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

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

Nov 17, 2022 15 likes •159 views

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

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SLIDE 1

A Randomized, Double A Randomized, Double-

  • blind Trial of

blind Trial of Anti Anti-

  • TNF Chimeric Monoclonal

TNF Chimeric Monoclonal 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

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SLIDE 2

JRA Study Design (40 centres) JRA Study Design (40 centres)

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

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SLIDE 3

Inclusion/Exclusion Criteria Inclusion/Exclusion Criteria

  • Polyarticular JRA
  • At least 5 active joints
  • Low dose prednisone (10

mg or 0.2 mg/kg/day) for >4 weeks

  • Methotrexate: stable dose

and route, Initiated at least 3 months prior to first study infusion

  • No systemic manifestation
  • No joints injections 4 w before
  • No previous infliximab or other

biologics

  • No previous use of

cyclophosphamide, nitrogen mustard, chlorambucil

  • No DMARDs other than MTX

Inclusion Criteria Inclusion Criteria Exclusion Criteria Exclusion Criteria

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SLIDE 4

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

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SLIDE 5

ACR ACR-

  • pediatric 30 Using ESR

pediatric 30 Using ESR*

*

20 40 60 80 100

% of Patients Responding

Weeks

p=0.0434 p=0.0027

2 6 14 28 52

p=0.0549

Placebo + MTX IFX 6 mg/kg + MTX IFX 3 mg/kg + MTX Phase I: Double Blind Phase II: All-active Treatment Extension *ESR: protocol specified analyses Placebo + MTX IFX 3 mg/kg + MTX IFX 6 mg/kg + MTX

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SLIDE 6

ACR ACR-

  • pediatric 30 Using ESR

pediatric 30 Using ESR*

*

20 40 60 80 100

% of Patients Responding

Weeks

p=0.0434 p=0.0027 p=0.9602 p=0.3928

2 6 14 28 52

p=0.0549

Placebo + MTX IFX 6 mg/kg + MTX IFX 3 mg/kg + MTX Phase I: Double Blind Phase II: All-active Treatment Extension *ESR: protocol specified analyses Placebo + MTX IFX 3 mg/kg + MTX IFX 6 mg/kg + MTX

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SLIDE 7

48 33 12 65 52 25 67 67 50 74 67 49 20 40 60 80 100 30% 50% 70% 30% 50% 70%

Placebo 3 mg/kg 6 mg/kg

ACR ACR-

  • pedi 30, 50, and 70 Using ESR

pedi 30, 50, and 70 Using ESR

Week 14 Week 52

% of Patients Responding

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SLIDE 8

JRA Study Design JRA Study Design

Infusion Week 14 Week 52 Week 0

Infliximab 3 mg/kg +MTX

Randomized=60

Placebo infusions +MTX

Randomized=62 Week 196 Infliximab 6 mg/kg

Part 1

54 completed study 55 completed study

Part 2

36 (30%) completed study

OLE extension

78 pts (64%) 7 pts in remission

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SLIDE 9

Improvement in ACR Improvement in ACR-

  • Pedi

Pedi-

  • 30, 50, 70, 90

30, 50, 70, 90

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SLIDE 10

Infusion reactions/immunogenicity 0 Infusion reactions/immunogenicity 0-

  • 52 w

52 w

  • 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

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SLIDE 11

Infliximab immunogenicity Infliximab immunogenicity

Infusion Reactions Week 52- 204 Infliximab + MTX (n=78) Subjects POSITIVE for ATIs from Week 52 through Week 216 26/71 (36.6%) Infusion Reactions 15 (57.7%) Serious Infusion Reactions (possible anaphylactic

reaction)

1 (3.8%) Subjects negative for ATIs from Week 52 through Week 216 22/71 (31%) 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)

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SLIDE 12

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.

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SLIDE 13

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)
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SLIDE 14

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