Statistical Analysis Plan The PLasma for Alzheimer SymptoM Amelioration (PLASMA) Study (PLASMA)

1 1 Abbreviations and Definitions AE Adverse Event CRF Case Report Form CTCAE Common Terminology Criteria for Adverse Events IMP Investigational Medical Product SAP Statistical Analysis Plan

2 2 Introduction

3 2.1 Preface 4 The Plasma for Alzheimer SymptoM Amelioration (PLASMA) Study: Intravenously- 5 Administered Plasma from Young Donors for Treatment of Mild-To-Moderate 6 Alzheimer’s Disease

7 2.2 Purpose of the analyses 8 These analyses will assess 1) number of subjects with adverse events as a 9 measure of safety and tolerability and number of subjects who comply with 10 the research protocol as a measure of feasibility 2) the neuropsychological, 11 functional and neuropsychiatric outcomes 3) other outcomes such as 12 functional connectivity assessed by resting state functional MRI, 13 compositional assessment of plasma, in vivo assessment of plasma 14 samples, and differential effect of outcomes related to ApoE genotype .

15 3 Study Objectives and Endpoints

16 3.1 Study Objectives 17 The objective of the study is to determine the safety and tolerability and feasibility 18 of once per week infusion of young plasma into this patient population and with 19 experimental endpoints to assess efficacy in cognition, behaviour and mood.

20 3.2 Endpoints 21 The primary outcome measure is the number of subjects with AEs as a measure of 22 safety and tolerability, and number of subjects who comply with the research 23 protocol as a measure of feasibility. Changes from baseline (as derived variables) in

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24 laboratory parameters (cbc, chemistry, liver function), vital signs, EKG, and physical 25 examination.

26 The secondary outcome measures are:

27 1) Change on the 13-item ADAS-Cog

28 2) Change on the Trail Making Test (TMT); Parts A and B

29 3) Change on the Clinical Dementia Rating scale Sum of Boxes (CDR-SB)

30 4) Change on the Functional Activities Questionnaire (FAQ)

31 5) Change on the Alzheimer’s Disease Cooperative Study Activities of Daily 32 Living Inventory in mild cognitive impairment (ADCS-MCI-ADL)

33 6) Change on the Geriatric Depression Scale (GDS)

34 7) Change on the Neuropsychiatric Inventory Questionnaire (NPI-Q)

35 The other outcome measures are:

36 1) Change in functional connectivity in the default mode network as assessed 37 by resting state functional MRI

38 2) Compositional assessment of plasma using in vitro analytical methods. The 39 goal is to assess plasma components that might be associated with aging 40 and/or Alzheimer’s disease. These studies will focus initially on known 41 proteins (e.g. eotaxin, B2M, amyloid beta) but may extend to full plasma 42 proteome and other component (e.g. metabolites, lipids, nucleic acids) 43 profiling in the future.

44 3) In vivo assessment of plasma samples to determine their potential 45 histological effects on the hippocampus and their potential behavioral effects 46 in animal models of cognition.

47 4) Differential effect of therapy on above outcomes as a function of ApoE 48 genotype

49 3.3 Derived variables 50 Derived Boolean variables will be created from metabolic and hematologic labs as 1 51 or 0 indicating if there was a change from baseline. An AE is change in vital signs

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52 will be as follows: temperature >38.5 or <36.0 C, SBP >180 or <100 or 20% change 53 from baseline, DBP >110 or <40 or 20% change from baseline, HR >100 or <50 or 54 20% change from baseline, RR >24 or <10 or 20% change from baseline.

55 4 Study Methods

56 4.1 General Study Design and Plan 57 (ICH E3;9)

58  The study began in September 2014 as a double blind, cross 59 over, placebo (saline) controlled study. It was amended in October 2015 60 to a single arm open label study. After the amendment the 61 randomization assignment for all subjects in the original protocol 62 continued to be blinded to the investigator and 63 raters. Nine subjects were enrolled and treated under the double blind 64 crossover protocol with four weeks of weekly infusions of ~250mL of 65 plasma from 18-30 year-old male donors, followed by a 6-week washout 66 and then crossover to four weeks of weekly infusion of the alternate 67 treatment. An additional 9 subjects were enrolled and treated under 68 the open label amendment for four weeks with once weekly infusions of 69 ~250mL of plasma from male donors aged 18-30. 70  This is a randomized, blinded, cross-over study to determine the safety 71 and tolerability of once per week infusion of young male donor plasma in 72 subjects with AD. Starting within 2 weeks of Baseline Assessment: 73 o Blood draw: confirmation of ABO/Rh typing prior to first plasma 74 administration. 75 o Administer test agent (Young Male Donor Plasma or placebo saline) 76 once weekly for 4 weeks (+ day for each infusion), followed by 77 crossover to other test agent (placebo saline or Young Male Donor 78 Plasma) 79 o Concomitant medication review 80 o AEs review 81 o Journal review 82  Level and method of blinding: double-blind. 83  Method of treatment assignment: randomization 1:1.

84 85 o SCHEDULE OF EVENTS (09/2014)

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Screening Block 1a Block 2b Close

Visit #: 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Week #: –2 0 1c 2c 3c 3d 9e 9f 10c 11c 12c 12d 18f

Informed Consent X

MMSE X

Physical/Neurological X X X X X Exam

Medication Review X X X X X

Adverse Symptom X X X X Review

Journal Review X X X X

Randomization X

ADAS-Cog-13 X X X X X

Trail-Making Test X X X X X

CDR X X X X X

FAQ X X X X X

ADCS-MCI-ADL X X X X X

GDS X X X X X

NPI-Q X X X X X

Blood draw Xg Xh Xi Xh Xh Xi Xh Xh

MRI X Xj Xj

ECG X

Infusion X X X X X X X X

86  aRandomization (1:1) of test agent to plasma or placebo prior to visit #3. 87  bTest agent assignment switches 88  c± 1 day, timed from the first infusion of the current block 89  d1–2 days after the last infusion 90  e1–2 days prior to visit #9 91  f± 3 days, timed from the day of the last infusion of the last block 92  gscreening laboratory tests to include: ABO/RH typing, infectious disease 93 screening (Human Immunodeficiency Virus, Hepatitus B, Hepatitus C), Page 4 of 29

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94 coagulation (Prothrombin Time, Partial Thromboplastin Time), urine pregnancy (if 95 applicable), metabolic and hematologic panels, blood for central banking 96  hmetabolic and hemtologic panels for safety monitoring 97  iconfirmation of ABO/RH type prior to plasma administration 98  jwithin 7 days after the last infusion, but ideally on the same day as the 99 neuropsychological assessment 100 Schedule of Events (10/15/2016) 101

Screening Infusions Close Visits Visit #: 1 2 3 4 5 6 7 8 a a a b c Week #: –2 0 1 2 3 3 7-9 Informed Consent X MMSE X Physical/Neurological X X X

