Supplementary Appendix

Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Ramanan AV, Dick AD, Jones AP, et al. Adalimumab plus methotrexate for uveitis in juvenile idiopathic arthritis. N Engl J Med 2017;376:1637-46. DOI: 10.1056/NEJMoa1614160

Adalimumab)in)Combination)with)Methotrexate)for)the)Treatment)of)Juvenile)Idiopathic) Arthritis)Associated)Uveitis:)the)SYCAMORE)Trial)) Supplementary)Data)) Table)of)contents) ) ) ) ) TableS1:TheSYCAMOREStudyGroup...2 TableS2:SUNWorkingGroupGradingSchemeforACcells...4 TableS3:Reasonsfortreatmentfailure Adalimumab...5 TableS4:Reasonsfortreatmentfailure Placebo...7 TableS5:Sensitivityanalysestoassessrobustnessoftheconclusionregardingtheeffectofthe intervention...11 TableS6:AdalimumabAdverseEventData:NumberofEventsObserved[Numberofparticipants]and (Rate)...14 TableS7:PlaceboAdverseEventData:NumberofEventsObserved[Numberofparticipants]and (Rate)...21 TableS8:SecondaryOutcomesandSecondaryOutcomeanalyses...24 TableS9:ModelParametersforJointModellingofLogMarXAnalysis1...31 TableS10:ModelParametersforJointModellingofLogMarXAnalysis2...32 TableS11:ModelParametersforJointModellingofACR30,ACR50,ACR70,ACR90andACR100...33 TableS12:ModelParametersforJointModellingofJADAS10,JADAS27andJADAS71...34 TableS13:ModelParametersforJointModellingofCHQ(Psychosocial(PsS)andPhysical(PhS))...35 TableS14:ModelParametersforJointModellingofCHAQ...36 TableS15:Listofreasonsforcensoringandeventsfor timetotreatmentresponse analysis...37 FigureS1:Enrolment,followXupandanalysisofthestudyparticipants...38 FigureS2:CumulativeIncidencePlotfortimetoreductionto0drops...39 FigureS3:KaplanMeierplotoftimetotreatmentresponse...40 ) ) 1

Table&S1:&The&SYCAMORE&Study&Group& Participating)Site) The)Leeds)Teaching) Hospitals)NHS)Trust) University)Hospitals)of) Leicester)NHS)Trust) ) Norfolk)and)Norwich) University)Hospitals)NHS) Foundation)Trust) The)Newcastle)upon)Tyne) Hospitals)NHS)Foundation) Trust) Hull)and)East)Yorkshire) Hospitals)NHS)Trust) University)Hospital) Southampton)NHS) Foundation)Trust) University)Hospitals) Bristol)NHS)Foundation) Trust) Birmingham)Children s) Hospital)NHS)Foundation) Trust) Alder)Hey)Children s)nhs) Foundation)Trust) Central)Manchester) University)Hospitals)NHS) Foundation)Trust) Sheffield)Children s)nhs) Foundation)Trust) Principle)Investigator) MarkWood,ConsultantRheumatologist AraniSridhar,ConsultantRheumatologist KateArmon,ConsultantRheumatologist MarkFriswell,ConsultantRheumatologist ElaineBaguley,ConsultantRheumatologist KristinaMay,ConsultantOphthalmologist AthimalaipetRamanan,ConsultantRheumatologist CliveRyder ConsultantRheumatologist GavinCleary,ConsultantRheumatologist AliceChieng,ConsultantRheumatologist DanHawley,ConsultantRheumatologist 2

Great)Ormond)Street) Hospital)for)Children)NHS) Trust) ) Royal)Hospital)for)Sick) Children)Edinburgh) )NHS) Lothian) ) Royal)Belfast)Hospital)for) Sick)Children)) CliveEdelsten,ConsultantOphthalmologist BrianFleck,ConsultantOphthalmologist MadeleineRooney,ConsultantRheumatologist 3

Table&S2:&SUN&Working&Group&Grading&Scheme&for&AC&cells& Grade CellsinField 0 <1 0.5+ 1X5 1.0+ 6X15 2.0+ 16X25 3.0+ 26X50 4.0+ >50 *SUN=StandardisationofUveitisNomenclature Fieldsizeisa1mmby1mmslitbeam *TherearenointernationallyagreedXuponminimallyimportantdifferences inthisscale 4

Table&S3:&Reasons&for&treatment&failure& &Adalimumab& Patient Dateof Randomisation Dateof treatment failure Timetofail (days/months) Reasonfortreatmentfailure Furtherdetails 1 0114011 11/4/2012 2/1/2013 266/8.74 Permittedconcomitantmedicationusedagainst Continuedfollowup acceptablecriteriadefinedintheprotocol 2 0116006 26/1/2012 14/3/2013 413/13.57 Permittedconcomitantmedicationusedagainst Continuedfollowup acceptablecriteriadefinedintheprotocol 3 0116026 8/11/2012 25/4/2013 168/5.52 Permittedconcomitantmedicationusedagainst Continuedfollowup acceptablecriteriadefinedintheprotocol 4 0243023 12/10/2012 19/6/2013 250/8.21 NonDpermittedconcomitantmedicationused Continuedfollowup 5 0249024 16/10/2012 21/6/2013 248/8.15 Permittedconcomitantmedicationusedagainst acceptablecriteriadefinedintheprotocol Continuedfollowup 6 0249043 16/8/2013 28/10/2013 73/2.4 NonDpermittedconcomitantmedicationused 7 0249040 17/5/2013 5/12/2013 202/6.64 Permittedconcomitantmedicationusedagainst acceptablecriteriadefinedintheprotocol Continuedfollowup Continuedfollowup 8 0069039 2/5/2013 27/1/2014 270/8.87 Intermittentorcontinuoussuspensionofstudy Continuedfollowup treatment(adalimumab) 9 0133058 31/12/2013 24/3/2014 83/2.73 NonDpermittedconcomitantmedicationused Nofollowup,consenttousecollecteddata 10 0246055 5/12/2013 23/4/2014 139/4.57 Sustainedscoresasrecordedatentrygrade measuredover2consecutivereadings(grades1to 2)stillpresentafter6monthsoftherapy 11 0249031 1/2/2013 9/5/2014 462/15.18 Permittedconcomitantmedicationusedagainst acceptablecriteriadefinedintheprotocol Continuedfollowup; SUNScore BaselineVisit:2+; FollowupVisit1:1+on07/03/2014; FailureVisitDUnscheduledVisit:1+on 23/04/2014 Continuedfollowup 5

