This study was sponsored by Pfizer Inc (New York, NY, USA) and was conducted in 41 centers in nine countries (Australia, Germany, India, Italy, Mexico, Portugal, Spain, Ukraine, and the US). The final protocol, amendments, and informed consent documentation were reviewed and approved by the institutional review boards and the independent ethics committees at each of the investigational centers participating in the study. This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with the International Conference on Harmonization Good Clinical Practice guidelines. All patients provided informed consent prior to screening and enrollment. The trial is registered as http://ClinicalTrials.gov number NCT00427934.
Patients
Eligible patients had to be at least 18 years old, had to have an active-RA diagnosis based on the American College of Rheumatology (ACR) 1987 revised criteria, and had to meet the ACR 1991 Revised Criteria for Global Functional Status in RA (class I, II, or III). Patients had to be receiving MTX therapy for at least 12 weeks prior to study entry at a stable dose for at least 4 weeks prior to study entry which remained unchanged throughout the 12 week treatment period. MTX dosage had to be at least 10 mg/week and not more than 25 mg/week (oral or parenteral) unless documented intolerance required a lower dose. In the safety/PK component, there were no disease activity requirements. However, in the proof-of-concept (POC) component, a minimum disease activity requirement of at least six tender/painful joints on motion (28-joint count), at least six swollen joints (28-joint count), a CRP of at least 0.7 mg/dL, or an erythrocyte sedimentation rate of at least 28 mm/hour was necessary for inclusion.
Patients were excluded if they were receiving or unable to washout other medications that could interfere with disease activity assessments. Such medications would include the following: auranofin, injectable gold, sulfasalazine, d penicillamine, azathioprine, cyclosporine, high-dose corticosteroids (> 10 mg/day prednisone or the equivalent), anakrinra, etanercept, herbal supplements that included fish oil, or leflunomide (within 4 weeks); infliximab, adalimumab, or any experimental RA therapy (within 8 weeks); abatacept (within 3 months); or rituximab (within 12 months). Other exclusion criteria included the following: a history of chronic life-threatening infection; severe, progressive, and/or uncontrolled renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, cardiac, or neurologic disease; tuberculosis without treatment and/or positive tuberculin reaction without known Bacilli Calmette-Guérin vaccination; positive homozygous CCR5Δ32 mutation; history or evidence of postural hypotension; New York Heart Association class III-IV congestive heart failure requiring treatment; mean corrected QT (QTc) interval of greater than 450 ms; evidence of any current active infection; or history of cancer and in remission for less than 3 years.
Study design
This phase IIa study investigated oral maraviroc in patients who had RA and who were receiving background MTX. The study comprised two components: an open-label safety/PK component and a randomized, double-blind, placebo-controlled POC component (Figure 1).
Safety/pharmacokinetics component
This component comprised a 4-week, open-label study conducted only in the US. Two dose levels of oral maraviroc (150 mg and 300 mg BID) were investigated in patients who had no disease activity requirements and who were on stable doses of background MTX (Figure 1A). This component of the study was conducted to confirm the safety and lack of clinically significant DDIs when maraviroc was co-administered with MTX. Patients enrolled in this portion of the study were not eligible for inclusion in the POC component of the study, and replacements could be recruited if patients were discontinued from the study for reasons other than safety.
Blood samples were obtained at screening visits and were used to assess each patient's steady-state MTX PK parameters. Additional blood samples were collected at week 1 in order to assess steady-state MTX PK parameters in the presence of maraviroc. PK analyses for potential DDIs, coupled with weekly safety monitoring, were used by an internal risk management committee to select a dose for the POC component of the study. If the safety and PK profiles of the 150- and 300-mg doses were similar and there was no evidence of DDI with MTX, the 300-mg dose would be selected for the 12-week POC component.
Proof-of-concept component
Eligible patients on stable background doses of MTX were randomly assigned 2:1 to either oral maraviroc 300 mg BID or placebo BID for 12 weeks (Figure 1B). Safety and efficacy assessments were performed at baseline and at weeks 1, 2, 4, 8, and 12, and a follow-up visit took place at week 16. An interim futility analysis was planned after approximately 57 patients had completed their week 12 visit and was performed by an internal data-monitoring committee.
