supplementary appendix 20062018 final
TRANSCRIPT
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SupplementaryAppendix
TableofContents
Inclusioncriteria
Exclusioncriteria
Studydrugadministration
Drugstorageandsupply
Co-primaryendpoints–definitions
Dosefrequencycommittee(DFC)charter
Supplementarytables
TableS1:Doseandfrequencyallocationaccordingtocohort
TableS2:Doseandfrequencyallocationaccordingtopopulation
TableS3:Adverseeventsbyseverityandtypeinthesafetypopulation(N=37)
TableS4:Safetyparameters(safetypopulation)
TableS5:Clinicalfluorescence-activatedcellsorting(FACS)
TableS6:AICforallmodels(analysispopulation)
TableS7:Estimatedtargetdose/frequency
TableS8:Bestestimatedallowabledoes/frequencyaccordingtoMahalanobisdistanceandjointprobability–Lineardose,quadraticfrequency,interaction(analysispopulation)
TableS9:Bestestimatedallowabledose/frequencyaccordingtoMahalanobisdistanceandjointprobability-Lineardose,quadraticfrequency,interaction(evaluablepopulation)
Supplementalfigures
FigureS1:Eosinophiliaforindividualparticipants(safetypopulation)
FigureS2:TPOantibodiesandTSHreceptorantibodies
FigureS3:Clinicalimagesandimmunohistochemicalstainingofpsoriasisinoneparticipantreceivingtreatmentwithaldesleukin0.32x106IU/m2everythreedays
FigureS4:PercentagechangeofCD19%inindividualparticipantsbydoseandfrequency(safetypopulation)
FigureS5:PercentagechangeofCD19totalBcellsinindividualparticipantsbydoseandfrequency(safetypopulation)
FigureS6:PercentagechangeofCD3%inindividualparticipantsbydoseandfrequency(safetypopulation)
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FigureS7:PercentagechangeofCD3totalTcellsinindividualparticipantsbydoseandfrequency(safetypopulation)
FigureS8:PercentagechangeofCD4%inindividualparticipantsbydoseandfrequency(safetypopulation)
FigureS9:PercentagechangeofCD4total%inindividualpatientsbydoseandfrequency(safetypopulation)
FigureS10:PercentagechangeofCD56%inindividualparticipantsbydoseandfrequency(safetypopulation)
FigureS11:PercentagechangeofCD56totalNKcellsinindividualparticipantsbydoseandfrequency(safetypopulation)
FigureS12:PercentagechangeofCD8%inindividualparticipantsbydoseandfrequency(safetypopulation)
FigureS13:PercentagechangeofCD8totalinindividualpatientsbydoseandfrequency(safetypopulation)
FigureS14:Percentagechangeoflymphocytescountinindividualparticipantsbydoseandfrequency(safetypopulation)
FigureS15:PercentagechangeofTreg%CD4Tcellsinindividualparticipantsbydoseandfrequency(safetypopulation)
FigureS16:PercentagechangeofTregabsoluteinindividualparticipantsbydoseandfrequency(safetypopulation)
FigureS17:PercentagechangeofTregCD25MeanFIinindividualparticipantsbydoseandfrequency(safetypopulation)
FigureS18:PercentagechangeofTregCD25MEFinindividualparticipantsbydoseandfrequency(safetypopulation)
FigureS19:PercentagechangeofNon-TregNaïve%inindividualparticipantsbydoseandfrequency(safetypopulation)
FigureS20:PercentagechangeofNon-TregNaïveabsoluteinindividualparticipantsbydoseandfrequency(safetypopulation)
FigureS21:PercentagechangeofNon-TregTemra%inindividualparticipantsbydoseandfrequency(safetypopulation)
FigureS22:PercentagechangeofNonTregTemraabsoluteinindividualparticipantsbydoseandfrequency(safetypopulation)
FigureS23:PercentagechangeofNonTregtotalmemory%inindividualparticipantsbydoseandfrequency(safetypopulation)
FigureS24:PercentagechangeofNonTregtotalmemoryabsoluteinindividualparticipantsbydoseandfrequency(safetypopulation)
FigureS25:PercentagechangeofNonTregnaïve/memoryratioinindividualparticipantsbydoseandfrequency(safetypopulation)
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FigureS26:IL-2levelsinindividualparticipantsbydoseandfrequency(safetypopulation)
FigureS27:HbA1c(%)inindividualparticipantsbydoseandfrequency(analysispopulation)
StatisticalAnalysisPlan(SAP)
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Inclusioncriteria
• Type1diabetes
• 18-70yearsofage
• Durationofdiabeteslessthan60monthsfromdiagnosis
• Writteninformedconsenttoparticipate
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Exclusioncriteria
• Hypersensitivitytoaldesleukinoranyoftheexcipients
• Historyofseverecardiacdisease
• Historyofmalignancywithinthepast5years(withtheexceptionoflocalizedcarcinomaoftheskinthathadbeenresectedforcureorcervicalcarcinomainsitu
• Historyorconcurrentuseofimmunosuppressiveagentsorsteroids.
