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Guideline (E6)). Examples of source data include Subject in source documents (original records or certified copies). (ICH reconstruction and evaluation of the trial. Source data are contained observations, or other activities in a clinical trial necessary for the The information may include, but is not limited to, clinical findings, record containing patient information for use in clinical research. product(s)/protocol defined as the first day that protocol specified investigational would include these additional parts defined as the last day that protocol used for the reconstruction and evaluation of a trial. source European Medicines Agency electrocardiogram efficacy assessment phase Common Terminology Criteria for Adverse Events chronic kidney disease calcium sensing receptor a Active pharmaceutical absolute neutrophil count information parts (eg, safety follow intervention for evaluation in the study; if the study includes multiple defined as when the last subject is assessed or receives an endpoint(s). intervention for the purposes of final collection of data for the primary defined as when the last subject is assessed or receives an m rea rea under the curve for plasma etelcalcetide aximum plasma etelcalcetide concentration data captured initially into a permanent electronic record - corrected calcium from an original record or certified copy of the original - required therapies is/are administered to the - agent up or survival - specified procedures are assessment), the end of study Page 7 7 of 64 Date: 18 February 2016 Protocol Number: 20140336 Product: Etelcalcetide CONFIDENTIAL LAR IUD ICF iCa EU ESRD Abbreviation or Term USRDS T TIW TBIL t sHPT QT QT PTH PK/ PK PIP PDCO PD NAPRTS IV 1/2 max b c PD three times a week end stage renal disease Definition/Explanation time to Cmax half Bazett correctedBazett QT interval corrected QT interval ionized calcium legally authorized representative intrauterine device European Union United States Renal Data System total bilirubin secondary hyperparathyroidism parathyroid hormone pharmacokinetic/pharmacodynamic pharmacokinetic Paediatric Investigation Plan Paediatric Committee pharmacodynamic group North American Pediatric Renal Trials and Collaborative Studies intravenous informed consent form - life of plasma etelcalcetide Page 8 8 of 64 1. Study Glossary Study andTreatment Design Schema 2. 3. 5. Protocol SynopsisProtocol 4. 6. Date: 18 February 2016 Protocol Number: 20140336 Product: Etelcalcetide CONFIDENTIAL 1.1 1.2 2.2 3.2 3.1 3.3 3.4 3.5 OBJECTIVES OBJECTIVES BACKGROUND AND RATIONALE AND BACKGROUND 2.5 2.4 2.3 2.1 EXPERIMENTAL PLAN EXPERIMENTAL 4.1 SUBJECT ENROLLMENT SUBJECT 4.2 SUBJECT ELIGIBILITY TREATMENT PROCEDURES TREATMENT 6.2 6.1 6.4 6.3 Primary Primary Secondary Amgen ProductBackground Investigational NumberSites of Study Design NumberSubjects of Replacement ofSubjects 3.5.1 Estimated Study Duration 2.2.2 2.2.1 Clinical HypothesesClinical Rationale Assessment Risk Paediatric Disease 3.5.2 Inclusion CriteriaInclusion Exclusion CriteriaExclusion Investigational Product Classification ofProduct(s)and/or Device(s) Medical 6.2.1 6.2.2 Concomitant Therapy Hepatotoxicity Criteria Safety for Additional duetoPotential Assessment ...... 7 ...... 3 ...... ...... Study for Subjects Duration Clinical PharmacokineticsClinical Experience Clinical ...... End ofStudy Amgen ProductEtelcalcetide Investigational Cohort StoppingRules (AMG (AMG 6.2.1.1 6.2.1.2 ...... ...... ...... 416) ...... ...... TABLE OF CONTENTS OF TABLE ...... ...... Dosage, Administration, andSchedule Safety andData Review Monitoring ...... ...... ...... 6 ...... ...... ...... ...... ...... ...... ...... ...... Page 9 9 of 13 13 13 18 18 18 18 19 19 13 15 17 17 16 13 15 18 19 19 20 19 19 21 22 22 22 22 23 23 25 26 24 64 8. 9. 7. Date: 18 February 2016 Protocol Number: 20140336 Product: Etelcalcetide CONFIDENTIAL 7.3 7.4 WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY AND PROCEDURES, TREATMENT, FROM WITHDRAWAL 8.1 9.2 7.1 7.2 9.3 SAFETY DATA COLLECTION, RECORDING,SAFETY AND REPORTING DATA 9.1 8.2 6.5 6.6 STUDY PROCEDURES STUDY 6.7 7.2.14 7.2.13 7.2.12 7.2.11 7.2.10 7.2.9 Antibody Procedures Testing Sample Storage andDestruction Sample Storage 7.2.7 7.2.8 7.2.6 7.2.5 7.2.4 7.2.3 7.2.2 7.2.1 Subjects’ Decision toSubjects’ Withdraw 9.1.2 9.1.1 Safety Event ReportingSafety Procedures Event Schedule of Schedule Assessments General Study Procedures Pregnancy andLactation Reporting 9.2.2 9.2.1 8.2.2 Definition of Definition Safety Events 8.2.1 Participation PriorSubjects’ toStudy Completion to Investigator or SponsorDecision Withdraw or Terminate Other Treatment - Procedures Pro During Study Period DeviceExcluded Treatments, Medical Use,and/or Procedures duct Complaintsduct Anticipated Anticipated VolumesBlood Collection Pharmacokinetic MeasurementsPharmacokinetic Pharmacodynamic Measurements Clinical LaboratoryClinical Assessments Safety Electrocardiograms Physical Examination Physical Medical HistoryMedical Vital Signs Vital End ofStudy Visit Safety Follow Treatment Baseline Screening Informed Consent Serious AdverseSerious Events Adverse Events Reporting for Procedures Adverse Serious Events Reporting for Procedures Adverse ThatDo Events Not Reasons forReasons Removal From Study Reasons forReasons Removal From Treatment 9.2.2.2 9.2.2.1 Meet Criteria Serious ...... ...... ...... ...... Reporting of Reductions Reporting ofReductions Serumin Calcium the Protocol Reporting Adverse Serious Events After -up Visit(s) ...... ...... ...... ...... ...... Haemodialysis ...... ...... -required Reporting Period ...... - Adverse Ev ...... ...... ...... ...... ents ...... ...... ...... ...... ...... ...... Page 10 of ...... 34 34 33 33 33 32 35 36 36 32 32 31 31 31 30 30 30 38 39 40 27 27 41 43 42 43 40 40 39 39 38 39 39 38 26 26 26 64 Date: 18 February 2016 Protocol Number: 20140336 10. Product: Etelcalcetide CONFIDENTIAL 13. 14. 11. 12. 10.1 STATISTICAL CONSIDERATIONS 12.4 12.3 12.5 12.6 12.7 10.4 10.2 10.3 REFERENCES REFERENCES APPENDICES APPENDICES 11.1 11.3 11.2 11.4 12.1 12.2 REGULATORY OBLIGATIONS ADMINISTRATIVE AND LEGAL OBLIGATIONS LEGAL AND ADMINISTRATIVE 10.1.1 and Sets, Analysis Study Covariates Endpoints, Investigator Responsibilities for Data Collection Study and Data Collection Monitoring Language...... Publication Publication Policy Compensation Planned Methods ofAnalysis 10.3.1 Sample Considerations Size 10.1.2 Planned Analysis 10.4.1 10.4.2 10.4.3 10.4.4 Informed Consent Subject Confidentiality Subject Institutional CommitteeReview Ethics Board/Independent Investigator Signatory Obligations Protocol AmendmentsProtocol andStudy Termination Study andArchive Documentation ...... Study Endpoints Primary Analysis Primary SetsAnalysis General Considerations PrimaryEndpoints Secondary Endpoint(s) Additional AnalysesAdditional 10.1.1.1 10.1.1.2 10.4.2.2 10.4.2.1 10.4.3.1 10.4.3.2 10.4.4.1 10.4.3.4 10.4.3.3 ...... ...... ...... PrimaryEndpoints Secondary Endpoints Signs LaboratoryClinical Tests, Events rgentCommon Adverse -eme Treatment Pharmacokinetic EndpointsPharmacokinetic Pharmacodynamic Endpoints Subject AccountaSubject bility Treatment-emergent Events Adverse Antibody ...... ...... ...... ...... ...... ...... ...... ...... ...... ...... ...... ...... ...... ...... ...... ...... ...... ECG Vital and ...... ...... ...... ...... Page 11 of 44 44 44 44 50 50 51 51 44 44 44 44 44 52 53 55 44 45 45 44 45 45 45 46 46 45 46 46 46 47 48 48 48 49 46 48 64 Product: Etelcalcetide Protocol Number: 20140336 Date: 18 February 2016 Page 12 of 64 List of Tables Table 1. Schedule of Assessments ...... 28 Table 2. List of Analytes ...... 34 Table 3. Approximate Blood Draw Volume ...... 36 List of Appendices Appendix A. Additional Safety Assessment Information ...... 56 Appendix B. Sample Serious Adverse Event Form ...... 58 Appendix C. Pregnancy and Lactation Notification Worksheets ...... 63 CONFIDENTIAL calcium (totalcalcium calcium To evaluate thepharmacokinetic profile ofplasma Date: 18 February 2016 Protocol Number: 20140336 To evaluate thesafety andtolerability ofetelcalcetide 1.1 1. Product: Etelcalcetide CONFIDENTIAL single single 1.2 (sHPT dialysis, includingdialysis, haemodialysis the in patients United with States chronic kidney (CKD) disease requiringmaintenance were approximatelyand 1,000incident 2,000prevalent paediatric Data UnitedRenal States Data from System(USRDS) thatin the reveals 2.1 2. paediatric agedsubjects 2toless than paediatric rate children in is receiving30 dialysis to150timesgreater than thatofthe general Secondary hyperparathyroidism ( manifest in themanifest in paediatric Unfortunately,ions. of thelimitations therapy traditional for secondary HPT appear to and relative hypercalcemia gastrointestinal duetoenhanced absorption of D iPTH reduce derivatives these concentrations, can agents tohyperphosphatemia lead andanalogs] phosphate may binders) for beinadequate diseasecontrol. vitamin While traditionalOnce ondialysis, therapies for secondary D HPT[1,25(OH)2D3 (vitamin and secondary HPT. by hyperplasia gland and parathyroid by toward directed therapies of treatment established secondary HPT caused notonly is by renalfailurebut exacerbated itself also receiving dialysis therapy. mineral Thedisordered metabolism thatcharacterizes towardincreases as CKD endstage ubiquitous progresses amongand is patients ofiPTHaction ( 1,25-dihydroxy vitamin phosphate D, retentionand resistance skeletal tothe calcemic These includefunction. disturbances hypocalcemia, of renalsynthesis reduced acorrectiveas conducted among belongingconducted totheNorth 18sites American Paediatric ) intravenous ( receiving maintenancehaemodialysis population ( Primary OBJECTIVES Secondary Disease RATIONALE AND BACKGROUND response to metabolic disturbances tometabolic response resulting from declining kidney Martine 1997). Theprevalencez, andseverity ofsecondary HPT IV , , ) USRDS, McDonald, 2004). 2009; ionized calciumionized levels calcium) andalbumin corrected following a administration ofetelcalcetide. as wellasas dialysisthe adult population. A recent survey and peritoneal s HPT) develops relatively early thecourse in ofCKD 18 yearswith secondary old hyperparathyroidism . dialysis ( etelcalcetide, serum PTH and serum after USRDS, 2009). single dose single dose (0 to 19 years old) Renal Trials andRenal Trials administration to The mortality 2007, there these divalentthese Page 13 of 64 guidelines ( between theagesof2to lessthan18 yearsolddisplayCaxPabovetheNK-K/DOQI dialysis population, including Specifically,18%ofpaediatric CaxP. dialysis patients inadequate control of other biochemicalparametersofsecondarythe paediatric HPTin In addition, similar towhatisobserved intheadult population, thissurvey revealed < 55 mg 55 < age-groupspecificNKF K/DOQIrecommended target forCaxPof<65 and old, and44% ofthepopulation from lessthan the 12yearsto 18 yearsoldwereabove results,where22%ofchildrenbetweenby thesurvey theagesof6toless than12years toincrease withincreasingage,The prevalenceofelevatedCaxPappears asshown Foundation NKF K/DOQIguidelines for allpaediatricagegroups ( by theNationalKidney iPTH levelsabove300pg/mL,theupperlimitrecommended less than18. Theresultsshowthatoverall,49%ofthepaediatricdialysispopulation has 320 paediatric haemodialysisandperitoneal dialysispatients,betweentheagesof2to Collaborative Studiesgroup (NAPRTCS,unpublisheddata), included data from Date: 18 February 2016 Protocol Number: 20140336 Product: Etelcalcetide CONFIDENTIAL for mortality and cardiovascularmorbidity ( isariskfactorsecondary HPT,epidemiological data demonstratethatsecondaryHPT resistance (Kari, 2005; Tonshoff, 2005the classical). Beyond skeletal complications of secretion of growth hormoneaswell as toovercomeperipheralgrowth hormone inaneffortrecombinant humangrowthhormone tocorrectdisturbances in pulsatile through the optimal control ofiPTHlevels(Waller, with 2003 ), andbytreatment growth velocityinthispopulation can bepromotedbyminimizingrenalosteodystrophy CKD, particularlythose on dialysis(Kuizon,1999). Ithasbeen suggested thatnormal (Chesney, 2006 contributetogrowthHPT may retardation,which has beenlinked touncontrolled SHPT Coen, 1996;Sanchez,2003; Salusky,1987;Slatopolsky,1999). Inaddition,secondary and fractures inadults and children with advancedCKD( disease whichresultsin reducedbone massandincreases the riskofbone deformities frequently associated withsecondaryofhigh-turnover bone HPTisthedevelopment is associated withsubstantial adverseclinical consequence. Theclinicaloutcomemost K/DOQI biochemicaltargetsFailure toachieveNKF forthetreatment ofsecondaryHPT less than18 yearsold. less than6 years old,16%for6tolessthan 12yearsold,and9% for12yearsto (NKF K/DOQI,2005) guidelineswasinfrequentacross allage groups:5% for2yearsto for the2biochemical NKFK/DOQI parameters (iPTHandCaxP)recommendedbythe 2 /dL NKF K/DOQI,2005 2 , respectively. Finally,simultaneousac ) and also to over-suppression of iPTH with vitamin Dinchildrenwith ) andalsotoover-suppressionof iPTHwithvitamin ) recommended target forthatagegroup of <65mg ) recommendedtarget Moe, 2006; Melamed, 2006 hievement oftargetconcentrations hievement Cundy, 1985;Spasovski, 2003; Cundy, NKF K/DOQI,2005 ). Thismaybe Page 14 of 64 2 /dL ). 