EConcomitantxam Medication X X X X X X X X Review Adverse Reaction X X X X X X

RJouevrinaewl Review X X X X X X ADAS-Cog-13 X X X Trail-Making Test X X X

CDR X X X FAQ X X X ADCS-MCI-ADL X X X GDS X X X NPI-Q X X X Digit Span X X X X X X X X Blood draw Xd Xe,f Xe Xe g MRI X X ECG X Infusion Xf Xf Xf Xf 102 

103  a ± 1 day, timed from the first infusion

104  b 1-3 days after the last infusion

105  c 4-6 weeks after the last infusion d 106  screening laboratory tests to include: ABO/RH typing, infectious 107 disease screening (Human Immunodeficiency Virus, Hepatitis B, Hepatitis 108 C), coagulation (Prothrombin Time, Partial Thromboplastin Time), urine

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109 pregnancy (if applicable), metabolic and hematologic panels, blood for 110 central banking e 111  metabolic and hematologic panels for safety monitoring f 112  confirmation of ABO/RH type prior to plasma administration

113  gwithin 7 days of last infusion, but ideally on the same day as the 114 neuropsychological assessments

115 4.2 Equivalence or Non-Inferiority Studies 116 (ICH E3; 9.2, 9.7.1, 11.4.2.7. ICH E9; 3.3.2)

117 Not Applicable

118 4.3 Inclusion-Exclusion Criteria and General Study Population 119 (ICH E3;9.3. ICH E9;2.2.1)

120 4.3.1 Inclusion Criteria

121 Subjects are eligible for inclusion into the study if they met each of the following 122 criteria:

123  Aged 50-90

124  Diagnosis of probable Alzheimer's disease (NIA-AA criteria)

125  Mini-Mental State Examination (MMSE) score 12-24

126  Availability of a study partner who knows the patient well and is willing to 127 accompany the subject to all trial visits, to participate in questionnaires and to 128 complete daily journal assessments

129 4.3.2 Exclusion Criteria

130 Subjects are excluded from the study if they meet any of the following criteria:

131  Pregnancy or unwilling to use adequate birth control method for duration of and 132 6 months beyond study participation

133  Positive for Hepatitis B, Hepatitis C or human immunodeficiency virus (HIV) at 134 screening

135  Any other condition or situation that the investigator believes may interfere with 136 the safety of the subject or the intent and conduct of the study

137  Related to medical history:

138  Stroke

139  Anaphylaxis

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140  Prior adverse reaction to any human blood product

141  Any history of a blood coagulation disorder or hypercoagulability

142  Congestive heart failure

143  Uncontrolled hypertension

144  Renal failure

145  Prior intolerance to intravenous fluids

146  Recent history of uncontrolled atrial fibrillation

147  Immunoglobulin A deficiency (by history)

148  Related to medications or other treatments:

149  Any concurrent use of an anticoagulant therapy. Antiplatelet drugs (e.g., 150 aspirin or clopidogrel) are acceptable.

151  Initiation or change in the dosage of a cholinesterase inhibitor or memantine 152 during the trial. A participant already on a cholinesterase inhibitor or 153 memantine must be on a stable dose for at least one month prior to 154 Screening.

155  Concurrent participation in another treatment trial for Alzheimer’s disease. If 156 there was prior participation, the last dose of the investigational agent must 157 have been at least 6 months prior to Screening.

158  Treatment with any human blood product, including intravenous 159 immunoglobulin, during the 6 months prior to Screening or during the trial.

160  Concurrent daily treatment with benzodiazepines, typical or atypical 161 antipsychotics, long-acting opioids, or other medications that, in the 162 investigator’s opinion, interfere with cognition. Intermittent treatment with 163 short-acting benzodiazepines or atypical antipsychotics may be permitted, 164 provided that no dose is administered within the 72 hours preceding any 165 cognitive assessment.

166  Related to magnetic resonance imaging (MRI):

167  Claustrophobia

168  Any metallic surgical implant, like a pacemaker or clip that is incompatible 169 with 3-Telsa MRI (3T MRI).

170 Note: Certain metallic implants like joint replacements may be permitted, provided 171 that specific manufacturer specifications are available and that the device is known 172 to be safe for 3T MRI.

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173 4.4 Randomization and Blinding 174 The study coordinator, prior to dosing, receives a request form the PI to randomize 175 the subject. The request is sent to the regulatory coordinator to randomize the 176 subject. The regulatory coordinator accesses the randomization envelope and 177 randomly selects a slip of paper that contains treatment assignment group (group A 178 = saline, group B = plasma) and hands the assignment to the study coordinator. 179 The study coordinator requests the plasma from the Stanford Blood Bank or saline 180 for each subject). On the day of dosing the study coordinator sends the order to the 181 transfusion unit specifying treatment allocation. To ensure the subject remains 182 blinded to treatment assignment IV tubing is wrapped in brown plastic “sham” to 183 ensure blinding. For saline administration, the IV tubing is maintained by the study 184 coordinator for 45 minutes prior to administration. After the protocol change, study 185 coordinator sent the order to the transfusion unit for blood. No sham was required 186 as all participants received plasma.

187 Primary Endpoints

188 1. Safety and tolerability: The number of patients with adverse events will be 189 tallied. Changes from baseline in clinical laboratory parameters (CBC, 190 chemistry, liver function), vital signs, EKG, and physical examination.

191 2. Feasibility: The number of patients who comply with the research protocol 192 (completed all visits) will be tallied.

193 Secondary Endpoints

194 1. Cognition

195 a. ADAS-Cog-13. The ADAS-Cog-13 provides a global measure of 196 cognition, which is the Total Score of 85 points. Higher scores reflect 197 greater cognitive impairment. Individual cognitive domains include 198 memory, language, praxis, orientation, and number cancellation. 199 Please see below for specific domains.

200 i. Word Recall—Trials 1 to 3, 10 items each. Total = Mean 201 Number of Incorrect Items (0-10)

202 ii. Commands—5 items. Total = Number Incorrect (0-5)

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203 iii. Constructional Praxis—4 items. Total = Number Incorrect (0-5 204 points, 5 if no figures drawn (or scribbles, parts of form), 1-4 = 205 number of incorrect drawings, 0 if all 4 drawings correct)

206 iv. Delayed Word Recall—10 items. Total = Number Incorrect (0- 207 10).

208 v. Naming Objects and Fingers—17 items. Total = Number 209 Incorrect (0-5 points, 0 = 0-2 items named incorrectly, 1 = 3- 210 5 items named incorrectly, 2 = 6-8 items named incorrectly, 3 211 = 9-11 items named incorrectly, 4 = 12-14 items named 212 incorrectly, 5 = 15-17 items named incorrectly).

213 vi. Ideational Praxis—5 items. Total = Number Incorrect (0-5).

214 vii. Orientation—8 items. Total = Number Incorrect (0-8).

215 viii. Word Recognition—24 items. Number Incorrect (0-12 X .05).