Patient Dateof Randomisation Dateof treatment failure Timetofail (days/months) Reasonfortreatmentfailure Furtherdetails 12 0030035 19/4/2013 5/9/2014 504/16.56 Permittedconcomitantmedicationusedagainst acceptablecriteriadefinedintheprotocol and Intermittentorcontinuoussuspensionofstudy treatment(adalimumab) 13 0030073 30/7/2014 17/11/2014 110/3.61 Permittedconcomitantmedicationusedagainst acceptablecriteriadefinedintheprotocol 14 0069076 28/8/2014 17/2/2015 173/5.68 Sustainedscoresasrecordedatentrygrade measuredover2consecutivereadings(grades1to 2)stillpresentafter6monthsoftherapy 15 0116062 17/2/2014 9/4/2015 416/13.67 Intermittentorcontinuoussuspensionofstudy treatment(adalimumab) 16 0116066 25/4/2014 9/4/2015 349/11.47 Intermittentorcontinuoussuspensionofstudy treatment(adalimumab) Continuedfollowup Continuedfollowup Continuedfollowup; SUNScore BaselineVisit(1+); UnscheduledVisitD1+on06/01/2015; FailureVisitDVisit4D6Months Treatment:1+on17/02/2015 Continuefollowup Continuefollowup 6

Table&S4:&Reasons&for&treatment&failure& &Placebo& Patient Dateof RandomC isation Dateof treatment failure Timetofail (days/months) Reasonfortreatmentfailure Furtherdetails 1 0116003 23/11/2011 19/1/2012 57/1.87 Intermittentorcontinuoussuspensionof studytreatment(placebo) 2 0116008 15/3/2012 16/8/2012 154/5.06 Sustainedscoresasrecordedatentry grademeasuredover2consecutive readings(grades1to2)stillpresentafter 6monthsoftherapy 3 0249019 27/7/2012 27/9/2012 62/2.04 NonDpermittedconcomitantmedication used Continuedtofollowup Continuedfollowup; SUNScores BaselineScore(1+); Visit3D3MonthsTreatment:2+on 31/05/2012; FailureVisit(PrematureWithdrawal): 1+on16/08/2012. DeclinedtoenterNofollowup, consenttousecollecteddata. 4 0036018 17/7/2012 21/1/2013 188/6.18 Sustainedscoresasrecordedatentry grademeasuredover2consecutive readings(grades1to2)stillpresentafter 6monthsoftherapy 5 0249025 2/11/2012 13/2/2013 103/3.38 NonDpermittedconcomitantmedication used Continuedfollowup; SUNScores BaselineScore(2+); Visit3D3MonthsTreatment:3+on 16/10/2012; FailureVisitDPrematureWithdrawal:2+ on21/01/2013 Nofollowup,consenttousecollected data 6 0114033 13/2/2013 11/4/2013 57/1.87 Permittedconcomitantmedicationused againstacceptablecriteriadefinedinthe protocol Continuedfollowup 7

Patient Dateof RandomC isation Dateof treatment failure Timetofail (days/months) Reasonfortreatmentfailure Furtherdetails 7 0246030 29/1/2013 24/4/2013 85/2.79 NonDpermittedconcomitantmedication used Continuedfollowup 8 0116005 15/12/2011 4/7/2013 567/18.63 Sustainedscoresasrecordedatentry grademeasuredover2consecutive readings(grades1to2)stillpresentafter 6monthsoftherapy 9 0243032 11/2/2013 17/7/2013 156/5.13 NonDpermittedconcomitantmedication used Continuedfollowup; SUNScores BaselineVisit(1+); EndofTreatmentDFollowupVisit2:1+ on02/05/2013; FailureVisit:UnscheduledVisit:2+on 04/07/2013. Continuedfollowup 10 0540037 30/4/2013 24/7/2013 85/2.79 NonDpermittedconcomitantmedication used Continuedfollowup 11 0243049 18/9/2013 6/11/2013 49/1.61 CriteriaPermittedconcomitant medicationusedagainstacceptable criteriadefinedintheprotocol 12 0249029 25/1/2013 20/12/2013 329/10.81 Sustainedscoresasrecordedatentry grademeasuredover2consecutive readings(grades1to2)stillpresentafter 6monthsoftherapy Continuedfollowup Continuedfollowup; SUNScore BaselineVisit(1+); Visit5D9MonthsTreatment:2+on 27/09/2013; FailureVisitDVisit6D12Months Treatment:1+on20/12/2013 8

Patient Dateof RandomC isation Dateof treatment failure Timetofail (days/months) Reasonfortreatmentfailure Furtherdetails 13 0249047 12/9/2013 28/2/2014 169/5.55 Sustainedscoresasrecordedatentry grademeasuredover2consecutive readings(grades1to2)stillpresentafter 6monthsoftherapy 14 0116051 31/10/2013 17/4/2014 168/5.52 Sustainedscoresasrecordedatentry grademeasuredover2consecutive readings(grades1to2)stillpresentafter 6monthsoftherapy 15 0249059 2/1/2014 20/6/2014 169/5.55 Sustainedscoresasrecordedatentry grademeasuredover2consecutive readings(grades1to2)stillpresentafter 6monthsoftherapy 16 0116067 5/6/2014 24/7/2014 49/1.61 Permittedconcomitantmedicationused againstacceptablecriteriadefinedinthe protocol 17 0393075 21/8/2014 16/10/2014 56/1.84 NonDpermittedconcomitantmedication used Continuedfollowup; SUNScore BaselineVisit:1+; Visit2D2MonthsTreatment:1+on 15/11/2013; FailureVisit=SYCAMOREEndof TreatmentDFollowupVisit1:3+on 28/02/2014 Continuedfollowup; SUNScore BaselineVisit:1+; Visit3D3MonthsTreatment:1+on 23/01/2014; FailureVisitDVisit4D6Months Treatment:1+on17/04/2014 Nofollowup,consenttousecollected data; BaselineVisit(1+); SYCAMOREUnscheduledVisit:2+on 16/05/2014; FailureVisitDVisit4D6Months Treatment:3+on20/06/2014 Continuedfollowup Continuedfollowup 9

