X X X X X X X Binge Eating Scale 3,4 X X X questionnaire Haematology Haemoglobin X X X X X X X X X Haematocrit X X X X X X X X X Thrombocytes X X X X X X X X X Erythrocytes X X X X X X X X X Leucocytes X X X X X X X X X Differential count: X − Eosinophils − Neutrophils X X X X X X X X − Basophils − Monocytes − Lymphocytes Biochemistry Creatinine X X X X X X X X X Creatine kinase X X X X X X X X X Urea X X X X X X X X X Albumin X X X X X X X X X Bilirubins, total X X X X X X X X X ALAT X X X X X X X X X ASAT X X X X X X X X X Alkaline phosphatase X X X X X X X X X Sodium X X X X X X X X X

Downloaded From: https://jamanetwork.com/ on 09/26/2021 6697 Liraglutide Revised Protocol - Appendix E Date: 06 March 2012 Status: Final Novo Nordisk Trial ID: NN8022-1922 EudraCT No.: 2008-002199-88 Version: 6.0 Page: 6 of 8 6698 Dose End Rando- Screening escalation Maintenance period of Observational follow-up misation period treat 1 Visit Number 1 2 3 4 5a 5b 6 7 8 9 10 11 12 13 14 15 16 16x 17 18 19 20 Weeks in relation to Visit 2 -2 0 2 4 6 8 12 16 20 24 28 32 36 40 44 50 56 56 58 60 64 68 Visit Window, days ± 5 Baseline ± 3 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 3 ± 5 ± 3 ± 5 ± 5 ± 5 Potassium X X X X X X X X X Calcium X X X X X X X X X Amylase X X X X X X X X X Lipase X X X X X X X X X Calcitonin X X X X X X X X X TSH X X X X X X X X X 5 Pregnancy test Blood sample X X X Urine-sticks (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) Liraglutide antibodies X X6 X Mental health 7 questionnaires 8 C-SSRS X X X X X X X X X X X X X X X X X X X X X 8 PHQ-9 X X X X X X X X X X X X X X X X X X X X X OTHER ASSESSMENTS PK (liraglutide plasma X X X concentration) TRIAL MATERIAL Dispense trial card X 6699 6700 6701 5 For all women of childbearing potential: a serum pregnancy test will be performed at Visit 1, 16 and 20. Furthermore, pregnancy urine tests will be performed at any 6702 other clinic visits during the trial if a menstrual period is missed or as required by local law 6703 6 For subjects discontinuing the trial prematurely before Visit 16 liraglutide antibodies will be measured at the end of treatment visit (Visit 16) while subjects that 6704 complete the treatment will have liraglutide antibodies measured at the first follow-up (Visit 17). 6705 7 For subjects discontinuing the trial prematurely before Visit 16 the mental health questionnaires will be completed at the end of treatment visit (Visit 16) 6706 8 The Investigator must assess the PHQ-9 and C-SSRS scores at Visit 1 (screening visit) and Visit 2 (randomisation) to exclude subjects with major depression (PHQ-9 ≥ 6707 15) or any suicidal ideation (of type 4 or type 5).The investigator or his delegate must review the C-SSRS and PHQ-9 questionnaires for completeness and AEs 6708 immediately following administration.

Downloaded From: https://jamanetwork.com/ on 09/26/2021 6709 Liraglutide Revised Protocol - Appendix E Date: 06 March 2012 Status: Final Novo Nordisk Trial ID: NN8022-1922 EudraCT No.: 2008-002199-88 Version: 6.0 Page: 7 of 8 6710 Dose End Rando- Screening escalation Maintenance period of Observational follow-up misation period treat 1 Visit Number 1 2 3 4 5a 5b 6 7 8 9 10 11 12 13 14 15 16 16x 17 18 19 20 Weeks in relation to Visit 2 -2 0 2 4 6 8 12 16 20 24 28 32 36 40 44 50 56 56 58 60 64 68 Visit Window, days ± 5 Baseline ± 3 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 5 ± 3 ± 5 ± 3 ± 5 ± 5 ± 5 Diary Dispense diabetes diary X X X X X X X X X X X X X X X X X X X X Transcribe diabetes X X X X X X X X X X X X X X X X X X X X diary into CRF Dispense 3-day food X X X X X X X X diary Collect 3-day food X X X X X X X X diary Diet and physical activity X9 X X9 X X9 X X9 X X9 X X9 X X X9 X X9 X counselling Recording of dietary compliance and physical X X X X X X X X 10 activity Supply of device(s)/ancillaries Glucose meter X Pedometer X Dispensing visit X X X X X X X X X X X X X Drug accountability X X X X X X X X X X X X X IV/WRS call X X X X X X X X X X X X X X X X X End of treatment/End of X 11 X X Trial 6711 6712 6713 6714 9 Diet counselling based on a 3-day food diary 6715 10 At Visit 2 only physical activity will be recorded 6716 11 Subjects discontinuing the trial prematurely before Visit 16 will be asked to attend a last visit at which procedures according to Visit 16 will be performed and the EOT 6717 form completed. For subjects discontinuing the trial prematurely after Visit 16 the following will apply: at Visit 17; procedures according to Visit 17 will be performed 6718 and the EOT form completed - after Visit 17; procedures according to Visit 20 will be performed and the EOT form completed

Downloaded From: https://jamanetwork.com/ on 09/26/2021 6719 Liraglutide Revised Protocol - Appendix E Date: 06 March 2012 Status: Final Novo Nordisk Trial ID: NN8022-1922 EudraCT No.: 2008-002199-88 Version: 6.0 Page: 8 of 8 6720 6721 6722

6723 3$*( ,17(17,21$//< /()7 %/$1.

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6724 liraglutide 6729 6732 Date: 06 March 2012 Novo Nordisk 6725 Trial ID: NN8022-1922 6730 CONFIDENTIAL 6733 Version: 6.0 6726 Revised Protocol - Appendix F 6731 6734 Status: Final 6727 EudraCT No.: 2008-002199-88 6735 Page: 1 of 10 67366728 6737 6738 Appendix F 6739 6740 6741 6742 6743 6744 6745 6746 6747 6748 6749 PRO Questionnaires 6750 6751 6752 6753 6754 6755 6756 6757 6758 6759 6760 6761 6762 6763 6764 6765

6766 This confidential document is the property of Novo Nordisk. No unpublished information contained herein 6767 may be disclosed without prior written approval from Novo Nordisk. Access to this document must be 6768 restricted to relevant parties.