2 . Date: 18 February 2016 Protocol Number: 20140336 children, havechildren, cardiovascular anannual (betweenpopulation of25 theages and 34years), as many dialysis whom ofbegan (Cheung 2000;Oh etal, 2002). etal, Indeedthe youngest dialysis membersoftheadult -onset CKDchildhood displaya also ESRDhaveadult population, studies shownthatyoung with ESRD adults and morbidityand cardiovascular with associated risk secondary HPT are derived from the (Abdelfatah, arterialmayincreased stiffness ventricular toandleft lead hypertrophy due topromotion ofvascularcalcification by disordered mineral metabolism in which turn Product: Etelcalcetide CONFIDENTIAL placebo subjects (p <0.001). subjects placebo InStudy of 20120230,75.3% etelcalcetide treated week secondary HPT CKD in activatorallosteric sensingreceptor ofthecalcium (CaSR) intended weight of1048Da, of7 comprised D currentlyIt is to estimatedthat60% ofthe 80% membersthe general (above of population ofage) ( 75years Etelcalcetide 2.2 phosphorus, andCa xconcentration. P HPT patients, these in with agoal of simultaneously improving serum iPTH, calcium, oflimitations currenttherapy theneedfor better underscore treatments for secondary burden ofcomplications of secondary paediatric HPT the in from baseline in meanfrom in PTH baseline during etelcalcetide 20120229(Studies and 20120230) in population adult s e.etelcalcetid Etelcalcetide been two has in -controlled studied studies 3 placebo phase moreIn total, than1700 subjectsadult from 14 clinical studies have received 2.2.1 Refer totheEtelcalcetide Brochure Investigator’s for additional information. levels. d that noadditional invasive injectionis needed.In the context use, ofexpected clinical calcimimetic formulateda for IV administration treatment for secondary HPT D with vitamin (U ose levels ose of ) as a as dose bolus at theendof thehaemodialysis 2001; Klassen,most 2002).available While data describing themortality treated (AMG 416 (AMG etelcalcetide Amgen Investigational Product Background Clinical Experience subjects achievedsubjects theprimary endpoint , patients receivingpatients haemodialysis formerly 4169) is KAI a synthetic withpeptide amolecular are adjusted individually on based PTH andserum calcium versus 8.3% of 8.3% Efficacy Assessment Phase versus (EAP) high incidencehigh ofcardiovascular complications acid backbone backbone andoneL-cysteine.-amino-acid It is an mortality risk that is mortality thatis tothatsimilar risk oftheoldest nd SRDS, 2009; paediatric is administeredis TIW(three times a % of . InStudyof 20120229, 74.0% treatment back duringrinse such . dialysis population receives Etelcalcetide dialysis population and NAPRTCS, 2006) NAPRTCS, of at least 30% of atleast reduction ). Foley 1998). etal, for the treatment of is theonly Page 15 of . The 64 p = = p i subjects achieved reduction >50% mean fromin PTH baseline duringtheEAP compared with p als inbaseline meanduring theefficacy PTH was assessment (EAP). Etelcalcetide phase Date: 18 February 2016 Protocol Number: 20140336 demonstrated In ahead-to Refer totheEtelcalcetide Brochure Investigator’s for additional information. primary collectivelysecondary endpoints andthe demonstrated of efficacy etelcalcetide . significanceand 20120230achievedafter statistical adjusting for multiplicity. The predialysis PTH,P duringtheEAP)Studies in cCa,cCaXP, andevaluated 20120229 predialysis mean PTH with theprimary achievedsubjects endpoint this versusofplacebo 9.6% subjects (p <0.001). Consistent Product: Etelcalcetide CONFIDENTIAL In theadult thepopulation, pharmacokineticsof etel 2.2.2 calcium. hypocalcemia events andassociated secondary thatmayserum in toreductions occur with etelcalcetide are related mechanismto its ofactionacalcimimetic as andare consistent Etelcalcetide pathway CKD in requiringhaemodi patients with patients in normal renalfunction, whilehaemodialysis Etelcalcetide rapidlywhen three is timesaweekfollowing dosed hemodialysis. cleared etelcalcetide plasmalevelsreached near steady atthedosing endofeach 3to4hour haemodialysis exponential decaytri- following IV administration. three Following timesaweekIV CKD with secondary patients haemodialysis HPT requiring overchange (5 time single following to 60mg) andmultipleIV (2.5 doses to20mg) in haemodialysis bound toplasma albumin by covalent reversible In binding. Etelcalcetide by notmetabolized is CYP450 is Etelcalcetide predominately enzymes. observed ratioof2- accumulation = 0.004). o superior tocinacalcet endpoint for this (68.2% AMG 416versuscinacalcet, 57.7% 0.001). the known safety ofcinacalcet. profile Themostofetelcalcetide important risk is n the cinacalcet group (52.4%etelcalcetideversus A greater proportionrandomized ofsubjects totheetelcalcetide group -head phase 3study(Study with cinacalcet was etelcalcetide 20120360), was generally well , etelcalcetide waspredominantly eliminated by haemodialysis to be Clinical Pharmacokinetics endpoint, all secondary all endpoint, (proportion endpoints with ofsubjects non-inferior for achievement tocinacalcet from reduction of>30% ≤ duringthe 300pg/mL EAP, from change percent in baseline -tolerated. Most oftherisks characterized for to andthe3-fold, was effective-life half 3 to5days alysis -state . calcetide are session adult in after . Etelcalcetide exhibited is the predominant elimination 4 weeks adult 40.2% cinacalcet; cinacalcet; 40.2% linear andlinear not does CKD requiring patients of dosing with an CKD patients, Page 16 of . 64 paediatric ofa pharmacodynamics dosesingle subjects corresponds toa2.5mg for dose Date: 18 February 2016 Protocol Number: 20140336 The purpose 2.3 Product: Etelcalcetide CONFIDENTIAL dose givenThe2.5dose subjects. toadult mg wasthe dose Amgen anticipates on subjects haemodialysis . population potentialknown andadditional risks refer Please QTc ventricular prolongation, arrhythmi associated events occur thatcan secondary toreductions in serum( calcium ofacalcimimetic. action Themostofetelcalcetide important risk secondary toPTH were reduction observed, also consistent with thepharmacologic w reductions in PTH, difficult includingin tomanage subgroupsthose as ofpatients, such administration resulted ofetelcalcetide in 499 receivedsubjects 1700 than atleast of onedose thedrug with approximately developmentdemonstrated duringaclinical program population theadult in where more maintenance receiving haemodialysis safety, PKof andPD characteristics etelcalcetide paediatric in subject This phase phase This intended1 study is toinvestigate the safety Pa Pa study isThis carried being outtofulfill Amgen’s commitment totheetelcalcetide 2.4 (EC) characteristics ofetelcalcetide after dosea single paediatric in administration inconducted paediatric that may asafe dose titratable starting for represent this drug. Thedose of 0.035mg/kg ith baseline PTH > 1000 pg/mL. Reductions baselineith PTH >1000pg/mL.in Reductions serum calcium andserum phosphorus ediatric Committeeediatric with (PDCO) accordance in thePaediatric Investigationediatric Plan (PIP) agreed with theEuropean Medicines Agency (EMA) patients having received forstudies, etelcalcetide >12 Inclinical months. ) the in No EU 1901/2006 ( after dose . asingle receiving haemodialysis. receivinghaemodialysis. subjects agedsubjects 2toless than to theEtelcalcetideInvestigator’s Brochure, section 7for adescription of of this studyof this toevaluate is thesafety, tolerability, pharmacokinetic and Paediatric Rationale minimal with risk noprospect benefit ofdirect tothepaediatric patients, afavorablepatients, risk Risk Assessment . . The EMEA study to likely is yield generalizable about knowledge a 70 individual kg A based onexperiencebased with etelcalcetide theadult in IV ofe administration dose of0.03 dose . . , decision dated13, decision 01 -001554-PIP01- 18 years a a Although no previous studieshave been convulsions). and statistically significant andclinically relevant old. Thisold. weight based dose benefit profile-benefit ofetelcalcetide was 5 mg/kg e which , , lowest dose studied dose lowest tolerability, PK andPD telcal is halfis ofthe5 mg starting l telca subjects withsubjects s cetide in cetide Regulation ( is hypocalcemiais and will begivenwill IV in paediatric Page 17 of in Oct such such as Regulation HPT HPT population adult ). 2014). 64 Date: 18 February 2016 Protocol Number: 20140336 Etelcalcetide 2.5 adult in studied subjects onhaemodialysis. of the5mg dose starting given subjects. toadult The2.5mg was dose dosethe lowest for studyselected correspondsthis to a2.5mg for a70kg dose individual half is which Product: Etelcalcetide CONFIDENTIAL interchangeable. paediatric withsubjects etelcalcetide attheendof haemodialysis haemodialysis subjectspharmacodynamic (PD)study paediatric with in sHPT receiving maintenance a is single (PK)This arm, safety, single -dose open-label, pharmacokinetic and 3.1 3. 10 At least 10childrenAt least and adolescents ( 3.3 sites.across protocol The collected The study endpoints areThe study endpoints Section in defined Subjects 3.2 than 18years with sHPT receiving maintenance least At have beenperformed. on based sample size is practical consideration. No formal samplesize be 12toless than18years old. Participants clinicalParticipants this in investigationbereferred shall “subjects”. toas bydefined for ICHstudying guidelines paediatric patients. day overall study described design is by astudy schema s s 5 subjects post dose with dose post a safety follow synopsis section will beenrolled at approximately 1 on Day min after and4hours etelcalcetide 1at10 administration and will besafewill andwelltolerated after . The study haemodiafitration considers andprocedures haemodialysis Clinical Hypotheses StudyDesign PLAN EXPERIMENTAL Number of SubjectsNumber of Number of SitesNumber of Subjects shouldbe sHPT . . will receive 2 toless than 12years and old 5subjects at least on These are cohorts consistentt with maintenance m -up periodto a a s andfemale)ale with ages . Intensive PK single IVsingle of 0.035 administration mg/kg 5 sites 10.1.1 haemodialysis a a haemodialysis . single single Recruitment becompetitive will 30 days and IV in administration dose at theendof PD samples will be will samples PD . . post dose. dose. post will will be enrolled. ranging he agecategories calculations from 2 to less from 2toless Page 18 of for should The 64 must from beobtained bject’s thesu Beforestudy any screening). thatcandidates includes limitedinformation aboutthepotential candidate (eg, date of beexpectedInvestigators will tomaintain ascreeningof log potentialall study ofresolution theadverse event is it or until considered clinically stable. with clinically attheendadverse significant events ofstudy befollowed will until intervention offinal for thepurposes of collection datafor the primarySubjects analysis. 3.5.2 Date: 18 February 2016 Protocol Number: 20140336 and 6weeks,The estimatedstudy includesupto durationis which a 3.5.1 3.5 investigator consultationin with Amgen. whoSubjects are withdrawn study frommay bereplaced the atdiscretionof 3.4 Product: Etelcalcetide CONFIDENTIAL 101 4.1 onlocal regulations.based ofthe mustassent child beobtained also appropriate as to the ageofand/or subject toIn addition written informed from consent alegally acceptable representative, the Section 4. PrimaryCompletion 102 104 Su 105 Su 103 106 30 guidelines guidelines prior toanyactivities/procedures being-specific study initiated. providedthe subject has written assent based on legallySubject’s acceptable representative provided has and informed consent Male subjects or female sHPT Screening and Screening Baseline of thestudy ≥ (1. 30 > Screening and Screening Baseline days onstudy. 