• Historyofunstablediabeteswithrecurrenthypoglycaemia
• ActiveautoimmuneHyperorhypothyroidism
• Historyoflivevaccinationtwoweekspriortofirsttreatment
• Activeclinicalinfection
• Majorpre-existingorgandysfunctionorpreviousorganallograft
• Femaleswhoarepregnant,lactatingorintendtogetpregnantduringthestudy
• Maleswhointendtofatherapregnancyduringthestudy
• Donationofmorethan500mlofbloodwithin2monthspriortoaldesleukinadministration
• Participationinaprevioustherapeuticclinicaltrialwithin2monthspriortoaldesleukinadministration
• AbnormalECG
• Abnormalfullbloodcount,chronicrenalfailure(Stage3,4,5)and/orevidenceofseverelyimpairedliverfunction(ALT/AST>3xULNatscreening;alkalinephosphataseandbilirubin2xULNatscreening(isolatedbilirubin>2xULNisacceptableifbilirubinisfractionatedanddirectbilirubin<35%)).
• PositiveHBsAgorHepCserologyorHIVtest
• Anymedicalhistoryorclinicallyrelevantabnormalitythatisdeemedbytheprincipalinvestigator/delegateand/ormedicalmonitortomakethepatientineligibleforinclusionbecauseofasafetyconcern.
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Studydrugadministration
Thetrialdrugwillbethestandardcommercialstockofaldesleukin(MarketingAuthorisationHolder:Novartis Pharmaceuticals UK Limited). Aldesleukin is produced by recombinant DNA technologyusinganEscherichiacolistrain,whichcontainsageneticallyengineeredmodificationofthehumaninterleukin2(IL-2)gene.
Thedrugisprovidedaspowderforsolutionforinjectionorinfusion.Forallinjections,aldesleukinisfirst reconstituted under aseptic conditions as per Proleukin® SmPC. Solutions are then furtherdiluted to the required concentration in glucose 5% and the appropriate volume drawn up intosterileU-100insulinsyringes.
The first dose of aldesleukin will be self-administered by participants at the trial site followinginstructionbyanappropriately traineddelegatedmemberof the trial team.Participants can thenadminister further doses either at the trial site or in the community. Alternatively, dosesmay beadministered by an appropriately qualifiedmember of the trial team. The date and time of eachdoseadministeredatthetrialsitewillberecordedinthesourcedocuments.Inthecommunity,thedateandtimeofeachdoseadministeredwillberecorded intheparticipant’sstudydiarythatwillbecome part of the source documents. The study diary, injection sites and count of unusedmedicationwillbecarriedoutateachstudyvisitwhileontreatmenttoconfirmcompliance.
Drugstorageandsupply
Commercialsupplyofaldesleukin,obtainedviausualhospitalroute,willbeusedforthisstudy.VialswillbestoredasperSmPC.at2ºCto8ºC(inarefrigerator)intheoriginalpackageinordertoprotectfrom light. The vials must not be frozen. Vials will be stored securely with access restricted toappropriateindividuals.