216 ix. Remembering Test Instructions—0-5 points. (0 = patient never 217 needs extra reminders or instructions, 1 = very mild, forgets 218 once, 2 = mild, must be reminded twice, 3 = moderate, must 219 be reminded 3 or 4 times, 4 = moderately severe, must be 220 reminded 5 or 6 times, 5 = severe, must be reminded 7 or 221 more times).

222 x. Spoken Language Ability—0-5 points. (0 = no impairment, no 223 instance of lack of understandability, 1 = very mild, one 224 instance of lack of understandability, 2 = mild, subject has 225 difficulty less than 25% of the time, 3 = moderately, subject has 226 difficulty 25-50% of the time, 4 = moderately severe, subject 227 has difficulty more than 50% of the time, 5 = severe, one or two 228 word utterances, fluent, but empty speech, mute.

229 xi. Word Finding Difficulty—0-5 points. (0 = no impairment in 230 finding desired word in spontaneous speech, 1 = very mild, 1-2 231 instances, not clinically significant, 2 = mild, noticeable 232 circumlocution or synonym substitution, 3 = moderate, loss of 233 words without compensation on occasion, 4 = moderately

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234 severe, frequent loss of words without compensation, 5 = 235 severe, nearly total loss of content words; speech sounds 236 empty, 1-2 word utterances).

237 xii. Comprehension of Spoken Language—0-5 points. (0 = no 238 impairment, subject understands speech, 1 = very mild, 1 or 2 239 instances of misunderstanding, 2 = mild, 3-5 instances of 240 misunderstanding, 3 = moderately, requires several repetitions 241 and rephrasing, 4 = moderately severe, subject only 242 occasionally responds correctly, i.e., to yes-no questions, 5 = 243 severe, subject rarely responds to questions appropriately, not 244 due to poverty of speech).

245 xiii. Number Cancellation—0-5 points. (0 = Final Number 246 Cancellation score > 23, 1 = Final Cancellation score 19-22, 2 247 = Final Number Cancellation score 13-17, 3 = Final 248 Cancellation score 9-12, 4 = Final Number Cancellation score 249 5-8, 5 = Final Number Cancellation score 0-4).

250 b. Trail Making Test. The Trail Making Test consists of two parts. Part A 251 is a measure of processing speed and Part B is a measure of executive 252 functioning. In the first part, the targets are all numbers (1, 2, 3, etc.) 253 and the test taker needs to connect them in sequential order. In the 254 second part, the subject alternates between numbers and letters (1, A, 255 2, B, etc.). If the subject makes an error, the test administrator 256 corrects them before the subject moves on to the next circle. The 257 subject is requested to finish both parts as quickly as possible. A 258 higher score indicates greater impairment. 259 i. Part A—Total Time = 0-180 seconds, Total Errors = Sequencing 260 Errors + Incomplete Errors. Sequencing Errors = 0-24, 261 Incomplete Errors = 0-24 262 ii. Part B—Total Time = 0-300 seconds, Total Errors = Sequencing 263 Errors + Set-shifting Errors + Incomplete Errors. Sequencing 264 Errors = 0-24, Set-shifting Errors = 0-24, Incomplete Errors = 265 0-24. 266 2. Functional Abilities

267 a. Functional Activities Questionnaire (FAQ). The FAQ measures 268 instrumental activities of daily living. There are 10 items that the 269 informant answers. Total Score= 0-30. There are 10 items that are Page 10 of 29

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270 scored from 0-3. Dependent = 3, Requires assistance = 2, Has 271 difficulty but does by self = 1, Normal = 0, Never did [the activity] but 272 could do now = 0, Never did and would have difficulty now = 1. A 273 higher score indicates greater functional impairment.

274 b. Alzheimer’s Disease Cooperative Study Activities of Daily Living 275 Inventory in Mild Cognitive Impairment (ADCS-MCI-ADL). The ADCS- 276 MCI-ADL is an instrument used to assess the competence of 277 performing basic and instrumental activities of daily living. The 278 information is asked to rate the patient on the prior 4 weeks. There 279 are 18 questions. Total Score = 0-53. A higher score indicates greater 280 functional ability.

281 c. Clinical Dementia Rating Sum of Boxes (CDR-SB).

282 The CDR-SB is used in persons with AD to stage dementia. It is a five- 283 point scale in which CDR-0 connotes no cognitive impairment. The 284 informant is asked to rate the patient. Total Score = 0 to 18.0. 0 = 285 Normal. 0.5 to 4.0 = Questionable cognitive impairment. Within the 286 category of questionable cognitive, 0.5 to 2.5 = Questionable 287 impairment and 3.0 to 4.0 = Very mild dementia. 4.5 to 9.0 = Mild 288 dementia. 9.5 to 15.5 = Moderate dementia. 16.0 to 18.0 = Severe 289 dementia.

290 3. Mood/Behavior

291 a. Geriatric Depression Scale-Short Form (GDS). The GDS measures level 292 of depression over the past one week. There are 15 items answered by 293 the participant. Total Score = 0-15; 15 items that are scored from 0- 294 1. A higher score indicates a greater level of depression.

295 b. Neuropsychiatric Inventory (NPI-Q). The NPI-Q is comprised of 12 296 items assessing 12 domains of neuropsychiatric symptoms. The 297 informant indicates whether each symptom is present. For each “yes” 298 response, the informant is then asked to rate the frequency of the 299 symptom (1 = Rarely, less than once per week, 2 = Sometimes, about 300 once per week, 3 = Often, several times per week but less than every 301 day, 4 = Very often, once or more per day), the severity of the

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302 symptom (1 = Mild, 2 = Moderate, 3 = Severe) and the distress it 303 causes the informant (0 = Not at all, 1 = Minimally, 2 = Mildly, 3 = 304 Moderately, 4 = Severely, 5 = Very Severely or Extremely). This results 305 in 3 scores, Frequency Total = 1-4 (X 12 questions = max of 48), 306 Severity Total = 1-3 (X 12 questions = max of 36) and Distress Total 307 = 0-5 (X 12 questions = max of 60). A higher score indicates greater 308 frequency, severity and distress of the neuropsychiatric symptom.

309 5 Sample Size

310 5.1 Under the original guidelines for the study, nine subjects were planned to be 311 enrolled and treated under the randomized, double blind, crossover protocol 312 with four weeks of weekly infusions of ~250mL of plasma from 18-30 year- 313 old male donors or 250ml of saline, followed by a 6-week washout and then 314 crossover to four weeks of weekly infusion of the alternate treatment.

315 5.2 The study protocol was changed in October 2015. The randomized, double 316 blind crossover protocol was discontinued. An additional 9 subjects were 317 planned to be enrolled and treated under the open label amendment for four 318 weeks with once weekly infusions of ~250mL of plasma from male donors 319 aged 18-30.

320 6 Statistical Methods

321 6.1 Primary Endpoints 322 Safety results will be summarized by the number of treatment emergent 323 adverse events, proportion of patients experiencing the adverse events, and 324 the compliance rate. Different types of adverse events will be tabulated. 325 Measurements from laboratory test and physical examination will be compared 326 between baseline and 4 week using paired nonparametric rank test.