11.1 9 mg/ 25 bject must ≥weighbject must beonadialysatebject of calcium concentration days prior toscreening. ). ). mmol/L) for atleast 1month and receivingand End of Study forDuration Subjects Estimated Study Duration Replacement of Subjects Inclusion Criteria ELIGIBILITY SUBJECT dL specific activities/procedure,-specific the appropriate written informed consent 25 25 (2. . . : the time when the last subject is assessed: thetime subjectis when thelast or receives an Study Study mmol/L) maintenance haemodialysismaintenance 7 kg serum PTH>2 level (aged 2toless than18years) diagnosed with CKD serum calcium corrected from the . . at Baseline l egally representative acceptable (LAR) prior toenrollment (Day (Day . -2). (21 00 pg/mL(21 or h or local regulations and/orlocal aemodiafiltration and throughout theduration ≥ 2.5mEq/L 14 dayperiod screening local pmol/L) . laboratory Page 19 of (see for and 64 1 Concurrentorwithin28 days priortoenrollmentuse of medicationsthat prolong 211 Historyofprolongation theQTinterval(eg,congenitallong QTinterval, 210 Subject’s unstablescreening 12-leadECGsuggests arrhythmiaorothercardiac 209 Anewonsetofseizureor worseningofapre-existingseizure disorder within 208 Subjectreceived cinacalcettherapywithin 207 Historyofhypersensitivity orallergic reaction toany oftheexcipients listed in 206 cancers,within thelast Malignancyexceptnon-melanomaskin 5years. 205 Useofanyover-the-counterorprescriptionmedications within the14days or 204 Allherbalmedicines(eg, St.John’s andsupplements consumedwort), vitamins, 203 Subjectpreviouslyhasentered thisstudy 202 ExclusionCriteria orhas received Currentlyreceiving any investigationaldrug (or iscurrently using 201 4.2 Freeofanydiseaseor condition other thanthosediseases or conditions related 108 0 Subjectson anti-convulsant medication 107 Date: 18 February 2016 Protocol Number: 20140336 Product: Etelcalcetide CONFIDENTIAL 1 Subjecthas ventricularorTorsades de a historyofsymptomatic dysrhythmias 213 Subjectswith (QTc)>500msduringscreening, using acorrected QTInterval 212 http://www.crediblemeds.org/pdftemp/pdf/CompositeList.pdf refer tothe complete QT prolongationmedicationlistat QT interval(eg,sotalol, amiodarone, erythromycin,orclarithromycin). Please interval) orhistoryofventriculararrhythmias. second orthird degreeheart blockor otherconditions which prolong theQT Investigator’s opinion. that couldplacethesubjectatincreasedabnormality risk, based uponthe 2 monthspriortoetelcalcetideadministration. dosing. Section 6.2.1. Paracetamol (upto2gper day)foranalgesiawillbeallowed. isrequiredforreview andAmgenacknowledgment subjectparticipation. Investigator andtheAmgenMedicalMonitor.Writtendocumentationofthis Principal conditions secondarytorenaldiseasewillbereviewedbythe that arenot established therapies for subjects with renal disease orother 5 half-lives(whichever islonger)prior toreceivingthefirstdose ofetelcalcetide isrequiredforAmgen acknowledgment subjectparticipation. and theAmgenMedicalMonitor.Writtendocumentationofthis reviewand and continuinguseifapplicable, willbe by thesubjectwithin 30 dayspriortoreceivingthefirstdose ofetelcalcetide, while participatinginthisstudyareexcluded. prior toreceivingthefirst doseofetelcalcetide. Otherinvestigational procedures an investigational device) withinthe 30 day subject’s safety ortheintegrityofstudydata. to theirrenaldiseasethat, intheopinion oftheinvestigator, wouldimpactthe Pointes. Bazett’s formula. reviewed bythePrincipalInvestigator must beonastable dose for3months. or previously exposedtoetelcalcetide. orpreviously lessthan 30dayspriortoetelcalcetide s or5half-lives(whicheverislonger), Page 20 of 64 Date: 18 February 2016 Protocol Number: 20140336 214 Product: Etelcalcetide CONFIDENTIAL menarchal subject menarchal pregnantwho is Post- or or breastfeeding, planning is to 216 F 215 eligibility c will beperformedwill remains eligible toconfirm thatthesubject for thestudy. Ifsubject facilityresearch onDay for admission -2 Provided eligibility criteria all be havewill toreturn beenmet,asked subjects tothe investigational ( product Adverse Events informed consent forminformed consent before commencementofstudy legallysubject’s acceptablerepresentatives (LAR) subject informationsubject and/or recruitment material, if applicable committee (IRB/IEC) acopyrequires written ofthesite’s participationBefore begin subjects in any study 5. 217 of normal (ULN) has Subject a screening fromALT or AST the after etelcalcetide become pregnant or during breastfeed treatment andfor an 3 additional months isspermicide notavailable. partners use acondom. Thetwo acceptable-barrier is countries in where becausefemale notanoption thereof is condom is a risk eitherfemale may select adiaphragm, or contraceptive cap cervical sponge. A method [themale acondom must use material) (latexsynthetic andthe or other by partner) each andthefemale partner spermicide must use with thebarrier (IUD); Intrauterine hormonal intravaginal, transdermal, injectable, or implantableroute); Intrauterine device and progestogen or progesterone-only contraception hormonal given via oral, the preferred andusual ofthelifestyle subject.); Hormonal estrogen (Combined (The reliability ofsexualby abstinence must beevaluated theinvestigator andbe Ac during treatment andfor anadditional 3months after receiving thestudy drug. counseling and beadvised oftherisk tothefetus they if become pregnant whosubjects have puberty reached must receive pregnancy prevention (sexual) aresubjects considered of childbearing potential following during treatment sexual abstinence or use anacceptable method(s) ofeffective birthcontrol at screening subject and subject investigator’s knowledge. procedures, and/or tocomply required withstudy all tothebest procedures ofthe likelySubject tonotbeavailable tocomplete all protocol emale subjects ceptable ceptable methods ofeffective birth include control T riteria on based screening and D SUBJECT ENROLLMENT SUBJECT are tobe collectedfor they asubject once have receivedof thedose . . val informed oftheprotocol, appro form, other consent andall . . IP . through 3months after receiving. theetelcalcetide of childbearing administration . . A subject is considered is ). Aenrolled subject theyonce have met all institutional review ethics board/independent -releasing system (IUS); methods (one Two barrier potential who are to unwilling true practice (Baseline Visit) where Visit) additional (Baseline assessments Femalesubjects ay ay -2 -2 - specific activities/procedures,specific Amgen (Baseline Visit) (Baseline must personally sign andmust personally sign datethe local specific activities/procedures-specific with apositive pregnancy test lab ≥lab 1.5times theupper limit (see Section (see rue -required studyor visits assessments tearing when both sexual abstinence menarche. Female 11.2). Female Page 21 of . . The . 64 distributed using Amgendistributed study clinical procedures. drug The distribution active Etelcal 6.2.1 A physician atthe must beavailable time of ofadministration Investigational Product. member. staff investigationalAll product(s) be will 6.2 and containsdetailedprotocol, information regarding thestorage, preparation, destruction, ProductThe Investigational Instruction Manual (IPIM), tothis adocument external InvestigationalThe Amgen Product(s) 6.1 theLAR signs informedreceives consent) subjectEach whothescreening into period enters for thestudy when as the (defined recordmedical andin/on theenrollment CRF. 6. rescreened. study; must it notbechanged after initial assignment, asubject includingif is The subject identification remain number constant throughout must theentire clinical Monitor. rescreened at thediscretionofinvestigator in consultation with theAmgen Medical onall and must beused study documentationrelatedtothat Subjects maysubject. be manually. areany studyperformed. procedures Thesubjectidentification number beassigned will The i subjects in subjects Cumulativedata from enrolled 2subjects in Date: 18 February 2016 Protocol Number: 20140336 subject’s agesubject’s atscreening: eligibility confirmed, will is thesubject beassigned toCohort 1or Cohort onthe 2based Product: Etelcalcetide CONFIDENTIAL • • e administration of nvestigator todocument and is theenrollment decision the date, in subject’s cetide Cohort age2 5subjects 2→ At least to<12years Cohort 1→ This number This beused will throughoutto identify thesubject the studyclinical section Cohort section 2(see drug product Amgen Investigational Product (AMG Etelcalcetide Investigational Product Classification of Product(s) and/orDevice(s) Medical TREATMENT PROCEDURES TREATMENT At least 5 subjects age12 5subjects At least to<18years telcalcetid e. will bemanufacturedwill and packaged by Inc. Amgen 6.2.1 ). administered used in this in studyused include: Etelcalcetide. a unique subject a unique subject identification numberbefore Cohort be 1will reviewed prior toenrolling at theresearch facility by aqualified 416) Page 22 of and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¶V 1RFDVHVRIRYHUGRVHZHUHUHSRUWHGLQWZRSLYRWDOGRXEOHEOL DIIPHPEHURWKHUWKDQWKHVWDIIPHPE \]DEOHKDHPRGLDO\VLVKDVQRWEHHQV KHVWKHV\VWHPLFFLUFXODWLRQ LVWREHDGPLQLVWHUHGE\,9EROX HGSK\VLFLDQ7KHGDWHWLPH REHSUHVHQWWRHQVXUHVWXG\GUXJ LQLVWHUHGGXULQJULQVHEDFNW FWDQGWKHLQYHVWLJDWLRQDOSU VVDU\IRUHYHQWVUHTXLULQJF CCI CCI I CC I C C (WHOFDOFHWLGH,QYHVWLJDWRU¶V DTXDOLILHGVWDIIPHPEHU PJP/7KHVROXWLRQLV DWWKHHQGRIKDHPRGLDO\VLV VXEMHFWVDIHW\GXULQJWKH HUYDWLYHIUHHDTXHRXV RHQVXUHWKH RGXFWLVZLWKLQH[SLUDWLRQ QYHVWLJDWLRQDOSURGXFWKDV VDGPLQLVWUDWLRQDW RQDOSURGXFWZLOOEH HOHFWURQLFFDVHUHSRUW DGPLQLVWHUHGYROXPH WYLDOFRQWDLQVP/RI HFKQLFLDQRURWKHU FSHSWLGHSUHSDUHGDVD WXGLHGDVDWUHDWPHQWIRU HUZKRSUHSDUHGWKH RQWLQXHGPRQLWRULQJ I C C WKRXWFOLQLFDOV\PSWRPV &SURWHFWIURPOLJKW LVSUHSDUHG RLHDG PJ ORULGHDQG QG DJH I CC reviewed evidence ofrelationship totreatment for andclinical orsignificance. medical The review team be convened, will andtheevent relevant andall safety be datawill in vitalin signs, ECGs occurrence occurrence of thefollowing: riskhealth to the in thesubject. Inaddition,with dosing within Dosing the Date: 18 February 2016 Protocol Number: 20140336 Manager (CRSM) designee Investigator(s), Amgen Monitor, Medical Amgen Global Safety Officer (GSO) or Cohort 1,cumulative study bereviewedby datawill ofthe ateam composed study (GSO) beyond endofstudy.Monitor TheAmgen Medical Global Safety andAmgen Officer Product: Etelcalcetide CONFIDENTIAL Additionally, after endof study visits have beencompletedfor 2 6.2.2 meetingin minutes level,dose additionalenroll subject safety andPK may data,thereview other decisions (eg,. make committee lower the Cohort 1anduponunanimous by decision thereview Based committee. on emerging reasonably toleratedbased onavailable verifiedor source . and PK results will history,medical medications, concomitant adverse events, ECGs, laboratory vital signs, available All Officer or designee. study IP data,includingdemographics, administration, Investigator orPrincipal Amgendesignee, Monitor,Global andAmgenSafety Medical • • or • • on an ongoing basis.on anongoing or designee will review will or designee cumulative subject’s each safety datathrough endof suspected treatmentsuspected (SAE) -related serious adverse event subjectsingle treatmentsuspected -related 2 separate, treatment2 separate, suspected -related a single a single subject; (CTCAE treatmentsuspected -related and Research additional needed(eg,Study Amgenmembers Clinical as Cohort Rules Stopping ) v4.0 , , cohort Cohort open 2will for enrollmentbeen whenhas thedose foundto be Biostatistician, PKBiostatistician, , Scientist . . be reviewed. review Data notrequire will queriesthat all beresolved or clinical laboratoryor clinical results are observed andpos or Grade 2or in mo 2adversere events subjects; or will bestoppedwill suspected if treatment-related AEsor changes s CTCAE v4.0 Common TerminologyCommon Criteria for Adverse Events in Cohort decisions All 1, etc.). will be documented study datafor atleast ). ). etc. CTCAE v4.0 Grade 3or greaterGrade adverse event The voting membersinclude the cohort Grade 2adverseGrade events in will bestoppedwill for any 2 subjects 2 subjects enrolled subjects in a single asingle in subject e a significant enrolled enrolled Page 24 of in in in a in 64 if ALLif ofthe below criteria are met: (Additional Safety drug Information) liver Assessment for possible -induced injury (DILI), should befollowedSubjects according totherecommendations Appendix in B 6.3 awrittenAmgen issue will notification ofthedosing decision totheInve stigator(s). The reviewof safety dataanddosing decisions bedocumentedwill minutes. meeting in by Amgen theInvestigator(s), Monitor,GSO. andAmgen Medical Date: 18 February 2016 Protocol Number: 20140336 Dosing ofadditionalDosing subjects in Product: Etelcalcetide CONFIDENTIAL AND AND AND < < Baseline AST or ALT value ULN • • • Increased ASTIncreased or ALT from baseline valuebelow: therelevant specified as TBIL > o o o o o and/or elevated TBIL values include, butare notlimited to: immediately apparent; important for elevated alternative causes AST/ALT forNo thecombination other cause oftheabove laboratory abnormalities is o o o o o o Viral Hepatotoxicity CriteriaAdditional for Safety Assessment dueto Potential syndrome,Crigler Heritable and plants, supplements, mushrooms Exposure ischemiacausing