| 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 | 7.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10039073 |
|
| 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 compare the efficacy of 3 dose levels of oral CP 690,550 monotherapy (5 mg, 15 mg, and 30 mg twice daily [BID]) versus placebo administered over 6 weeks for the treatment of the signs and symptoms of subjects with active RA. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are:
-To evaluate the safety and tolerability over 12 weeks of CP 690,550 administered for 6 weeks, plus 6 weeks post-dosing follow up, to subjects with active RA.
- To evaluate the pharmacokinetics of CP 690,550 and its correlation with clinical responses and with biomarkers of inflammation and immunosuppression.
- To evaluate health status and functional status. |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
- The subject can give written informed consent.
- Male or female subjects at least 18 years of age. However, for subjects >70 years old, the site must discuss subject eligibility with the study team to ensure that these subjects are sufficiently healthy to participate.
- If the subject is a sexually active woman of childbearing potential, she and any male partner are required to simultaneously use 2 effective contraceptive methods, one of which must be a barrier (condoms, diaphragm or cervical cap) with spermicide. The other may be an oral or other acceptable contraceptive, which includes, but is not limited to: injectable, implanted or patch hormone therapy, IUD, or documented surgical sterilization for at least 4 weeks before screening, or partner vasectomy. She and any male partner must be willing to continue all of these contraceptive methods for 6 months after receiving study treatment. Within these limits, the specific forms of contraception employed are left to the discretion of the subject, the principal investigator, and/or the subject’s physician.
- 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.
- The subject has a diagnosis of RA based upon the American College of Rheumatology (ACR; formerly American Rheumatism Association) 1987 Revised Criteria,9 ie, fulfilling at least 4 of the following 7 criteria for at least 6 consecutive months preceding participation:
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 (PIP), 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.
- The subject has active disease at both Screening and Baseline, as defined by both:. ≥9 joints tender or painful on motion, AND. ≥6 joints swollen;and fulfills 2 of the following 3 criteria at Screening:
. at least 45 minutes duration of morning stiffness,
. at least 28 mm/hour erythrocyte sedimentation rate (ESR) (Westergren method),
. at least 10 mg/L C-reactive protein (CRP).
- The subject meets ACR 1991 Revised Criteria for Global Functional Status in RA, Class I, II or III (Appendix A protocol).
- Subjects must have had an inadequate response to, or discontinued for unacceptable toxicity to, either methotrexate, etanercept, infliximab, or adalimumab, according to the following criteria:
. For methotrexate: an inadequate clinical response to doses of at least 15 mg weekly for at least 3 months, unless lower doses can be justified due to documented unacceptable toxicity.
. For etanercept, infliximab, or adalimumab: either inadequate clinical response to an approved dose/regimen for at least 3 months or discontinuation for documented unacceptable toxicity.
- The subject has discontinued all DMARD and immunosuppressive/immunomodulatory therapy for at least 4 weeks prior to first dose of study drug:
. DMARDs: auranofin (oral gold), injectable gold (aurothioglucose or aurothiomalate), methotrexate, sulfasalazine, d-penicillamine, antimalarials (chloroquine and hydroxychloroquine).
. Immunosuppressive/immunomodulatory therapies used in RA in similar fashion to DMARDs: azathioprine, cyclosporine, and PROSORBA® device/column.
. Intra-articular, intramuscular, or intravenous corticosteroids.
- Other therapies that must be discontinued prior to first dose of study drug are: leflunomide, anakinra (Kineret®), etanercept (Enbrel®), adalimumab (Humira®), and infliximab (Remicade®). Subjects must have discontinued 4 weeks for leflunomide with an elimination procedure as follows: cholestyramine at a dosage of 8 grams 3 times daily for at least 24 hours, or activated charcoal at a dosage of 50 grams 4 times a day for at least 24 hours;4 weeks for anakinra and etanercept; 8 weeks for adalimumab and infliximab.None of these therapies should be discontinued by a subject to allow participation in this study if these therapies are currently effective and tolerated.
