Men and women at least 18 years of age were eligible to participate if they had met the American College of Rheumatology (ACR) criteria for RA for at least one year and were in functional Class I, II, or III . All patients had to have had at least one failed trial of a disease-modifying antirheumatic drug (DMARD) and had to have at least 10 painful and 10 swollen joints at entry. No DMARD therapy was allowed within 4 weeks of randomization. Patients receiving nonsteroidal anti-inflammatory drugs, corticosteroids (≤ 10 mg per day), or both were allowed in the trial if they had been on stable doses for at least four weeks before randomization. Required baseline laboratory values included serum creatinine and blood urea nitrogen ≤ 1.5 × the upper limit of normal and alanine aminotranferase and aspartate aminotransferase ≤ 2.0 × the upper limit of normal. Exclusionary laboratory values included a platelet count of > 500,000/mm3, hematocrit <30%, and a white-blood-cell count < 3000/mm3. Other exclusionary criteria included use of intravenous or intra-articular corticosteroids within four weeks of randomization, any prior use of cyclosporine or cyclophosphamide, use of any investigational agent within 30 days of randomization, severe extra-articular manifestations of RA, acute infection requiring antibiotic therapy within two weeks of randomization, other autoimmune disease (e.g. systemic lupus erythematosus), or any other condition that the investigator thought might have placed the patient at undue risk if they had participated in the trial. Men and women of childbearing potential were required to use approved methods of birth control. Women had to have a negative result on a test of serum beta human chorionic gonadotropin at screening.
Medications including cyclosporine, cyclophosphamide, and any DMARD were not allowed. The use of intravenous or intra-articular corticosteroids was not permitted. The following analgesics were permitted: acetaminophen, acetaminophen with codeine, acetaminophen with oxycodone, and propoxyphene. Patients were instructed not to take analgesics within 12 hours of their planned study visit.
An Institutional Review Board approved the protocol at each of the 12 participating centers. Patients gave prior written, informed consent to any study-related procedures. Within 14 days before randomization, patients had a complete medical history taken and a complete physical examination. A standard hematology profile was prepared, including white-blood-cell count with differential count, and a serum-chemistry profile was prepared, consisting of sodium, potassium, chloride, blood urea nitrogen, creatinine, glucose, phosphorus, total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, albumin, uric acid, total protein, C-reactive protein (CRP), fibrinogen, and a microscopic urinalysis. An additional serum specimen was taken on days 1, 28, 84, and 112 to measure for the presence of IL-6. Screening clinical assessments included vital signs, counts of tender and swollen joints, the patient's global assessment and assessment of their pain, and a physician's global assessment using a 7-point Likert scale (0 = none, or good, to 7 = severe, or very bad). Rheumatoid factor was also measured. A serum pregnancy test was done in all female patients of childbearing potential. Disease activity and clinical laboratory values were assessed again on day 1, and then every 2 weeks for 12 weeks, and at 4 weeks post dosing. Day-1 procedures were performed before the first dose of study drug was administered.
Rheumatologists or trained study coordinators performed clinical assessments. To minimize variability, the same person assessed disease activity during the trial whenever possible.
Patients could withdraw from the trial at any time for any of the following reasons: at the patient's request, if a serious adverse event occurred, if a concomitant medication not permitted by the protocol was required, or if a patient became pregnant, did not comply with study-related procedures, or needed surgery.
Twelve centers randomized patients, using a central randomization to one of five treatment groups: placebo, 2.5 or 7.5 μg/kg of rhIL-11 twice per week, or 5.0 or 15 μg/kg of rhIL-11 given subcutaneously once per week. The maximum dose in any single injection was 1000 μg. The study coordinator taught patients how to administer the study drug subcutaneously themselves. Either rhIL-11 or a placebo (saline) was supplied as 1 mg lyophilized powder in a phosphate/glycine formulation and reconstituted with 1 ml water for injection.
The primary objective of this trial was to evaluate the safety and tolerability of rhIL-11 given to patients with active RA. The safety endpoints were the incidence and severity of reported adverse events and abnormal laboratory findings. Adverse events are reported without regard to causality and are described for the study as a whole and by treatment group. Descriptive statistics summarizing the incidence and severity of adverse events are presented.
The secondary objective of this trial was to evaluate and characterize the clinical activity of rhIL-11. The endpoint used to characterize clinical activity was the proportion of patients whose disease improved according to the 20% ACR criteria . The overall proportion of patients whose disease improved within each individual category of the ACR criteria is also presented. Exploratory comparative tests on differences in the proportions of improvement between the rhIL-11-treated groups and the placebo group were done, using a two-sided Fisher's exact test. Logistic regression was used to explore the effect of total weekly dose, dosing schedule, treatment duration, and outcome on clinical activity. Missing data were handled by both the ad hoc last-observation-carried-forward method and the worst-case-scenario method. In the last-observation-carried-forward approach, when an observation for a 12-week time point was lacking for a patient, the last available observed value was carried forward. In the worst-case-scenario approach, dropouts were treated as failures. The sample size was based on an assumed 10% placebo success rate. The sample size had a >80% power to detect a 0.51 difference from the placebo success rate in at least one of the rhIL-11 treatment groups at the α = 0.05 level of significance.