Treatments
All doses of maraviroc were self-administered and taken at approximately 12 hour intervals on an empty stomach, specifically 1 hour before a meal or 4 hours after the last meal. Both maraviroc and placebo treatments were added to ongoing stable background MTX therapy.
Concomitant treatments
All medications taken 28 days prior to the first dose of study treatment had to be recorded. Patients were permitted to continue on their stable background RA therapy, which could have included nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors, low-dose oral corticosteroids (not more than 10 mg of prednisone per day or the equivalent), and opioid analgesics (not more than 30 mg of oral morphine per day or the equivalent). Concomitant use of not more than 325 mg/day of aspirin was acceptable if taken for nonarthritic reasons. In addition, concomitant use of folic acid was encouraged for patients receiving MTX. Use of moderate to strong CYP3A4 inhibitors/inducers and grapefruit products was prohibited during the study. In the POC component, patients on stable doses of antimalarials (chloroquine and hydroxychloroquine) for at least 60 days were allowed to continue these medications.
Rescue medications
Acetaminophen (paracetamol) (not more than 2.6 g/day for not more than four consecutive days) was allowed as a rescue medication. If a patient was already taking stable background doses of acetaminophen, the dose could be increased up to 2.6 g/day for up to four consecutive days for rescue purposes. Rescue medication was not permitted within 24 hours of a study visit. Patients who required rescue medication for more than four consecutive days were discontinued from the study for lack of efficacy.
Evaluations
Safety/pharmacokinetics component
In addition to the general safety evaluations outlined below, maraviroc and MTX PK parameters were calculated for each patient for each treatment by using noncompartmental analysis of concentration-time data. Peak plasma concentration (Cmax) and time to Cmax (Tmax) were determined by inspection of the individual concentration-time profiles. The area under the plasma concentration-time profile from time 0 to 4 hours postdose (AUC0-4) was determined by the linear/log linear trapezoidal method.
Proof-of-concept component
The primary efficacy variable was ACR20 (American College of Rheumatology 20% improvement criteria) response rate at week 12. Other efficacy variables included the following: ACR50, ACR70, patient's assessment of arthritis pain, patient's global assessment of arthritis, physician's global assessment of arthritis, health assessment questionnaire-disability index, CRP variable of the four-variable disease activity score using 28 joint counts (DAS28-4 [CRP]) and the two component scores of the Short Form-36 (physical and mental component summary) health questionnaire. Patients had to remain 'on study, off drug' up to 28 days after the last dose, at which time the week 16 visit procedures had to be completed.
Safety evaluations
Safety was evaluated by monitoring adverse events (AEs), clinical laboratory evaluations, vital signs, and 12-lead electrocardiograms (ECGs) and by conducting physical examinations. All treatment-emergent AEs were summarized by body system and preferred term within each treatment group by using the Medical Dictionary for Regulatory Activities (MedDRA version 11.1; Maintenance and Support Services Organization).
Statistical analyses
In the POC component, it was anticipated that 30% of patients assigned to receive placebo and 55% of patients assigned to receive maraviroc 300 mg BID would achieve an ACR20 response at week 12. Sample sizes of 38 patients for the placebo group and 76 patients for the maraviroc group were considered sufficient to detect an absolute difference of 25% in ACR20 response with 81% power and a type I error of 0.05 in a one-sided test, taking the planned futility interim analysis into account. The primary efficacy endpoint in the POC component was performed on the full analysis set (FAS), which was defined as all randomly assigned patients who received at least one dose of study drug. ACR20 response rate at week 12 was also analyzed for the interim analysis set (IAS) and observed cases. Categorical variables (ACR20, ACR50, and ACR70) were analyzed by the chi-squared test unless the normal approximation to the binomial distribution was not appropriate. If this was the case, the Barnard exact test was used. Analysis of covariance models, with treatment and region as fixed effect and baseline as covariate, was performed for the components of ACR response and DAS28 endpoints.