Right Parvovirus) Cytomegalovirus, Herpes SimplexVaricella, and Toxoplasmosis, Virus, Hepatobilliary disease tract Autoimmune Alcoholic Alpha-one antitrypsin defic glucuronidation (eg, indinavir, atazanavir) Wilson’s Non Non 2x upper limitof 2x upper normal (ULN)or INR > alcoholic Fatty-alcoholic Liver including Steatohepatitis Disease (NASH) hepatic causes (e.g. causes rhabdomyolisis, hemolysis) -hepatic Barr Virus, hepatitis A/B/C/D/E, (eg, Hepatitis Virus, -Barr Epstein sided sided heart failure, hypotension or anyofhypoxia cause totheliver disease andhemochromatosis disorders causingimpaired glucuronidation (eg, Gilbert’s hepatitis to hepatotoxic agents/drugs including herbal and dietary hepatitis the -Najjar syndrome) anddrugs bilirubin that inhibit cohort iency mayonly beresumed uponunanimousvote > > AST or ALT elevation 3x ULN 3x 1.5 Page 25 of 64 Haemodialysis information Haemodialysis - Date: 18 February 2016 Protocol Number: 20140336 Throughout thestudy, i 6.4 Product: Etelcalcetide CONFIDENTIAL 6.7 reported according tothe instructions provided theIPIM. in Any complaint(s) product associated with etelcalcetide /modified by Amgen. or device(s) includes Drug(s) investigational product. includesanymaterial. This drug(s) or device(s) provisioned and/or repackaged byclinic by eitherAmgen distributors or andpartners for whom manufactures Amgen the performance ofadrug(s) or device(s) afteris it released for distribution to market or deficiencies related tothe identity, quality, durability, reliability, safety, effectiveness, or A complaint product is any that written, electronic or oralcommunication alleges 6.6 andreportedchart onthe appropriate report case form. and thedialysate ofcalcium (amount must andpotassium) becaptured thesubject’s in 6.5 and approved by Investigator thePrincipal Monitor andAmgen Medical 30 herbalsupplements,All vitamins, andnutritional within taken supplements thelast 7.5 ofIn cases hypocalcemiasymptomatic than ortheserum if calcium less level is frequency, route, andstart dateand date. stop through the end ofsafety-up period.Collect follow are to therapies the applicableCRF. becollected Concomitant from informed consent jeopardized. ofconcomitant use All medications andsupplements berecorded will on the in as, the studylong as judgment oftheinvestigator, thesubjects’ safety not is An Section in listed treatments deemed toprovide necessary adequatesupportive except care for those sotalol, amiodarone,sotalol, erythromycin, or clarithromycin) for thedurationofstudy. Useofany cinacalcetprohibitedTreatment is with within30 days prior toreceiving etelcalcetide days on prior todosing Day continued appropriate) if use, 1(and attempt bemade should nottochange the mg/dL (1.875 mmol/L),will oralor IV calcium beadministered necessary. as Concomitant Therapy Excluded Treatments, Medical Device Product Complaints Other Procedures- Treatment During 6.7. Study Period nvestigato rs may anyor prescribe medications concomitant includi ng date(s),mode start ofdialysis, and times stop - medications thatprolongmedications QT interval (eg, subjects’ subjects’ treatment duringthecourse of Haemodialysis therapy name, indication, dose, unit, within 28days prior toreceiving supplied by are tobe Amgen Use , , and/or Procedures must bereviewed . . Page 26 of and 64 7.1 7. maintain subjectsafety. and procedures notbe will allowedduring thestudy necessitated in unless order to Date: 18 February 2016 Protocol Number: 20140336 http://www.crediblemeds.org/pdftemp/pdf/CompositeList.pdf QT medication prolongation at list etelcalcetide Product: Etelcalcetide CONFIDENTIAL and for the duration ofthe study Schedule of Assessments STUDY PROCEDURES STUDY is is . prohibited referPlease tothecomplete . These excluded therapiesThese Page 27 of 64 Product: Etelcalcetide Protocol Number: 20140336 Date: 18 February 2016 Page 28 of 64 Table 1. Schedule of Assessments Screening Baseline Treatment Follow up EOS Study Day -14 to -3 -2 1 3 5a 8 10 30 Study Time 0 10 min 4 hour General and Safety Assessments Informed consent X Medical history X Weight (kg) X X X Height (cm) X Vital signs (BP, HR, Temp) X X X Physical examination X X 12-lead ECG X X X Serious adverse events X------X Adverse Events X------X Concomitant medications X------X Dosing Etelcalcetide administrationb X Laboratory Assessments Clinical chemistry X X Hematology X X Ionized Ca, Serum albumin, Serum cCac, d X X X X X X X Serum PTHc X X X X X X X Serum pregnancy test X (females of child bearing potential only)e Pharmacokinetic and Other Blood Samples Etelcalcetide PK plasma collectionc, f X X Xf X X X X Antibody sample collectiong X X Footnotes defined on next page of table CONFIDENTIAL Product: Etelcalcetide Protocol Number: 20140336 Date: 18 February 2016 Page 29 of 64 cCa = albumin-corrected calcium; EOS = End of Study; iCa = ionized calcium; HD = haemodialysis; IV = intravenous a. Subjects will continue to receive HD per their regular schedule (Day -2, 1, 3, 5 [or Day 6 depending on the day of the week the study begins], 8 and 10). b. On Day 1, etelcalcetide will be administered as an IV bolus dose after HD during rinse back. c. All procedures (except those scheduled on Day 1 at time 0, 10 min and 4 hour and Day 3 post-HD) will be performed prior to HD on the respective study day. d. Serum samples for albumin and calcium for screening and routine monitoring of pre-HD cCa. When albumin is less than 4.0 mg/dL, the calcium level will be corrected according to the formula: cCa (mg/dL) = total Ca (mg/dL) + (4 – albumin (g/dL))*0.8. e. Pregnancy tests will be performed in female subjects of child-bearing potential within 7 days prior to start of investigational product. f. PK plasma collection pre-HD and post-HD on Day 3 g. Subjects with positive titers for antibodies to etelcalcetide at EOS may be asked to return to the clinical research unit to provide additional serum samples. CONFIDENTIAL • • • • • • • • • designated indesignated theSchedule ofAssessments( The following procedures are tobecompleted duringthescreening period attime points 7.2.2 fromobtained legally representative. acceptable thesubject’s Beforestudy any 7.2.1 Key in are assessments described the subsections below. and laws local regulations may discretion. attheInvestigator’s beperformed proceduresAdditional deemed part ofstandard as necessary orof care as required by week • • • • follows: Throughout thestudy,be will thepermittedfor scheduledassessments timeas windows withon Daythealign subject’s 6to procedures beperformedshould prior to Date: 18 February 2016 Protocol Number: 20140336 coincide with haemodialysiscoincide thesubject’s During thestudy,effort should every bemade toperform thestudy procedures 7.2 Product: Etelcalcetide CONFIDENTIAL indicated inindicated the Schedule1 ofAssessments(Table al signsal (eg,pressure, blood Vit heart rate, temperature) Heightand Documentation Serious Serious Physical Examination Physical 12-Lead association with study theirpossible dataincludingDemographic sex, age, been signed Laboratory assessments Confirmation thattheInformed Form form andAssent Consent + 3 days for Day +1 day for Day 5 for Day± 30minutes 3 for events± onDay 15minutes that each subject that each thestudybegins (Day 1),may Day 5assessments beperformed Adverse Adverse ECG Screening Informed Consent General Study Procedures Weight specific procedure,-specific theappropriate written informed must be consent HD) (pre- of concomitant medications (EOS) (EOS) 30 Event reporting as per standardas (including ofcare medical/surgical history) through 10 HD) (pre- 1 1 HD schedule. HD schedule. subject subject safety HD) (pre- HD (HD) race, and race, ethnicity will becollected order in to 1 Table schedule. schedule. , Section Section ) (Section) 7.1). . Depending ontheDepending day ofthe Unless otherwise noted all HD) (pre- ). 7.1). Study should visits (as applicable)(as Page 30 of as as have 64 the Schedule1 ofAssessments (Table Safety 10. Thefollowing be will procedures completed atthesafety follow Safety followupvisits on occur will Day6 (depending 3,5or onstudy day), start 8and 7.2.5 during rinse during rinse back After theinvestigator has confirmed eligibility • • • Date: 18 February 2016 Protocol Number: 20140336 If If Product: Etelcalcetide CONFIDENTIAL • • • the administered beenrolled thesubjectwill assessments, • • • indesignated theSchedule1 ofAssessments(Table The following procedures becompleted will duringthetreatment periodatthetimes 7.2.4 age. The following procedures w toconfirmtesting eligibility final andtoestablish assessments baseline prior todosing. Two days before dosing (Day subjects -2)return eligible will to theresearch for center 7.2.3 been • • the Schedule1 ofAssessments(Table • • a subject is Documentation Adverse Event Serious Serious Anti Documentation Serious Laboratory assessments (10 min PK Etelcalcetide administration Vital signsVital (eg,pressure, blood heart rate, Weight 12-Lead ECG Laboratory assessments 4 hour PK sampleis collected. < 30days etelcalcetide antibody-etelcalcetide collection Adverse Adverse Adverse Event reporting after thecompletion required ofall assessmentspre-dose ed rescreen Treatment Baseline ) dose and 4hour post since theprevious ICFwasobtained. signature since . . HD) (pre- Subjects remain will theclinical in research for unit observation reporting of concomitant medications of concomitant medications Event reporting Follow , a new informed consent form must be signed unless it, anewbesigned form informedunless has consent must i ll becompleted and ll atbaseline designatedat time in points HD) (pre- HD) (pre- -up Visit(s) ). ). ) (Section) 7.1). HD) (pre- to Cohort 1or Cohort 2 based onscreening andDaybased -2 temperature) ). ). On Day 1etelcalcetide HD) (pre- based based on -up visits according to , and after HD, the subject’s the subject’s Page 31 of is tobeis until until 64 M 7.2.7 Common Terminology Criteria forCommon Adverse TerminologyCriteria (CTCAE) Events version 4.0( on theappropriate CRF. Any unresolved history medical will begraded toaccording historyRelevant medical findings historysubject’s kidney disease andsecondary ofchronic hyperparathyroidism. and within14 days prior toenrollment ofastudy subject. The investigator orobtain qualified designeehistorya completemedical will atscreening • • • • • at thesafety follow The endofstudy onDay occur visitwill procedures 30.Thefollowing will be completed • • • • • 7.2.6 • • • Schedule of Schedule Assessments • n) anddiscretio must bereported onthe CRF. Whenvital signsandblood sample Abnormal maymeasurements. berepeated measurements (upon investigator mustasupine bein positionSubjects for hemodialysis. Date: 18 February 2016 Protocol Number: 20140336 • Product: Etelcalcetide CONFIDENTIAL recorded by thei signs,Vital includingsystolic/diastolic pressure, blood heart rate, andtemperature will be 7.2.8 Adverse Adverse PKassessments PKassessments Anti Laboratory Serious Documentation Physical 12-Lead signsVital (eg,pressure, blood heart rate, temperature) Weight Documentation Adverse reporting Event Serious Serious Laboratory ) Day 10) etelcalcetide antibody-etelcalcetide collection Adverse Event reporting Adverse Adverse Event reportingEvent ECG Examination as per standardExamination as ofcare End of Study Visit Vital Signs Assessments Assessments edical History nvestigator or qualified designee atthe HD) (pre- up visits according-up visits totheSchedule ofAssessments(Table1 of concomitant medications of concomitant medications HD) (pre- HD (pre- Event reporting 1 (Table HD) (pre- HD) (pre- -HD and post will berecordedwill source thesubject’s in document and ). ). All measurementsAll prior beobtained will to HD) (pre- at least 5minutes prior to vital signs Day 3 on Day HD on ; pre-HD time points specifiedtime points the in Medical history include will the HD) (pre- Day 5 Day or 6 or Appendix , , Page 32 of Day 8& ). A). 