327 The effect of ApoE -4 status on primary endpoints will be examined. 328 Aforementioned analysis will be repeated within subgroups according to APoE 329 -4 status. We will compare the average number of treatment emergent 330 adverse events, proportion of patients experiencing the adverse events, the 331 compliance rate and 4-week change in laboratory test, EKG, and physical

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332 examination between carrier and no-carrier and between heterozygote carrier 333 and homozygote carrier using two-sample Wilcoxon rank or Chi-squared test.

334 6.2 Secondary Endpoints 335 Data analysis for the secondary endpoints takes into consideration the change 336 in protocol. For each of the secondary endpoints, we will perform a linear 337 mixed effects regression analysis to compare the effects of the placebo and 338 plasma treatment. Specifically, the linear mixed effects model will include a 339 binary variable indicating the stage (1 vs 2) at which the response is measured 340 and a treatment indicator (plasma vs placebo), which is the independent 341 variable of primary interest. The regression coefficient for the treatment 342 indicator summarizes the effect of plasma on the endpoint of interest. The 343 subject-specific random intercept will be included to account for the within 344 patient correlations. For the subgroup of patients who only received the 345 plasma at the first stage per the revised protocol, the potential response at the 346 second stage if the placebo is administrated is considered as missing data. 347 The linear mixed effects regression allows missing data at random.

348 The effect of ApoE -4 status will be further examined by conducting subgroup 349 analysis and comparing the average change between subgroups of patients 350 with different ApoE-4 status.

351 We will not adjust for multiple testing due to the exploratory nature of the 352 analysis. However, we will report all the test results regardless of their 353 significance level.

354 6.3 Other endpoints 355 Change in functional connectivity will be analysed by SBGneuro using a 356 paired-sample t-test comparing the baseline to post treatment MRI. Any 357 networks that demonstrate significant differences in the baseline versus active 358 scan will be analyzed in a repeated-measures ANOVA.

359 Compositional assessment of plasma using in vitro analytical methods will be 360 performed. A discovery proteomics analysis using array based targeted 361 methodology will be used to assess the plasma proteome and its changes 362 prior to treatment arm and at the end of each treatment arm for each 363 individual subject. Using a paired sample t-test significant differences will be 364 assessed in prior vs post treatment and for treatment vs placebo (where Page 13 of 29

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365 relevant). Additionally, a population based analysis will be performed to 366 compare the grouped pre-treatment vs grouped post-treatment data using a 367 paired-sample t-test. Any analyses of particular interest may be specifically 368 assessed by other means in post hoc analyses and may incorporate the use of 369 other donor and subject plasma samples.

370 Timing of Analyses

371  The final analysis will be performed after the completion of the last subject is 372 enrolled and completed the Open Label arm of the study and the database is 373 locked. 374

375 6.4 Analysis Populations 376 (ICH E3; 9.7.1, 11.4.2.5. ICH E9; 5.2)

377 6.4.1 Full Analysis Population 378 Primary endpoints for safety for number of adverse events will include all 379 subjects who received any study drug (safety population). This is assuming all 380 subjects who received any study treatment (including control) but excluding 381 subjects who drop out prior to receiving any treatment. Primary endpoints will 382 be performed for laboratory, physical examination, and EKG and for all subjects 383 who received any study drug and who participated in at least one post-baseline 384 assessment. Secondary analysis will be performed on all randomized or enrolled 385 subjects who received study drug or placebo and who participated in at least 386 one post-baseline assessment (modified intention to treat). For subjects who 387 deviated from the protocol, data may be removed on a per-patient basis for 388 exploratory analysis. 389 390 MRI scanning will be performed at screening and after each block of infusions 391 using a 3T GE scanner. Patients will complete one T1-weighted anatomical scan 392 (3D-FSPGR, flip angle=15, matrix size=256x256, 158 axial slices, in-plane 393 resolution=0.85mm, slice thickness=1mm) and two resting-state scans fMRI 394 scans (GE-EPI, TE=30 ms, flip angle=80, in-plane resolution=3.4mm, slice 395 thickness=4.0mm, gap=0.5mm, 31 axial slices, TR=2 sec, 240 volumes). All 396 resting state fMRI scans will be preprocessed using the FSL software package10 397 integrated in-house processing pipelines. Preprocessing includes correction for

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398 head motion through volume realignment, correction for magnetic field in- 399 homogeneities (B0 correction), spatial smoothing (6mm FWHM), advanced head 400 motion de-noising using ICA-AROMA11, and a 0.01Hz high-pass filter. All 401 further analyses will be performed in MNI152 standard space to allow between- 402 patient comparisons. Where available, we will combine results for the two 403 within-session resting state functional scans by means of within-patient fixed- 404 effects analyses. 405 406 Resting state fMRI analyses. Resting state fMRI analyses allows for the 407 investigation of characteristics of spontaneous brain activity, which has been 408 found to cluster into meaningful large-scale networks. We will assess network 409 integrity and identifiability of 10, well-described, and replicated resting state 410 networks. To assess network integrity, we will conduct group-level analyses for 411 three differential within-patient effects: 1) Baseline + Plasma (mean effect); 2) 412 Baseline > Plasma; 3) Plasma > Baseline. Group-level statistics will be obtained 413 using non-parametric testing (FSL randomize13). Results will be considered 414 significant at p<0.005 (i.e., p < 0.05/10 investigated networks). To assess 415 network identifiability, we will extract the mean Z-statistic within the 10 resting 416 state networks and compare those to the mean Z-statistic outside each 417 respective network mask. A higher inside/outside ratio indicates that the 418 network is easier to identify against the background noise. We will assess the 419 effect of session on these scores using unpaired t-tests across all networks, 420 including all available patients. Effects are considered significant at p<0.05. 421 Finally, we will obtain seed-based functional connectivity maps for left and right 422 hippocampus regions of interest (ROI). These connectivity maps will be entered 423 into group-level comparisons as above. In addition, we will extract for each 424 patient and each session the connectivity strength between each of the 425 hippocampus ROIs and each of the 10 large-scale networks. We will use these 426 mean Z-values for correlation analyses against behavioral metrics obtained for 427 each patient 428 429 Plasma proteomic analysis will be performed on all subjects where samples were 430 plasma samples were collected prior to treatment and immediately post- 431 treatement (i.e. both visits 1 and 7 and, where relevant both visits 8 and 13). 432 Analysis will not be performed where any plasma samples are unavailable from 433 these specific study visits. Page 15 of 29

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434 6.5 Covariates and Subgroups 435 (ICH E3; 9.7.1, 11.4.2.1. ICH E9; 5.7)

436 Due to small sample size, the only subgroup exploratory analysis for treatment 437 effects will be performed based upon ApoE4 status. See above.

