| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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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 |
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| 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 in doses of 5 mg BID and 10 mg BID versus placebo for the treatment of signs and symptoms of RA in patients with active RA who have had an inadequate response to a DMARD (traditional or biologic), as measured by ACR20 response rates at Month 6.
2. To compare physical function status of patients after administration of CP-690,550 in doses of 5 mg BID or 10 mg BID versus placebo using the HAQ-DI at Month 3 compared to baseline in patients with active RA on background traditional DMARDs.
3. To compare the rate of achieving DAS28-4(ESR)<2.6 at month 6 in patients with active RA after administration of CP-690,550 in doses of 5 mg BID or 10 mg BID versus placebo.
4. To evaluate the safety and tolerability of CP-690,550 in doses of 5 mg BID and 10 mg BID versus placebo in patients with active RA on background traditional DMARDs. |
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| E.2.2 | Secondary objectives of the trial |
1. To compare the efficacy of CP-690,550 in doses of 5 mg BID and 10 mg BID versus placebo for the treatment of signs and symptoms of rheumatoid arthritis (RA) in patients with active RA on background traditional DMARDs, as measured by ACR20 response rates at Months 1 and 3 and ACR50, ACR70 and DAS 28 response rates at Months 1, 3, and 6.
2. To compare the durability of ACR20, ACR50, and ACR70 and DAS 28 response rates.
3. To compare the incidence of DAS 28 remission and low disease activity state at each visit.
4. To compare effects on all health outcomes measures in the study at each visit, as appropriate for the specific outcome, compared to baseline. |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
MOLECULAR PROFILING SUPPLEMENT, Version and Date 09 December 2008
The primary objective of this additional research component is to collect, store, and use samples to investigate possible associations between genomic and metabonomic variation:
• in relation to response to the study drugs, and
• in relation to characteristics of the disease/condition under study in the associated clinical trial, and related conditions.
In addition, samples may be used as controls in genomic and metabonomic investigations of the causes, natural history, and other aspects of important diseases and conditions for which Pfizer is researching new or improved drug therapies.
Scientific information about these differences among groups of subjects can help researchers to better understand the response of subjects to investigational drugs and to learn more aboutdiseases/conditions for which we are developing treatments.
Samples collected will be stored in Pfizer’s Exploratory Research Biobank in the USA. |
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| E.3 | Principal inclusion criteria |
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1.Rheumatoid arthritis with evidence of disease activity by joint counts and laboratory markers of inflammation.
2.Ongoing treatment with a traditional background DMARD.
3.Meet all other eligibility criteria.
1.Rheumatoid Arthritis Disease Activity:
To be eligible for participation in this trial, a patient must meet the following criteria:
1.The patient must meet the American College of Rheumatology classification criteria for the diagnosis of rheumatoid arthritis.
2.The patient must have active disease at both screening and baseline, as defined by having both:
a.≥4 tender/painful joints on motion (out of 68 joints assessed); and
b.≥4 swollen joints (out of 66 joints assessed).
3.The patient must also have active disease as defined fulfilling 1 of the 2 following criteria at screening only:
a.Erythrocyte sedimentation rate >28 mm/hr; or
b.C reactive protein >7 mg/L.
4.The patient must meet Class I, II or III of the ACR 1991 Revised Criteria for Global Functional Status in RA.
2.Background DMARD:
To be eligible for participation in this trial, a patient must meet the following criteria: 1.Patient must have had an inadequate response to at least one DMARD (traditional or biologic) due to lack of efficacy or toxicity.
2.Patient must remain on at least one background traditional DMARD and be dosed in accordance with the local regulatory label and be willing to remain on that traditional DMARD throughout the course of the study. Combination therapy will be allowed as consistent with local standards.
a.Methotrexate: Maximum dose of 25 mg/week. Minimum duration of therapy 4 months and dose stable for 6 weeks prior to first dose of study drug. Patients on methotrexate should be on an adequate and stable dose of folic acid (not less than 5 mg weekly, unless higher doses would violate the local label) for at least 4 weeks prior to the first dose of study drug.
b.Sulfasalazine: Maximum dose of 3 gm/day. Minimum duration of therapy 2 months and dose stable for 4 weeks prior to first dose of study drug.
c.Leflunomide: Maximum dose of 20 mg/day. Minimum duration of therapy 4 months and dose stable for 4 weeks prior to first dose of study drug.
d.Hydroxychloroquine sulfate: Maximum dose of 400 mg/day. Minimum duration of therapy 2 months and dose stable for 4 weeks prior to first dose of study drug.
e.Injectable Gold: Maximum dose of 50 mg/week. Minimum duration of therapy 6 months and dose stable for 3 months prior to first dose of study drug.
f.Penicillamine: Maximum dose of 1000 mg/day. Minimum duration of therapy 6 months and dose stable for 3 months prior to first dose of study drug.
g.Other traditional DMARDs may be considered after discussion with the Sponsor.
3.Other Inclusion Criteria:
Patients must meet all of the following inclusion criteria:
1.Evidence of a signed and dated informed consent document indicating that the patient (or a legally acceptable representative) has been informed of all pertinent aspects of the study.