Previous (unlicensed)datasupportsstabilityandsterilityof reconstituteddiluted IL-2preparations(reconstitutedwithWaterforInjectionaspertheProleukin®SmPCandfurtherdilutedwithglucose5%) for up to 14 days at 2-8ºCwhen syringes are preparedby qualified health-care professionalsunderasepticconditions.Amaximumshelflifeof7dayswillbeassignedtotheprepareddosesforthisstudy.
The pharmacy at the participating site will dispense aldesleukin for this trial upon receipt of asuitablysignedtrialspecificprescription.Foreachindividualparticipant,multipleindividualdosesofa single concentration of the aldesleukin may be prepared under aseptic conditions foradministration in individual insulin syringes foreach7daysof the treatmentperiod.Alldosesnotusedwithinthe7-dayperiodwillbereturnedtothepharmacyatparticipatingsiteandarecordoftheirdisposalwillbemade.
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Co-primaryendpoints-DefinitionsofTregs,TeffsandCD25expressionwithintheCD3+CD4+fluorescence-activatedcellsorting(FACS)gate
Tregs:Tregs%CD25highCD127lowwithintheCD3+CD4+gate
CD25expressiononTregs:Meanfluorescenceintensity(MFI)ofCD25allophycocyanin(APC)withintheTreg(CD3+CD4+CD25highCD127low)gate
Teffs:Teffpopulations(non-Tregs)accountforalltheotherCD3+CD4+cellsthatarenotdefinedasTregswithintheCD3+CD4+gate:
• Effectormemory%CD45RA−CD62L−
• Centralmemory%CD45RA−CD62L+
• NaïveTeffs%CD45RA+CD62L+
• EffectormemoryRA+(TEMRA)CD45RA+CD62L−
• Centralmemory%+Effectormemory%=TotalMemoryeffectors%
• ChangeintheratioNaïveeffectors%:TotalMemoryeffectors%definestheTeffprimaryendpoint.
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Supplementarytables
TableS1DoseandfrequencyallocationaccordingtocohortLEAR
NING
COHORT1
0.09x106IU/m2
0.47x106IU/m2
0.20x106IU/m2
0.32x106IU/m2
14daily 2 2
10daily 2
5daily 2
2daily 2 2
COHORT2
10daily 1
5daily 2
4daily 1 1
3daily 1 2
CONFIRM
ING COHORT3
3daily 5 4
COHORT4
3daily 8
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TableS2Doseandfrequencyallocationaccordingtopopulation.
SAFETYPOPULATION
0.09x106IU/m2
0.47x106IU/m2
0.20x106IU/m2
0.32x106IU/m2
14daily 2 2 0 0
10daily 1 2 0 0
5daily 2 2 0 0
4daily 1 1 0 0
3daily 1 2 5 12
2daily 2 2 0 0
ANALYSISPOPULATION
14daily 1 2 0 0
10daily 1 2 0 0
5daily 2 2 0 0
4daily 1 0 0 0
3daily 1 2 4 8
2daily 1 1 0 0
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TableS3.Adverseeventsbyseverityandtypeinthesafetypopulation(N=37)
TypeofAdverseevent
Category Events Participants
TotalAEs MostcommonAEs(>10%)- Hypoglycaemia- Injectionsiteerythema- Injectionsitenodule
94(13.5%)230(33.1%)234(33.7%)
20(54.1%)35(94.6%)33(89.2%)
Adverseevents- Unexpected- Expectedadverseevents- Related- Unrelated
127(18.3%)567(81.7%)479(69.1)215(31.0%)
34(91.9%)37(100%)