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6769 liraglutide 6776 6779 Date: 06 March 2012 Novo Nordisk 6770 Trial ID: NN8022-1922 6777 CONFIDENTIAL 6780 Version: 6.0 6771 Revised Protocol - Appendix F 6778 6781 Status: Final 6772 EudraCT No.: 2008-002199-88 6782 Page: 2 of 10 6773 6774 Table of contents 67836775 6784 Page

6785 Table of contents ...... 2 6786 1 Impact of Weight on Quality of Life (IWQoL-Lite) ...... 3 6787 2 Diabetes Treatment Satisfaction Questionnaire (DTSQs) ...... 6 6788 3 Binge Eating Scale (BES) questionnaire ...... 7

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6789 liraglutide 6794 6797 Date: 06 March 2012 Novo Nordisk 6790 Trial ID: NN8022-1922 6795 CONFIDENTIAL 6798 Version: 6.0 6791 Revised Protocol - Appendix F 6796 6799 Status: Final 6792 EudraCT No.: 2008-002199-88 6800 Page: 3 of 10 68016793 6802 1 Impact of Weight on Quality of Life (IWQoL-Lite) 6803 6804 Please answer the following statements by circling the number that best applies to you in the past week. Be 6805 as honest as possible. There are no right or wrong answers. 6806 ALWAYS USUALLY SOMETIMES RARELY NEVER Physical Function TRUE TRUE TRUE TRUE TRUE 1. Because of my weight I have trouble picking up 5 4 3 2 1 objects. 2. Because of my weight I have trouble tying my 5 4 3 2 1 shoelaces. 3. Because of my weight I have difficulty getting 5 4 3 2 1 up from chairs. 4. Because of my weight I have trouble using 5 4 3 2 1 stairs. 5. Because of my weight I have difficulty putting 5 4 3 2 1 on or taking off my clothes. 6. Because of my weight I have trouble with 5 4 3 2 1 mobility (getting around). 7. Because of my weight I have trouble crossing 5 4 3 2 1 my legs. 8. I feel short of breath with only mild exertion 5 4 3 2 1 (e.g. climbing a single flight of stairs). 9. I am troubled by painful or stiff joints. 5 4 3 2 1

10. My ankles and lower legs are swollen at the end 5 4 3 2 1 of the day. 11. I am worried about my health. 5 4 3 2 1

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6807 liraglutide 6812 6815 Date: 06 March 2012 Novo Nordisk 6808 Trial ID: NN8022-1922 6813 CONFIDENTIAL 6816 Version: 6.0 6809 Revised Protocol - Appendix F 6814 6817 Status: Final 6810 EudraCT No.: 2008-002199-88 6818 Page: 4 of 10 68196811 6820 6821 Self-esteem ALWAYS USUALLY SOMETIMES RARELY NEVER TRUE TRUE TRUE TRUE TRUE 1. Because of my weight I am self-conscious. 5 4 3 2 1

2. Because of my weight my self-esteem is not 5 4 3 2 1 what it could be. 3. Because of my weight I feel unsure of myself. 5 4 3 2 1 4. Because of my weight I don’t like myself. 5 4 3 2 1

5. Because of my weight I am afraid of being 5 4 3 2 1 rejected. 6. Because of my weight I avoid looking in 5 4 3 2 1 mirrors or seeing myself in photographs. 7. Because of my weight I am embarrassed to be 5 4 3 2 1 seen in public places. Sexual Life ALWAYS USUALLY SOMETIMES RARELY NEVER TRUE TRUE TRUE TRUE TRUE 1. Because of my weight I do not enjoy sexual 5 4 3 2 1 activity. 2. Because of my weight I have little or no sexual 5 4 3 2 1 desire. 3. Because of my weight I have difficulty with 5 4 3 2 1 sexual performance. 4. Because of my weight I avoid sexual 5 4 3 2 1 encounters whenever possible.

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6822 liraglutide 6827 6830 Date: 06 March 2012 Novo Nordisk 6823 Trial ID: NN8022-1922 6828 CONFIDENTIAL 6831 Version: 6.0 6824 Revised Protocol - Appendix F 6829 6832 Status: Final 6825 EudraCT No.: 2008-002199-88 6833 Page: 5 of 10 68346826 6835 6836 Public Distress ALWAYS USUALLY SOMETIMES RARELY NEVER TRUE TRUE TRUE TRUE TRUE 1. Because of my weight I experience ridicule, 5 4 3 2 1 teasing, or unwanted attention. 2. Because of my weight I worry about fitting into 5 4 3 2 1 seats in public places (e.g. theatres, cinemas, restaurants, cars, or aeroplanes). 3. Because of my weight I worry about fitting 5 4 3 2 1 through aisles or turnstiles. 4. Because of my weight I worry about finding 5 4 3 2 1 chairs that are strong enough to hold my weight. 5. Because of my weight I experience 5 4 3 2 1 discrimination by others. Work (Note: For those not in paid ALWAYS USUALLY SOMETIMES RARELY NEVER employment, answer with TRUE TRUE TRUE TRUE TRUE respect to your daily activities.) 1. Because of my weight I have trouble getting 5 4 3 2 1 things done or carrying out my responsibilities. 2. Because of my weight I am less productive than 5 4 3 2 1 I could be. 3. Because of my weight I don’t receive 5 4 3 2 1 appropriate pay rises, promotions or recognition at work. 4. Because of my weight I am afraid to go for job 5 4 3 2 1 interviews.