- If the subject is taking a stable dosage of acetaminophen (≤2.6 gm/day), opioid (no greater than the equivalent potency of 30 mg oral morphine /d [Appendix F]), NSAID, COX-2 inhibitor, or oral corticosteroids(≤10 mg prednisone or equivalent per day), he/she is expected (in the judgment of the investigator) to be able to remain on a stable dosage throughout the treatment period. |
|
| E.4 | Principal exclusion criteria |
- Subjects with evidence of hematopoietic disorders or evidence of hemoglobin levels <10 gm/dL or hematocrit <32% at screening visit or within the 3 months prior to randomization.
- An absolute white blood cell (WBC) count of <3.0 x 109/L (<3000/mm3) at screening visit.
- Thrombocytopenia, as defined by a platelet count <100 x 109/L (<100,000/mm3) at screening visit.
- Estimated GFR≤ 60 ml/min based on Cockcroft-Gault calculation (Appendix D).
- Pregnant or lactating women.
- Total bilirubin, AST or ALT more than 1.2 times the upper limit of normal at screening visit.
- Current or recent history of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, metabolic, endocrine, pulmonary, cardiac, or neurological disease.
- History of an infected joint prosthesis at any time, with the prosthesis still in situ.
- Current immunization with any live virus vaccine (eg, FluMist™) or history of immunization with any live virus vaccine within 1 month of randomization, or during the 6 weeks of treatment and the first 4 weeks of the follow-up period.
- Current routine household contact with children who have received varicella or oral polio vaccine within 2 months of randomization, or during the 6 weeks of treatment and the first 4 weeks of the follow-up period.
- History of any lymphoproliferative disorder (such as EBV-related lymphoproliferative disorder, as reported in some subjects on other immunosuppressive drugs), history of lymphoma, leukemia, myeloproliferative disorders, multiple myeloma, or signs and symptoms suggestive of current lymphatic disease.
- History of previously untreated infection with Mycobacterium tuberculosis (TB) or current treatment for same, as defined by any of the following:
. A positive Mantoux Purified Protein Derivative (PPD) skin test, within the 3 months prior to randomization or
. Chest radiograph, within the 3 months prior to randomization, that has changes suggestive of active TB infection
- Subjects with clinically significant infections currently or within the past 6 months
- A subject who has received any experimental therapy for RA (within or outside a clinical trial) within 6 months prior to randomizations. However, subjects who have received an experimental NSAID or selective COX-2 inhibitor may participate once they have stopped the experimental therapy for more than 30 days.
- Any prior treatment with lymphocyte-depleting agents/therapies
- Subjects with any condition possibly affecting oral drug absorption
- History of alcohol abuse with less than 6 months of sobriety.
- History of drug abuse within 3 years.
- Screening 12-lead ECG that demonstrates clinically relevant abnormalities that may affect subject safety or interpretation of study results.
- Unwillingness to refrain from consumption of grapefruit or grapefruit juice within 7 days prior to the first dose of study medication until the end of the treatment period.
- Donation of blood in excess of 500 mL within 56 days prior to dosing.
- Subjects with an oral temperature at Baseline visit of 38°C or higher.
- Subjects with a first-degree relative with a hereditary immunodeficiency.
- 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.
- Recent (within 1 month of screening) significant trauma or major surgery.
- Subjects requiring prohibited concomitant medications listed in Appendix E or subjects unwilling to discontinue herbal medications for at least 4 weeks prior to the first dose of study medication. 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 randomization.
- Subjects infected with human immunodeficiency virus (HIV) or hepatitis B or C viruses.
- EBV DNA levels above safety limits specified by the Central Laboratory.
- Any other condition which would make the subject unsuitable for inclusion in the study.
- Subjects who, in the opinion of the investigator or Pfizer, will be uncooperative or unable to comply with study procedures.
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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 6 visit (see Appendi A of the protocol). |
|
| 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 | Information not present in EudraCT |
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| 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 | Information not present in EudraCT |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 13 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 13 |
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