Patient Dateof RandomC isation Dateof treatment failure Timetofail (days/months) Reasonfortreatmentfailure Furtherdetails 18 0249086 5/1/2015 2/4/2015 87/2.86 NonDpermittedconcomitantmedication used Continuefollowup 10

Table&S5:&Sensitivity&analyses&to&assess&robustness&of&the&conclusion&regarding&the&effect&of&the&intervention&& Analysis N Adalimumab Placebo LogC HR (95%CI) n Treatment Censored n Treatment Censored rankpc failures failures value IntentionTo 90 60 16 44 30 18 12 <0.0001 0.25 (0.12,0.49) Treat Sensitivity 90 60 15 45 30 16 14 <0.0001 0.22 (0.11,0.46) Analysis(1) bestcase Sensitivity 90 60 24 36 30 23 7 <0.0001 0.25 (0.14,0.46) Analysis(2) worstcase Sensitivity 90 60 21 39 30 18 12 0.0007 0.34 (0.18,0.65) Analysis(3) 11

MTX Sensitivity 90 60 16 44 30 18 12 <0.0001 0.25 (0.12,0.49) Analysis(4) Component1 Sensitivity 90 60 16 44 30 18 12 <0.0001 0.25 (0.12,0.49) Analysis(5) Component2 Sensitivity 90 60 16 44 30 18 12 <0.0001 0.25 (0.12,0.49) Analysis(6) Component3 Sensitivity Analysis(7) MissingPrimary Outcome Sensitivity 90 60 16 44 30 18 12 <0.0001 0.25 (0.12,0.49) 90 D D D D D D D D D Analysis(8) 12

LosstoFollow Up* Sensitivity 90 60 14 46 30 17 13 <0.0001 0.25 (0.12,0.51) Analysis(9) Incorrect Treatment Failure** *NolossestofollowDupobservedsothissensitivityanalysisisnotapplicable ** There were three patients who were incorrectly classified as treatment failures(two in the adalimumab and one in the placebo group). Theywereallreportedasfailingtreatmentdueto Permittedconcomitantmedicationusedoutsideacceptablecriteria.Thesethreepatients were all included in the primary analysis as treatment failures as per the a"priori statistical analysis plan. In sensitivity analysis nine, these patientswereclassifiedasawithdrawalattheirtimeof treatmentfailure.theresultsofthisspecificsensitivityanalysis(p<0.0001)didnot changetheconclusionoftheprimaryanalysis. A"complete"description"of"sensitivity"analyses"are"provided"in"the"Statistical"Analysis"Plan"(SAP)." 13

Table&S6:&Adalimumab&Adverse&Event&Data:&Number&of&Events&Observed&[Number&of&participants]&and&(Rate)& Mild Moderate Severe Total BodySystem(Event) Related NotRelated Related NotRelated Related NotRelated Related NotRelated R+NR Bloodandlymphaticsystemdisorders Increasedtendencytobruise 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Lymphadenopathy 3[3](5%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 3[3](5%) 0[0](0%) 3 Neutropenia 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 1 Eyedisorders Cataract 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 1[1](2%) 1 Dryeye 1[1](2%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1[1](2%) 2 Eyedischarge 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Eyeinflammation 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 1 Eyepain 1[1](2%) 3[3](5%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 3[3](5%) 4 Eyeswelling 0[0](0%) 2[2](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 2[2](3%) 2 Iridocyclitis 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Irisdisorder 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Photopsia 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Uveitis 0[0](0%) 2[2](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 2[2](3%) 2 Visionblurred 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Visualimpairment 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 1 Gastrointestinaldisorders Abdominaldiscomfort 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Abdominalpain 2[1](2%) 2[2](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 2[1](2%) 2[2](3%) 4 Abdominalpainupper 0[0](0%) 2[2](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 2[2](3%) 2 Constipation 0[0](0%) 2[2](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 2[2](3%) 2 Dentalcaries 0[0](0%) 2[2](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 2[2](3%) 2 Diarrhoea 6[4](7%) 4[3](5%) 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 6[4](7%) 5[4](7%) 11 Dyspepsia 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Total Events 14

Mild Moderate Severe Total BodySystem(Event) Related NotRelated Related NotRelated Related NotRelated Related NotRelated R+NR Foodpoisoning 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 1 Haematochezia 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Nausea 3[2](3%) 3[2](3%) 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 3[2](3%) 4[3](5%) 7 Toothache 0[0](0%) 2[2](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 2[2](3%) 2 26[13] 28[14] Vomiting 9[7](12%) (22%) 0[0](0%) 2[2](3%) 0[0](0%) 0[0](0%) 9[7](12%) (23%) 37 Generaldisordersandadministrationsiteconditions Chestdiscomfort 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 1 Crying 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Drugintolerance 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Fatigue 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Hangover 0[0](0%) 2[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 2[1](2%) 2 Influenzalikeillness 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 1 Injectionsitebruising 0[0](0%) 3[2](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 3[2](3%) 3 Injectionsiteerythema 4[3](5%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 4[3](5%) 0[0](0%) 4 Injectionsitemass 8[2](3%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 8[2](3%) 1[1](2%) 9 Injectionsitepain 15[5](8%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 15[5](8%) 0[0](0%) 15 Injectionsitepruritus 3[3](5%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 3[3](5%) 0[0](0%) 3 Injectionsitereaction 21[5](8%) 1[1](2%) 16[3](5%) 0[0](0%) 1[1](2%) 0[0](0%) 38[6](10%) 1[1](2%) 39 Injectionsiteswelling 6[2](3%) 2[1](2%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 7[3](5%) 2[1](2%) 9 Injectionsitevesicles 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 1 Malaise 1[1](2%) 2[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 2[1](2%) 3 Pain 0[0](0%) 2[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 2[1](2%) 2 Pyrexia 23[8](13%) 9[7](12%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 24[8](13%) 9[7](12%) 33 Swelling 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](1.7%) 0[0](0%) 1 Immunesystemdisorders Immunisationreaction 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Seasonalallergy 0[0](0%) 2[2](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 2[2](3%) 2 Total Events 15