438 6.6 Missing Data 439 (ICH E3; 9.7.1, 11.4.2.2. ICH E9;5.3. EMA Guideline on Missing Data in Confirmatory 440 Clinical Trials)

441 In the main analysis, missing data for a particular endpoint will exclude this subject 442 from analysis for this specific endpoint. Due to small sample size, every effort will 443 be made to minimize missing data. We will choose statistical analyses that are less 444 sensitive to missing data, e.g., the linear mixed effects model for secondary 445 endpoints does not require imputation for missing data. For the primary endpoints, 446 there will be no attempt to impute missing data due to the small sample size.

447 6.7.2 Data Monitoring Process

448 6.7 An independent consultant will perform quality assurance on a subset 449 (approximately 33%) of the data. In addition to quality, the monitor will also 450 review adverse events, protocol deviations, and confirm all data is compliant 451 with Good Clinical Practice (GCP) requirements. Per GCP, the confirmation and 452 follow-up letters, as well as all findings, will be documented and stored in the 453 regulatory binder. Subject Disposition: A flow chart will be provided for 454 number of patients screened, randomized (for the first half of the study), 455 number that dropped out, number of completed trial.

456 6.8 Protocol Deviations 457 A major deviation would include a subject completing testing 4 weeks outside of 458 the window required. Protocol deviations for inclusion into analyses will be assessed 459 on a per-case basis as described above. Protocol deviations that have the potential 460 to affect the integrity of study data or the safety of subjects are classified as “Major 461 Protocol Deviations"; all others are classified as “Minor Protocol Deviations.

462 6.9 Demographic and Baseline Variables 463 We will include gender, age, education, ApoE status, CDR-SB, MMSE.

464 6.10 Concurrent Illnesses and Medical Conditions Page 16 of 29

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465 Past medical history, including previous malignancy, will be recorded as well as the 466 patient’s current medications and any past medications specific to dementia.

467 6.11 Treatment Compliance 468 Assessment of treatment compliance includes protocol deviation for timing of 469 infusions or missing infusions.

470 6.12 Adverse Events 471 The summary statistics will be produced in accordance with section describing 472 primary endpoints.

473 The list of Adverse Events was taken from the CTCAE version 4.0 (Published May 28, 474 2009) as defined by the US Department of Health and Human Services. System 475 Organ Class, the highest level of the MedDRA hierarchy, is identified by 476 anatomical or physiological system, etiology, or purpose (e.g., SOC 477 Investigations for laboratory test results). CTCAE terms are grouped by 478 MedDRA Primary SOCs. Within each SOC, AEs are listed. A list of these AE terms 479 was added to Appendix 1. A list of these terms was added to Appendix 1.

480 6.13 Deaths, Serious Adverse Events and other Significant Adverse

481 Events 482 The summary statistics will be produced in accordance with section describing 483 primary endpoints.

484 The list of Adverse Events was taken from the CTCAE version 4.0 (Published May 28, 485 2009) as defined by the US Department of Health and Human Services. System 486 Organ Class, the highest level of the MedDRA hierarchy, is identified by 487 anatomical or physiological system, etiology, or purpose (e.g., SOC 488 Investigations for laboratory test results). CTCAE terms are grouped by 489 MedDRA Primary SOCs. Within each SOC, AEs are listed. A list of these AE terms 490 was added to Appendix 1. A list of these terms was added to Appendix 1.

491 7 Technical Details 492 A biostatistician was consulted for appropriate statistical methods. SPSS version 21 493 will be used.

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494 Appendix 1: 495 CTCAE v4.0 List of AE Terms categorized by MeDRA SOC:

496 ------Blood/lymphatic system ------521 Left ventricular systolic dysfunction 497 Anemia 522 Mitral valve disease 498 Bone marrow hypocellular 523 Mobitz (type) II atrioventricular block 499 Disseminated intravascular coagulation 524 Mobitz type I 500 Febrile neutropenia 525 Myocardial infarction 501 Hemolysis 526 Myocarditis 502 Hemolytic uremic syndrome 527 Palpitations 503 Leukocytosis 528 Paroxysmal atrial tachycardia 504 Lymph node pain 529 Pericardial effusion 505 Spleen disorder 530 Pericardial tamponade 506 Thrombotic thrombocytopenic purpura 531 Pericarditis 507 Blood and lymphatic system disorders - Other 532 Pulmonary valve disease 508 ------Cardiac ------533 Restrictive cardiomyopathy 509 Acute coronary syndrome 534 Right ventricular dysfunction 510 Aortic valve disease 535 Sick sinus syndrome 511 Asystole 536 Sinus bradycardia 512 Atrial fibrillation 537 Sinus tachycardia 513 Atrial flutter 538 Supraventricular tachycardia 514 Atrioventricular block complete 539 Tricuspid valve disease 515 Atrioventricular block first degree 540 Ventricular arrhythmia 516 Cardiac arrest 541 Ventricular fibrillation 517 Chest pain - cardiac 542 Ventricular tachycardia 518 Conduction disorder 543 Wolff-Parkinson-White syndrome 519 Constrictive pericarditis 544 Cardiac disorders - Other 520 Heart failure 545 553 Middle ear inflammation 546 ------Congenital/familial/genetic ------554 Tinnitus 547 Congenital, familial and genetic disorders - Other 555 Vertigo 548 ------Ear/labyrinth ------556 Vestibular disorder 549 Ear pain 557 Ear and labyrinth disorders - Other 550 External ear inflammation 558 551 External ear pain 559 552 Hearing impaired 560

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561 ------Endocrine ------568 Hypoparathyroidism 562 Adrenal insufficiency 569 Hypothyroidism 563 Cushingoid 570 Precocious puberty 564 Delayed puberty 571 Virilization 565 Growth accelerated 572 Endocrine disorders - Other 566 Hyperparathyroidism 567 Hyperthyroidism 573 587 Night blindness 574 ------Eye ------588 Optic nerve disorder 575 Blurred vision 589 Papilledema 576 Cataract 590 Photophobia 577 Conjunctivitis 591 Retinal detachment 578 Corneal ulcer 592 Retinal tear 579 Dry eye 593 Retinal vascular disorder 580 Extraocular muscle paresis 594 Retinopathy 581 Eye pain 595 Scleral disorder 582 Eyelid function disorder 596 Uveitis 583 Flashing lights 597 Vitreous hemorrhage 584 Floaters 598 Watering eyes 585 Glaucoma 599 Eye disorders - Other 586 Keratitis 600 618 Colonic obstruction 601 ------GI ------619 Colonic perforation 602 Abdominal distension 620 Colonic stenosis 603 Abdominal pain 621 Colonic ulcer 604 Anal fistula 622 Constipation 605 Anal hemorrhage 623 Dental caries 606 Anal mucositis 624 Diarrhea 607 Anal necrosis 625 Dry mouth 608 Anal pain 626 Duodenal fistula 609 Anal stenosis 627 Duodenal hemorrhage 610 Anal ulcer 628 Duodenal obstruction 611 Ascites 629 Duodenal perforation 612 Bloating 630 Duodenal stenosis 613 Cecal hemorrhage 631 Duodenal ulcer 614 Cheilitis 632 Dyspepsia 615 Colitis 633 Dysphagia 616 Colonic fistula 634 Enterocolitis 617 Colonic hemorrhage 635 Enterovesical fistula Page 19 of 29

