| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| CP 690,550 is being studied as a DMARD for the treatment of moderate to severe active RA in adults. |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| 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 |
1. To compare the efficacy of CP 690,550, as monotherapy, in doses of 5 mg BID and 10 mg BID versus placebo for the treatment of signs and symptoms of rheumatoid arthritis (RA), in subjects with RA who have had an inadequate response to a DMARD (traditional or biologic), as measured by ACR20 response rates at Month 3.
2. To compare physical function status of patients with active RA after administration of CP 690,550, as monotherapy, in doses of 5 mg BID and 10 mg BID versus placebo, as measured by the HAQ DI response at Month 3.
3. To compare the rate of achieving DAS28-4(ESR) <2.6 at Month 3 in patients with
active RA after administration of CP-690,550, as monotherapy, in doses of 5 mg BID
and 10 mg BID versus placebo.
4. To compare the safety of two doses of CP 690,550 monotherapy versus placebo monotherapy in patients with RA. |
|
| E.2.2 | Secondary objectives of the trial |
1. To compare the incidence of DAS 28 remission and low disease activity state at each visit.
2. To compare effects on all health outcomes measures in the study at each visit, as appropriate for the specific outcome, compared to baseline. |
|
| 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 patient has been informed of all pertinent aspects of the study.
2. Patients must be at least 18 years of age.
3. Sexually active women of childbearing potential and men whose partners are women of childbearing potential are required to use adequate contraceptive methods during participation in this study.
4. The patient has a diagnosis of RA based upon the American College of Rheumatology (ACR) 1987 Revised Criteria.
5. The patient has active disease at both Screening and Baseline, as defined by both: a. ≥6 joints tender or painful on motion; AND b. ≥6 joints swollen and fulfills 1 of the following 2 criteria at Screening: 1. ESR (Westergren method) >28 mm in the local laboratory. 2. CRP >7 mg/L in the central laboratory.
6. The patient meets ACR 1991 Revised Criteria for Global Functional Status in RA,10 Class I, II or III.
7. No evidence of active or latent or inadequately treated infection with Mycobacterium tuberculosis (TB) as defined by all of the following:
• A negative QuantiFERON Gold®™ test or, if unavailable, a negative Mantoux PPD skin test using 5 TU PPD (<5 mm of induration performed within the 3 months prior to screening).
• A chest radiograph(CXR) within the 3 months prior to screening without changes suggestive of active TB infection.
• No hx of either untreated or inadequately treated latent or active TB infection.
• If a patient has previously received acceptable treatment for either latent or active TB infection, only a CXR need be obtained, if not done within the prior 3 months. A patient who is currently being treated for either latent or active TB infection can only be enrolled with prior approval by the Sponsor.
8. Patient had an inadequate response to at least one DMARD (traditional or biologic) due to lack of efficacy or toxicity.
9. For traditional DMARDS, the following minimum washout criteria apply:
• Methotrexate, Minocycline, Penicillamine, Sulfasalazine: must have been discontinued for 4 weeks prior to the first dose of study drug.
• Leflunomide (Arava®) must have been discontinued 8 weeks prior to the first dose of study drug if no elimination procedure is followed. Alternately, it should have been discontinued with the following elimination procedure at least 4 weeks prior to the first dose of study drug: Cholestyramine at a dosage of 8 grams three 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.
• Auranofin (Ridaura®), Injectable Gold (aurothiglucose or aurothiomalate): must have been discontinued for 8 weeks prior to first dose of study drug.
• Antimalarials (Hydroxychloroquine, Chloroquine): Antimalarials will be allowed in this study. If discontinued, they must discontinued for 4 weeks prior to the first dose of study drug. If continued, the dose must be stable for at least 8 weeks prior to first dose of study drug.
10. Biologic Response Modifiers. All must be discontinued for entry into this study:
• Anakinra (Kineret®), Enbrel (Etanercept®): Discontinued 4 weeks prior to the first dose of study drug;
• Adalimumab (Humira®): Discontinued for 6 weeks prior to first dose of study drug;
• Infliximab (Remicade®): Discontinued 8 weeks prior to the first dose of study drug;
• Certolizumab pegol (CimziaTM), Golimumab (SimponiTM) must be
discontinued for 10 weeks prior to the first dose of study drug;
• Abatacept (Orencia®), Tocilizumab (Actemra®): Discontinued 12 weeks prior to first dose of study drug;
• Rituximab or other selective B lymphocyte depleting agents (both marketed or investigational): Discontinued for 1 year prior to the first dose of study drug and if CD19/20+ counts are normal by FACS analysis.
