Treatment of rheumatoid arthritis (RA) MedDRA version: 8.1 Level: LLT Classification code 10039073 Term: Rheumatoid arthritis
Conditions
Interventions
Product Code: PH-797804
Pharmaceutical Form: Capsule*
CAS Number: 586414-48-4
Current Sponsor code: PH-797804
Other descriptive name: S(-)-3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
Sponsors
Pfizer Luxembourg SARL Branch Office Estonia
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the trial: 1. Has provided written informed consent and is willing to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures; 2. Is >18 years of age; 3. Has had at least 1 DMARD regimen failure; 4. In the last 6 months prior to the Screen visit, has been diagnosed with RA based upon the American College of Rheumatology (ACR) 1987 Revised Criteria, ie, fulfilling at least 4 of the following 7 criteria: • Morning stiffness in and around any joint for more than 1 hour; • Soft tissue swelling of 3 or more joint areas; • Swelling of the proximal interphalangeal (PIP), metacarpophalangeal (MCP), or wrist joints; • Symmetrical joint swelling; • Rheumatoid nodules; • Serum rheumatoid factor positive; • Radiographic erosions and/or periarticular osteopenia in hand and/or wrist joints. 5. In their current treatment regimen, maintains a minimum current level of disease activity characterized by: • =6 joints tender or painful on motion (28-joint count), • =6 joints swollen (28-joint count), AND • C-reactive protein (CRP) =1 mg/dL (10 mg/L); 6. Meets the ACR 1991 Revised Criteria for Global Functional Status in RA, Class I, II, or III (see Appendix 1of the protocol); 7. Has observed the washout periods if treated with any of the following therapies: • Within 4 weeks of first dose: Biologics —anakinra (Kineret®), etanercept (Enbrel®); DMARDs —leflunomide (Arava® —see additional washout information for leflunomide in 5.7), auranofin (oral gold), injectable gold (aurothioglucose or aurothiomalate), methotrexate, sulfasalazine, and d-penicillamine; Immunosuppressive/Immunomodulatory therapies —azathioprine, cyclosporine, minocycline, and PROSORBA® device/column; NSAIDs —any experimental nonselective or selective NSAID (COX-2 inhibitor) within a clinical trial setting with the exception of celecoxib [Celebrex®] for which a washout interval of 72 hours shall apply); Other —herbal medications, immunization with any live virus vaccination (eg, FluMist®), intra-articular, intramuscular, or intravenous corticosteroids; • Within 8 weeks of first dose: infliximab (Remicade®), adalimumab (Humira®); • Within 6 months of first dose: abatacept (Orencia®); • Within 12 months of first dose: rituximab (Rituxan®), alemtuzab (CamPath®). 8. If female, has met either of criterion “a.” or “b.” below: a. If of nonchildbearing potential, has met 1 of the following criteria: • Amenorrheic for at least 2 years, or • Has had a hysterectomy and/or bilateral oophorectomy at least 8 weeks prior to screening; Hence, all other female subjects (including those with tubal ligations) will be considered of childbearing potential. b. If of childbearing potential, must be willing to use the acceptable methods of contraception and abide by the timelines of each method as outlined in Section 4.4.1.1 (protocol); 9. If male, must be willing to use the acceptable methods of contraception and abide by the timelines as outlined in Section 4.4.1.2 (protocol); Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. A diagnosis of any other inflammatory arthritis (eg, spondyloarthropathies) or fibromyalgia (active RA with secondary osteoarthritis is acceptable); 2. A history of: • Severe, progressive, and/or uncontrolled renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, cardiac, neurological disease within 6 months of first dose; • Significant associated cardiac disease (eg, prior Coronary Artery Bypass Graft [CABG], myocardial infarction, ischemic myocardial disease, congestive heart failure, known arrhythmias of ventricular etiology, cardiomyopathy, unexplained syncope or syncope/seizures related to arrhythmia); • Chronic or recent serious or life-threatening infection within 6 months of first dose; • Tuberculosis without treatment and/or positive tuberculin reaction to PPD (Purified Protein Deriviative) without known vaccination with the bacilli Calmette-Guerin vaccine (BCG). Refer to Section 7.2.3.1 of the protocol for additional clarification; • A positive T-SPOT .TB, where used; • Significant trauma or major surgery within 8 weeks of first dose of study medication; • Alcohol abuse with less than 6 months of sobriety; drug abuse within 3 years of study start; • Cancer, which has been in remission for 38°C (98.6°F) at Baseline; • An infection with human immunodeficiency virus (HIV) or Hepatitis B or C; • Any clinically significant active infection including herpes lesions; • New York Heart Association (NYHA) Class III-IV congestive heart failure requiring treatment (Appendix 3 of protocol); • A confirmed mean of the Screen triplicate QTc interval >450 ms; • A clinically significant abnormal ECG finding. 4. Evidence of organ dysfunction or hematopoietic disorder based on any of the following assessments: • Hgb 1.2 ULN; • Total bilirubin >1.2 × ULN; • Alkaline phosphatase >1.2 × ULN; • Albumin ULN. 5. Subjects requiring prohibited concomitant medications (Appendix 4of the protocol); 6. Pregnant or breastfeeding subjects.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of this study is to evaluate the safety and tolerability of PH-797804 monotherapy in subjects with active RA on their current treatment regimen and having failed in the past at least 1 DMARD regimen. This will be accomplished in a 2-stage design, with an initial Safety/PK evaluation stage (Stage 1) in the first 50 treated subjects. A successful Stage 1 will launch the second stage (Stage 2) to complete the full enrollment of the study to evaluate the overall safety and tolerability of QD, oral PH-797804 versus placebo in all subjects through 12 weeks of treatment.;Secondary Objective: 1. To compare the efficacy of 4 dose levels of PH-797804 (0.5, 3, 6, and 10 mg QD) versus placebo, administered over 12 weeks for the treatment of the signs and symptoms of subjects with active RA; 2. To evaluate the PK profiles of multiple doses of PH-797804 administered for 12 weeks to subjects with active RA; 3. To evaluate the dose- and concentration-response of PH-797804 against measures of disease activity through 12 weeks of treatment.;Primary end point(s): Safety: • Incidence and severity of AEs; • Incidence and severity of clinical findings on physical examination; • Incidence and severity of clinical laboratory abnormalities; • Mean change from Baseline in vital signs (blood pressure [BP], heart rate [HR], temperature) measurements; • Categorical summary of absolute vital signs and vital signs changes compared to Baseline by subject; • Mean change from Baseline in 12-lead ECG parameters; and • Categorical summary of absolute ECG parameters and ECG changes compared to Baseline by subject. The determination of the primary QTc endpoint will be based on the adequacy of the correction of a potential positive linear relationship between the QT interval and the RR interval. Pharmacokinetics: Plasma PH-797804 concentrations will be determined by a validated assay. Efficacy • American College of Rheumatology 20 (ACR20) responder rate at Week 12; | — |
Countries
Czech Republic, Estonia, Spain
Outcome results
None listed