| 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. |
|
| 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 |
There are four primary objectives, to be assessed in the following sequence:
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 a stable background of methotrexate, as measured by
ACR20 response rates at Month 6.
2. To compare physical function status of patients after administration of 5 mg BID and 10 mg BID of CP-690,550 versus placebo using the HAQ-DI at Month 3 compared to baseline in patients with active RA on a stable background of methotrexate.
3. To compare the rate of achieving DAS28-4(ESR)<2.6 at Month 6 after administration of 5 mg BID and 10 mg BID of CP-690-550 versus placebo in patients with active RA on stable background methotrexate.
4. To evaluate the safety and tolerability over 12 months of CP-690,550 in doses of
5 mg BID and 10 mg BID versus placebo in patients with active RA on a stable
background of methotrexate. |
|
| E.2.2 | Secondary objectives of the trial |
1. To compare the efficacy of oral CP-690,550 in doses of 5mg BID & 10mg BID plus MTX versus placebo plus MTX for the treatment of signs & symptoms of rheumatoid arthritis
2. To compare the efficacy of adalimumab (Humira®) 40mg SC q2 weeks plus MTX versus placebo plus MTX for the treatment of signs & symptoms of rheumatoid arthritis
3. To compare the durability of ACR20, ACR50, & ACR70 & DAS 28 response rates at all visits.
4. To compare the incidence of DAS 28 remission & low disease activity state at all visits.
5. To compare effects on all health outcomes measures compared to baseline in the study at all visits, as appropriate for the specific outcome.
6. To estimate the efficacy of adalimumab (Humira®) 40mg SC q2 weeks versus CP 690,550 in doses of 5 & 10mg BID for the treatment of signs & symptoms in patients with active RA on a stable background of methotrexate |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
To be eligible for inclusion in this study, patients must have:
1. Rheumatoid arthritis with evidence of disease activity by joint counts and laboratory markers of inflammation as described in Section 4.1.1.
2. Ongoing treatment with an adequate and stable dose of 7.5 to 25 mg weekly of methotrexate, inclusive
3. Meet all eligibility criteria for ACR classification for RA as specified in the protocol
4.The patient must have active disease at both screening and baseline, as defined by having both:
≥6 tender/painful joints on motion (out of 68 joints assessed); and;
≥6 swollen joints (out of 66 joints assessed).
5.The patient must also have active disease, as defined by one of the following criteria at screening:
a.Erythrocyte sedimentation rate (ESR) (Westergren method) >28 mm/hr; or
b.C reactive protein (CRP) >7 mg/L in the central laboratory.
6.The patient must meet Class I, II or III of the ACR 1991 Revised Criteria for Global Functional Status in RA..
7. Background Methotrexate:All local standard of care practices for the administration of methotrexate, including laboratory testing, follow up care, contraindications, and folic acid administration should be performed according to local standards of care
guidelines for methotrexate and folic acid therapy during study:
8.The patient must have taken oral or parenteral methotrexate continuously for at least 4 months prior to the first dose of study medication and be on a stable dose of 7.5 mg to 25 mg weekly, for at least 6 weeks prior to the first dose of study medication. Stable weekly doses less than 15 mg are allowed only in the presence of intolerance to or toxicity from higher doses or where higher doses would violate the local label. Doses higher than 25 mg weekly are not permitted under any circumstances.
9.The patient must have an inadequate clinical response to methotrexate defined as the presence of sufficient residual disease activity to meet the entry criteria.
10.A patient with a diagnosis of rheumatoid arthritis, on an appropriate regimen of methotrexate, who has discontinued other DMARD therapies
11. Evidence of a signed and dated informed consent document
12.Patient must be at least 18 years of age or older.
13.Patient has discontinued all disallowed concomitant medications for the required time prior to the first dose of study medication and is taking only those concomitant medications in doses and frequency allowed by the protocol.
14.Women of childbearing potential must test negative for pregnancy prior to enrollment in this study.
15.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, as required for men and women on methotrexate therapy.
16.No history or evidence of active or latent or inadequately treated infection with Mycobacterium tuberculosis (TB).
17. 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. |
|
| E.4 | Principal exclusion criteria |
A patient who presents with any of the following will not be included in the study:
1.Pregnant or lactating females.
2.Blood dyscrasias within 3 months prior to the first dose of study medication, including confirmed:
a.Hemoglobin <9 g/dL or Hematocrit <30%;
b.White blood cell count <3.0 x 10 to the power of 9/L;
c.Absolute neutrophil count <1.2 x 10 to the power of 9/L;
d.Platelet count <100 x 10 to the power of 9/L.
3.Estimated GFR <40 ml/min based on Cockcroft-Gault calculation.
4.AST or ALT >1.5 the upper limit of normal or any uncontrolled clinically significant laboratory abnormality.
5.Current or recent history of uncontrolled renal, hepatic, hematological, gastrointestinal, metabolic, endocrine, pulmonary, cardiac, or neurological disease.
6.History of any other autoimmune rheumatic disease, other than Sjogren’s syndrome.
7.History of an infected joint prosthesis at any time, with the prosthesis still in situ.
8.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.
9.History of recurrent (more than one episode) herpes zoster or disseminated (a single episode) herpes zoster or disseminated (a single episode) herpes simplex.
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 medication.
11.History of infection requiring antimicrobial therapy within 2 weeks prior to the first dose of study medication.
12.Patients who have failed any TNFi for either lack of efficacy or a TNFi mechanism related adverse event.
13.Patients who have previously received adalimumab therapy for any reason.
14.Patients who are contraindicated for treatment with adalimumab in accordance with the approved local label. Patients meeting the New York Heart Association Class III and Class IV Congestive Heart failure:
15.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..
16.Any patient who has been vaccinated with live or attenuated vaccines within the 6 weeks prior to the first dose of study medication or is to be vaccinated with these vaccines at any time during treatment or within 6 weeks following discontinuation of study medication.
17. A patient with any condition possibly affecting oral drug absorption,
18.History of alcohol or drug abuse with less than 6 months of abstinence prior to first dose of study medication.
19.Screening 12-lead electrocardiogram (ECG) that demonstrates clinically relevant abnormalities which may affect patient safety or interpretation of study results.
20.A patient with a first degree relative with a hereditary immunodeficiency.
21.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, cervical carcinoma in situ.
22.Significant trauma or surgery procedure within 1 month prior to first dose of study medication.
23.A patient requiring prohibited concomitant medications.
24.A patient known to be infected with human immunodeficiency virus (HIV), hepatitis B virus or hepatitis C virus.
25.A patient who has previously participated in any study of CP 690,550.
26.Participation in studies of other investigational compounds within 4 weeks or 5 half lives (whichever is longer) prior to the first dose of study medication. 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.
27.A patient who has an allergy/hypersensitivity to methotrexate, or previous serious toxicity when administered methotrexate.
28.Other severe acute or chronic medical, psychiatric condition, laboratory abnormality, or investigational product administration that would make the patient inappropriate for entry into this study. |
|
| 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 & 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 all timepoints at participating sites (dependent upon availability of a local laboratory that can report directly to the central laboratory, to ensure blinding of data).
Other endpoints for Physical Function, Patient Reported Outcomes and Safety are described in 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 | Yes |
| 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 | 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 |
|
| 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
| 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 | 88 |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 20 |
| 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 | 20 |
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