Mild Moderate Severe Total BodySystem(Event) Related NotRelated Related NotRelated Related NotRelated Related NotRelated R+NR Infectionsandinfestations Candidainfection 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 1 Cellulitis 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 1 Cestodeinfection 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Conjunctivitis 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Conjunctivitisviral 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 1 Earinfection 3[2](3%) 3[3](5%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 4[3](5%) 3[3](5%) 7 Eyeinfection 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 1 Herpessimplex 2[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 2[1](2%) 0[0](0%) 2 Impetigo 4[3](5%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 4[3](5%) 0[0](0%) 4 Infectedbites 0[0](0%) 0[0](0%) 1[1](2%) 1[1](2%) 0[0](0%) 0[0](0%) 1[1](2%) 1[1](2%) 2 Infection 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 1 Lowerrespiratorytractinfection 4[3](5%) 0[0](0%) 5[5](8%) 0[0](0%) 0[0](0%) 0[0](0%) 9[8](13%) 0[0](0%) 9 Molluscumcontagiosum 2[2](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 2[2](3%) 0[0](0%) 2 12[10] 12[10] Nasopharyngitis 8[6](10%) (17%) 2[2](3%) 0[0](0%) 0[0](0%) 0[0](0%) 10[6](10%) (17%) 22 Oralherpes 2[2](3.3%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 2[2](3%) 1[1](2%) 3 Otitismedia 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Paronychia 1[1](2%) 1[1](2%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 2[2](3%) 1[1](2%) 3 Pharyngitis 2[2](3%) 2[2](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 2[2](3%) 2[2](3%) 4 Pneumonia 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 1 Rhinitis 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 1 Rubella 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Scarletfever 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 1 Skininfection 1[1](2%) 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 2[2](3%) 0[0](0%) 2 Staphylococcalinfection 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 1 Streptococcalinfection 0[0](0%) 0[0](0%) 1[1](2%) 2[1](2%) 0[0](0%) 0[0](0%) 1[1](2%) 2[1](2%) 3 Tonsillitis 12[9](15%) 4[4](7%) 5[3](5%) 0[0](0%) 0[0](0%) 1[1](2%) 17[10] 5[5](8%) 22 Total Events 16

Mild Moderate Severe Total BodySystem(Event) Related NotRelated Related NotRelated Related NotRelated Related NotRelated R+NR (17%) Tonsillitisstreptococcal 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Upperrespiratorytractinfection 5[2](3%) 1[1](2%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 6[3](5%) 1[1](2%) 7 Urinarytractinfection 8[6](10%) 3[3](5%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 9[6](10%) 3[3](5%) 12 Varicella 1[1](2%) 0[0](0%) 0[0](0%) 2[2](3%) 0[0](0%) 0[0](0%) 1[1](2%) 2[2](3%) 3 Viralinfection 10[7](12%) 6[6](10%) 1[1](12%) 0[0](0%) 0[0](0%) 0[0](0%) 11[8](13%) 6[6](10%) 17 Injury,poisoningandproceduralcomplications Animalbite 0[0](0%) 1[1](12%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](12%) 1 Arthropodbite 0[0](0%) 2[2](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 2[2](3%) 2 Bite 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Contusion 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 1 Fall 0[0](0%) 3[3](5%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 3[3](5%) 3 Foreignbody 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Jointinjury 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Laceration 0[0](0%) 2[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 2[1](2%) 2 Ligamentsprain 0[0](0%) 1[1](2%) 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 2[2](3%) 2 Upperlimbfracture 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Investigations Alanineaminotransferaseincreased 5[3](5%) 3[3](5%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 5[3](5%) 3[3](5%) 8 Aspartateaminotransferaseabnormal 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Aspartateaminotransferaseincreased 2[1](2%) 1[1](2%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 3[2](3%) 1[1](2%) 4 Bloodalkalinephosphataseincreased 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 1 Bloodpotassiumincreased 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 CDreactiveproteinabnormal 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 CDreactiveproteinincreased 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Haematocritabnormal 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Intraocularpressureincreased 0[0](0%) 4[3](5%) 0[0](0%) 3[2](3%) 0[0](0%) 0[0](0%) 0[0](0%) 7[4](7%) 7 Total Events 17

Mild Moderate Severe Total BodySystem(Event) Related NotRelated Related NotRelated Related NotRelated Related NotRelated R+NR Liverfunctiontestabnormal 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 1 Redbloodcellcountabnormal 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Redbloodcellsedimentationrateabnormal 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 1 Redbloodcellsedimentationrateincreased 0[0](0%) 3[2](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 3[2](3%) 3 Rubulavirustestpositive 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 1 Urineprotein/creatinineratioabnormal 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Metabolismandnutritiondisorders Decreasedappetite 2[2](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 2[2](3%) 0[0](0%) 2 Dehydration 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 1 Musculoskeletalandconnectivetissuedisorders 16[10] 17[11] Arthralgia 6[3](5%) (17%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 6[3](5%) (18%) 23 Arthritis 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 1[1](2%) 0[0](0%) 1 Backpain 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Jointstiffness 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 1 Jointswelling 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Paininextremity 1[1](2%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1[1](2%) 2 Paininjaw 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Neoplasmsbenign,malignantandunspecified(inclcystsandpolyps) Skinpapilloma 4[4](7%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 4[4](7%) 1[1](2%) 5 Nervoussystemdisorders Headache 4[4](7%) 16[9](15%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 5[5](8%) 16[9](15%) 21 Hypoaesthesia 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Hyposmia 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Migraine 0[0](0%) 0[0](0%) 0[0](0%) 3[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 3[1](2%) 3 Paraesthesia 0[0](0%) 3[2](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 3[2](3%) 3 Psychomotorhyperactivity 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Syncope 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Total Events 18

Mild Moderate Severe Total BodySystem(Event) Related NotRelated Related NotRelated Related NotRelated Related NotRelated R+NR Psychiatricdisorders Anxiety 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Emotionaldistress 0[0](0%) 2[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 2[1](2%) 2 Irritability 0[0](0%) 2[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 2[1](2%) 2 Reproductivesystemandbreastdisorders Dysmenorrhoea 0[0](0%) 3[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 3[1](2%) 3 Pruritusgenital 2[1](2%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 2[1](2%) 1[1](2%) 3 Vulvovaginalpruritus 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Respiratory,thoracicandmediastinaldisorders Asthma 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Chronicobstructivepulmonarydisease 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 17[14] 17[14] Cough 12[9](15%) (23%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 12[9](15%) (23%) 29 Epistaxis 0[0](0%) 5[3](5%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 5[3](5%) 5 Nasaldiscomfort 4[2](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 4[2](3%) 0[0](0%) 4 Oropharyngealpain 20[8](13%) 15[9](15%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 21[8](13%) 15[9](15%) 36 Productivecough 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 1 Sinuscongestion 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Snoring 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 1 Tonsillarhypertrophy 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 1 Skinandsubcutaneoustissuedisorders Acne 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Erythema 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 1 Ingrowingnail 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 1 Pruritus 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Rash 4[1](2%) 2[2](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 4[1](2%) 2[2](3%) 6 Rashpapular 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Swellingface 0[0](0%) 1[1](2%) 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 2[1](2%) 2 Total Events 19