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636 -----GI Continued----- 675 Jejunal stenosis 637 Esophageal fistula 676 Jejunal ulcer 638 Esophageal hemorrhage 677 Lip pain 639 Esophageal necrosis 678 Lower gastrointestinal hemorrhage 640 Esophageal obstruction 679 Malabsorption 641 Esophageal pain 680 Mucositis oral 642 Esophageal perforation 681 Nausea 643 Esophageal stenosis 682 Obstruction gastric 644 Esophageal ulcer 683 Oral cavity fistula 645 Esophageal varices hemorrhage 684 Oral dysesthesia 646 Esophagitis 685 Oral hemorrhage 647 Fecal incontinence 686 Oral pain 648 Flatulence 687 Pancreatic duct stenosis 649 Gastric fistula 688 Pancreatic fistula 650 Gastric hemorrhage 689 Pancreatic hemorrhage 651 Gastric necrosis 690 Pancreatic necrosis 652 Gastric perforation 691 Pancreatitis 653 Gastric stenosis 692 Periodontal disease 654 Gastric ulcer 693 Peritoneal necrosis 655 Gastritis 694 Proctitis 656 Gastroesophageal reflux disease 695 Rectal fistula 657 Gastrointestinal fistula 696 Rectal hemorrhage 658 Gastrointestinal pain 697 Rectal mucositis 659 Gastroparesis 698 Rectal necrosis 660 Gingival pain 699 Rectal obstruction 661 Hemorrhoidal hemorrhage 700 Rectal pain 662 Hemorrhoids 701 Rectal perforation 663 Ileal fistula 702 Rectal stenosis 664 Ileal hemorrhage 703 Rectal ulcer 665 Ileal obstruction 704 Retroperitoneal hemorrhage 666 Ileal perforation 705 Salivary duct inflammation 667 Ileal stenosis 706 Salivary gland fistula 668 Ileal ulcer 707 Small intestinal mucositis 669 Ileus 708 Small intestinal perforation 670 Intra-abdominal hemorrhage 709 Small intestinal stenosis 671 Jejunal fistula 710 Small intestine ulcer 672 Jejunal hemorrhage 711 Stomach pain 673 Jejunal obstruction 712 Tooth development disorder 674 Jejunal perforation 713 Tooth discoloration Page 20 of 29

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714 Toothache 716 Upper gastrointestinal hemorrhage 715 Typhlitis 717 Vomiting 718 Gastrointestinal disorders – Other 719 720 ------General/administration site ------733 Infusion related reaction 721 Chills 734 Infusion site extravasation 722 Death neonatal 735 Injection site reaction 723 Death NOS 736 Irritability 724 Edema face 737 Localized edema 725 Edema limbs 738 Malaise 726 Edema trunk 739 Multi-organ failure 727 Facial pain 740 Neck edema 728 Fatigue 741 Non-cardiac chest pain 729 Fever 742 Pain 730 Flu like symptoms 743 Sudden death NOS 731 Gait disturbance 744 General disorders and administration site 732 Hypothermia 745 conditions - Other 746 755 Gallbladder perforation 747 ------Hepatobiliary ------756 Hepatic failure 748 Bile duct stenosis 757 Hepatic hemorrhage 749 Biliary fistula 758 Hepatic necrosis 750 Cholecystitis 759 Hepatic pain 751 Gallbladder fistula 760 Perforation bile duct 752 Gallbladder necrosis 761 Portal hypertension 753 Gallbladder obstruction 762 Portal vein thrombosis 754 Gallbladder pain 763 Hepatobiliary disorders - Other 764 768 Autoimmune disorder 765 ------Immune system ------769 Cytokine release syndrome 766 Allergic reaction 770 Serum sickness 767 Anaphylaxis 771 Immune system disorders - Other 772 781 Bone infection 773 ------Infection/infestation ------782 Breast infection 774 Abdominal infection 783 Bronchial infection 775 Anorectal infection 784 Catheter related infection 776 Appendicitis 785 Cecal infection 777 Appendicitis perforated 786 Cervicitis infection 778 Arteritis infective 787 Conjunctivitis infective 779 Biliary tract infection 788 Corneal infection 780 Bladder infection 789 Cranial nerve infection Page 21 of 29

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790 Device related infection 820 Pelvic infection 791 Duodenal infection 821 Penile infection 792 Encephalitis infection 822 Periorbital infection 793 Encephalomyelitis infection 823 Peripheral nerve infection 794 Endocarditis infective 824 Peritoneal infection 795 Endophthalmitis 825 Pharyngitis 796 Enterocolitis infectious 826 Phlebitis infective 797 Esophageal infection 827 Pleural infection 798 Eye infection 828 Prostate infection 799 Gallbladder infection 829 Rash pustular 800 Gum infection 830 Rhinitis infective 801 Hepatic infection 831 Salivary gland infection 802 Hepatitis viral 832 Scrotal infection 803 Infective myositis 833 Sepsis 804 Joint infection 834 Sinusitis 805 Kidney infection 835 Skin infection 806 Laryngitis 836 Small intestine infection 807 Lip infection 837 Soft tissue infection 808 Lung infection 838 Splenic infection 809 Lymph gland infection 839 Stoma site infection 810 Mediastinal infection 840 Tooth infection 811 Meningitis 841 Tracheitis 812 Mucosal infection 842 Upper respiratory infection 813 Nail infection 843 Urethral infection 814 Otitis externa 844 Urinary tract infection 815 Otitis media 845 Uterine infection 816 Ovarian infection 846 Vaginal infection 817 Pancreas infection 847 Vulval infection 818 Papulopustular rash 848 Wound infection 819 Paronychia 849 Infections and infestations - Other 850 859 Dermatitis radiation 851 ------Injury/poison ------860 Esophageal anastomotic leak 852 Ankle fracture 861 Fall 853 Aortic injury 862 Fallopian tube anastomotic leak 854 Arterial injury 863 Fallopian tube perforation 855 Biliary anastomotic leak 864 Fracture 856 Bladder anastomotic leak 865 Gastric anastomotic leak 857 Bruising 866 Gastrointestinal anastomotic leak 858 Burn 867 Gastrointestinal stoma necrosis Page 22 of 29