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6837 liraglutide 6842 6845 Date: 06 March 2012 Novo Nordisk 6838 Trial ID: NN8022-1922 6843 CONFIDENTIAL 6846 Version: 6.0 6839 Revised Protocol - Appendix F 6844 6847 Status: Final 6840 EudraCT No.: 2008-002199-88 6848 Page: 6 of 10 68496841 6850 2 Diabetes Treatment Satisfaction Questionnaire (DTSQs) 6851 6852 The following questions are concerned with the treatment for your diabetes (including insulin, tablets 6853 and/or diet) and your experience over the past few weeks. Please answer each question by circling a 6854 number on each of the scales. 6855 6856 6857 1. How satisfied are you with your current treatment?

6858 very satisfied 6 5 4 3 2 1 0 very dissatisfied 6859 6860 2. How often have you felt that your blood sugars have been unacceptably high recently? 6861 most of the time 6 5 4 3 2 1 0 none of the time 6862 6863 3. How often have you felt that your blood sugars have been unacceptably low recently? 6864 most of the time 6 5 4 3 2 1 0 none of the time 6865 6866 4. How convenient have you been finding your treatment to be recently?

6867 very convenient 6 5 4 3 2 1 0 very inconvenient 6868 6869 5. How flexible have you been finding your treatment to be recently? 6870 very flexible 6 5 4 3 2 1 0 very inflexible 6871 6872 6. How satisfied are you with your understanding of your diabetes? 6873 very satisfied 6 5 4 3 2 1 0 very dissatisfied 6874 6875 7. Would you recommend this form of treatment to someone else with your kind of diabetes? 6876 6877 Yes, I would definitely6881 6 5 4 3 2 1 0 No, I would definitely 6878 recommend the 6882 not recommend the 6879 treatment 6883 treatment 68846880 6885 8. How satisfied would you be to continue with your present form of treatment?

6886 very satisfied 6 5 4 3 2 1 0 very dissatisfied 6887 6888 6889 Please make sure that you have circled one number on each of the scales.

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6890 liraglutide 6895 6898 Date: 06 March 2012 Novo Nordisk 6891 Trial ID: NN8022-1922 6896 CONFIDENTIAL 6899 Version: 6.0 6892 Revised Protocol - Appendix F 6897 6900 Status: Final 6893 EudraCT No.: 2008-002199-88 6901 Page: 7 of 10 69026894 6903 3 Binge Eating Scale (BES) questionnaire

6904 Code no. 6905 6906 Eating Habits Checklist 6907 6908 6909 Instructions: Below are groups of numbered statements. Read all of the statements in each group 6910 and check the one that best describes the way you feel about the problems you have controlling 6911 your eating behavior. 6912 6913 6914 #1 6915 1. I don’t feel self-conscious about my weight or body size when I’m with others. 6916 2. I feel concerned about how I look to others, but it normally does not make me feel disappointed 6917 with myself. 6918 3. I do get self-conscious about my appearance and weight which makes me feel disappointed in 6919 myself. 6920 4. I feel very self-conscious about my weight and frequently, I feel intense shame and disgust for 6921 myself. I try to avoid social contacts because of my self-consciousness. 6922 6923 6924 #2 6925 1. I don’t have any difficulty eating slowly in the proper manner. 6926 2. Although I seem to “gobble down” foods, I don’t end up feeling stuffed because of eating too 6927 much. 6928 3. At times, I tend to eat quickly and then, I feel uncomfortably full afterwards. 6929 4. I have the habit of bolting down my food, without really chewing it. When this happens I 6930 usually feel uncomfortably stuffed because I’ve eaten too much. 6931 6932 6933 #3 6934 1. I feel capable to control my eating urges when I want to. 6935 2. I feel like I have failed to control my eating more than the average person. 6936 3. I feel utterly helpless when it comes to feeling in control of my eating urges. 6937 4. Because I feel so helpless about controlling my eating I have become very desperate about 6938 trying to get in control.

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6939 liraglutide 6944 6947 Date: 06 March 2012 Novo Nordisk 6940 Trial ID: NN8022-1922 6945 CONFIDENTIAL 6948 Version: 6.0 6941 Revised Protocol - Appendix F 6946 6949 Status: Final 6942 EudraCT No.: 2008-002199-88 6950 Page: 8 of 10 69516943 6952 #4 6953 1. I don’t have the habit of eating when I’m bored. 6954 2. I sometimes eat when I’m bored, but often I’m able to “get busy” and get my mind off food. 6955 3. I have a regular habit of eating when I’m bored, but occasionally, I can use some other activity 6956 to get my mind off eating. 6957 4. I have a strong habit of eating when I’m bored. Nothing seems to help me break the habit. 6958 6959 6960 #5 6961 1. I’m usually physically hungry when I eat something. 6962 2. Occasionally, I eat something on impulse even though I really am not hungry. 6963 3. I have the regular habit of eating foods that I might not really enjoy, to satisfy a hungry feeling 6964 even though physically, I don’t need the food. 6965 4. Even though I’m not physically hungry, I get a hungry feeling in my mouth that only seems to 6966 be satisfied when I eat a food, like a sandwich, that fills my mouth. Sometimes, when I eat the 6967 food to satisfy my mouth hunger, I then spit the food out so I won’t gain weight. 6968 6969 6970 #6 6971 1. I don’t feel any guilt or self-hate after I overeat. 6972 2. After I overeat, occasionally I feel guilt or self-hate. 6973 3. Almost all the time I experience strong guilt or self hate after I overeat. 6974 6975 6976 #7 6977 1. I don’t loose total control of my eating when dieting even after periods when I overeat. 6978 2. Sometimes when I eat a “forbidden food” on a diet, I feel like I “blew it” and eat even more. 6979 3. Frequently, I have the habit of saying to myself, “I’ve blown it now, why not go all the way” 6980 when I overeat on a diet. When that happens I eat even more. 6981 4. I have a regular habit of starting strict diets for myself, but I break the diets by going on an 6982 eating binge. My life seems to be either a “feast” or “famine.” 6983 6984 6985 #8 6986 1. I rarely eat so much food that I feel uncomfortable stuffed afterwards. 6987 2. Usually about once a month, I eat such a quantity of food; I end up feeling very stuffed. 6988 3. I have regular periods during the month when I eat large amounts of food, either at mealtime or 6989 at snacks. 6990 4. I eat so much food that I regularly feel quite uncomfortable after eating and sometimes at bit 6991 nauseous.

