Trial Information

Infliximab Therapy in Patients With Refractory Polymyalgia Rheumatica: a Double Blind Placebo Controlled Trial

The duration of the study will be 1 year, and it will be divided in several phases:

A) Initial phase (double-blind trial): Between week 0 and week 24. Placebo or Infliximab at
a dose of 3 mg/kg/day at weeks 0, 2 and 6.

After the screening process, patients who meet the inclusion/exclusion criteria of the
protocol will be randomized to receive three infusions of placebo or infliximab as
previously described.

After the first infusion (week 0), the prednisone dose will be tapered according to the
following schedule: Prednisone (or equivalent) should be decreased at a rate of 1.25 mg per
week until complete withdrawal of corticosteroids. In case of relapse, the dose of
prednisone will be increased up to the previous dose that controlled the symptoms of PMR,
and after 4 weeks of stable dose, prednisone will be again tapered but with a slower
schedule: 1.25 mg every 2 weeks until complete withdrawal of corticosteroids. In case of a
new relapse, the dose of prednisone will be managed according to the physician criteria.

B) Extension phase (open trial): Between week 24 and week 48. Infliximab at a dose of 3
mg/kg/day at weeks 24, 26 and 30.

At 24 weeks, all the patients included into the trial and still on corticosteroid therapy
with or without clinical manifestations of PMR, will receive three infusions of infliximab
according to the previous described schedule.

After the first infusion (week 24) the dose of prednisone will be decreased according to the
same schedule previously described in the initial phase of the trial.

The schedule therapy proposed in the extension phase is going to be for:

- (GROUP A) To evaluate time response to Infliximab in responders concerning active
treatment group in phase 1.

- (GROUP B). To incorporate patients placebo- treated to treatment who have showed
efficacy (in case of favorable results in the interim analysis)

- (GROUP C). To offer maintenance treatment to patients who have showed complete response
during phase 1 and this treatment is associated to a significant corticosteroid
tapering dose or maintenance response.

- (GROUP D). Discontinuation of the treatment in patients who have been receiving active
treatment during phase 1 and have not showed response in any time.

After the first infusion (week 24), it will be reduced prednisone dose following same
regimen described in the clinical phase of the study.

Treatment duration.

•Study will be administrate for 24 + 24 weeks. In the end of the study the patient will
continue treatment the most efficacy in the investigator opinion.

Objectives:

Primary objective: Proportion of responders (complete remission without corticosteroids) at
24 weeks.

Secondary objectives:

- Proportion of responders at 48 weeks.

- Time to response

- Number of relapses / recurrences.

- Response duration

- Cumulative dose and side effects of steroids at 24 and 48 weeks.

- Number of patients that should be re-treated with infliximab.

- Side effects of Infliximab in this patient population.

- Serum cytokine analysis

I) CLINICAL ASSESSMENT:

Evaluations will be performed at screening, baseline, every 2 weeks during the first 2
months of treatment and monthly thereafter.

The following data will be recorded at each visit:

- A structured questionnaire on symptoms of PMR.

- Global evaluation of disease activity by the patients and physicians (visual analogue
scale, 0-100).

- Global evaluation of pain by the patients (visual analogue scale, 0-100).

- Acute phase reactants: ESR (Westergren) and CRP (nephelometry).

- Complete blood cell count, glucose (glycosylated hemoglobin in case of diabetes), blood
urea and creatinine, liver enzymes and albumin.

- Steroid dosage. Cumulative steroid dosage during the study period.

- Presence of relapse

- Side effects, with special emphasis in infections and corticosteroid side effects.

All patients will have a PPD test and chest X-rays performed at screening following the
current recommendations for anti-TNF therapy (50-52). Those patients with a positive PPD
test (induration ≥ 5 mm) or with chest X-ray images showing lesions consistent with latent
tuberculosis infection, will have prophylactic treatment with isoniazid, 300 mg daily during
9 months (in case of isoniazid toxicity: rifamycin, 600 mg/day during four months).

In addition, the patients will be instructed to the possible development of infections and
other side effects, and new manifestations of GCA, which should be immediately reported to
the attending physician.

II) SERUM CYTOKINE STUDY During the study period and after informed consent, patients will
be asked to provide a serum sample (around 200 ml) at 7 different time points (week 0 or
pre-treatment, and weeks 2, 6, 24, 26, 30 and 48). The blood will be obtained at the same
time that the scheduled venipuncture for routine tests.

The analysis will be done using a Cytometric Bead Array (CBA) methodology. The
investigators will use the CBA Flex Set system (Becton Dickinson) that includes the
following cytokines: IL-1, IL-6, TGF-beta, TNF-alfa, IL-10, IL-12, IL-2, IL-4, IFN-gamma.
Following acquisition of sample data using the FACSCalibur flow cytometer (Becton
Dickinson), the sample results are generated in graphical and tabular format using the CBA
Analysis Software (Becton Dickinson).

Group I:

Infliximab 5 mg/kg. i.v. at week 0, 2, 6, 14 and 22.

Group II:

Infliximab Placebo i.v. weeks 0, 2, 6, 14 and 22.

Extension Phase (weeks 24-48):

1. Responders at week 24: Treatment discontinuation (GROUP A).

2. No-responders at week 24:

- Placebo group: infliximab (5 mg/kg) at weeks 24, 26, 30, 36 y 42 (GROUP B).

- Infliximab group:

- Patients who have lost response during phase 1 before week 24 will receive
infliximab (5 mg/kg) at weeks 30, 36 and 42 (GROUP C).

- Patients who never have fulfilled response criteria during Phase 1: will not
receive treatment in extension phase. (GROUP D)