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868 Hip fracture 900 Postoperative thoracic procedure complication 869 Injury to carotid artery 901 Prolapse of intestinal stoma 870 Injury to inferior vena cava 902 Prolapse of urostomy 871 Injury to jugular vein 903 Radiation recall reaction (dermatologic) 872 Injury to superior vena cava 904 Rectal anastomotic leak 873 Intestinal stoma leak 905 Seroma 874 Intestinal stoma obstruction 906 Small intestinal anastomotic leak 875 Intestinal stoma site bleeding 907 Spermatic cord anastomotic Leak 876 Intraoperative arterial injury 908 Spinal fracture 877 Intraoperative breast injury 909 Stenosis of gastrointestinal stoma 878 Intraoperative cardiac injury 910 Stomal ulcer 879 Intraoperative ear injury 911 Tracheal hemorrhage 880 Intraoperative endocrine injury 912 Tracheal obstruction 881 Intraoperative gastrointestinal injury 913 Tracheostomy site bleeding 882 Intraoperative head and neck injury 914 Ureteric anastomotic leak 883 Intraoperative hemorrhage 915 Urethral anastomotic leak 884 Intraoperative hepatobiliary injury 916 Urostomy leak 885 Intraoperative musculoskeletal injury 917 Urostomy obstruction 886 Intraoperative neurological injury 918 Urostomy site bleeding 887 Intraoperative ocular injury 919 Urostomy stenosis 888 Intraoperative renal injury 920 Uterine anastomotic leak 889 Intraoperative reproductive tract injury 921 Uterine perforation 890 Intraoperative respiratory injury 922 Vaginal anastomotic leak 891 Intraoperative skin injury 923 Vas deferens anastomotic leak 892 Intraoperative splenic injury 924 Vascular access complication 893 Intraoperative urinary injury 925 Venous injury 894 Intraoperative venous injury 926 Wound complication 895 Kidney anastomotic leak 927 Wound dehiscence 896 Large intestinal anastomotic leak 928 Wrist fracture 897 Pancreatic anastomotic leak 929 Injury, poisoning and procedural complications - 898 Pharyngeal anastomotic leak 930 Other 899 Postoperative hemorrhage 931 938 Blood bilirubin increased 932 ------Investigations ------939 Blood corticotrophin decreased 933 Activated partial thromboplastin time prolonged 940 Blood gonadotrophin abnormal 934 Alanine aminotransferase increased 941 Blood prolactin abnormal 935 Alkaline phosphatase increased 942 Carbon monoxide diffusing capacity decreased 936 Aspartate aminotransferase increased 943 Cardiac troponin I increased 937 Blood antidiuretic hormone abnormal 944 Cardiac troponin T increased Page 23 of 29

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945 CD4 lymphocytes decreased 958 Lipase increased 946 Cholesterol high 959 Lymphocyte count decreased 947 CPK increased 960 Lymphocyte count increased 948 Creatinine increased 961 Neutrophil count decreased 949 Ejection fraction decreased 962 Pancreatic enzymes decreased 950 Electrocardiogram QT corrected interval prolonged 963 Platelet count decreased 951 Fibrinogen decreased 964 Serum amylase increased 952 Forced expiratory volume decreased 965 Urine output decreased 953 GGT increased 966 Vital capacity abnormal 954 Growth hormone abnormal 967 Weight gain 955 Haptoglobin decreased 968 Weight loss 956 Hemoglobin increased 969 White blood cell decreased 957 INR increased 970 Investigations - Other 971 984 Hypertriglyceridemia 972 ------Metabolism/nutrition ------985 Hyperuricemia 973 Acidosis 986 Hypoalbuminemia 974 Alcohol intolerance 987 Hypocalcemia 975 Alkalosis 988 Hypoglycemia 976 Anorexia 989 Hypokalemia 977 Dehydration 990 Hypomagnesemia 978 Glucose intolerance 991 Hyponatremia 979 Hypercalcemia 992 Hypophosphatemia 980 Hyperglycemia 993 Iron overload 981 Hyperkalemia 994 Obesity 982 Hypermagnesemia 995 Tumor lysis syndrome 983 Hypernatremia 996 Metabolism and nutrition disorders - Other 997 1010 Generalized muscle weakness 998 ------Musculoskeletal/connective tissue ------1011 Growth suppression 999 Abdominal soft tissue necrosis 1012 Head soft tissue necrosis 1000 Arthralgia 1013 Joint effusion 1001 Arthritis 1014 Joint range of motion decreased 1002 Avascular necrosis 1015 Joint range of motion decreased cervical spine 1003 Back pain 1016 Joint range of motion decreased lumbar spine 1004 Bone pain 1017 Kyphosis 1005 Buttock pain 1018 Lordosis 1006 Chest wall pain 1019 Muscle weakness left-sided 1007 Exostosis 1020 Muscle weakness lower limb 1008 Fibrosis deep connective tissue 1021 Muscle weakness right-sided 1009 Flank pain 1022 Muscle weakness trunk Page 24 of 29

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1023 Muscle weakness upper limb 1032 Pelvic soft tissue necrosis 1024 Musculoskeletal deformity 1033 Scoliosis 1025 Myalgia 1034 Soft tissue necrosis lower limb 1026 Myositis 1035 Soft tissue necrosis upper limb 1027 Neck pain 1036 Superficial soft tissue fibrosis 1028 Neck soft tissue necrosis 1037 Trismus 1029 Osteonecrosis of jaw 1038 Unequal limb length 1030 Osteoporosis 1039 Musculoskeletal and connective tissue disorder - 1031 Pain in extremity 1040 Other 1041 1046 Treatment related secondary malignancy 1042 ------Neoplasms benign/malignant/unspecified 1047 Tumor pain 1043 ------1048 Neoplasms benign, malignant and unspecified (incl 1044 Leukemia secondary to oncology chemotherapy 1049 cysts and polyps) - Other 1045 Myelodysplastic syndrome 1050 1075 Facial nerve disorder 1051 ------Nervous system ------1076 Glossopharyngeal nerve disorder 1052 Abducens nerve disorder 1077 Headache 1053 Accessory nerve disorder 1078 Hydrocephalus 1054 Acoustic nerve disorder NOS 1079 Hypersomnia 1055 Akathisia 1080 Hypoglossal nerve disorder 1056 Amnesia 1081 Intracranial hemorrhage 1057 Aphonia 1082 Ischemia cerebrovascular 1058 Arachnoiditis 1083 IVth nerve disorder 1059 Ataxia 1084 Lethargy 1060 Brachial plexopathy 1085 Leukoencephalopathy 1061 Central nervous system necrosis 1086 Memory impairment 1062 Cerebrospinal fluid leakage 1087 Meningismus 1063 Cognitive disturbance 1088 Movements involuntary 1064 Concentration impairment 1089 Myelitis 1065 Depressed level of consciousness 1090 Neuralgia 1066 Dizziness 1091 Nystagmus 1067 Dysarthria 1092 Oculomotor nerve disorder Asymptomatic 1068 Dysesthesia 1093 Olfactory nerve disorder 1069 Dysgeusia 1094 Paresthesia 1070 Dysphasia 1095 Peripheral motor neuropathy 1071 Edema cerebral 1096 Peripheral sensory neuropathy 1072 Encephalopathy 1097 Phantom pain 1073 Extrapyramidal disorder 1098 Presyncope 1074 Facial muscle weakness 1099 Pyramidal tract syndrome Page 25 of 29