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6992 liraglutide 6997 7000 Date: 06 March 2012 Novo Nordisk 6993 Trial ID: NN8022-1922 6998 CONFIDENTIAL 7001 Version: 6.0 6994 Revised Protocol - Appendix F 6999 7002 Status: Final 6995 EudraCT No.: 2008-002199-88 7003 Page: 9 of 10 70046996 7005 7006 #9 7007 1. My level of calorie intake does not go up very high or go down very low on a regular basis. 7008 2. Sometimes after I overeat, I will try to reduce my caloric intake to almost nothing to 7009 compensate for the excess calories I’ve eaten. 7010 3. I have a regular habit of overeating during the night. It seems that my routine is not to be hungry 7011 but overeat in the evening. 7012 4. In my adult years, I have had week long periods when I overeat. It seems I live a life of either 7013 “feast” or “famine.” 7014 7015 7016 #10 7017 1. I usually am able to stop eating when I want to. I know when “enough is enough.” 7018 2. Every so often, I experience a compulsion to eat which I can’t seem to control. 7019 3. Frequently, I experience strong urges to eat which I seem unable to control, but at other times I 7020 can control my eating urges. 7021 4. I feel incapable of controlling urges to eat. I have to fear of not being able to stop eating 7022 voluntarily. 7023 7024 7025 #11 7026 1. I don’t have any problem stopping eating when I feel full. 7027 2. I usually can stop eating when I feel full but occasionally overeat leaving me feeling 7028 uncomfortably stuffed. 7029 3. I have a problem stopping eating once I start and usually I feel uncomfortable stuffed after I eat 7030 a meal. 7031 4. Because I have a problem not being able to stop eating when I want, I sometimes have to induce 7032 vomiting to relieve my stuffed feeling. 7033 7034 7035 #12 7036 1. I seem to eat just as much when I’m with others (family, social gatherings) as when I’m by 7037 myself. 7038 2. Sometimes, when I’m other persons, I don’t eat as much as I want to eat because I’m self- 7039 conscious about my eating. 7040 3. Frequently, I eat only a small amount of food when others are present, because I’m very 7041 embarrassed about my eating. 7042 4. I feel so ashamed about overeating that I pick times to overeat when I know no on will see me. I 7043 feel like a “closet eater.”

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7044 liraglutide 7049 7052 Date: 06 March 2012 Novo Nordisk 7045 Trial ID: NN8022-1922 7050 CONFIDENTIAL 7053 Version: 6.0 7046 Revised Protocol - Appendix F 7051 7054 Status: Final 7047 EudraCT No.: 2008-002199-88 7055 Page: 10 of 10 70567048 7057 #13 7058 1. I eat three meals a day with only an occasional between meal snack. 7059 2. I eat 3 meals a day, but I also normally snack between meals. 7060 3. When I am snacking heavily, I get in the habit of skipping regular meals. 7061 4. There are regular periods when I seem to be continually eating, with no planned meals. 7062 7063 #14 7064 1. I don’t think much about trying to control unwanted eating urges. 7065 2. At least some of the time, I feel my thoughts are pre-occupied with trying to control my eating 7066 urges. 7067 3. I feel that frequently I spend much time thinking about how much I ate or about trying not to eat 7068 more. 7069 4. It seems to me that most of my waking hours are pre-occupied with thoughts about eating or not 7070 eating. I feel like I’m constantly struggling not to eat. 7071 7072 #15 7073 1. I don’t think about food a great deal. 7074 2. I have strong cravings for food but they last only for brief periods of time. 7075 3. I have days when I can’t seem to think about anything else but food. 7076 4. Most of my days seem to be pre-occupied with thoughts about food. I feel like I live to eat. 7077 7078 #16 7079 1. I usually know whether or not I’m physically hungry. I take the right portion of food to satisfy 7080 me. 7081 2. Occasionally, I feel uncertain about knowing whether or nor I’m physically hungry. At these 7082 times, its hard to know how much food I should take to satisfy me. 7083 3. Even though I might know how many calories I should eat, I don’t have any idea what is a 7084 “normal” amount of food for me.

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7085 Liraglutide 7090 7093 Date: 06 March 2012 Novo Nordisk 7086 Trial ID: NN8022-1922 7091 CONFIDENTIAL 7094 Version: 6.0 7087 Revised Protocol - Appendix G 7092 7095 Status: Final 7088 EudraCT No.: 2008-002199-88 7096 Page: 1 of 11 70977089 7098 Appendix G 7099 7100 7101 7102 7103 7104 7105 7106 7107 7108 Mental Health Questionnaires 7109 7110 7111 7112 7113 7114 7115 7116 7117 7118 7119 7120 7121 7122 7123 7124 7125

7126 7127 This confidential document is the property of Novo Nordisk. No unpublished information contained herein 7128 may be disclosed without prior written approval from Novo Nordisk. Access to this document must be 7129 restricted to relevant parties.

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7130 Liraglutide 7137 7140 Date: 06 March 2012 Novo Nordisk 7131 Trial ID: NN8022-1922 7138 CONFIDENTIAL 7141 Version: 6.0 7132 Revised Protocol - Appendix G 7139 7142 Status: Final 7133 EudraCT No.: 2008-002199-88 7143 Page: 2 of 11 7134 7135 Table of contents 71447136 7145 Page

7146 Table of contents ...... 2 7147 1 Colombia Suicide Severity Rating Scale (C-SSRS), Baseline ...... 3 7148 2 Colombia Suicide Severity Rating Scale (C-SSRS), Since last visit ...... 7 7149 3 Patient Health Questionnaire-9 (PHQ-9) ...... 11

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7150 Liraglutide 7155 7158 Date: 06 March 2012 Novo Nordisk 7151 Trial ID: NN8022-1922 7156 CONFIDENTIAL 7159 Version: 6.0 7152 Revised Protocol - Appendix G 7157 7160 Status: Final 7153 EudraCT No.: 2008-002199-88 7161 Page: 3 of 11 71627154 7163 1 Colombia Suicide Severity Rating Scale (C-SSRS), Baseline 7164