Unexpected Unexpectedadverseeventsbyseverity(N/%)- Mild- Moderate
108(85%)19(15%)
32(86.5%)11(29.7%)
Mostcommon(>10%)unexpectedAEs- Headache- Nasopahryngitis
22(17.3%)18(14.2%)
12(32.4%)16(43.2%)
Unexpectedadverseevents(N/%)byrelatedness- Unrelated- Related
120(94.5%)7(5.5%)
Expected Expectedadverseeventsbyseverity(N/%)- Mild- Moderate
562(99.1%)5(0.9%)
37(100%)3(8.1%)
MostcommonexpectedAEs(>10%AEs)- Hypoglycaemia- Injectionsiteerythema- Injectionsitenodule
94(16.6%)230(40.6%)234(41.3%)
20(54.1%)35(94.6%)33(89.2%)
ExpectedAEs- Related- Unrelated
472(83.2%)95(16.8%)
UnrelatedAEs Unrelatedadverseeventsbyseverity(N/%)- Mild- Moderate
196(91.2%)19(8.8%)
35(94.59%)11(29.73%)
MostcommonunrelatedAEs(>10%)- Headache- Hypoglycaemia
22(10.2%)94(43.7%)
12(32.4%)20(54.1%)
Unrelatedadverseevents(N/%)- Expected- Unexpected
95(44.2%)120(55.8%)
21(56.7%)34(91.9%)
RelatedAEs Drug-relatedAEsaccordingtocohortsCohort1
- Injectionsiteerythema- Injectionsitenodule- Nauseaandvomitingsymptoms
Cohort2- Acne- Eosinophilia- Injectionsiteerythema- Injectionsitenodule
55(49.1%)56(50.0%)1(0.9%)2(2.0%)1(1.0%)50(49.0%)
11(91.7%)10(83.3%)1(8.3%)2(25.0%)1(12.5%)7(87.5%)
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- Malaise- Migraineheadaches
Cohort3- Injectionsiteerythema- Injectionsitenodule- Oropharyngealpain
Cohort4- Astheniccondition- Dryeye- Injectionsiteerythema- Injectionsitenodule- Nasopharyngitis
Nauseaandvomitingsymptoms
47(46.1%)1(1.0%)1(1.0%)68(55.3%)54(43.9%)1(0.8%)3(2.1%)1(0.7%)57(40.1%)77(54.2%)3(2.1%)1(0.7%)
6(75.0%)1(12.5%)1(12.5%)9(100%)9(100%)1(11.1%)3(37.5%)1(12.5%)8(100%)8(100%)3(37.5%)1(12.5%)
Drugrelatedinjectionsitereactionspernumberofdoses
- Injectionsiteerythemapernumberofdose
- Injectionsitenodulepernumberofdose
230/323(71.2%)234/323(72.4%)
DrugrelatedinjectionsitereactionspernumberofdosespercohortCohort1
- Injectionsiteerythemapernumberofdose
- InjectionsitenodulepernumberofdoseCohort2
- Injectionsiteerythemapernumberofdose
- InjectionsitenodulepernumberofdoseCohort3
- Injectionsiteerythemapernumberofdose
- InjectionsitenodulepernumberofdoseCohort4
- Injectionsiteerythemapernumberofdose
- Injectionsitenodulepernumberofdose
55/78(70.5%)56/78(71.8%)50/80(62.5%)47/80(58.8%)68/85(80.0%)54/85(63.5%)57/80(71.3%)77/80(96.3%)
11(91.7%)10(83.3%)7(87.5%)6(75.0%)9(100%)9(100%)8(100%)8(100%)
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TableS4.Safetyparameters(safetypopulation)
Parameter Baseline Followup Normalrange
hsCRP(mg/L)
2.55(±5.72) 1.90(±2.47) ≤3
Sodium(mmol/L)
138.75(±2.32) 138.6(±2.4) 133-146
Potassium(mmol/L)
4.36(±0.25) 4.35(±0.28) 3.5-5.3
Albumincorrectedcalcium(mmol/L)
2.32(±0.09) 2.36(0.13±) 2.08-2.65
Urea(mmol/L)
5.55(±1.6) 5.69(±1.34) 2.5-7.8
Creatinine(umol/L)