2.Patient must be at least 18 years of age or older.
3.Patient has discontinued all disallowed concomitant medications for the required time prior to the first dose of study drug and is taking only those concomitant medications in doses and frequency allowed by the protocol.
4.Women of childbearing potential must test negative for pregnancy prior to enrollment in this study.
5.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 trial.
6.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 Mantoux Purified Protein Derivative skin test.
•A chest radiograph taken within the 3 months prior to screening without changes suggestive of active TB infection.
•No history of either untreated or inadequately treated latent or active TB infection.
A patient who is currently being treated for either latent or active TB infection can only be enrolled with confirmation of current incidence rates of multi drug resistant TB infection, documentation of an adequate treatment regimen, and with prior approval by the Sponsor.
7.Patients 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.
Please refer to the protocol for a complete list of the inclusion criteria. |
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| E.4 | Principal exclusion criteria |
Patients presenting with any of the following will not be included in the study:
1. Any DMARD use that would be contraindicated according to the local prescribing information, including use as a background medication.
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 9/L;
• Absolute neutrophil count <1.2 x 10 to the power 9/L;
• Platelet count <100 x 10 to the power 9/L.
4. Estimated GFR <40 ml/min based on Cockcroft-Gault calculation.
5. AST or ALT greater than 1.5 times the upper limit of normal at screening or any uncontrolled clinically significant laboratory abnormality that would affect interpretation of study data or the patient’s participation in the study.
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 rheumatic autoimmune 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 recurrent (more than one episode) herpes zoster or disseminated (a single episode) herpes zoster or disseminated (a single episode) herpes simplex.
11. 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.
12. History of any infection requiring antimicrobial therapy within 2 weeks prior to the first dose of study drug.
13. Any prior treatment with non B cell-specific lymphocyte depleting agents/therapies [eg, alemtuzumab (Campath®), alkylating agents (eg, cyclophosphamide or chlorambucil), total lymphoid irradiation, etc]. Patients who have received rituximab or other selective B lymphocyte depleting agents (including experimental agents) are eligible if they have not received such therapy for at least 1 year prior to study baseline and have normal CD 19/20+ counts by FACS analysis.
14. Any patient who has been vaccinated with live or attenuated vaccines within the 6 weeks prior to the first dose of study drug or is to be vaccinated with these vaccines at any time during treatment or within 6 weeks following discontinuation of study drug.
15. 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.
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 patient safety or interpretation of study results.
18. A patient with a first-degree relative with a hereditary immunodeficiency.
19. 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.
20. Significant trauma or major surgery within 1 month of screening visit.
21. A patient requiring prohibited concomitant medications including prohibited dietary supplements.
22. A patient known to be infected with human immunodeficiency virus (HIV) or hepatitis B or C virus.
23. A patient who has previously participated in any study of CP-690,550.
24. Participation in studies of other investigational compounds within 4 weeks or 5 half-lives (whichever is longer) prior to the first dose of study drug. Patients cannot participate in studies of other investigational compounds at any time during their participation in this study. Exposure to investigational biologics should be discussed with the Pfizer Medical Monitor.
25. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product 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. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Multiple endpoints will be evaluated during the study to meet the stated objectives.
Signs and Symptoms
• ACR20 responder rates analyzed at all timepoints;
• ACR50 and ACR70 responder rates at all timepoints;
• DAS 28-3 and DAS 28-4 (CRP) at all timepoints;
• DAS 28-3 and DAS 28-4 (ESR) at baseline, 3 months, 6 months and 12 months at participating sites (dependent upon availability of a local laboratory that can report ESR results directly to the central laboratory, to ensure blinding of data).
• Rate of patients achieving a DAS 28-4(ESR)<2.6 at Month 6 ;
Physical Function and Patient Reported Outcomes
• Assessed at Baseline, Week 2 and Months 1, 2, 3, 4.5, 6, 9, and 12 / Early Termination:
• Health Assessment Questionnaire – Disability Index;
• Patient Assessment of Arthritis Pain;
• Patient Global Assessment of Arthritis;
• Physician Global Assessment of Arthritis.
• Assessed at Baseline, and Months 1, 3, 6, 9, and 12 / Early Termination:
• SF-36 (Version 2, Acute).
• Assessed at Baseline and Months 1, 3, 6, and 12 / Early Termination:
• MOS Sleep Scale;
• FACIT – Fatigue Scale.
• Assessed at Baseline and Months 3, 6, and 12 / Early Termination:
• Euro Qol EQ-5D;
• RA Healthcare Resource Utilization Questionnaire;
• Work Limitations Questionnaire.
Safety Endpoints
All safety data will be summarized descriptively through appropriate data tabulations,
descriptive statistics, and graphical presentations, including:
• Incidence and severity of adverse events;
• Incidence and severity of clinical laboratory abnormalities;
• Summary of changes in physical examination compared to baseline by patient;
• Mean change from baseline in vital signs (blood pressure, heart rate, and temperature) measurements.
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| 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 | No |
| 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 |
| 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 | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| 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 |
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| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 11 |
| 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 | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 11 |
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