11. Other:
a. Oral corticosteroids: Patients who are already on oral corticosteroids must be on a stable dose of ≤10 mg/day of prednisone or equivalent for 4 weeks prior to first dose of study drug.
b. Intraarticular, intramuscular, or intravenous corticosteroids: None may be administered within 4 weeks prior to first dose of study drug.
c. Cyclosporine, Tacrolimus, Azathioprine: All must be discontinued 4 weeks prior to the first dose of study drug.
d. Prosorba Device/Column: This must be discontinued 4 weeks prior to the first dose of study drug.
e. Experimental NSAIDS (including Cox 2 inhibitors): These must be discontinued 4 weeks prior to the first dose of study drug.
f. Any investigational or marketed treatment not mentioned elsewhere must be discontinued for 4 weeks or 5 half lives, whichever is longer. Exposure to investigational biologics should be discussed with the Sponsor.
12. Patients receiving non prohibited concomitant medications for any reason must be willing to stay on a stable regimen. |
|
| E.4 | Principal exclusion criteria |
1. Any prior treatment with non B lymphocyte selective lymphocyte depleting agents/therapies, such as alemtuzumab (Campath®) OR alkylating agents (eg, cyclophosphamide or chlorambucil) OR total lymphoid irradiation, etc.
2. Pregnant or lactating females.
3. Blood dyscrasias including confirmed:
• Hemoglobin <9 g/dL or Hematocrit <30%;
• White blood cell count <3.0 x 10 to the power of 9/L;
• Absolute neutrophil count <1.2 x 10 to the power of 9/L;
• Platelet count <100 x 10 to the power of 9/L.
4. Estimated GFR ≤40 ml/min based on Cockcroft Gault calculation.
5. Total bilirubin, AST or ALT more than 1.5 times the upper limit of normal at screening visit.
6. Current or recent history of uncontrolled clinically significant renal, hepatic, hematological, gastrointestinal, endocrine, metabolic, pulmonary, cardiac, or neurological disease
7. History of any other autoimmune rheumatic disease other than Sjogren’s syndrome.
8. History of an infected joint prosthesis at any time, with the prosthesis still in situ.
9. History of any lymphoproliferative disorder, such as Epstein Barr Virus (EBV) related lymphoproliferative disorder, history of lymphoma, leukemia, or signs and symptoms suggestive of current lymphatic disease.
10. History of infection requiring hospitalization, parenteral antimicrobial therapy, or as otherwise judged clinically significant by the investigator, within the 6 months prior to the first dose of study drug.
11. History of any infection requiring antimicrobial therapy within 2 weeks prior to the first dose of study drug.
12. A history of recurrent (more than one episode) herpes zoster, disseminated (a single episode) herpes zoster or disseminated (a single episode) herpes simplex.
13. A patient who was vaccinated or exposed to a live or attenuated vaccine within the 6 weeks prior to the first dose of study drug, expects to be vaccinated or exposed to these vaccines during treatment, or during the 6 weeks following discontinuation of study drug.
14. A patient with any condition possibly affecting oral drug absorption, eg, gastrectomy, clinically significant diabetic gastroenteropathy, or certain types of bariatric surgery such as gastric bypass. Procedures such as gastric banding, that simply divide the stomach into separate chambers, are NOT exclusionary.
15. History of alcohol or drug abuse with less than 6 months of abstinence prior to first dose of study drug.
16. Screening 12 lead ECG that demonstrates clinically relevant abnormalities which may affect patient safety or interpretation of study results.
17. A patient with a first degree relative with a hereditary immunodeficiency.
18. A patient with a malignancy or with a history of malignancy, with the exception of adequately treated or excised non metastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in situ.
19. Significant trauma or major surgery within 1 month of screening visit.
20. A patient requiring prohibited concomitant medications including prohibited dietary supplements.
21. A patient infected with human immunodeficiency virus (HIV) or hepatitis B or C viruses.
22. A patient who has previously participated in any study of CP 690,550.
23. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
24. A patient who, in the opinion of the Investigator or Pfizer, will be uncooperative or unable to comply with study procedures. This includes patients who are blind or
otherwise unable to complete a visual analog scale (VAS). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. American College of Rheumatology 20 (ACR20) responder rate versus placebo at the Month 3 visit.
2. Change from baseline in the Health Assessment Questionnaire (HAQ DI) at the Month 3 visit.
3. Rate of patients achieving a DAS28-4(ESR) <2.6 versus placebo at the Month 3 visit.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Information not present in EudraCT |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Information not present in EudraCT |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Molecular Profiling Supplement (optional) |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | 28 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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