64 Date: 18 February 2016 Protocol Number: 20140336 are drawn. occurcollection atthesame signs time,should vital beperformed beforesamples blood Product: Etelcalcetide CONFIDENTIAL the time examinationA physical beperformed will investigator by the or designated physician at 7.2.9 Record all onthevital signsmeasurements CRF. for selected a subject should bethe same thatis throughout used thestudy. throughout the study anddocumentedCRF. onthevital sign Thetemperature location Assessments1 (Table 12-leadA single ECGbeperformed designated attimepoints will theSchedule in of time (notBlood sampling toexceed 5.6 7.2.11 toAmgen.ECG bemadewill available the subject’s documents. source Atof therequest thesponsor, acopyal oftheorigin The PIreviewtheoriginal will Once signed, ECG ECGs. all be will tracing retainedwith measurements:following Heart Rate, QRS,QTc beobtained will measurements prior tohemodialys theposition, subject should as most bein recumbent position possible. before conducted. ECGassessment is unable Ifthesubject is the tobein supine mustsupine bein Subject position in and arested calm state for atleast 5 minutes 7.2.10 or the CRF. findings Anyabnormal worsening findings Abnormal found screeningbe will findings during reported history onthemedical page of CRF receivedetelcalcetide . points points indesignated theSchedule ofAssessments 2 Table points specifiedpoints theSchedule in ofAssessments The position selected for The position selected asubject should bethe used same thatis below Physical Examination Clinical Laboratory Safety Assessments Electrocardiograms outlines thepaneloutlines ofanalytes required for safety laboratory ). Data bereported will ontheCRF will be reported ontheEvent CRF . mL) formL) safety laboratory be will at testing conducted , andPR intervals. is. found after thesubject has . . . The ECG must include the. TheECGmust Results willResults be reported onthe All All Page 33 of testing. 64 Date: 18 February 2016 Protocol Number: 20140336 Product: Etelcalcetide CONFIDENTIAL andcalcium) PTH becollected determinationswill attime (total ofserum calcium Measurements calcium, albumincalcium corrected andionized 7.2.12 a Schedule of Schedule Assessm are Collection Notebook.Collection and storage laboratoryshipment tothecentral are provided aseparate in Sample and dateof of collection sample.each Detailedinstructions on samplecollection, logcomplete ashipping include thatwill subject identification information andthetime at collected time points indesignated theSchedule ofAssessments.Study staff site will (0. 15 Blood samples 7.2.13 Section drawn part oftheClinical as Laboratory indescribed SafetyAssessments The calcium level determinationsdescribed in this section are derived from thesamples corrected calcium, and ionized calcium ionized and calcium, -corrected albumin calcium, total include To Alanine aminotransferase Alkaline phosphatase bilirubin Direct bilirubin Total Uric Acid Creatinine Blood urea nitrogen Phosphorus Magnesium PTH Calcium Albumin Total protein Bicarbonate Chloride Potassium Sodium Chemistry Aspartate shown in3 Table 7.2.11 . Results bereportedwill theCRF in a aminotransferase (HCO3) Pharmacodynamic Measurements Pharmacokinetic Measurements (BUN) . mL) for thedetermination ofetelcalcetide be PK will parameters ents (ALT) (SGPT) (ALT) 1 (Table (AST) (SGOT) (AST) 2 Table ). . List of Analytes • • • Hematology • White blood cell d Platelets Mean corpuscular volume Hematocrit Hemoglobin . Approximate draw blood volumes Lymphocytes Basophils Eosinophils Total neutrophils s s point designated the in ifferential s Page 34 of 64 Date: 18 February 2016 Protocol Number: 20140336 (see todonateasked approximately 28.8 anticipatedIt is enrolled thatsubjects this in study greater than withwill weights 12kg be 7.2.14 Product: Etelcalcetide CONFIDENTIAL pregnancy atscreening. testing On Day -2( bearing child potential havewill blood anadditional sample(0.5 mL) for obtained serum drawn for safety (including laboratory Females assessments Baseline PDof endpoints). ubjects thatSubjects weigh PK and (0.15 mL) be drawn. Approximately 6.2 safetyeach followupvisit(Day 3,5(or 6), 8and10), approximatelyto 3.3 0.15 be drawn for antibody (0.45 mL) andsafety lab/PD endpoints (3.1 mL). Dayat On 1and approximately 16.7 will notrequirewill of aserum(Baseline) approximately pregnancymL On2.3 test. Day-2 weighing 12 or less kg are notanticipated tobe bearingof child potential andtherefore safety laboratory (includingPD assessments Baseline Female endpoints). subjects Day 1andat be will blood drawn for antibody (0.45(1.8mL). mL) endpoints On andsafety lab/PD timepaediatric per regulatory on guidance volume blood total duringaperiodof four weeks not and will exceed atany 1% single study bloodSpecified are approximate volumes andmay vary, the however, per individual, (0.45 2.1 mL bedrawn will Approximately. 3.4 3 Table related blood loss-related blood any in (including the maneuver) losses notexceed will ofthe 3% mL) safety laboratory ( assessments for estimatedvolumes). At screening approximately will of blood 5.6mLbe each safetyeach followupvisit Anticipated Blood Collection Volumes safety laboratory(5.6 assessments mL) attheendofstudy visit. mL. 7 to At screening approximately blood 2.8mL of 12 kg will be will todona12 kg asked te mL of blood will be will blood mL drawn of for antibody (0.45 mL) mL over ofblood ofthestudy thecourse period (Day approximately, 8and10), 3,5(or 6) mL bedrawn will ofblood for antibody 2.8 mL) attheendofstudy visit. clinical trials. aseline) approximately Baseline) 3.6 smaller amounts ofblood, will bewill drawn for mL will ofblood Page 35 of , mL will 0.15 64 to Any PK blood 7.4 and thelaboratory for detailed manual collection and handlingructions. inst reanalysis, reanalysis, forand analyses method transferand comparability. include,also notlimited butis of to,investigation unexpected results, incurred sample methods reliable produce andvalid datathroughout thecourse ofthestudy. ca This n tonecessary to minimizestudy risks This subjects. includes g toensuretestin analytical Refer of totheSchedule Assessments maytoreturnresponse beasked also for additional follow 1 (Table Date: 18 February 2016 Protocol Number: 20140336 Product: Etelcalcetide CONFIDENTIAL antibodies. positiveSamples testing antibodies formay binding Blood sample(s)for AntibodyDay ( areatBaselin tobecollected e testing 7.3 out anti and presence complexes. ofimmune Additional m samples blood andneutralizing antibodies may characterizedfor befurther quantity/titer, isotype, affinity sequelae thatsequelae are considered potentially related toananti whoSubjects positive test forantibodies binding, non-neutralizing andhave clinical Schedule of(Schedule Assessments, Total Antibody PK PTH albumin, cCA, (including Calcium, PTH) Safety Lab Tests Sample -etelcalcetide ) can beanalyzed for anyoutlined the in ofthetests andproto col for any tests or Sample Storage andDestruction Antibody Procedures Testing antibody antibodies during thestudy. 3 Table sample collected 1 Table Volume Subject > > 12 kg Weight . Approximate Blood Draw Volume . Approximate Blood Draw (mL) 0.45 0.15 3.1 5.6 ) for themeasurement ofanti 1 (Table Volume Subject 7- Weight (mL) 0.45 0.15 12 kg 1.8 2.8 according ), applicable,as for specific time points Samples Subjects to the of dule Sche Assessments No All 2 2 5 5 2 8 8 -etelcalc -up testi of of al -etelcalcetidebinding ay be obtained toruleay beobtained ng. etideantibody so be tested for betested so Volume Subject > > Weight Total (mL) 15.5 11.2 28. 12 kg 0.9 1. 2 2 8 -2) Page 36 of and atEOS 7 Volume Subject Weight – – Total (mL) 16. 5.6 0.9 1. 12 kg 9 9 2 2 7 64 Samples will be destroyed once all protocolSamples bedestroyed will all once samples blood provide with thesponsor therequired number study andsubject thatany so remaining thecontacting investigator. Following from therequest thesubject, therightThe subject retains torequest thatthesample bedestroyed material by consent. the personal or physician, other third exceptparties, specified as the informed in recordmedical andare nottobemade available tothesubject,members ofthefamily, treatment theresults ofother course, areexploratory instudies not placed thesubject’s theevaluationsareSince notexpected tobenefit thesubject directly or to alterthe reported as study.part beretained ofthis can for Samples up to20years. fromResults are tobe analysis this documented andmaintained, butare notnecessarily ofcharacterize aspects the (eg, molecule mechanism ofaction/target, metabolites). See Section discoveries, or gained producedor derivative materials from thesample. tosuchcommercial rights and product nocommercial has tothedata, rights information, project,research thesponsor owns product.the commercial no Thesubject has longer justifiesthe product keeping sample). Ifacommercial developedis from this appropriate rationale(eg, thescientific for experimentation with acertain sample type no ofthethroughrequest subject theinvestigator, at the endof period, storage or as responsiblethe samplematerialsandis for thedestruction of thesample(s)at theexclusiveThe sponsor is owner ofany data,discoveries, or derivative materials from retained by Amgen. However, from prior samples collected for totherequest destruction, information will be and/or prediction ofresponse toetelcalcetide, secondary hyperparathyroidism duetochronic kidney disease, thedose response and remaining (ie,residual samples back Date: 18 February 2016 Protocol Number: 20140336 If confidentiality. the samples for thestudy. arein stored database Results a secure toensure analysis samples All and associated results becodedwill prior tobeing from shipped for thesite Product: Etelcalcetide CONFIDENTIAL informed consent is provided is informed consent subject by the or storage. Samplesbe will using tracked aunique that identifier assigned is to 11.3 and any otherfrom components thecells can andbe located destroyed. for subjectconfidentiality. -up) toinvestigate andbetter understand the -defined procedures ’s LAR ’s characterize antibody respons , Amgen can doadditional can , Amgen testing on are completed. the to Investigator is Page 37 of e , and 64 Subjects (orSubjects to alegally acceptable representative decline (LAR)) can continue rec without prejudice totheir by futurecare medical the physician or attheinstitution. haveSubjects therighttowithdraw from thestudy atany andfor any time reason 8.1 the subject the forthe subject options continuation oftheSchedule ofAssessments( from product investigational or other required protocol therapies with andmust discuss investigator todiscussis with thesubjectappropriate processes for ntinuationdisco time participation duringthestudy butcontinue in occurs, thestudy. Ifthis the investigational and/or product required other protocol therapies or procedures atany Section country’slocal regulatory onparameters mechanism, based consistent with and/or required other protocol therapies by aseparate may Subjects beeligible for continued treatment withinvestigational Amgen product(s) w and/orproduct required other protocol therapies, procedures,protocol or the study a as The investigator cantowithdraw and/or sponsor decide from asubject(s) investigational 8.2 withto discuss thesubject appropriate procedures for withdrawal from thestudy. data publically beincluded available can after withdrawal ofconsent. The investigator is willwithdrawal ofconsent beincluded theanalysis in ofthestudy, permitted, andwhere notwishdoes unable toor is tocontinue further study participation. Subject dataupto receive further protocol forWithdrawal ofconsent thatthe(orLAR) astudya means subject the family/friends, correspondence/communication in from with other physicians, reviewof follow to document thechange the Schedule ofAssessments ( of collection data, including endpoints andadverse events. The Investigator must Date: 18 February 2016 Protocol Number: 20140336 8. Product: Etelcalcetide CONFIDENTIAL hole atanyhole time prior to study completion. medical medical records). -up that agreed is (eg,to byin thesubject byperson, telephone/mail,through 12.1 . Subjects’ Decision to Withdraw Subjects’ Participation Prior to Study Completion Investigator or DecisionTerminate or to Sponsor Withdraw WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY AND PROCEDURES, TREATMENT, FROM WITHDRAWAL -required therapies or procedures, and thesubject (or aLAR) protocol provided or as for by the 1 Table ) andthe level of does not wish to notwish does 1 Table Page 38 of ) and eiving 64 or thestudy due toanadverse refer event, toSection legally acceptablerepresentative towithdraw requests protocol from removed duetoanadverse treatment from Intheevent event. asubject, or subject’s The investigator’s clinical judgment istodetermine used tobe asubjectis whether not considered anadverse event. elective as intervention such surgery cosmetic or procedurewhileonstudy, amedical is (ie,anticipated more fluctuation thanusual ofdisease) during thestudy, an or involves investigator’s assessment.pre A increased inincreased severity, frequency, and/or duration indicatesthatWorsening thepre -existing medical condition or underlying disease The definition ofadverse events worsening includes ofaprecondition.