72.39(±14.92) 71.3(±11.3) F:44-97M:62-115
Alaninetransaminase(U/L)
21.97(±15.42) 24.9(±22.7) 7-40
Aspartateaminotransferase(U/L)
20.31(±7.23) 22.71(±12.76) ≤34
GGT(U/l)
17.11(±12.04) 20.9(±23.8) F:0-37M:0-72
Alkalinephosphatase(U/L)
74.11(±20.25) 80.8(±23.9) 30-130
TSH(mU/L)
1.55(±0.92) 1.85(±1.06) 0.35-5.50
FreeT4(pmol/L)
15.42(±2.4) 15.06(±1.74) 10.0-19.8
Redbloodcells(109/l) 4.79(±0.42) 4.74(±0.40) F:3.90-5.20M:4.00-5.65
Haemoglobin 144.9(±12.2) 142.0(±13.3) F:120-156M:135-172
Haematocrit(L/L) 0.42(±0.03) 0.41(±0.03) F:0.355-0.455M:0.395-0.505
Meancellhaemoglobin(pg) 30.21(±1.53) 29.93(±1.8) F:27.0-33.5M:27.0-33.5
Redcelldistributionwidth(%) 13.2(±0.54) 13.05(±0.71) 11.0-16.0
Plateletcount(109/l) 224.4(±44.4) 234.5(±51.6) 150-370
Whitebloodcells(109/l) 5.71(±1.76) 5.57(±1.65) 3.90-10.20
Neutrophils(109/l) 3.49(±1.61) 3.36(±1.36) 1.50-7.70
Lymphocytes(109/l) 1.53(±0.37) 1.56(±0.34) 1.50-7.70
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Monocytes(109/l) 0.41(±0.14) 0.42(±0.16) 0.10-0.90
Eosinophils(109/l) 0.16(±0.16) 0.15(±0.10) 0.10-0.90
Basophils(109/l) 0.05(±0.04) 0.04(±0.02) 0.00-0.20
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TableS5.ClinicalFACSanalysis(safetypopulation)
Parameter Baseline Followup
CD19% 12.2(±3.9) 12.3(±4.3)
CD19TotalBcells(*109/L) 0.2168(±0.17) 0.19(±0.08)
CD3% 74.8(±6.1) 75.1(±5.6)
CD3TotalTcells(*109/L) 1.16(±0.30) 1.19(±0.27)
CD4% 47.1(±7.5) 48.1(±8.1)
CD4Total(*109/L) 0.73(±0.23) 0.76(±0.21)
CD56% 12.4(±5.8) 12.1(±5.6)
CD56(*109/L) 0.19(±0.09) 0.18(±0.08)
CD8% 25.4(±6.6) 24.9(±6.7)
CD8Total(*109/L) 0.39(±0.13) 0.39(±0.14)
Lymphocytescount(*109/L) 1.53(±0.37) 1.58(±0.33)
Treg%CD4Tcells 7.13(±1.66) 7.28(±1.87)
TregAbsoulte(*109/L) 0.05(±0.02) 0.05(±0.02)
TregCD25MeanFI 2401.8(±794.7) 2292.4(±748.1)
TregCD25MEF 2863.8(±754.9) 2558.7(±520.5)
Non-Treggatedpanel Naïve% 42.4(±15.1) 39.6(±15.3)
Naïveabsolute(*109/L) 0.28(±0.14) 0.28(±0.15)
Temra% 1.01(±1.95) 0.7(±1.7)
Temraabsolute(*109/L) 0.006(±0.013) 0.004(±0.01)
Totalmemory% 56.6(±15.9) 59.9(±15.9)
Totalmemoryabsolute(*109/L) 0.38(±0.16) 0.41(±0.14)
Naïve/memoryratio 0.94(±0.84) 0.84(±0.79)
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TableS6.AICforallmodels(analysispopulation)
Model TregAIC CD25AIC TeffAIC
Lineardose,linearferquency 245.8 235.93 243.89
Quadraticdose,linearfrequency
243.55 236.14 245.85
Lineardose,quadraticfrequency
245.72 219.52 240.79
Quadraticdose,quadraticfrequency
245.27 215.0 238.63
Logdose,linearfrequency 244.26 235.04 243.95
Lineardose,logfrequency 244.27 228.82 244.73
Logdose,logfrequency 242.88 228.29 244.71
Lineardose,quadraticfrequency,interaction
246.66 213.44 236.82
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TableS7.Estimatedtargetdose/frequency
Model Bestdose