Mild Moderate Severe Total BodySystem(Event) Related NotRelated Related NotRelated Related NotRelated Related NotRelated R+NR Surgicalandmedicalprocedures Antiviralprophylaxis 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Testesexploration 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](2%) 1 Total Events 20

Table&S7:&Placebo&Adverse&Event&Data:&Number&of&Events&Observed&[Number&of&participants]&and&(Rate)& Mild Moderate Severe Total TotalEvents BodySystem(Event) Related NotRelated Related NotRelated Related NotRelated Related NotRelated Related Eyedisorders Anteriorchamberflare 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 2[1](3%) 0[0](0%) 2[1](3%) 0[0](0%) 2 Eyelidoedema 0[0](0%) 1[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](3%) 1 Uveitis 1[1](3%) 2[2](7%) 1[1](3%) 0[0](0%) 1[1](3%) 0[0](0%) 3[3](10%) 2[2](7%) 5 Visionblurred 0[0](0%) 1[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](3%) 1 Gastrointestinaldisorders Constipation 0[0](0%) 3[2](7%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 3[2](7%) 3 Diarrhoea 0[0](0%) 1[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](3%) 1 Nausea 0[0](0%) 2[2](7%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 2[2](7%) 2 Vomiting 2[2](7%) 5[4](13%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 2[2](7%) 5[4](13%) 7 Generaldisordersandadministrationsite conditions Fatigue 1[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](3%) 0[0](0%) 1 Feelinghot 0[0](0%) 1[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](3%) 1 Injectionsiteerythema 2[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 2[1](3%) 0[0](0%) 2 Injectionsitepain 5[2](7%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 5[2](7%) 0[0](0%) 5 Pyrexia 4[1](3%) 3[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 4[1](3%) 3[1](3%) 7 Immunesystemdisorders Seasonalallergy 0[0](0%) 1[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](3%) 1 Infectionsandinfestations Earinfection 2[2](7%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 2[2](7%) 0[0](0%) 2 Herpeszoster 0[0](0%) 0[0](0%) 1[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](3%) 0[0](0%) 1 Impetigo 1[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](3%) 0[0](0%) 1 Localisedinfection 1[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](3%) 0[0](0%) 1 Lowerrespiratorytractinfection 4[2](7%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 4[2](7%) 0[0](0%) 4 Nasopharyngitis 2[2](7%) 5[4](13%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 2[2](7%) 5[4](13%) 7 Oralherpes 1[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](3%) 0[0](0%) 1 21

Mild Moderate Severe Total TotalEvents BodySystem(Event) Related NotRelated Related NotRelated Related NotRelated Related NotRelated Related Otitismedia 0[0](0%) 1[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](3%) 1 Paronychia 1[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](3%) 0[0](0%) 1 Upperrespiratorytractinfection 1[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](3%) 0[0](0%) 1 Urethritis 1[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](3%) 0[0](0%) 1 Urinarytractinfection 3[2](7%) 1[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 3[2](7%) 1[1](3%) 4 Viralinfection 1[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](3%) 0[0](0%) 1 Injury,poisoningandproceduralcomplications Arthropodbite 0[0](0%) 2[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 2[1](3%) 2 Jointdislocation 0[0](0%) 2[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 2[1](3%) 2 Investigations Alanineaminotransferaseincreased 0[0](0%) 2[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 2[1](3%) 2 Bloodglucoseabnormal 0[0](0%) 1[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](3%) 1 Neutrophilcountdecreased 1[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](3%) 0[0](0%) 1 Musculoskeletalandconnectivetissuedisorders Arthralgia 0[0](0%) 2[1](3%) 1[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](3%) 2[1](3%) 3 Jointstiffness 0[0](0%) 1[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](3%) 1 Juvenileidiopathicarthritis 0[0](0%) 1[1](3%) 0[0](0%) 1[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 2[2](7%) 2 Paininextremity 0[0](0%) 1[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](3%) 1 Nervoussystemdisorders Headache 2[1](3%) 8[3](10%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 2[1](3%) 8[3](10%) 10 Psychiatricdisorders Aggression 0[0](0%) 2[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 2[1](3%) 2 Respiratory,thoracicandmediastinaldisorders Asthma 0[0](0%) 0[0](0%) 0[0](0%) 1[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](3%) 1 Cough 2[2](7%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 2[2](7%) 0[0](0%) 2 Oropharyngealpain 0[0](0%) 2[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 2[1](3%) 2 Wheezing 0[0](0%) 0[0](0%) 0[0](0%) 2[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 2[1](3%) 2 Skinandsubcutaneoustissuedisorders 22

Mild Moderate Severe Total TotalEvents BodySystem(Event) Related NotRelated Related NotRelated Related NotRelated Related NotRelated Related Acne 0[0](0%) 1[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](3%) 1 Dermatitis 1[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](3%) 0[0](0%) 1 Pruritus 0[0](0%) 1[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](3%) 1 Rash 1[1](3%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 0[0](0%) 1[1](3%) 0[0](0%) 1 23