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1100 Radiculitis 1108 Syncope 1101 Recurrent laryngeal nerve palsy 1109 Transient ischemic attacks 1102 Reversible posterior leukoencephalopathy syndrome 1110 Tremor 1103 Seizure 1111 Trigeminal nerve disorder 1104 Sinus pain 1112 Vagus nerve disorder 1105 Somnolence 1113 Vasovagal reaction 1106 Spasticity 1114 Nervous system disorders - Other 1107 Stroke 1115 1120 Unintended pregnancy 1116 ------Pregnancy/puerperium/perinatal ------1121 Pregnancy, puerperium and perinatal conditions - 1117 Fetal death 1122 Other 1118 Fetal growth retardation 1123 1119 Premature delivery 1124 1136 Insomnia 1125 ------Psychiatric ------1137 Libido decreased 1126 Agitation 1138 Libido increased 1127 Anorgasmia 1139 Mania 1128 Anxiety 1140 Personality change 1129 Confusion 1141 Psychosis 1130 Delayed orgasm 1142 Restlessness 1131 Delirium 1143 Suicidal ideation 1132 Delusions 1144 Suicide attempt 1133 Depression 1145 Psychiatric disorders - Other 1134 Euphoria 1146 1135 Hallucinations 1147 1160 Urinary fistula 1148 ------Renal/urinary ------1161 Urinary frequency 1149 Acute kidney injury 1162 Urinary incontinence 1150 Bladder perforation 1163 Urinary retention 1151 Bladder spasm 1164 Urinary tract obstruction 1152 Chronic kidney disease 1165 Urinary tract pain 1153 Cystitis noninfective 1166 Urinary urgency 1154 Hematuria 1167 Urine discoloration 1155 Hemoglobinuria 1168 Renal and urinary disorders - Other 1156 Proteinuria 1169 1157 Renal calculi 1170 1158 Renal colic 1171 1159 Renal hemorrhage 1172 1173 1174 Page 26 of 29

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1175 ------Reproductive system/breast ------1202 Premature menopause 1176 Azoospermia 1203 Prostatic hemorrhage 1177 Breast atrophy 1204 Prostatic obstruction 1178 Breast pain 1205 Prostatic pain 1179 Dysmenorrhea 1206 Scrotal pain 1180 Dyspareunia 1207 Spermatic cord hemorrhage 1181 Ejaculation disorder 1208 Spermatic cord obstruction 1182 Erectile dysfunction 1209 Testicular disorder 1183 Fallopian tube obstruction 1210 Testicular hemorrhage 1184 Fallopian tube stenosis 1211 Testicular pain 1185 Female genital tract fistula 1212 Uterine fistula 1186 Feminization acquired 1213 Uterine hemorrhage 1187 Genital edema 1214 Uterine obstruction 1188 Gynecomastia 1215 Uterine pain 1189 Hematosalpinx 1216 Vaginal discharge 1190 Irregular menstruation 1217 Vaginal dryness 1191 Lactation disorder 1218 Vaginal fistula 1192 Menorrhagia 1219 Vaginal hemorrhage 1193 Nipple deformity 1220 Vaginal inflammation 1194 Oligospermia 1221 Vaginal obstruction 1195 Ovarian hemorrhage 1222 Vaginal pain 1196 Ovarian rupture 1223 Vaginal perforation 1197 Ovulation pain 1224 Vaginal stricture 1198 Pelvic floor muscle weakness 1225 Vaginismus 1199 Pelvic pain 1226 Reproductive system and breast disorders - Other 1200 Penile pain 1227 1201 Perineal pain 1228 1240 Bronchospasm 1229 ------Respiratory/thoracic/mediastinal ------1241 Chylothorax 1230 Adult respiratory distress syndrome 1242 Cough 1231 Allergic rhinitis 1243 Dyspnea 1232 Apnea 1244 Epistaxis 1233 Aspiration 1245 Hiccups 1234 Atelectasis 1246 Hoarseness 1235 Bronchial fistula 1247 Hypoxia 1236 Bronchial obstruction 1248 Laryngeal edema 1237 Bronchial stricture 1249 Laryngeal fistula 1238 Bronchopleural fistula 1250 Laryngeal hemorrhage 1239 Bronchopulmonary hemorrhage 1251 Laryngeal inflammation Page 27 of 29

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1252 Laryngeal mucositis 1271 Pulmonary edema 1253 Laryngeal obstruction 1272 Pulmonary fibrosis 1254 Laryngeal stenosis 1273 Pulmonary fistula 1255 Laryngopharyngeal dysesthesia 1274 Pulmonary hypertension 1256 Laryngospasm 1275 Respiratory failure 1257 Mediastinal hemorrhage 1276 Retinoic acid syndrome 1258 Nasal congestion 1277 Sinus disorder 1259 Pharyngeal fistula 1278 Sleep apnea 1260 Pharyngeal hemorrhage 1279 Sneezing 1261 Pharyngeal mucositis 1280 Sore throat 1262 Pharyngeal necrosis 1281 Stridor 1263 Pharyngeal stenosis 1282 Tracheal fistula 1264 Pharyngolaryngeal pain 1283 Tracheal mucositis 1265 Pleural effusion 1284 Tracheal stenosis 1266 Pleural hemorrhage 1285 Voice alteration 1267 Pneumonitis 1286 Wheezing 1268 Pneumothorax 1287 Respiratory, thoracic and mediastinal disorders - 1269 Postnasal drip 1288 Other 1270 Productive cough 1289 1307 Palmar-plantar erythrodysesthesia syndrome 1290 ------Skin/subcutaneous tissue ------1308 Periorbital edema 1291 Alopecia 1309 Photosensitivity 1292 Body odor 1310 Pruritus 1293 Bullous dermatitis 1311 Purpura 1294 Dry skin 1312 Rash acneiform 1295 Erythema multiforme 1313 Rash maculo-papular 1296 Erythroderma 1314 Scalp pain 1297 Fat atrophy 1315 Skin atrophy 1298 Hirsutism 1316 Skin hyperpigmentation 1299 Hyperhidrosis 1317 Skin hypopigmentation 1300 Hypertrichosis 1318 Skin induration 1301 Hypohidrosis 1319 Skin ulceration 1302 Lipohypertrophy 1320 Stevens-Johnson syndrome 1303 Nail discoloration 1321 Telangiectasia 1304 Nail loss 1322 Toxic epidermal necrolysis 1305 Nail ridging 1323 Urticaria 1306 Pain of skin 1324 Skin and subcutaneous tissue disorders - Other 1325 1327 1326 1328 Page 28 of 29

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1329 ------Social circumstances ------1331 Social circumstances - Other 1330 Menopause 1332 ------Surgical/medical procedures ------1334 1333 Surgical and medical procedures – Other 1335 1336 1346 Lymphocele 1337 ------Vascular ------1347 Peripheral ischemia 1338 Capillary leak syndrome 1348 Phlebitis 1339 Flushing 1349 Superficial thrombophlebitis 1340 Hematoma 1350 Superior vena cava syndrome 1341 Hot flashes 1351 Thromboembolic event 1342 Hypertension 1352 Vasculitis 1343 Hypotension 1353 Visceral arterial ischemia 1344 Lymph leakage 1354 Vascular disorders - Other 1345 Lymphedema 1355

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