7165

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7166 Liraglutide 7171 7174 Date: 06 March 2012 Novo Nordisk 7167 Trial ID: NN8022-1922 7172 CONFIDENTIAL 7175 Version: 6.0 7168 Revised Protocol - Appendix G 7173 7176 Status: Final 7169 EudraCT No.: 2008-002199-88 7177 Page: 4 of 11 71787170

7179

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7180 Liraglutide 7185 7188 Date: 06 March 2012 Novo Nordisk 7181 Trial ID: NN8022-1922 7186 CONFIDENTIAL 7189 Version: 6.0 7182 Revised Protocol - Appendix G 7187 7190 Status: Final 7183 EudraCT No.: 2008-002199-88 7191 Page: 5 of 11 71927184

7193

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7194 Liraglutide 7199 7202 Date: 06 March 2012 Novo Nordisk 7195 Trial ID: NN8022-1922 7200 CONFIDENTIAL 7203 Version: 6.0 7196 Revised Protocol - Appendix G 7201 7204 Status: Final 7197 EudraCT No.: 2008-002199-88 7205 Page: 6 of 11 72067198

7207

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7208 Liraglutide 7213 7216 Date: 06 March 2012 Novo Nordisk 7209 Trial ID: NN8022-1922 7214 CONFIDENTIAL 7217 Version: 6.0 7210 Revised Protocol - Appendix G 7215 7218 Status: Final 7211 EudraCT No.: 2008-002199-88 7219 Page: 7 of 11 72207212 7221 2 Colombia Suicide Severity Rating Scale (C-SSRS), Since last visit 7222

7223

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7224 Liraglutide 7229 7232 Date: 06 March 2012 Novo Nordisk 7225 Trial ID: NN8022-1922 7230 CONFIDENTIAL 7233 Version: 6.0 7226 Revised Protocol - Appendix G 7231 7234 Status: Final 7227 EudraCT No.: 2008-002199-88 7235 Page: 8 of 11 72367228

7237

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7238 Liraglutide 7243 7246 Date: 06 March 2012 Novo Nordisk 7239 Trial ID: NN8022-1922 7244 CONFIDENTIAL 7247 Version: 6.0 7240 Revised Protocol - Appendix G 7245 7248 Status: Final 7241 EudraCT No.: 2008-002199-88 7249 Page: 9 of 11 72507242

7251

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7252 Liraglutide 7257 7260 Date: 06 March 2012 Novo Nordisk 7253 Trial ID: NN8022-1922 7258 CONFIDENTIAL 7261 Version: 6.0 7254 Revised Protocol - Appendix G 7259 7262 Status: Final 7255 EudraCT No.: 2008-002199-88 7263 Page: 10 of 11 72647256

7265

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7266 Liraglutide 7271 7274 Date: 06 March 2012 Novo Nordisk 7267 Trial ID: NN8022-1922 7272 CONFIDENTIAL 7275 Version: 6.0 7268 Revised Protocol - Appendix G 7273 7276 Status: Final 7269 EudraCT No.: 2008-002199-88 7277 Page: 11 of 11 72787270 7279 3 Patient Health Questionnaire-9 (PHQ-9) 7280

7281

Downloaded From: https://jamanetwork.com/ on 09/26/2021 7287 7296 Liraglutide 7288 7297 Date7302: 06 March 2012 Novo Nordisk Trial ID NN8022-19227289 CONFIDENTIAL7298 Version7303 : 6.0 Protocol - Appendix H7290 7299 Status:7304 Final EudraCT No: 2008-002199-887291 7300 Page:7305 I of 8 7292 7293 7301 7294 Appendix H 7295

Medical Events of Special Interest (MESI)

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7351 Liraglutide 7356 7359 Date: 06 March 2012 Novo Nordisk 7352 Trial ID NN8022-1922 7357 CONFIDENTIAL 7360 Version: 6.0 7353 Protocol - Appendix H 7358 7361 Status: Final 7354 EudraCT No: 2008-002199-88 7362 Page: 2 of 8 73637355 MESIs Definitions Event Calcitonin Adjudication Monitoring Committee Committee (EAC) (CMC) Medication errors concerning The following should be reported: No N/A trial products • administration of wrong drug or adjudication use of wrong device • wrong route of administration, such as intramuscular instead of subcutaneous • administration of a high dose with the intention to cause harm, eg suicide attempt • administration of an accidental overdose, i.e. dose which may lead to significant health consequences, as judged by the Investigator, irrespective of whether the SAE criteria are fulfilled or not Suspected transmission of an Events which may be mediated by No N/A infectious agent via a trial transmission of an infectious agent adjudication product via a trial product (as judged by the Investigator)

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7364 Liraglutide 7369 7372 Date: 06 March 2012 Novo Nordisk 7365 Trial ID NN8022-1922 7370 CONFIDENTIAL 7373 Version: 6.0 7366 Protocol - Appendix H 7371 7374 Status: Final 7367 EudraCT No: 2008-002199-88 7375 Page: 3 of 8 73767368 MESIs Definitions Event Calcitonin Adjudication Monitoring Committee Committee (EAC) (CMC) Death All types of death must be reported: All events will N/A • Cardiovascular death, includes be adjudicated − Sudden cardiac death − Death due to acute myocardial infarction − Death due to heart failure or cardiogenic shock − Death due to stroke − Death due to other cardiovascular causes • Non-cardiovascular death (any death not covered by cardiac death or vascular death) • Undetermined cause of death Acute coronary syndrome All types of myocardial infarction All events will N/A • Myocardial infarction must be reported: be adjudicated (MI) • Acute MI • Hospitalisation for − Spontaneous MI Unstable angina − Percutaneous coronary intervention (PCI) related MI − Coronary artery bypass graft surgery (CABG) related MI • Silent or Prior MI (with or without symptoms) • Re-infarction All events with new onset or worsening unstable angina requiring hospitalisation must be reported. The EAC charter provides further details and definitions relevant to adjudication. Cerebrovascular event Stroke is defined as the rapid onset All events will N/A • Stroke of a new persistent neurological be adjudicated • Transient ischemic deficit attributed to an obstruction in attack (TIA) cerebral blood flow and/or cerebral haemorrhage with no apparent non-

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7377 Liraglutide 7382 7385 Date: 06 March 2012 Novo Nordisk 7378 Trial ID NN8022-1922 7383 CONFIDENTIAL 7386 Version: 6.0 7379 Protocol - Appendix H 7384 7387 Status: Final 7380 EudraCT No: 2008-002199-88 7388 Page: 4 of 8 73897381 MESIs Definitions Event Calcitonin Adjudication Monitoring Committee Committee (EAC) (CMC) vascular cause (eg, trauma, tumor, or infection).