-existing medical investigator or The investigator responsiblefor ensuring is thatanyevents adverseobserved by the Thesubject. event notnecessarily does relationship have acausal with study treatment. An adverse event defined any is occurrence as untoward medical aclinical in trial 9.1.1 9.1 9. • • • • forReasons from removala subject are: thestudy of 8.2.2 • • • • • includeassessments any ofthefollowing: forReasons removal protocol from Date: 18 February 2016 Protocol Number: 20140336 8.2.1 Product: Etelcalcetide CONFIDENTIAL lost tofollowlost death withdrawal of consent fromwithdrawal ofconsent study by decision sponsor decision by decision (othersponsor thansubjectrequest, safety concern,tofollow lost tofollowlost death deviation, non-compl safety concern (eg, duetoanadverse event, ineligibility determined, protocol request subject criteria (listcriteria pregnancy)criteria), Adverse Events Definition of Safety Events SAFETY DATA COLLECTION, RECORDING, AND REPORTING AND RECORDING, COLLECTION, DATA SAFETY Reasons forStudy Removal From Reasons for Removal Fro reported are by recorded medical thesubject subject’s in record. -up -up iance, requirementiance, for alternative therapy, protocol existing condition -existing thathas not worsened more than -required investigational product(s) or procedural m Treatment m more thanexpected 8.1 for additional instructions on -required therapies by the by the specified -specified Page 39 of -up) has has 64 • • product investigator or reported thatoccur by dose after first thesubject ofinvestigational The investigator for ensuring responsible thatall is adverse events observed by the • • • The investigator thefollowing must assign event adverse attributes: • • • • 9.2.1 9.2 emergency surgery, visit,outpatient room or urgent intervention. (DILI) Appendix (see allergicinclude bronchospasm, convulsions, blood dyscrasias, drug induced liver injury of“othercriterion medically event”. important serious ofsuch Examples of theserious criteria, the event beclassifiedaserious adverse as could event under the If aninvestigator anevent considers tobeclinically important, does butit not meet any necessitated anadmission toahealth facility care stay). (eg, overnight An adverse event would meet of“requires thecriterion hospitalization”, if theevent • Date: 18 February 2016 Protocol Number: 20140336 • seriousfollowing criteria: adverseA as serious defined anadverse1ofthe is event eventatleast thatmeets 9.1.2 the study. the procedures recommendedfor safe withdrawal from protocol Product: Etelcalcetide CONFIDENTIAL Action taken.Action Assessment ofrelatedness toetelcalcetide , Severity, andresolutionDates ofonset (ifresolved), Adverse diagnosis event or syndrome(s),known if (ifnotknown,or signs symptoms), anomaly/birthcongenital defect in results persistent or disability/incapasignificant city patient in requires or hospitalization prolongation ofexisting hospitalization threateninglife the at (places subject immediateofdeath) risk other medically event important serious fatal through theend of study Criteria forNot ReportingProcedures Events Adverse That Do SafetyEvent Serious Events Adverse A for DILI reporting criteria), or events thatnecessitate an - Procedures Reporting are reported using theEvent Adverse CRF -required therapies or Events . . events could Meet Serious Page 40 of 64 Date: 18 February 2016 Protocol Number: 20140336 Adverse (CTCAE) Events The adverse used event gradingscale bethe will Terminology Criteria Commonfor Product: Etelcalcetide CONFIDENTIAL Appendix in investigator’s knowledge oftheevent. AdverseSerious Event (eSAE) Report Contingency 24hours Form within ofthe adverseserious event, tobereported the information is toAmgen electronic via an If theelectronicdatacapture (EDC) unavailable to is staff system the site toreport th via CRF. theEvent following 24hours submitted toAmgen the within investigator’s knowledge oftheevent recordmedical and throughconsent the investigator or reported thatoccur by after signing thesubject ofthe informed The investigator for ensuring responsible thatall is serious adverse observed events by 9.2.2 reversibility. The investigator expected tofollow is reported until adverse or events stabilization recordresolution, asingle event level for each of severity ontheEvent CRF. event. sequelaeclinical (not the laboratory abnormality) theare toberecordedas adverse or current adjustmentin therapy are considered Whereadverse events. applicable, recorded as However,adverse laboratory events. thatrequire value changes treatment without significancefindings (based clinical onthe Investigator's judgment) are notto be nt changesignifica from thesubject’svalues. baseline Ingeneral, abnormal laboratory whether anindividual anabnormalin represents value studyaclinically subject The investigator responsiblefor reviewing is anddetermining laboratory results test a study activity/procedure?” the question: there “Is a reasonable possibility thattheevent caused mayby been have protocol whetherThe investigator must assess theadverse related event possibly is toother i Isquestion: possibility there areasonable thattheevent caused may have been investigational product. relationship is This indicated by ortothe “no” a“yes” response whetherThe investigator must assess theadverse related event possibly is tothe nvestigational? product If theseverity ofanadverse eventfrom changes thedateofonset to thedateo -required therapies. . A. Reporting Procedures for AdverseReportingProcedures Serious Events 30 days after etelcalcetide are submitted toAmgen. version 4.0.Thegrading scaleused this in study described is This relationshipThis is indicated by a“yes” or “no” response to See Appendix administration All serious adverse serious All events must B for asampleoftheSerious are recordedin thesubject’s Page 41 of be by the e f 64 Date: 18 February 2016 Protocol Number: 20140336 adverse must beconsistent event extractssummary from orrecord.Information themedical provided abouttheserious may toprovide beasked additional follow upinformation, may adischarge which include following 24hours Amgen knowledgeofthenew within information. Theinvestigator submitted toAmgen. for newserious All adverse information events mustto besent New relating information toapreviously adverse reported serious must eventbe or reversibility. The investigator expected adverse tofollow is eventsstabilization until reported serious been caused byactivity/procedure”? astudy “no” response tothequestion: there “Is areasonable possibility thatthe have event may any studyactivity mandated relationship or procedure.This is indicated by a“yes” or whetherThe investigator must assess theseriouspossibly adverse is event relatedto entered into available. systemagain the EDC is when system the Amgen eSerious via the Adverse Contingency Event Report Form, thedatamust be For EDCwhere the studies notification first ofaSerious Adverse Event reported to is Adverse Worksheet Event Adverse /electronicSerious Contingency Event Report Form. Product: Etelcalcetide CONFIDENTIAL the protocol There 9.2.2.1 procedures andstatutes.local andat thesite other adverse event reportsreceived with from accordance in Amgen, The investigator tonotify is theappropriate IRB/IEC adverse events ofserious occurring practice.clinical compliancein reporting with all requirements according tolocal regulations andgood asreactions required to regulatory authorities, investigators/institutions, and IRBs/IECs Amgen report will serious adverse events adverse and/or suspected unexpected serious adverseserious event, information this must besubmittedtoAmgen. If asubject is permanently from withdrawn protocol become aware ofafter end ofstudy. Ifserious areadverse reported, events the memb bereported can adverse events toAmgen. (eg, European Insome Union countries [EU] er states), investigators are requireder states), toreport serious that theyadverse events is no is requirement tomonitor study for subjects serious following adverse events - required reporting period or after endofstudy. However, serious these ReportingPeriod ReportingSerious Events Adverse After Protocol the-required with thatrecorded onthe Event CRF. -required therapies because ofa Page 42 of 64 monitor toIn addition reporting any occurring pregnancies duringthe study, investigators should is takingsubject etelcalcetide, If apregnancy 9.3 signsand theassociated andsymptoms should becaptured.also calciumcorrected < of“blooddecreased”.adverse calcium events Symptomaticin reductions serum management or thattheinvestigator significant be deemed should clinically reported as Asympt serum calcium corrected between 7.5and< Date: 18 February 2016 Protocol Number: 20140336 Pregnancy Notification ( Worksheet the investigator’s knowledge ofthe event Report apregnancy ofapregnancy. onthe The pregnancy should be reported toAmgen’s Global PatientSafety after administration etelcalcetide . 9.2.2.2 reporting. withincaptured thesafety trial clinical as database casesfor the purposes ofexpedited adverseSerious events oftheprotocol reported outside e knowledg of theevent. investigator toreport themis within24 toAmgen following hours theinvestigator’s Product: Etelcalcetide CONFIDENTIAL Notification ( Worksheet knowledgeof theInvestigator’s onthe ofevent. alactation case Report Lactation should bereportedAny case Global Patient lactation toAmgen’s Safety within24hours etelcalcetide administration. lactation toIn addition reporting a lactation case duringthe study, investigators monitorshould for lactation specified caseas toAmgenbelow. occursIf alactation case whilethefemaletaking etelcalcetide, is subject omatic reductions calcium in below 7.5 omatic for after pregnancies thatoccur etelcalcetide through administration cases thatoccur administration after etelcalcetide through 3months after Pregnancyand Lactation Reporting Reportingof Reductions inSerum Calcium occurs in in or femaleoccurs a femalepartner subject, whiletheof amale subject, 8.3 Appendix mg/dL bereportedadverse as should events of“hypocalcemia”, report specified thepregnancy as toAmgen below. C Appendix ). 8.3 C mg/dL or asymptomatic reductions mg/dL or asymptomaticin reductions ). ). mg/dL thatrequired medical -required reporting periodwill be within 24hourswithin of report the Page 43 of 3 months 64 performed uponachieving thePrimary milestone Completion described section in dosesingle of The objective oftheprimary toassess is safety, analysis tolerability, PK, andPD ofa measurements will include will measurements number ofobservations,means, medians, subjectsdata for all willDescriptive statistics beprovided for selecteddemographics, 10.4.1 10.4 10.3.1 10.1.1.1 10.1.1 10.1 Date: 18 February 2016 Protocol Number: 20140336 10.3 have beenperformed. is basedThe samplesize onpractical consideration.Nocalculations formal samplesize 10.2 Setas thatAnalysis defined subjects all areandreceive enrolled ofetelcalcetide adose . The analysis endpoints, ofall unless notedotherwise, be will conducted on theSafety 10.1.2 10.1.1.2 10. Product: Etelcalcetide CONFIDENTIAL No testing formal statistical beperformed. will categorical be data will summarized frequency using counts andpercentages. quartiles, • • • • • • Anti [ Pharmacodynamic phosphorus, potassium, Changes in key laboratory [ safety tests examinations] adverseCommon-emergent events treatment Pharmacokinetic parametersPharmacokinetic (AUC, C Incidence total calcium,total calcium ionized standard deviations etelcalcetide antibodies-etelcalcetide etelcalcetide General Considerations ofPlanned Analysis Methods Primary Analysis Primary Endpoints Study Endpoints Study Analysis Endpoints, Covariates Sets, and Planned Analysis ConsiderationsSample Size Analysis Sets SecondaryEndpoints STATISTICAL CONSIDERATIONS of treatment-emergent events adverse by cohort where appropriate. on Descriptive statistics continuous s: concentration concentration s: of in this patient this in population. Theprimary anal or standard error parathyroidPTH ( hormone and calcium]albumin corrected max parathyroid hormone (PTH), serum calcium , albumin calciumcorrected , t minimum and maximum, while max , [including changes [including physical in t 1/2 ) ofetelcalcetide )], ECGs safety data, PK andPD and vital signs over time first and ysis will be in (cCalcium Page 44 of plasma third 3.5.2. ), 64 descriptive statistics.descriptive graphically.presented besummarizedsubjects PKwill all parameters using for unless specifiedunless otherwise. with Commonconsistent Terminology Criteria for Adverse ( Events (MedDRA).Activities reportedAll becoded will theadverse using events Medical Dictionary for Regulatory Date: 18 February 2016 Protocol Number: 20140336 10.4.2.2 organ class and preferred term. incidence of all include thoseCommon events with occurrence adverse 2 in ors more subject 10.4.2.1 10.4.2 Product: Etelcalcetide CONFIDENTIAL and calcium, ionized calcium) overi time, For c 10.4.3.2 Individual Summaries ofkey laboratory statistics willstatistics betabulated. and change postfrom ateach -baseline time baseline beplotted will point and descriptive calculations. Thereasons for excluding from any will theanalyses