| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| 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 is to compare the efficacy of 6 dose levels of oral CP 690,550 (20 mg once daily [QD] and 15 mg, 10 mg, 5 mg, 3 mg and 1 mg twice daily [BID]), versus placebo, for the treatment of signs and symptoms, administered over 12 weeks, in subjects with active RA on a stable background of MTX who have had an inadequate response to MTX alone. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are:
• To examine the durability of the response of 6 dose levels/regimes of oral CP 690,550 (20 mg QD, 15 mg, 10 mg, 5 mg, 3 mg and 1 mg BID) versus placebo, in combination with MTX, administered over 6 months for the treatment of the signs and symptoms in subjects with active RA.
• To evaluate the safety and tolerability of all dose levels of oral CP 690,550 (20 mg QD, 15 mg, 10 mg, 5 mg, 3 mg and 1 mg BID) versus placebo administered over 6 months to subjects with active RA.
• To characterize the relationship between doses, plasma concentrations of CP 690,550 and efficacy and safety outcome measures in subjects with active RA.
• To evaluate health status and functional status in these subjects.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Evidence of a signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the trial.
2. Subjects must be at least 18 years of age.
3. The subject is a sexually active woman of childbearing potential, she and any male partner are required to simultaneously use 2 effective contraceptive methods, from the list of effective contraceptives found in Section 4.4 of this protocol.
4. Non vasectomized men must be willing to abstain from sexual intercourse or willing to use a condom in addition to having their female partner use another form of contraception such as an IUD, barrier method with spermicide, oral contraceptive, injectable progesterone, sub dermal implant, or a tubal ligation, if the woman could become pregnant from the time of the first dose of study medication until completion of follow up procedures.
5. The subject has a diagnosis of RA based upon the American College of Rheumatology 1987 Revised Criteria ,ie, fulfilling at least 4 of the following 7 criteria for at least 6 consecutive months preceding randomization:
a. morning stiffness in and around any joint for more than 1 hour;
b. soft tissue swelling of 3 or more joint areas;
c. swelling of the proximal interphalangeal, metacarpophalangeal (MCP) or wrist joints;
d. symmetrical joint swelling;
e. rheumatoid nodules;
f. serum rheumatoid factor positive;
g. radiographic erosions and/or periarticular osteopenia in hand and/or wrist joints.
6. The subject has active disease at both Screening and Baseline, as defined by both:
• ≥6 joints tender or painful on motion, AND
• ≥6 joints swollen;
and fulfills 1 of the following 2 criteria at Screening:
• Erythrocyte sedimentation rate above the upper limit of normal in the local laboratory;
• C reactive protein (CRP) >7 mg/L in the central laboratory.
7. The subject meets ACR 1991 Revised Criteria for Global Functional Status in RA, Class I, II or III Appendix A.
8. Subjects must have been taking oral or parenteral methotrexate continuously for at least 4 months, and on a stable dosage of 7.5 to 25 mg weekly for at least 6 weeks prior to first dose of study drug. Subjects must have an inadequate clinical response to MTX, defined, for the purpose of this study, by the Investigator’s and subject’s opinions that the subject did not experience adequate benefit from methotrexate plus the presence of sufficient residual disease activity to meet the entry criteria.
9. Folic acid must be dosed per local standards of care stably for at least 4 weeks before first study dose.
10. Subjects receiving non prohibited concomitant medications for any reason must be on a stable regimen, which is defined as not starting a new drug or changing dosage within 7 days or 5 half lives (whichever is longer) prior to first study dose.
11. Subjects having received the following treatment regimens are eligible, providing the following discontinuation periods are observed. Note that none of these therapies should be discontinued by a subject to allow participation in this study if they are currently effective and tolerated.
a. Within 4 weeks of first dose of study drug:
• Biologics anakinra (Kineret®), etanercept (Enbrel®);
• DMARDS leflunomide (Arava®) (see additional washout information for leflunomide in Appendix J), auranofin (oral gold), injectable gold (aurothioglucose or aurothiomalate), sulfasalazine, and d penicillamine, minocycline, antimalarials (chloroquine and hydroxychloroquine);
• Immunosuppressive/Immunomodulatory therapies azathioprine, cyclosporine, and staphylococcal protein A immuno absorbant pheresis columns (such as PROSORBA® device/column);
• NSAIDs any experimental non selective or selective NSAID (COX 2 inhibitor) within a clinical trial;
� Other herbal medications, immunization with any live virus vaccination (eg, FluMist®), intra articular, intramuscular, or intravenous corticosteroids;
b. Within 8 weeks of first dose: infliximab (Remicade®), adalimumab (Humira®);
c. Within 3 months of first dose: abatacept (Orencia®)
d. Within 6 months of first dose: any experimental therapy for RA other than an experimental non selective or selective NSAID.
12. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures. |
|
| E.4 | Principal exclusion criteria |
1.Subjects with evidence of hematopoietic disorders or evidence of hemoglobin levels< 9.0 gm/dL or hematocrit< 30 % at screening visit or within the 3 months prior to first study dose.
2.An absolute white blood cell (WBC) count of< 3.0E9/L or absolute neutrophil count of <1.2E9/L at screening visit or within the 3 months prior to first study dose.
3.Thrombocytopenia, as defined by a platelet count<100E9/L at screening visit or within the 3 months prior to first study dose.
4.Estimated GFR≤50 ml/min based on Cockcroft Gault calculation.
5. Pregnant or lactating women.
6.Total bilirubin, AST or ALT more than 1.5 times the upper limit of normal at screening visit.
7.Current or recent history of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, metabolic, endocrine, pulmonary, cardiac, or neurological disease.
8.History of an infected joint prosthesis at any time, with the prosthesis still in situ.
9.Current routine household contact with individuals who have received varicella or FluMist® vaccine within 4 w or oral polo vaccine within 8 w prior to first study dose, during the 24 w of treatment and for 8 w following completion of the study.
10.History of any lymphoproliferative disorder, history of lymphoma, leukemia, myeloproliferative disorders, multiple myeloma, or signs and symptoms suggestive of current lymphatic disease.
11.History of previously untreated infection with Mycobacterium tuberculosis or current treatment for same, as defined by any of the following:
a.A positive Mantoux Purified Protein Derivative skin test, which must have been performed within the 3 months prior to screening, if the test results in ≥5 mm of induration without adequate anti TB therapy. If a subject has had prior Bacille Calmette Guerin vaccination, subject may be tested using an ex vivo method and is excluded if determined to be immunoreactive to TB by that method;
OR
b.Chest radiograph, which must have been taken within the 3 months prior to screening, that has changes suggestive of active TB infection;
c.If a subject has received a previous 9 month course of TB prophylaxis with isoniazid, a PPD test need not be obtained, but a chest radiograph must still be obtained if not done so within the prior 3 months.
12.Subjects with clinically significant infections currently or within 6 months of first dose of study drug, or those with a history of more than one episode of herpes simplex or zoster, a history of disseminated zoster, a history of any infection otherwise judged by the investigator to have the potential for exacerbation by participation in the trial or any infection requiring antimicrobial therapy within 2 weeks of screening.
13.Failure of prior treatment with 3 TNF inhibitors: etanercept, infliximab and adalimumab.
14.Any prior treatment with lymphocyte depleting agents/therapies. Subjects who have received rituximab or other selective B lymphocyte depleting agents are eligible if they have not received such therapy for at least one year prior to study baseline and have normal CD19/20+ counts by FACS analysis.
15.Subjects with any condition possibly affecting oral drug absorption, gastrectomy, or clinically significant diabetic gastroenteropathy.
16.History of alcohol or drug abuse with less than 6 months of abstinence prior to first dose of study drug.
17.Screening 12 lead ECG that demonstrates clinically relevant abnormalities which may affect subject safety or interpretation of study results.
18.Donation of blood in excess of 500 mL within 2 months prior to first study dose.
19.Subjects with an oral or tympanic temperature at Baseline visit of 38˚C or higher at screening.
20.Subjects with a first degree relative with a hereditary immunodeficiency.
21.Subjects with malignancies or with a history of malignancies with the exception of adequately treated or excised non metastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in situ.
22.Significant trauma or major surgery within 4 w of screening visit.
23.Subjects requiring prohibited concomitant medications listed in Appendix E or subjects unwilling to discontinue herbal medications for at least 4 w prior to the first dose of study drug. Subjects receiving non prohibited concomitant medications for any reason must be on a stable regimen, which is defined as not starting a new drug or changing dosage within 7 days or 5 half lives (whichever is longer) prior to first dose of study drug.
24.Subjects infected with human immunodeficiency virus or hepatitis B or C viruses.
25.Subjects who have previously participated in any study of CP 690,550.
26.Subjects with allergy/hypersensitivity to methotrexate, or previous serious toxicity with this medication.
27.Subjects who, in the opinion of the investigator or Pfizer, will be uncooperative or unable to comply with study procedures.
28.Any other condition which would make the subject unsuitable for inclusion in the study.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the American College of Rheumatology 20 (ACR 20) Responder rate at the Week 12 visit. |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | 37 |
| 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
| |
| 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 | 3 |
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