TIA is defined as a transient (<24 hours) episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction Heart failure Clinical manifestations of new All heart N/A episode or worsening of existing failure heart failure. requiring hospitalisation defined as an admission to an inpatient unit or a visit to an emergency department that results in at least a 12 hour stay will be adjudicated Stent thrombosis Following should be reported: To be • Definite Stent Thrombosis adjudication • Probable Stent Thrombosis • Possible Stent Thrombosis Revascularisation procedure A coronary revascularisation Only coronary N/A procedure is defined as either will be CABG or a PCI (eg, angioplasty, adjudicated coronary stenting).

A peripheral revascularisation procedure is defined as vascular surgery or percutaneous intervention. Hospitalisation for Cardiac Specifically, atrial fibrillation, atrial No N/A Arrhythmia flutter, ventricular tachycardia, adjudication ventricular fibrillation, torsade de

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7390 Liraglutide 7395 7398 Date: 06 March 2012 Novo Nordisk 7391 Trial ID NN8022-1922 7396 CONFIDENTIAL 7399 Version: 6.0 7392 Protocol - Appendix H 7397 7400 Status: Final 7393 EudraCT No: 2008-002199-88 7401 Page: 5 of 8 74027394 MESIs Definitions Event Calcitonin Adjudication Monitoring Committee Committee (EAC) (CMC) pointes, second degree heart block type 2, third degree heart block, and symptomatic bradycardia requiring pacemaker placement Pancreatitis or Two of following diagnostic criteria To be N/A acute, severe and persistent fulfilling the diagnosis of acute adjudicated abdominal pain leading to a pancreatitis: suspicion of pancreatitis • severe acute upper abdominal pain • elevated blood levels of pancreatic enzymes (lipase, amylase) 3xUNR • characteristic imaging finding (ultrasound, computerised axial tomography (CT), magnetic resonance imaging (MRI))

Chronic pancreatitis will be defined by characteristic imaging finding (ultrasound, CT, MRI) with abnormal pancreatic function tests or characteristic histological findings Acute gallstone disease Gallbladder disease including No (biliary colic or acute biliary colic, symptomatic adjudication cholecystitis) cholelithiasis, cholecystitis. Elevated lipase or amylase ≥ No 3xUNR Adjudication Neoplasm All types of neoplasms must be To be N/A reported including: adjudicated

• Malign neoplasm • In situ neoplasm • Benign neoplasm • Neoplasms of uncertain or unknown behaviour Thyroid disease All disorders of thyroid gland must Only thyroid Can be

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7403 Liraglutide 7408 7411 Date: 06 March 2012 Novo Nordisk 7404 Trial ID NN8022-1922 7409 CONFIDENTIAL 7412 Version: 6.0 7405 Protocol - Appendix H 7410 7413 Status: Final 7406 EudraCT No: 2008-002199-88 7414 Page: 6 of 8 74157407 MESIs Definitions Event Calcitonin Adjudication Monitoring Committee Committee (EAC) (CMC) be reported. disorders identified by requiring the CMC or thyroidectomy by the will be Investigator adjudicated Any confirmed episode of All confirmed episodes of values ≥ No All calcitonin calcitonin value ≥ 20 ng/L, if 20 ng/L. adjudication values ≥ 10 not already reported as an ng/L will be ongoing MESI evaluated by the CMC Acute renal failure Acute renal failure, insufficiency or No N/A clinically significant paraclinical adjudication abnormalities indicating a decrease in renal function must be reported Severe hypoglycaemic event An episode requiring assistance of No N/A another person to actively adjudication administer carbohydrate, glucagon, or other resuscitative actions Immunogenicity event All events suspected to involve an No N/A (allergic reactions including immune reaction to trial product adjudication allergic reactions at injection must be reported. sites, and immune-complex disease Events to be reported can be defined according to the below:

A) Immediate hypersensitivity reactions

Typically occurring within minutes after administration of the antigen. Clinical symptoms include (but are not limited to):

• Urticaria (pruritic wheals with surrounding erythema, involving superficial layers of the skin). This includes local allergic reactions at

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7416 Liraglutide 7421 7424 Date: 06 March 2012 Novo Nordisk 7417 Trial ID NN8022-1922 7422 CONFIDENTIAL 7425 Version: 6.0 7418 Protocol - Appendix H 7423 7426 Status: Final 7419 EudraCT No: 2008-002199-88 7427 Page: 7 of 8 74287420 MESIs Definitions Event Calcitonin Adjudication Monitoring Committee Committee (EAC) (CMC) injection site

• Angioedema (Swelling of the affected area of the skin, involving deep layers of the skin and the subcutis; painful rather than pruritic)

• Allergic rhinitis (with symptoms like sneezing, itching, nasal congestion, itchy and watery eyes)

• Exacerbation of pre-existing or de novo development of allergic asthma (acute bronchoconstriction with symptoms like chest tightness, shortness of breath, wheezing and cough)

• Systemic anaphylaxis (typically presented as generalised skin lesions/pruritus, hypotension, upper/lower respiratory tract swelling/constriction, shock)

B) Delayed Hypersensitivity Reactions

Typically occurring 48 to 72 hours after exposure to the antigen and manifested by various types of skin rashes with or without pruritus