sample beprovided. for statistic time Actual each point. and dosing sampling time for all beused will pharmacok below thelower limitofquantifications beset will for tozero the estimation ofthe parameters non-compartmental using methods.concentrations Plasma etelcalcetide potassium, parathyroid hormone (PTH)], Etelcalcetide 10.4.3.1 10.4.3 -baseline beprovided. will post Incidence Subject collected. oflow (<7.5calcium mg/dL, < be from over also will baseline provided time time when ateach point samples are oncentrations and mean (SE inetic parameters forandinetic each ofthe subject for thecalculation summary concentration-time plasma datain beused will to determine thePK Clinical Laboratory Tests , Common Treatment-e Primary Endpoints Pharmacodynamic Endpoints Pharmacokinetic Endpoints SecondaryEndpoint(s) common treatment -emergent events betabulated will adverse by system of serum (total serum calcium PTH and Determination oftheseverityDetermination adverse ofall events (AE) be will ) plasma concentration [albumin corrected corrected (cCalcium),[albumin calcium phosphorus, mergent ECG ndividual and mean ( ECG Vital Signs and and v and -time datafor etelcalcetide Adverse EventsAdverse ital s ital ign ign 8.0 mg/dL and<8.3mg/dL) calcium, albumin corrected data over time ) of the absolute valueSE) oftheabsolute CTCAE ) version ) will be and Page 45 of . Subject changes changes 4.0 64 Date: 18 February 2016 Protocol Number: 20140336 A summarizing table theevaluation ofantibody formation toetelcalcetide 10.4.3.3 Product: Etelcalcetide CONFIDENTIAL physiciancare theagrees andif tohave subject primary his/her informed physician care The investigator also is responsible for the asking subject theif has aprimary subject to subject, the subject’s participation theclinical in study. other body under authorized applicablelaw toconsent, onbehalf ofaprospective is/product(s) are administered.A legally acceptable representative an is individualor of thestudy andbeforescreening any procedures specific protocol or any investigational after adequate explanation oftheaims, anticipated and methods, benefits, potential writtenobtaining informed participationBefore the in asubject’s study, is clinical responsible theinvestigator for language(s) of thepotential subjectpopulation. investigator. Thewritten document informed tobeprepared consent in is the formallybe communicated writing in from theAmgen documentinformed or consent athis Updates tobeused her site. tothe template are to sampleAn initial form consent informed provided is for theinvestigator toprepare the 11.1 11. receiving thesubjects for all etelcalcetide Age, sex, race, baseline characteristicswill weight height, andselected besummarized 10.4.3.4 provided. subjects. summarized. Inaddition, known significant deviations protocol benoted will for individual The number ofsubjects who receive etelcalcetide 10.4.4.1 10.4.4 events events, serious adverse fatal events, treatment adverse emergent by and class system preferred organ term. ofall Tables endpoints. allendpoints, treatmen t toIn addition treatment thecommon -emergent analyzed adverse events of interest will also will of interest beprovided. Subject incidence treatment ofall adverse emergent events betabulated will Antibody Informed OBLIGATIONS REGULATORY Treatment Subject Accountability Additional Analyses emergent beincluded will adverse events secondary as Consent -e consent from consent ’s legally thesubject mergent Adverse using descriptiveusing statistics. Events and completethestudy be will Clinical Clinical Study Mana treatmentadverse-related acceptable representativeacceptable in theprimaryin ger tothe will be Page 46 of risk 64 s the IRB/IEC and IECs The investigator responsiblefor obtaining is annual IRB from accordancewith in local Amgen, procedures. adverseserious at events occurring and the site other adverse event reportsreceived document. The investigator tonotify is subsequentfor all protocol andchanges totheinformed amendments consent The investigator must submitand,where necessary, approval obtain theIRB/IEC from shipment ofAmgen product. investigational receivedform by must be Amgenbefore recruitmentthe into study and ofsubjects written approval. A copy ofthewritten approval oftheprotocol andinformed consent information, andany advertising proposed material must besubmitted totheIRB/IEC A copyproposed oftheprotocol, informed form, consent othersubject written 11.2 wasconsent freely given andunderstood. and subject the witness themust sign form informed that consent toattest informed forminformed consent tothesubject andmust allowfor questions.Thereafter, both the representative,acceptable theinvestigator must provide toread an impartial witness the If apotential illiterate subject is or visually impaired anddoes nothave alegally representative . of the signed consentcopy ofthesigned form tobeprovided is ’s tothesubject forminformed toberetained consent is accordance with in institutional policy, and a the person who conducted theinformed discussion. Theoriginal consent signed Date: 18 February 2016 Protocol Number: 20140336 document such i document such andphysician theinvestigator be will that in acting capacity, the investigator to is participation subject’s in theclinical doesstudy. nothave Ifthesubject aprimary care notification, the investiga toinform primarytor is thesubject’s ofthe physician care participationof thesubject’s theclinical in study. Ifthesubjecttosuch agrees Product: Etelcalcetide CONFIDENTIAL andbe signed personally subjec datedby the to bedocumentedthe in records, medical andtheinformedsubject’s form to consent is the subject’s agreement of or refusal notificationhis/her ofthe primary physician care throughout the duration ofthe study. ofthe Copies investigator’s reportsand continuance ofapproval toAmgen. must besent Institutional Review Board/IndependentInstitutional Review Ethics Committee n n the subject’s medicalthe subject’s record. IRB/IEC the IRB/IEC t’s le t’s The acquisition ofinformedThe acquisition a consent gally acceptablerepresentative of deviations from orof deviations theprotocol approvaland leg ally acceptable ally acceptable ren IRBs ewalfor IRBs Page 47 of and by for for nd is is 64 If 12.1 12. Date: 18 February 2016 Protocol Number: 20140336 regulatory agency(s), andtheIRB/IEC investigator and institution permit representatives authorized ofthecompany, ofthe In compliance with Federal regulations/ICHis it required GCPGuidelines, thatthe • • • • • The investigator mustthatthe ensure confidentiality subject’s is maintained: 11.3 Product: Etelcalcetide CONFIDENTIAL acopysend oftheapproval letterfrom theIRB/IEC IRB/IEC • • me • The coordinating investigator, identified by beany will Amgen, ofthefollowing: or all studies,center thecoordinating investigator. clinicalEach study tobesigned report is by theinvestigator or,thecase in ofmulti 11.4 studyhis/her including relatedrecords, personal information. theconsentobtain oftheto individuals subject tohavepermit such to named access are important totheevaluation ofthe study. Theinvestigator obligated is and toinform examining,includes analyzing,verifying, any andreproducing and records reportsthat Amgen amends the protocol, agreement theprotocol, Amgen amends the Investigator from dical recordsdical for verificationof study relatedprocedures and data.Directaccess to be kept inconfidenceto bekept strict by theinvestigator, below. exceptdescribed as Documents thatare not informedsubmitted toAmgen signed forms) (eg, consent are regulations). and laws local regulations), anddate ofbirth(in lawsaccordance with local and subjectidentificationunique number, initials(for faxed accordancewith reports,in For Serious Adverse reported Events are toAmgen,subjects tobeidentified by their the include age atthetime ofenrollment. page,On addition in thedemographics totheunique subjectidentification number, and laws local regulations. dateofWhere permitted, tobe birthis documented andformatted accordance in with areSubjects tobeidentified by subject aunique identification number. an investigator contributing number ahigh subjects ofeligible interpretation ofthestudy an investigator who significant provided contributions toeither thedesign or a recognized expert area thetherapeutic in must beinformed amendments ofall must andgive approval. The investigator must Protocol Amendments andStudyProtocol Amendments Termination LEGALADMINISTRATIVEOBLIGATIONS AND Subject Confidentiality InvestigatorObligations Signatory direct access toreview access direct original thesubject’s to Amgen. must The beobtained. Page 48 48 of - 64 • Retention ofstudy begoverned will documents Agreement. by Trial theClinical maintained andbereadily available. In addition, originalall source documents entries supporting theCRFs in must be Date: 18 February 2016 Protocol Number: 20140336 according toaccording thestudy contract. The investigator tonotify is theIRB/IEC inve Amgen reserves therighttoterminate thestudy atanyandthe Both Amgen time. Product: Etelcalcetide CONFIDENTIAL • • • Elements toinclude: authorities. atinspection any timerepresentatives from by and/or Amgen applicable regulatory centralized filing system study ofall related (essential) documentation,suitable for The Investigator andstudy are responsiblefor staff maintainingacomprehensive and and correspondence. charts,and office laboratory diaries, andpharmacy records, microfiches, radiographs, CRF dataare obtained. includeThese butare not limitedto records,hospital clinical Source documents documents, are original data,andrecords from thesubj which on CRFs beincluded will DelegationofAuthority ontheAmgen Form. delegatedhas persons All study duties. authorized and/or tomake entries corrections The investigator tomaintain alist of is appropriately to persons qualified whom he/she 12.2 termination ofthestudy andbefore it available is commercially. whether investigational tosupply Amgen product(s), andby what mechanism, after theunilateralHowever, reserves right,at Amgen sole its discretion,to oran extension protocol provided as for bycountry’s thelocal regulatory mechanism. may Subjects beeligible for continued treatment withinvestigational Amgen by product completionorstudy’s early termination andsend acopy ofthenotification toAmgen. Non applicable. for Destruction Form(s), Investigational Final Product ReconciliationStatement, as Investigational applicable. Investigational- product and Amgen ofprestudycopies correspondence documentation,and all to andfrom theIRB/IEC Study containing the files with protocol amendments, all Brochure, Investigator’s identification list Subject stigator stigator reserve therighttoterminate theInvestigator’s participation in thestudy -investigational files containing forms,completed CRF, consent informed andsubject StudyDocumentation andArchive Product Accountability Record(s), Return ofInvestigational Product product(s) andor device(s) medical related correspondence Proof ofReceipts including (POR) documentation, as determine in writingin ofthe Page 49 of ect’s , 64 and data collection (includingand datacollection subjects notreceiving protocol The investigator responsiblefor is complying therequirements with for all assessments 12.4 Schedule of Schedule Assessments ( to completion protocol ofall stipulated in theprotocol the subject in for who each study. For subjects withdraw prior Date: 18 February 2016 Protocol Number: 20140336 In accordancewith ICH GCP and completing CRFs, are resolved. theproblems in ofthese detected course monitoringincluding visits, delays in The investigator agrees to cooperate monitor with theclinical thatto ensure any neededrecords to MonitorClinical tohave is to medical access recordssubject and other study related of thedata; tolocaland adherence regulations on theconduct ofclinical research. The the study toverify tothe completeness,protocol; adherence and accuracy, consistency The Clinical Monitor pertinent data) provided thatsubject confidentiality respected. is upon request, inspecting thevariousof records study clinical andother (eg, CRFs and thecontacting visiting investigator forofinspectingthefacilities thepurpose and, representative(s)The Amgen andregulatory authority are inspectors responsible for 12.3 Product: Etelcalcetide CONFIDENTIAL (eg,for field response aspecific updating theconfirming if datumprovided is the in with twice sent thesame datebutdifferent visits include thesame deletiondataAmgen ofobvious duplicate (or(ie, results designee) through the EDC system. Corrections theclinicalin database. trial SECs will be willAmgen perform(SECs) (or-evident designee) self corrections requirements. andconduct compliance ICH with theprotocol, GCP, regulatory andapplicable laboratories)areas, and review occur ofstudy will toevaluate