Table&S8:&Secondary&Outcomes&and&Secondary&Outcome&analyses& SecondaryOutcome SecondaryOutcomeAnalysis Tolerabilityandadherenceoftrial treatment, On average treatment compliance for the adalimumab group was 81.01% and 93.91% respectively, according to the patient diaries and accountability logs, and 74.61% and 83.40% for the placebo group. Four(6%)patientsintheadalimumabgroupandone(3%)intheplacebogroupfailedtreatmentdueto missingmorethantherequirednumberofdoseswhilstontreatment. Laboratoryparameters (haematologicalandbiochemical There were no significant findings identified in either of the two treatment groups for any of the laboratoryparameters. analysisandurinalysis) Useofsystemicandpulsed corticosteroids Six participants were on systemic corticosteroids at the time of randomisation (at permitted dose of <0.2mg/kg/day), five in the adalimumab group and one in the placebo group (median dose for both groups,0.14mg/kg).themediandurationofsystemiccorticosteroidusewas18.1weeksandthreeofthe fiveparticipantsonadalimumabstoppedsystemic"corticosteroids."the"placebo"patient"stopped"systemic" corticosteroids"after"5.6"weeks."there"was"no"significant"difference"between"groups"(hr"0.50"(0.03,"7.72)h" 24

p>0.99)"in"requirement"of"pulse"corticosteroid"therapy"(n=1"for"each"group"3%,"2%"respectively)." Useoftopicalcorticosteroids Ofthe63participantswhowereon 2dropsoftopicalcorticosteroidsatrandomisation(45(75%)inthe adalimumabgroupand18(60%)intheplacebogroup),asignificantlygreaterproportionofadalimumabd treatedpatientshadareductiontolessthan2drops(n=22(49%))comparedtoplacebodtreatedpatients (n=3(17%),(hr=3.4795%ci(1.01,11.95),p=0.049) seefigure2b.ofthe74participantswhowereon 1dropatrandomisation(49(66%)onadalimumaband25(34%)onplacebo),therewasasignificantly greater proportion of adalimumabdtreated patients who had a reduction in their topical corticosteroid doseto0drops(n=23(47%))comparedtoplacebodtreatedpatients(n=4(16%),(hr=3.38(95%ci)(1.24, 10.32),p=0.02)(seeFigureS1,SupplementaryAppendix). FlareofuveitisdefinedbySUN criteria, Therewerenoparticipantsintheadalimumabgroupandthreeparticipantsintheplacebogroup(10%) whohadadiseaseflareoftheiruveitisinthefirstthreemonthsoftreatment(rr=0.0795%ci(0.004,1.36), p=0.04). Visualacuity AnalysisofLogMARacrosstimeshowedthattherewasnosignificantdifferencebetweenthetreatments (seetabless9ands10,supplementaryappendix) 25

Resolutionofassociatedoptic nerveormacularoedema Twoparticipantsintheadalimumabgroup(2%)hadopticnerveoedemaatbaseline,three(3%)developed itduringthestudy,andofthesecases3(60%)wereresolvedduringthestudy.therewerenoparticipants who had optic nerve oedema at baseline or developed it during the course of the study in the placebo group. Two participants in the adalimumab group (2%) had macular oedema at baseline and one participant developed it during the course of the study. Two participants in the placebo group (7%) developed macular oedema during the course of the study. Two participants in the adalimumab group andnoparticipantsintheplacebogrouphadresolutionofthemacularoedema(rr=3.75,95%ci(0.27, 52.64),p=0.40). Control,remission,andduration ofinactivedisease(uveitis), Patientstreatedwithadalimumabhadasignificantlylongermeandurationofsustainedinactivedisease (zero cells, with 1 or without topical treatment) compared to those receiving placebo(179.28 days(se: 16.91) versus 14.50 days (SE: 23.94); estimated treatment effect 164.79 (104.41, 225.16), p<0.0001) although those on adalimumab were on treatment for twice as long 345.03 days (SD:165.41)versus 159.27(SD:154.22). A significantly higher proportion of patients in the adalimumabdtreated group achieved disease control (defined as zero cells for 3 months with topical treatment) compared to the placebodtreated group[22 26

(37%)versus1(3%);RR=11.0095%CI(1.56,77.74),p<0.001]anddiseaseremission(definedaszerocells for3monthswithouttopicaltreatment)[15(25%)versus1(3%)rr=7.5095%ci(1.04,54.12),p=0.02]. Thissignificantdifferencewasalsopresentat6months,bothfordiseasecontrol[17(28%)versus1(3%); RR=8.50 95% CI(1.19, 60.87), p=0.005] and disease remission[13(22%) versus 0(0%) RR=13.72 95% CI (0.84,223.26),p=0.004]. TheStandardAmericanCollegeof Rheumatology(ACR)paediatric coreoutcomesetvariables(26), flareofjia,minimumjiadisease activity(24)andjuvenilearthritis DiseaseActivityScore(JADAS) (25). Asmostofthechildrenenteredthestudywithminimalarthritis,theACR30,50,70,90and100(seeTable S11,SupplementaryAppendix)andJADAS10,27and71(seeTableS12,SupplementaryAppendix)were onlyminimallyimpacted.arthritisflareoccurredinthreepatients(10%)intheplacebotreatedarmduring thetreatmentperiod,comparedtononeintheadalimumabtreatedgroup[rr=0.07,95%ci(0.004,1.36), p=0.03]. The proportion of participants with disease activity of their JIA was not statistically significant betweenthetwotreatmentgroups(rr=2.3395%ci(0.87,6.24)p=0.08). MinimumJIAdiseaseactivity:foroligoarticularJIAdisease,definedasphysician sglobalassessment (PhGA)<2.5cmandnoswollenjoints;forpolyarticularJIAdefinedasPhGA<3.4cm,patient/parentglobal assessment(paga)<2.1cm,and<1swollenjoint. JADASiscalculatedasthelinearsumoffourcomponents:(i)PhGA:010cmVAS,(ii)PaGA:010cmVAS, 27

(iii)activejointcountassessedinoneofthreeways:jadasd10:anyinvolvedjointuptoamaximumof10 JADASD27:27jointsincludingcervicalspine,elbows,wrists,firsttothirdmetacarpophalangeals,proximal interphalangeals,hips,kneesandankles,jadasd71:all71joints(iv)esr:normalizedona0d10scaleusing theformulabelowtoavoidexcessiveweightintheoverallindex:[esr(mm/h)20]/10.minimumdisease activityisdefinedas2foroligoarticularand3.8forpolyarticulardisease. Changetobiologicand/or diseasedmodifyingantidrheumatic drugtherapyduetofailureof arthritissymptomstorespond HealthDrelatedqualityoflife (CHAQ(26)andCHQ(27)) One (3%) participant in the placebo group and two (3%) patients in the adalimumab group required a change in their biologic or diseasedmodifying antidrheumatic drugs due to failure to respond from their arthritis(rr=1.0095%ci(0.20,5.09)p=0.99). AnalysisofhealthDrelatedqualityoflife(CHAQandCHQ)acrosstimeshowedthattherewasnosignificant differencebetweenthetwotreatmentgroups(seetables13andtables14,supplementaryappendix). CHAQ:thiscomprisesascale0D3,minimalclinicallyimportantdifference(MCID):D0.188forimprovement and+0.125forworsening. CHQ:thisisascale0D100,higherscoresindicatebetterormorepositivehealthstates,nospecificMCID recognised. 28

