A Randomized, Double- -blind Trial of blind Trial of A Randomized, - PowerPoint PPT Presentation

A Randomized, Double- -blind Trial of blind Trial of A Randomized, Double Anti- -TNF Chimeric Monoclonal TNF Chimeric Monoclonal Anti Antibody (Infliximab) in Combination Antibody (Infliximab) in Combination With Methotrexate for the Treatment of With Methotrexate for the Treatment of Patients With Polyarticular Juvenile Patients With Polyarticular Juvenile Rheumatoid Arthritis Rheumatoid Arthritis Nicolino Ruperto, MD, MPH IRCCS G. Gaslini, Genova, EULAR Centre of Excellence in Rheumatology 2008–2013 for the Paediatric Rheumatology INternational Trials Organisation (PRINTO) EMA 2010

JRA Study Design (40 centres) JRA Study Design (40 centres) Placebo + MTX Infliximab 3 mg/kg + MTX Infusion 60 pts 60 pts Week 0 Week 2 Phase I; Double Blind Week 6 Week 14 6 mg/kg + MTX Week 16 Phase II: All Patients Week 20 Receive Infliximab; Original Blind Maintained Week 28 Week 36 Week 44 Week 52 Evaluation

Inclusion/Exclusion Criteria Inclusion/Exclusion Criteria Inclusion Criteria Exclusion Criteria Inclusion Criteria Exclusion Criteria • Polyarticular JRA • No systemic manifestation • At least 5 active joints • No joints injections 4 w before • Low dose prednisone (  10 • No previous infliximab or other mg or 0.2 mg/kg/day) for >4 biologics weeks • No previous use of • Methotrexate: stable dose cyclophosphamide, nitrogen and route, Initiated at least 3 mustard, chlorambucil months prior to first study infusion • No DMARDs other than MTX

Endpoints Endpoints • Primary Endpoint – The proportion of patients achieving ACR pediatric 30 response at Week 14 in the placebo/6 mg/kg infliximab + MTX group (Group I) compared with the 3 mg/kg infliximab + MTX group (Group II) • Major Secondary Endpoints – Infliximab pharmacokinetics – Adverse event profile of infliximab in the JRA population

ACR- -pediatric 30 Using ESR pediatric 30 Using ESR * * ACR Placebo Placebo IFX 3 mg/kg IFX 6 mg/kg IFX 6 mg/kg IFX 3 mg/kg + MTX + MTX + MTX + MTX + MTX + MTX 100 Phase I: Phase II: % of Patients Responding Double Blind All-active Treatment Extension 80 60 p=0.0549 40 p=0.0027 20 p=0.0434 0 2 6 14 28 52 Weeks *ESR: protocol specified analyses

ACR- -pediatric 30 Using ESR pediatric 30 Using ESR * * ACR Placebo Placebo IFX 3 mg/kg IFX 6 mg/kg IFX 6 mg/kg IFX 3 mg/kg + MTX + MTX + MTX + MTX + MTX + MTX 100 Phase I: Phase II: % of Patients Responding Double Blind All-active Treatment Extension 80 p=0.9602 60 p=0.3928 p=0.0549 40 p=0.0027 20 p=0.0434 0 2 6 14 28 52 Weeks *ESR: protocol specified analyses

ACR- -pedi 30, 50, and 70 Using ESR pedi 30, 50, and 70 Using ESR ACR Week 14 Week 52 100 % of Patients Responding 74 80 67 67 67 65 52 60 50 49 48 33 40 25 12 20 0 30% 50% 70% 30% 50% 70% Placebo 3 mg/kg 6 mg/kg

JRA Study Design JRA Study Design Placebo infusions +MTX Infliximab 3 mg/kg +MTX Infusion Randomized=62 Randomized=60 Week 0 Part 1 Week 14 Infliximab 6 mg/kg Part 2 Week 52 54 completed study 55 completed study 78 pts (64%) OLE extension 7 pts in remission Week 196 36 (30%) completed study

Improvement in ACR- -Pedi Pedi- -30, 50, 70, 90 30, 50, 70, 90 Improvement in ACR

Infusion reactions/immunogenicity 0- -52 w 52 w Infusion reactions/immunogenicity 0 • Infusions with infusion reactions – Infliximab 3 mg/kg (Week 0-52) = 46 (9.1%) – 6 mg/kg (Week 14-52) = 13 (4.2%) • Serious infusion reactions – Infliximab 6 mg/kg = 2 (3.5%) – Infliximab 3 mg/kg = 4 (6.7%) • Higher anti-infliximab antibody incidence in 3 mg/kg than in 6 mg/kg group – 37.7% in 3 mg/kg and 12.2% in 6 mg/kg – Incidence for 6 mg/kg group is similar to 3 mg/kg in adults with RA (ASPIRE trial data) • Antibody positive patients had lower serum infliximab concentrations

Infliximab immunogenicity Infliximab immunogenicity Infusion Reactions Week 52- 204 Infliximab + MTX (n=78) Subjects POSITIVE for ATIs from Week 52 through 26/71 (36.6%) Week 216 Infusion Reactions 15 (57.7%) Serious Infusion Reactions (possible anaphylactic 1 (3.8%) reaction) Subjects negative for ATIs from Week 52 through 22/71 (31%) Week 216 Infusion Reactions 5 (22.7%) Serious Infusion Reactions 1 (4.5%) Antinuclear antibodies (titer >1:320) Newly positive from Weeks 52-204 15/58 (25.9) Antibody to double-stranded DNA Newly positive from Weeks 52-204 4/61 (6.6)

Comparison of PK Profile in the Comparison of PK Profile in the 3 mg/kg group vs. 6 mg/kg group in JRA 3 mg/kg group vs. 6 mg/kg group in JRA Data on File; Centocor, Inc.

Comparison of PK Profile 3 and 6 mg/kg JRA Comparison of PK Profile 3 and 6 mg/kg JRA vs. 3 mg/kg ASPIRE (Adult Early RA Study) vs. 3 mg/kg ASPIRE (Adult Early RA Study) Data on File; Centocor, Inc.

Reasons for failure to achieve primary objectives Reasons for failure to achieve primary objectives • Errors in sample size assumptions – 5 patients excluded from efficacy analysis 1 for consent withdrawn and 4 for potential unblinding issues – Higher than anticipated placebo response (48%) ADDITIONAL REASONS • Errors in time to assess primary outcome (14 weeks too short) • Failure to have an adequate pK/safety model specific for children prior to the phase III trial