| 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 | LLD |
| 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 of age 18 to 70 years inclusive.
- If the subject is a 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. 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 ollowing 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:. e9 joints tender or painful on motion, AND. e6 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 20 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 up to 20 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.Inadequate clinical response is defined, for the purpose of this study, by the Investigator’s and subject’s opinions that the subject did not experience substantial benefit plus the presence of sufficient residual disease activity to meet the entry criteria.
- The subject has discontinued all DMARD and immunosuppressive/immunomodulatory therapy for at least 1 month 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 1 month 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;1 month for anakinra and etanercept; 2 months for adalimumab; and 3 months for 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 an NSAID, COX-2 inhibitor, or oral corticosteroids, 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 d60 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
- 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 randomization.
- 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 30 days 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.
- Opioid analgesics, including tramadol, are prohibited for 5 half-lives prior to Baseline.
- 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.
- The subject has a history of inadequate response to more than 4 of the following DMARDs: sulfasalazine, injectable gold, methotrexate, leflunomide, cyclosporine, or a thiopurine derivative (azathioprine or 6-mercaptopurine)
|
|
| 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 |
|
| 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 | 16 |
| 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 | 18 |
Print