Incremental costdeffectiveness Resultsfortheincrementalcosteffectiveness,costutility,healthstatusaccordingtothemultiDattribute and cost utility of adalimumab, health status according to the healthutilityindexandremissiononandoffmedicationwillbereportedattheendofthefollowupphase ofthestudy. multidattribute health utility index, and remission on and off medication(23) DevelopmentofuveitisinnonD studyeyeanddevelopmentof PreDspecified covariate analysis (development of uveitis in nondstudy eye and development of cod morbidity)couldnotbeconductedduetothelackofparticipantswhodevelopedtherequiredoutcome. codmorbidity * Timetotreatmentfailureinboth studyeyes * Time to treatment failure in both study eyes was also not possible, due to the lack of events for this analysis. ** Time-to-treatment response Figure S3 demonstrates a difference between the two groups in favour of adalimumab (log rank exploratory p-value=0.003; HR 3.15 95%CI 1.42, 7.00). ** Responders by three and six months There was a difference in the proportion of responders at three and six months in favour of adalimumab (exploratory p-values=0.004 and p=0.004 respectively) see Figure S3. 29

** Treatment Responders Thirty-four (57%) adalimumab-treated and five (17%) placebo-treated participants were classified as having responded to treatment (Table S15). *ThesewerepreCspecifiedcovariateanalysesandnotsecondaryoutcomes;**ThesewerepostDhocanalysescarriedout,notpreDspecifiedsecondary outcomes & 30

Table&S9:&Model&Parameters&for&Joint&Modelling&of&LogMar&O&Analysis&1& Component Parameter Estimate 95%ConfidenceInterval PDvalue Longitudinal (Intercept) 0.004 (D0.02,0.04) 0.81 Baseline 0.74 (0.53,0.97) <0.0001 Time D0.002 (D0.01,0.001) 0.20 Adalimumab D0.01 (D0.06,0.03) 0.59 Survival Adalimumab D1.33 (D2.16,D0.78) 0.0001 HazardRatio 0.26 (0.12,0.46) 0.0001 Association γ 0 D0.93 (D9.67,6.45) 0.80 Twoanalyseswereconductedusingjointmodelling,ineachanalysis,whenonlyoneeyeisinvolved;thesingleLogMaRvalueisused.When therearetwoeyesinvolved,thetwoanalysesare: Analysis1DTakingthebestLogMarmeasurement(theminimumofthe2values). Analysis2DTakingtheworstLogMarmeasurement(themaximumofthe2values) 31

Table&S10:&Model&Parameters&for&Joint&Modelling&of&LogMar&O&Analysis&2& Component Parameter Estimate 95%ConfidenceInterval PDvalue Longitudinal (Intercept) 0.01 (D0.02,0.05) 0.52 Baseline 0.83 (0.61,1.11) <0.0001 Time D0.002 (D0.01,0.0004) 0.20 Adalimumab D0.02 (D0.07,0.03) 0.53 Survival Adalimumab D1.33 (D2.15,D0.77) 0.0002 HazardRatio 0.27 (0.12,0.46) 0.0002 Association γ 0 0.63 (D6.46,6.22) 0.85 32

Table&S11:&Model&Parameters&for&Joint&Modelling&of&ACR30,&ACR50,&ACR70,&ACR90&and&ACR100& Outcome Component Parameter Estimate 95%ConfidenceInterval PDvalue ACR30 Longitudinal (Intercept) D1.48 (D2.51,D0.53) 0.004 Time 0.01 (D0.04,0.07) 0.64 Adalimumab D0.70 (D1.86,0.52) 0.23 Survival Adalimumab D1.64 (D2.47,D0.89) <0.001 HazardRatio 0.19 (0.08,0.41) <0.001 Association γ0 D0.33 (D0.71,D0.04) 0.02 ACR50 Longitudinal (Intercept) D1.92 (D2.89,D1.00) <0.001 Time 0.02 (D0.04,0.08) 0.59 Adalimumab D0.65 (D1.74,0.44) 0.25 Survival Adalimumab D1.61 (D2.39,D0.85) <0.001 HazardRatio 0.20 (0.09,0.43) <0.001 Association γ0 D0.32 (D0.73,D0.02) 0.03 ACR70 Longitudinal (Intercept) D3.22 (D4.36,D2.21) <0.001 Time 0.03 (D0.05,0.10) 0.48 Adalimumab D0.61 (D1.89,0.74) 0.34 Survival Adalimumab D1.69 (D2.60,D0.92) <0.001 HazardRatio 0.18 (0.07,0.40) <0.001 Association γ0 D0.33 (D0.79,D0.01) 0.04 ACR90* Longitudinal (Intercept) D6.58 (D10.16,D3.00) <0.001 Time 0.18 (0.07,0.29) 0.002 Adalimumab D0.46 (D3.38,2.46) 0.76 ACR100 Longitudinal (Intercept) D5.82 (D6.73,D4.93) <0.001 Time 0.16 (D0.02,0.30) 0.09 Adalimumab D1.23 (D2.34,D0.14) 0.03 Survival Adalimumab D1.77 (D3.01,D0.93) <0.001 HazardRatio 0.17 (0.05,0.39) <0.001 Association γ0 D0.09 (D2.83,3.66) 0.62 *JMbayespackagerequiresafittedseparatemodelforthelongitudinaloutcomeestimatedusingpenalizedquasiDlikehoodmethods(fittedinRusingtheglmmPQL()function)whichcouldnotbefittedforACR90.Estimatesfromaseparatelongitudinalmodel(usingtheglmer()fromthe lme4package)usingadaptivegaussdhermitequadraturearethereforerecorded 33