relatedrecords thestudy designees). facilities Inspection of site (eg, pharmacy, protocol for by audit representatives fromGlobal Amgen’s Compliancefunction Auditing (or document Instructions, andtheeCRF Specific both ofthese beavailablewill race, reasonrace, forstudy). ending Investigator Responsibilities for Data Collection StudyMonitoring andData Collection verify theentries on theCRFs. is responsible responsible foris verifying theCRFs atregular intervals throughout Examplesof obvious dataerrors that mayby becorrected T -required andarevisits or unable to unwilling thecontinue 1 able the sponsor’s sponsor’s plans, studyaudit the maythis beselected ), the investigator search can publically available documented the in eg, week4andearly termination) and - required therapies) as Standard -required therapy storage to obvious dataerrors “other, specify” Self Evident Page 50 of 64 and timing of,Amgen’s reviewtions. ofpublica Agreementamong theinstitution, investigator, detail and Amgen the will for,procedures onthisbased study for must corporate besubmittedtoAmgen review. TheClinical Trial publicationsAll (eg, manuscripts, abstracts,oral/slidepresentations, book chapters) • • • • • (International Committee ofMedical Editors Journal of theUniform Submitted Requirementfor Manuscripts Journals toBiomedical Authorship resultingof any publications from this study will be determined onthebasis publication. not guarantee authorship. Thecriteria described below are tobemet for every Charter. on thecommittee Membership (both for investigators andAmgen does staff) collaborate with appropriate authors as staff defined andAmgen as the in Publication committee expected input tosolicit is andassistance from other investigators andto the governance andresponsibilities areof which forth in set a Publication Charter. The a publication committee of consisting several and investigators appropriate staff, Amgen To coordinate dissemination ofdatafrom study, this encourages Amgenthe formation of Date: 18 February 2016 Protocol Number: 20140336 12.6 vocabularymust use that andlanguage are clearly understood. writtenAll information andother material tobeused by andinvestigative subjects staff 12.5 asproduced anoutcome ofthestudy is/are [whererecords permitted]) toascertain survival This status. that ensures thedataset(s) Product: Etelcalcetide CONFIDENTIAL responsibility for appropriate portions ofthecontent. have authorEach should participated sufficiently thework in public to take qualify should belisted. persons All qualifydesignated should authors as those andall for authorship, who group, alone, notjustify does authorship. Acquisition of collection of funding, data, or general oftheresearch supervision fully should meet for authorship thecriteria defined above. the individuals who acceptresponsibility direct for These themanuscript. individuals When alarge, multicenter conducted groupthework, has thegroup should identify version tobepublished. Authorsshould1, meet conditions 2,and3. or revising it article critically for important intellectual content; (3)approval final ofthe of acquisition design, data, andinterpretation or analysis of data; (2) drafting the creditAuthorship should onbe based (1) substantialcontributions toconception and Publication Policy Language as as comprehensive possible. as ), which states: Page 51 of 64 Product: Etelcalcetide Protocol Number: 20140336 Date: 18 February 2016 Page 52 of 64 12.7 Compensation Any arrangements for compensation to subjects for injury or illness that arises in the study are described in the Compensation for Injury section of the Informed Consent that is available as a separate document. CONFIDENTIAL Martinez I,SarachoR,MontenegroJ Miner Res Kuizon BD,SaluskyIB.Growthretardationinchildren withchronic renalfailure. patients undergoing maintenancehaemodialysis. JAMA Klassen S, et al.AssociationbetweenpulsepressureEdmund G,andmortality in Pediatr Nephrol Kari JA,ReesL.Growthhormoneforchildren with chronic renal failure and ondialysis. Publication. 2006. Manuscripts SubmittedtoBiomedicalJour for International CommitteeofMedicalJournalEditors, UniformRequirements renal disease.Am J Kidney Dis M.Clinicalepidemiologyofcardiovasculardiseasein Foley R,ParfreyP,Sarnak chronic EMEA-001554-PIP01-13, decision dated 01Oct2014 Etelcalcetide Investigator’sBrochure. Thousand Oaks,CA:AmgenInc.05Oct2015 dialysis? Cundy T,HandDJ,OliverDO,etal.Whogetsrenal bonediseasebefore beginning Transplant degrees of predialysis chronic renal failure: a cross-sectional study. S, Coen G,Mazzaferro BallantiP,et al.Renalbone disease in76patients withvarying chronic haemodialysis patients.Kidney Int SarnakMJ,YanG,etal.AtheroscleroticCheung AK, cardiovascular disease risksin 2006;21:14-25. on research priorities in chronic kidney diseaseinchildren. M,WatkinsS,etal. Report ofanNIHtaskforce E, Moxey-Mims Chesney RW,Brewer 3 REFERENCES 2001;15(11):775-779. and pulsepressure in chronic haemodialysispatients.JHumHypertens Chalopin J. ofmeanarterialpressureDucloux D, Determinants Abdelfatah A,MotteG, 13. Date: 18 February 2016 Protocol Number: 20140336 Product: Etelcalcetide CONFIDENTIAL Annual Report,In:https://web.emmes.com/study/ped/annlrept/annlrept.html Pediatric RenalTrials andCollaborativeNorth American Studies(NAPRTCS),2006 with ChronicKidneyDisease NKF K/DOQIClinicalPractice Guidelines forBone MetabolismandDisease inChildren Kidney Int.2006;69:1945-1953. Dr S, Moe 2006;70:351-357. risk ofdeath inincident dialysis patients: Alongitudinalstudy. EustaceJ, M, et al.Changesinserum Melamed calcium, phosphate, and PTHandthe NEJM McDonald SP,CraigJC.Long-termsurvivalofchildren with end-stage renal disease. Am J Kidney Dis. phosphorous ofpatientswithearlyrenalfailure. inthesecondary hyperparathyroidism A positionstatementDisease: from Kidney . 2004;350(26):2654-2662. . 2004;350(26):2654-2662. Br Med J(ClinResEd) ϋ . 1999;14:1680–1690. . 1996;11:813-819. eke T,etal. Definition, evaluation, andclassification ofrenal osteodystrophy: . 2005;20:618–621. 1997;29:496-502. http://www.icmje.org/ Am Kidney Disease2005;46, 4. Jof . 1998;32(5 Suppl 3):112-119. . 1985;290:271-275. , etal.The importance ofdietarycalciumand . 2000;58(1):353-62. nals: Writing and Editing forBiomedical ImprovingGlobalOutcomes(KDIGO). . 2002;287:1548-1555. Pediatr Nephrol. Kidney Int. Nephrol Dial . Page 53 of 64 J Bone Date: 18 February 2016 Protocol Number: 20140336 Kidney IntSuppl Kidney Slatopolsky A.E, Pathogenesis BrownDusso of secondary A, hyperparathyroidism. osteodystrophy childrenInt. in onCAPD.Kidney 1987;32(1):89-95. Salusky IB,RN, Fine Kangarloo H, "High etal. calcitriol-dose" for control ofrenal http://ec.europa.eu/health/files/eudralex/vol oftheJournal European Union 12December 2006. Regulation (EC) ofthe No European 1901/2006 Parliament ofOfficial andoftheCouncil With Adults Childhood-Onset ChronicRenal Failu re R, TurzerOh Wunsch J, M, Advanced etal. Coronary Arteriopathy andCarotid Young in Product: Etelcalcetide CONFIDENTIAL with renalchildren chronic Pediatr failure. Nephrol T 2003;18:1159-1166. renalend-stage failure not patients yet Nephrol ondialysis. Dial Transplant. Spasovski AR, GJ,GB, Behets etal. Bervoets Spectrum ofrenalbone in disease 2003;18(12):1236-1241. with normal parathyroid chronic in hormone levels renalfailure. Pediatr Nephrol S,Waller LedermannTrompeter S, R, van't W,Ridout D, Hoff ReesL.Catch-upgrowth Maryland, 2009. Health, NationalInstitute andDigestive ofDiabetes Bethesda, andKidney Diseases: andDisease End-Stage AnnualData Report:US System.ofChronicUSRDS Atlas Renal2009 Data Kidney pathogenesis andtreatment. Paediatr Drugs CP.Sanchez Secondary hyperparathyroidism with children renal in re: chronic failu onshoff B, onshoff Kiepe D, Ciarmatori S. Growthgrowth-like hormone/insulin system factor in . 1999;73:S14-S19. Renal Disease in theUnited in Renal Disease States. National Institutes of -1/reg_2006_1901/reg_2006_1901_en.pdf . 2003;5(11):763-776. . 2005;20:279– Circulation. 2002;106:100 -105. 289. Page 54 of . 64 Date: 18 February 2016 Protocol Number: 20140336 14. Product: Etelcalcetide CONFIDENTIAL APPENDICES Page 55 of 64 • • Section withheld (either permanently ordue conditionally) topotential in DILIspecified as in subjects All whom investigational orproduct(s) protocol events theyfor if aserious adverse meet event thecriteria Section in defined Other ofhepatotoxicity events DILI andpotential are tobereportedserious adverse as the following link: TerminologyThe common for Evens Adverse Version Criteria 4.0isavailable at • • levels. Assessmentsthat are tobe performed period duringthis include: observation”of “close abnormalitiesreturn until to normal baseline or tothesubject’s Date: 18 February 2016 Protocol Number: 20140336 Drug http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm Adverse GradingScale Event Product: Etelcalcetide CONFIDENTIAL Additional Clinical Assessments andObservation and TBL and/or INR elevation according tothecriteria specified Section in To facilitate appropriate monitoring for signals of DILI, cases ofconcurrent AST or ALT Reporting • • the following: I − TBL: ANDbeen discontinued thesubject is asymptomatic. or thestabilize investigational product(s) or protocol frequencyTesting oftheabove theabnormalities if laboratory may tests decrease − and INR to beperformed until hours is laboratory every 24 abnormalities improve ofIn cases TBL >2x or1.5,retesting INR ULN ofliver > tests, BIL (total anddirect), ALT,(totalRepeat ALP, AST, bilirubin anddirect), 24hours andINR within and sent totheand sent Amgen. facilitate the evaluation oftreatment-emergent livertobe abnormalities is completed The appropriate CRF (eg, Event information thatcaptures necessary CRF) to have beenconcluded) discovery or notification of theevent (ie,before additional etiologic investigations aseriousThe eventadverse tobereportedas toAmgen event is of within24hours nitiate investigationnitiate ofalternative for elevated causes ALT and/or elevated AST or induced Liver InjuryReporting &Assessments-induced Additional Obtain completeblood (CBC) withcount differential toassess for eosinophilia assess for autoimmuneassess hepatitis Antibody,Smooth antibody Muscle Kidney andLiver Microsomal 1(LKM1) to Obtain serum immunoglobulin total IgG, Anti 6.3 3 x AST3 or whoor ALT experience elevations> AppendixA . Additional Safety Information Assessment nuclear antibody-nuclear (ANA),Anti -required therapies has/have -required therapies is/are ULN are toundergo aperiod 6.3 Page 56 of . 9.2.2. requi re re 64 • • • medications andlaboratory results correspondingmust in becaptured CRFs. The potential DILI medical event as information andadditional history, such concomitant Date: 18 February 2016 Protocol Number: 20140336 Product: Etelcalcetide CONFIDENTIAL Follow thesubject andthe laboratory (ALT, AST, tests TBL, INR) until hepatologist) Obtain hepatology consult (liver biopsy in may beconsidered consultation with an already beencollected Obtain appropriate blood for sampling pharmacokinetic analysis this if has not product(s) andproduct(s) protocol for continue a minimumof 4weeks after ofall discontinuation investigational returnabnormalities tobaseline or normal. observation The“close to period” is − − − − − Perform liver imagingclinically if appropriate indicated Obtain haptoglobin, CPK, LDH, andperipheralblood smear Obtain viral serologies o o o o o historyObtain detailed amore of: (paracetamol)Obtain serumlevels acetaminophen herbal anddietary supplements), andmushrooms plants, (includingConcomitant ofmedications use non-prescription andmedicines Prior use and/or concurrent ofalcohol, recreational and drugs special diets hypersensitivity right applicable) including Symptoms (if upper quadrant pain, Exposure toenvironmentaland/or industrial chemical agents Prior and/or concurrent diseases Prior diseases and/or concurrent or illness type reactions, fatigue, reactions, -type nausea, vomiting andfever - required therapies. all laboratory Page 57 of 64 Date: 18 February 2016 Protocol Number: 20140336 Product: Etelcalcetide CONFIDENTIAL AppendixB . SampleSerious Adverse Event Form Page 58 of 64 Date: 18 February 2016 Protocol Number: 20140336 Product: Etelcalcetide CONFIDENTIAL Page 59 of 64 Date: 18 February 2016 Protocol Number: 20140336 Product: Etelcalcetide CONFIDENTIAL Page 60 of 64 Date: 18 February 2016 Protocol Number: 20140336 Product: Etelcalcetide CONFIDENTIAL Page 61 of 64 Date: 18 February 2016 Protocol Number: 20140336 Product: Etelcalcetide CONFIDENTIAL Page 62 of 64 Date: 18 February 2016 Protocol Number: 20140336 Product: Etelcalcetide CONFIDENTIAL AppendixC . Pregnancy Notification andLactation Worksheets Page 63 of 64 Date: 18 February 2016 Protocol Number: 20140336 Product: Etelcalcetide CONFIDENTIAL Page 64 of 64