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7429 Liraglutide 7434 7437 Date: 06 March 2012 Novo Nordisk 7430 Trial ID NN8022-1922 7435 CONFIDENTIAL 7438 Version: 6.0 7431 Protocol - Appendix H 7436 7439 Status: Final 7432 EudraCT No: 2008-002199-88 7440 Page: 8 of 8 74417433 MESIs Definitions Event Calcitonin Adjudication Monitoring Committee Committee (EAC) (CMC) C) De novo development or exacerbation of pre-existing immune complex disease. Most frequent clinical syndromes include:

• Lupus erythematosus • Vasculitis syndromes • Non-viral hepatitis • Pneumonitis • Arthritis • Glomerulonephritis

D) Anti-liraglutide antibody formation:

• Detected based on laboratory assessment of antibody titres undertaken due to suspected immunological reaction to trial product

• Detected based on suspicion of neutralising effect of antibodies, i.e. in case of unexplained rapid deterioration of glycaemic control Adverse events leading to If not any of the mentioned MESIs No N/A withdrawal adjudication Psychiatric Disorders All Mental and Behavioural No N/A Disorders included in ICD-10 or adjudication DSM-IV classification systems, included those diagnosed by C- SSRS or PHQ-9 score must be reported

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7442 Liraglutide 7447 7450 Date: 06 March 2012 Novo Nordisk 7443 Trial ID: NN8022-1922 7448 CONFIDENTIAL 7451 Version: 6.0 7444 Protocol - Appendix I 7449 7452 Status: Final 7445 EudraCT No.: 2008-002199-88 7453 Page: 1 of 7 74547446 7455 7456 Appendix I 7457 7458 7459 7460 7461 7462 7463 7464 7465 7466 7467 Calcitonin Monitoring Committee - 7468 Screening of Calcitonin (CT) Levels 7469 7470 7471 7472 7473 7474 7475 7476 7477 7478 7479 7480 7481 7482 7483 7484 7485

7486 This confidential document is the property of Novo Nordisk. No unpublished information contained herein 7487 may be disclosed without prior written approval from Novo Nordisk. Access to this document must be 7488 restricted to relevant parties.

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7489 Liraglutide 7496 7499 Date: 06 March 2012 Novo Nordisk 7490 Trial ID: NN8022-1922 7497 CONFIDENTIAL 7500 Version: 6.0 7491 Protocol - Appendix I 7498 7501 Status: Final 7492 EudraCT No.: 2008-002199-88 7502 Page: 2 of 7 7493 7494 Table of contents 75037495 7504 Page

7505 Table of contents ...... 2 7506 1 Background ...... 3 7507 2 Procedure ...... 4 7508 3 Evaluation and follow-up ...... 5 7509 3.1 CT ≥ 100 ng/l ...... 5 7510 3.2 CT ≥ 50 ng/l and < 100 ng/l ...... 5 7511 3.3 CT ≥ 20 ng/l and <50 ng/l ...... 5 7512 3.4 CT ≥ 10 ng/l and < 20 ng/l ...... 6 7513 4 References ...... 7

Downloaded From: https://jamanetwork.com/ on 09/26/2021 7522 7526 Liraglutide 7523 7527 Date7532: 06 March 2012 Novo Nordisk Trial ID: NN8022- I 9227524 CONFIDENTIAL7528 Version7533 : 6.0 Protocol - Appendix l 7525 7529 Status7534: Final EudraCT No.: 2008-002199-88 7530 Page:7535 3 of 7 7531 1 Background

The approach that follows was developed in collaboration with two leading clinical thyroid experts:

7542 and represents a synthesis of the medical literature and extensive personal experience.

All previous calcitonin screening studies in the literature have been performed in patients with thyroid nodular disease. The nodular status of the subjects in the current trial will mostly be unknown. Nevertheless, for the purpose of follow-up, it will be assumed that the same calcitonin cut-offs will apply. Up to 50% of subjects in the age group to be studied in the current trial will have clinical or subclinical thyroid nodules1the majority of which will be clinically apparent. Subjects with a known personal or family history of medullar thyroid cancer (MTC) or multiple endocrine neoplasia type 2 (MEN 2) and subjects with a screening calcitonin of 2: 50ng/I will be excluded from the trial.

Downloaded From: https://jamanetwork.com/ on 09/26/2021 7559 7563 Liraglutide 7560 7564 Date7569 : 06 March 2012 Novo Nordisk Trial ID: NN8022-19227561 CONFIDE7565NTIAL V7570ersion : 6.0 Protocol - Appendix I 7562 7566 Statu7571s: Final EudraCT No.: 2008-002199-88 7567 Pag7572e: 4 of 7 7568 2 Procedure

A blood sample will be drawn at trial visits 1, 2, 4, 7, 10, 13, 16, 17 and 20 for measurement of calcitonin.

Monitoring of calcitonin at regular intervals will be implemented in the trial and performed by an independent Calcitonin Monitoring Committee (CMC) of thyroid experts. The CMC will be blinded to trial treatment. The CMC may require additional information from the site, require more frequent calcitonin measurements or will provide Investigators with recommendations as to individual follow-up (i.e. laboratory tests and/or other relevant diagnostic procedures) in subjects with elevated calcitonin levels.

All calcitonin values 10 ng/I will be flagged on the laboratory reports from the central laboratory and will be submitted to the CMC, together with relevant supplementary data, i.e. subject's demographics, diabetes history, concomitant medical history, concomitant medications, smoking status, results of other laboratory tests conducted as part of trial procedures as well as events reported during the trial.

For subjects with a calcitonin value 20 ng/l (from Visit 2 and onwards) a repeat measurement of calcitonin must be done preferably within four weeks, and the event "elevated calcitonin" should be reported as a MESI.

In cases where the follow-up action recommended by the CMC, based on the elevated calcitonin levels, results in establishing the presence of a thyroid disease, the thyroid disease should be reported as a new MESI.