Table&S12:&Model&Parameters&for&Joint&Modelling&of&JADAS10,&JADAS27&and&JADAS71& Outcome Component Parameter Estimate 95%ConfidenceInterval PDvalue JADAS10 Longitudinal (Intercept) 0.63 (0.26,1.10) 0.002 Baseline 0.41 (0.25,0.56) <0.001 Time D0.01 (D0.03,0.01) 0.26 Adalimumab D0.35 (D0.79,D0.005) 0.07 Survival Adalimumab D1.97 (D3.55,D1.29) 0.0001 HazardRatio 0.14 (0.03,0.27) 0.0001 Association γ0 0.72 (D0.29,1.92) 0.17 JADAS27 Longitudinal (Intercept) 0.63 (0.27,1.06) 0.003 Baseline 0.41 (0.23,0.56) <0.0001 Time D0.01 (D0.03,0.01) 0.28 Adalimumab D0.34 (D0.78,0.03) 0.08 Survival Adalimumab D1.97 (D3.55,D1.29) 0.0001 HazardRatio 0.14 (0.03,0.28) 0.0001 Association γ0 0.71 (D0.35,1.90) 0.17 JADAS71 Longitudinal (Intercept) 0.64 (0.27,1.10) 0.002 Baseline 0.41 (0.24,0.56) <0.0001 Time D0.01 (D0.03,0.01) 0.26 Adalimumab D0.36 (D0.80,D0.0004) 0.07 Survival Adalimumab D1.97 (D3.55,D1.29) 0.0001 HazardRatio 0.14 (0.03,0.27) 0.0001 Association γ0 0.71 (D0.29,1.90) 0.17 34

Table&S13:&Model&Parameters&for&Joint&Modelling&of&CHQ&(Psychosocial&(PsS)&and&Physical&(PhS))& Component Parameter Estimate 95%ConfidenceInterval PDvalue PsS Longitudinal (Intercept) 15.48 (7.81,23.37) 0.0002 Baseline 0.68 (0.54,0.81) <0.0001 Time 0.03 (D0.25,0.25) 0.83 Adalimumab 2.69 (D0.26,5.86) 0.06 Survival Adalimumab D1.73 (D2.76,D1.07) <0.0001 HazardRatio 0.18 (0.06,0.34) <0.0001 Association γ 0 D0.12 (D0.27,D0.03) 0.03 PhS Longitudinal (Intercept) 19.77 (11.49,30.43) <0.0001 Baseline 0.60 (0.38,0.74) <0.0001 Time D0.02 (D0.24,0.13) 0.81 Adalimumab 1.36 (D2.28,5.05) 0.49 Survival Adalimumab D1.54 (D2.67,D0.87) 0.001 HazardRatio 0.21 (0.07,0.42) 0.001 Association γ 0 D0.08 (D0.15,D0.002) 0.06 35

Table&S14:&Model&Parameters&for&Joint&Modelling&of&CHAQ& Component Parameter Estimate 95%ConfidenceInterval PDvalue Longitudinal (Intercept) 0.20 (0.06,0.35) 0.005 Baseline 0.65 (0.50,0.76) <0.0001 Time D0.01 (D0.01,0.002) 0.10 Adalimumab D0.14 (D0.32,0.01) 0.08 Survival Adalimumab D1.46 (D2.33,D0.89) <0.0001 HazardRatio 0.23 (0.10,0.41) <0.0001 Association γ0 1.32 (0.11,2.81) 0.04 36

Table&S15:&List&of&reasons&for&censoring&and&events&for& time&to&treatment&response &analysis& Type Description Adalimumab Placebo Total Overall Total 60 30 90 Censored Completed18months 2(3%) 2(7%) 4(4%) Completedtreatmentphaseduetoearlytrialclosure 0(0%) 1(3%) 1(1%) Stillonstudytreatment 5(8%) 1(3%) 6(7%) Treatmentfailure 4(7%) 14(47%) 18(20%) Treatmentfailure(inthefollowDupperiodafterwithdrawingfromtreatment ) 1(2%) 2(7%) 3(3%) Treatmentfailurebutrespondedtotreatmentlateronpriorto18months 1(2%) 0(0%) 1(1%) WithdrawnandspecifiednofollowDup 2(3%) 1(3%) 3(3%) WithdrawnandtakenlastfollowDupdate 1(2%) 2(7%) 3(3%) Total 16 23 39 Event Respondedtotreatment 34(57%) 5(17%) 39(43%) Respondedtotreatmentbutwereatreatmentfailurelateronpriorto18months 10(17%) 2(7%) 12(13%) Total 44 7 51 37

Figure'S1:'Enrolment,'follow4up'and'analysis'of'the'study'participants'' Enrolment Assessedforeligibility:n=332patients Excludedn=242patients Allocatedtoadalimumab+MTX(n=60 * ) Receivedallocatedintervention(n=60) Allocatedtoplacebo+MTX(n=30 * ) Receivedallocatedintervention(n=30) LosttofollowGup(n=0) Discontinuedintervention(n=9) Continue(follow(up((n=7)( o Adverse(event((n=1)( o Needle(phobia((n=1)( o MTX(intolerance((n=4)( o Use(of(medications(not(permitted((n=1)( No(follow(up,(consent(to(use(collected(data((n=2)( o Withdrawal(of(consent((n=1)( o Refused(injections((n=1)( ( Follow,Up Analysis LosttofollowGup(n=0) Discontinuedintervention(n=7) Continue(follow(up((n=6)( o Serious(adverse(event((n=1)( o Flare(of(JIA((n=1)( o Family(circumstances((n=1)( o Participant(felt(no(benefit((n=1)( o Worsening(of(uveitis((not(meeting(exit(criteria)(n=2)( No(follow(up,(consent(to(use(collected(data((n=1)( o Unable(to(tolerate(IMP((n=1)( Analysed(n=60) TreatmentFailure(n=16) o Withdrawnfromtreatmentandfailedin followup(n=1) Censored(n=44) o Completed18monthstreatment(n=22) o Earlytrialclosure(n=14) o Withdrawnfromtreatmentanddidnot failinfollowupsohaveusedlastfollowup date(n=8) Excludedfromanalysis(n=0) Analysed(n=30) TreatmentFailure(n=18) o Withdrawnfromtreatmentandfailed duringfollowup(n=2) Censored(n=12) o Completed18monthstreatment(n=3) o Earlytrialclosure(n=4) o Withdrawnfromtreatmentanddidnot failinfollowupsohaveusedlastfollow update(n=5) Excludedfromanalysis(n=0) 38

Figure'S2:'Cumulative'Incidence'Plot'for'time'to'reduction'to'0'drops' FigureLegend:ACumulativeIncidencePlotdemonstratingtimetoreductionto0dropsineachof thetreatmentarms 39

Figure'S3:'Kaplan'Meier'plot'of'time'to'treatment'response FigureLegend:KaplanMeierplotoftimetotreatmentresponseforeachofthetreatmentarms 40