| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Treatment of rheumatoid arthritis (RA) | |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 | | E.1.2 | Level | LLT | | E.1.2 | Classification code | 10039073 | | E.1.2 | Term | Rheumatoid arthritis | |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial | | 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. | |
| E.2.2 | Secondary objectives of the trial | 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. | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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); | |
| E.4 | Principal 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 <5 years excluding subjects with adequately treated or excised nonmetastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in situ.
3. Presenting with:
• Any condition possibly affecting oral drug absorption (eg, gastrectomy or clinically
significant diabetic gastroenteropathy);
• Any clinically significant skin lesions as described in CTCAE Version 3.0
(Appendix 2 of protocol);
• A body temperature >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 <10 gm/dL, Hct <32%;
• Absolute WBC count <3.0 × 109/L (<3000/mm3);
• Neutrophil count ≤1.2 × 109/L (<1200/mm3);
• Platelet count <100 × 109/L (<100,000/mm3);
• AST (aspartate aminotransaminase), ALT (alanine aminotransaminase) >1.2 ULN;
• Total bilirubin >1.2 × ULN;
• Alkaline phosphatase >1.2 × ULN;
• Albumin <3.5 g/dL or 35 g/L due to known liver disease;
• Serum creatinine >ULN.
5. Subjects requiring prohibited concomitant medications (Appendix 4of the protocol);
6. Pregnant or breastfeeding subjects. | |
| E.5 End points |
| E.5.1 | 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;
• ACR20 responder rate at Weeks 1, 2, 4, 8, and 16;
• ACR50/70 responder rate at Weeks 1, 2, 4, 8, 12, and 16;
• Tender/painful joint count (28) at Baseline and Weeks 1, 2, 4, 8, 12, and 16;
• Swollen joint count (28) at Baseline and Weeks 1, 2, 4, 8, 12, and 16;
• Patient’s Assessment of Arthritis Pain (100 mm visual analog scale [VAS]) at Baseline and Weeks 1, 2, 4, 8, 12, and 16;
• Patient’s Global Assessment of Arthritis (VAS) at Baseline and Weeks 1, 2, 4, 8, 12,
and 16;
• Physician’s Global Assessment of Arthritis (VAS) at Baseline and Weeks 1, 2, 4, 8, 12, and 16;
• Health Assessment Questionnaire —Disability Index (HAQ-DI) at Baseline and Weeks 1, 2, 4, 8, 12, and 16;
• C-reactive protein (CRP) at Baseline and Weeks 1, 2, 4, 8, 12, and 16;
• Disease Activity Score —[DAS28-4 (CRP)] at Baseline and Weeks 1, 2, 4, 8, 12, and 16;
• Incidence and time to withdrawal due to lack of efficacy;
• Modified Brief Pain Inventory-Short Form (mBPI-SF) at Baseline and Weeks 1, 2, 4, 8, and 12;
• SF-36v2 (Acute) Health Survey at Baseline and Weeks 4 and 12. | |
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description | |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 | The trial involves single site in the Member State concerned | Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned | |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 | Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial | The end of trial is the last visit of the last subject.
Poor recruitment (recruiting less than the anticipated number in the CTA) by a Member State is not a reason for premature termination but is considered a normal
conclusion to the trial in that Member State. | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 17 |
