Trial Information

Efficacy, Safety, and Tolerability of Infliximab (Remicade; Schering-Plough) in Juvenile Spondyloarthropathies: a Three-Month, Randomized, Double-Blind, Placebo-Controlled Trial and 52-Week Open Extension.

Background Tumor necrosis factor (TNF) alpha is a pro-inflammatory cytokine playing a
significant role in the pathogenesis of the spondyloarthropathies (SpA). Infliximab is a TNF
alpha blocking monoclonal antibody efficacious and safe as treatment of adult-onset SpA.

Hypothesis Infliximab will reduce the number of joints with active arthritis and improve
additional parameters of disease activity and functioning more significantly than placebo
over 12 weeks. Infliximab will demonstrate sustained efficacy and its administration will be
safe and well tolerated over 52 weeks.

Objectives To demonstrate superior clinical efficacy with infliximab administered at 5mg/kg
compared with placebo, in juvenile onset SpA over a period of 12 weeks. To demonstrate
sustained efficacy, safety, and tolerability of infliximab at 5 mg/kg over 52 weeks.

Study Design This is a two-phase study. First phase: 12-week, randomized, double-blind,
placebo-controlled period to evaluate efficacy, safety, and tolerability of infliximab 5
mg/kg.

Thirty-four patients allocated and randomized to infliximab 5 mg/kg or placebo.
Randomization: restricted by blocks of four and by stratification in two diagnostic
categories (undifferentiated SpA and ankylosing spondylitis). Efficacy analysis: change of
the primary efficacy measure and secondary measures on weeks 2, 6, and 12, and any visit of
discontinuation compared to week 0 and compared to changes in the placebo group.

Patients completing the 1st phase and those discontinued due to lack of efficacy after week
6 will continue into the 2nd phase to complete a total of 52 weeks. The 2nd open-phase will
demonstrate the sustained efficacy, safety, and tolerability of infliximab along 52 weeks
(weeks 12, 18, 24, 30, 36, 42 and 48). Efficacy analysis will focus on the change of the
primary efficacy measurement and secondary measures on each scheduled visits- and any
discontinuation visit compared to week 0.

Safety Evaluation Safety evaluations will included a search for clinical serious and
non-serious adverse events; blood cytology, hepatic function tests, blood chemistry,
urinanalysis, antinuclear antibodies by immunofluorescence, anti-DNA antibodies, rheumatoid
factor, and chest X-rays.

Statistical Analysis The primary analysis will follow the "intention to treat" model. The
data of patients who have been prematurely discontinued from the study- since V2.0- will be
included in the primary analysis. The comparison between infliximab and placebo will be
sequential.

Double-blind phase: step-down analysis; changes from baseline will be computed from a
time-weighted average of the responses across weeks 2, 4, and 6 -and any discontinuation
visit. 95% confidence intervals to evaluate the magnitude of the difference between
infliximab and placebo will be used.

Open phase: mean changes from baseline on the time weighted average of responses over the
whole length of the study.

Statistical tests: parametric and non parametric to evaluate the inter and intragroupal
differences; ANCOVA, Mann Whitney, Wilcoxon, t of student and x2.

Sample size: 17 patients per group, plus 2 patients per group because of loss, supposes an
improvement in the study group of 60% to 90%, with a confidence level of 95% to 99% (two
tails test) and a power of 80% to 90%, with improvement in the control group of only 10%.
The basis of such calculations is indirect because there are no data about juvenile SpA;
yet, data on adults treated with infliximab and children and teenagers treated with
sulfasalazine compared to placebo exist.

Budget The project and protocol are the result of the initiative of the investigators who
are the intellectual proprietaries of it. Schering Plough, owner of the patent of Infliximab
(Remicade; Schering Plough), has accepted to finance the project.