DoseSE
DoseCI
BestFrequency
FrequencySE
FrequencyCI
Lineardose,linearfrequency
-0.082 1.927 -3.858,3.694
-2.9 31.9 65.4,59.6
Quadraticdose,linearfrequency
0.133 0.154 -0.17,0.435
-0.7 10.1 -20.4,19.0
Lineardose,quadraticfrequency
0.240 0.114 0.017,0.463
3.0 0.5 1.7,3.5
Quadraticdose,quadraticfrequency
0.186 0.048 0.093,0.279
2.6 0.5 1.7,3.5
Logdose,linearfrequency
0.067 0.420 -0,757,0.891
-2.5 27.4 -56.3,51.2
Lineardose,logfrequency
0.170 0.482 -0.775,1.115
2.4 2.7 -2.8,7.7
Logdose,logfrequency
0.168 0.252 -0.327,0.662
2.5 2.2 -1.8,6.9
Lineardose,quadraticfrequency,interaction
0.239 0.126 -0,008,0.485
2.9 0.8 1.4,4.4
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TableS8.Bestestimatedallowabledoes/frequencyaccordingtoMahalanobisdistanceandjointprobability–Lineardose,quadraticfrequency,interaction(analysispopulation)
Dose Frequency MahalanobisDistance
JointProbability
0.26
3 0.044 0.742
0.25 3 0.062 0.7370.27 3 0.111 0.7160.24 3 0.134 0.7020.28 3 0.186 0.661
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TableS9.Bestestimatedallowabledose/frequencyaccordingtoMahalanobisdistanceandjointprobability-Lineardose,quadraticfrequency,interaction(evaluablepopulation)
Dose Frequency MahalanobisDistance
Joint
Probability
0.21 3 0.124 0.696
0.22 3 0.12 0.694
0.2 3 0.16 0.663
0.23 3 0.151 0.658
0.19 3 0.213 0.603
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SupplementaryFigures
FigureS1.Eosinophiliaforindividualparticipants(safetypopulation)
Oneparticipantonaldesleukin0.47x106IU/m2every4daysdevelopedtransienteosinophilia(red);pre-existingeosinophiliaresolvedintwoparticipantsreceiving0.32x106IU/m2every3days(purple),and0.09x106IU/m2every2days(blue),respectively.
1 2 3 4 5 6 7 8 9 10 11 120.0
0.5
1.0
1.5
Visit number
Eosi
noph
ils (1
09 /L)
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FigureS2.TPOantibodiesandTSHreceptorantibodies.Datashownforindividualpatientsinsafetypopulation.
NoparticipantdevelopeddenovoTPOantibodies(A)orTSHreceptorantibodies(B)duringthetrial.Tickedlineindicatesupperlimitofnormalrange.
1 1210
100
1000
Visit number
Log1
0 TP
O a
ntib
odie
s (IU
/ml)
1 120.0
0.5
1.0
1.5
Visit number
TSH
rece
ptor
ant
ibod
ies
(IU/L
)
A B
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FigureS3.Clinicalimagesandimmunohistochemicalstainingofpsoriasisinoneparticipantreceivingtreatmentwithaldesleukin0.32x106IU/m2everythreedays.
(A-F)Clinicalimages:Therewasnochangeinplaquesize,andplaquenumber(threelesionsonrightelbow, abdomen, and left ear; data not shown) during treatment. Image A to E show plaque onelbowat subsequentdosing visits 3 (A), 4 (B), 8 (C), 9 (D), and10 (E).At followup, anadditionalplaquewasobservedontheabdomen,whilethesizeofpre-existingplaquesremainedstable(F).