Downloaded From: https://jamanetwork.com/ on 09/26/2021 7602 7606 Liraglutide 7603 7607 Date7612: 06 March 2012 Novo Nordisk Trial ID:NN8022-l 9227604 CON FIDENTI7608AL Ver7613sion : 6.0 Protocol - Appendix I7605 7609 Statu7614s: Final EudraCT No .: 2008-002199-88 7610 Page:7615 5 of ? 7611 3 Evaluation and follow-up

The summary for a rationale for the use of specific calcitonin (CT) values to trigger medical evaluation and overview of the algorithm to be followed by the CMC is provided below:

3.1 CT 100 ng/l These values were found in 0.15% of the population published by Costante et al;, and in one subject (on active com parator) in the liraglutide development program. For a baseline (pre-randomisation) or post-randomisation value of 2: I 00 ng/I, the subject should be assumed to have significant C-cell disease and a high likelihood of having medullary carcinoma of the thyroid. Diagnostic evaluation should consist of thyroid ultrasound, fine needle aspiration of any nodules > 1 cm and potentially surgery with neck dissection . Fam ily history of MTC or MEN2 should be evoked and a rearranged during transfection (RET) proto-oncogene analysis should be undertaken.

3.2 CT 50 ng/l and < 100 ng/1 These values were found in 0.18% of the population published by Costante et alJ. If baseline values are in this range subjects should have a repeat measurement of calcitonin to be reviewed by the CMC for recommendation of diagnostic evaluation which will likely include ultrasound examination. Ifthere is no contraindication, subjects should undergo a pentagastrin stimulation test (EU and Europe) [NB: pentagastrin is contraindicated in subjects with known coronary artery disease].

Ifsubjects develop a calcitoni n value within this specified range post-randomisation, specific medical evaluation will be indicated by the CMC including a thyroid ultrasound and a pentagastrin stimulation test if available and if not contraindicated . Those subjects with positive pentagastrin stimulation tests will be considered to undergo surgery. In the US where pentagastrin is not available, thyroid ultrasound and fine needle aspiration biopsy may add important clinical information informing the need for surgery. Further, all individual subject data will be reviewed by the CMC that will make diagnostic and therapeutic recommendations to the Investigator of that subject.

3.3 CT 20 ng/I and <50 ng/l These values will be found in up to I % of subjects. At th is level of calcitonin based on data from Costante et alJ, the predictive value of the level itself for clinically significant C-cell disease begins to fall. However, up to 25% of these subjects have a positive pentagastrin stimulation test. The likelihood of harboring a medullary carcinoma > 1 cm with calcitonin in this range is extremely low.

Downloaded From: https://jamanetwork.com/ on 09/26/2021 7660 7664 Liraglutide 7661 7665 Dat7670e: 06 March 2012 Novo Nordisk Trial ID: NN8022- I 9227662 CONFIDENTI7666AL V7671ersion : 6.0 Protocol - Appendix I 7663 7667 Statu7672s: Final EudraCT No.: 2008-002199-88 7668 Page7673: 6 of 7 7669 Subjects with calcitonin levels in this range at baseline should have the measurement repeated for confirmation. This cohort will provide valuable insights into any potential effect that liraglutide may have on calcitonin levels in subjects with values above the normal range at basel ine.

Ifthe repeat value is 50 ng/l or if any subsequent value measured during the trial exceeds 50 ng/l then the subject moves into the evaluation category listed above for values 50 ng/l.

The decision to proceed or not to proceed with surgery in subjects without cytological confirmation of disease should be made by the attending physician in consultation with subject, based on recommendation from the CMC.

3.4 CT 2: 10 ng/I and < 20 ng/I These values may be found in - 2.5 to 4% of the trial population. Costante et ali had 216 patients in this category. 11216 had a subsequent basal (unstimulated) CT of 33 ng/I, and had C-cell hyperplasia at surgery, a lesion of unknown clinical significance. Two other studies used a cutoff of CT > I 0 ng/I to screen for C cell disease, but they do not provide sufficient information on patients with basal CT > I 0 ng/I and <20 ng/I to allow conclusions.H

In cases of calcitonin values of I 0 ng/l and <20 ng/I the Investigator should evaluate confounding factors and repeat calcitonin at next protocol scheduled calcitonin visit.

Specific history should be elicited to identify these confounders. Confounders: i.e. drugs (H2 blockers, Proton Pump Inhibitors (PPis)), other causes of hypergastrinemia (e.g. pernicious anemia), smoking, autoimmune thyroiditis, presence of heterophilic antibodies should be factored into the interpretation of the values on a case-by-case basis. Ifdrugs can be discontinued safely, basal calcitonin can be repeated after a washout period. Gastrin levels return to the normal range by - l 0 days after stopping PPis.2

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7708 06 March 2012 Novo Nordisk Liraglutide 7709 7712 7717Date: Trial ID: NN8022-19227710 CONFIDENTIAL7713 7718Version: 6.0 Protocol - Appendix I 7711 7714 7719Status: Final EudraCT No.: 2008-002199-88 7715 7720Page: 7 of 7 7716 4 References

Mazzaferri EL. Management of a solitary thyroid nodule. N Engl J Med 1993; 328(8):553-559 .

2 Costante G, Meringolo D, Durante C, Bianchi D, Nocera M, Tumino S et al. Predictive value of serum calcitonin levels for preoperative diagnosis of medullary thyroid carcinoma in a cohort of 5817 consecutive patients with thyroid nodules. Journal of Clinical Endocrinology and Metabolism 2007; 92(2):450-455.

3 Scheuba C, Kaserer K, Moritz A, Drosten R, Vierhapper H, Bieglmayer C et al. Sporadic hypercalcitoninemia: clinical and therapeutic consequences. Endocrine-Related Cancer 2009; 16(1):243-253.

4 Verga U, Ferrero S, Vicentini L, Brambilla T, Cirella V, Muzza M et al. Histopathological and molecular studies in patients with goiter and hypercalcitoninemia: reactive or neoplastic C-cell hyperplasia? Endocr Relat Cancer 2007; 14(2):393-403.

5 Klinkenberg-Knot EC, Jansen JB, Lamers CB, Nelis F, Meuwissen SG. Temporary cessation of long-term mai ntenance treatment with omeprazole in patients with H2-receptor-antagonist-resistant reflux oesophagitis. Effects on symptoms, endoscopy, serum gastrin, and gastric acid output. Scand J Gastroenterol 1990; 25( 11):1144- 1150.

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