(G-L)Immunohistochemicalstaining:skinpunchbiopsiesofthepsoriaticplaqueonrightelbowweretakenatvisit10andatfollowupvisit12.HistopathologysectionswerestainedforCD3before(G)andafter (J) treatment,CD4before(H)andafter (K)treatment,andFOXP3before(I)andafter (L)treatment.Imagesareshown10xenlarged.CD3,CD4andFOXP3positivecellswerecountedinfiverandomfieldsofviewat100xmagnification.FOXP3toCD3ratio(0.17before,0.17after)andFOXP3toCD4ratio(0.13before,0.15after)remainedunchanged.
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FigureS4:PercentagechangeofCD19%inindividualparticipants(eachline)bydoseandfrequency(safetypopulation)
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FigureS5:PercentagechangeofCD19totalBcellsinindividualparticipants(eachline)bydoseandfrequency(safetypopulation)
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FigureS6:PercentagechangeofCD3%inindividualparticipants(eachline)bydoseandfrequency(safetypopulation)
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FigureS7:PercentagechangeofCD3totalTcellsinindividualparticipants(eachline)bydoseandfrequency(safetypopulation)
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FigureS8:PercentagechangeofCD4%inindividualparticipants(eachline)bydoseandfrequency(safetypopulation)
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FigureS9:PercentagechangeofCD4totalinindividualparticipants(eachline)bydoseandfrequency(safetypopulation)
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FigureS10:PercentagechangeofCD56%inindividualparticipants(eachline)bydoseandfrequency(safetypopulation)
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FigureS11:PercentagechangeofCD56totalNKcellsinindividualparticipants(eachline)bydoseandfrequency(safetypopulation)
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FigureS12:PercentagechangeofCD8%inindividualparticipants(eachline)bydoseandfrequency(safetypopulation)
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FigureS13:PercentagechangeofCD8totalinindividualparticipants(eachline)bydoseandfrequency(safetypopulation)
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FigureS14:Percentagechangeoflymphocytescountinindividualparticipants(eachline)bydoseandfrequency(safetypopulation)
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FigureS15:PercentagechangeofTreg%CD4Tcellsinindividualparticipants(eachline)bydoseandfrequency(safetypopulation)
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FigureS16:PercentagechangeofTregabsoluteinindividualparticipants(eachline)bydoseandfrequency(safetypopulation)
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FigureS17:PercentagechangeofTregCD25MeanFIinindividualparticipants(eachline)bydoseandfrequency(safetypopulation)
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FigureS18:PercentagechangeofTregCD25MEFinindividualparticipants(eachline)bydoseandfrequency(safetypopulation)
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FigureS19:PercentagechangeofNon-TregNaïve%inindividualparticipants(eachline)bydoseandfrequency(safetypopulation)
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FigureS20:PercentagechangeofNon-TregNaïveabsoluteinindividualparticipants(eachline)bydoseandfrequency(safetypopulation
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FigureS21:PercentagechangeofNon-TregTemra%inindividualparticipants(eachline)bydoseandfrequency(safetypopulation)
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FigureS22:PercentagechangeofNon-TregTemraabsoluteinindividualparticipants(eachline)bydoseandfrequency(safetypopulation)
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FigureS23:PercentagechangeofNon-Tregtotalmemory%inindividualparticipants(eachline)bydoseandfrequency(safetypopulation)
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FigureS24:PercentagechangeofNon-Tregtotalmemoryabsoluteinindividualparticipants(eachline)bydoseandfrequency(safetypopulation)
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FigureS25:PercentagechangeofNon-Tregnaïve/memoryratioinindividualparticipants(eachline)bydoseandfrequency(safetypopulation)
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FigureS26:IL-2levelsinindividualparticipantsbydoseandfrequency(safetypopulation)
0.001
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FigureS27:HbA1c(%)inindividualparticipants(eachline)bydoseandfrequency(analysispopulation)
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