| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate to severe active Rheumatoid Arthritis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Active, moderate to severe rheumatoid arthritis |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10039073 |
| E.1.2 | Term | Rheumatoid arthritis |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
|
| 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 evidence of preservation of joint structure after administration of CP-690,550 in doses of 5 mg BID and 10 mg BID versus MTX alone in MTX-naïve patients with active RA, as measured by changes from baseline using a standardized, validated method, such as the van der Heijde modified Sharp score at Month 6.
2. To compare the efficacy of CP-690,550 in doses of 5 mg BID and 10 mg BID versus MTX alone for the treatment of signs and symptoms of rheumatoid arthritis (RA) in MTX-naïve patients with active RA, as measured by ACR70 response rates at Month 6.
3. To evaluate the safety and tolerability of CP-690,550 in doses of 5 mg BID and 10 mg BID versus MTX alone in MTX-naïve patients with active RA for 24 months. |
|
| 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 MTX for the treatment of signs and symptoms of rheumatoid arthritis (RA) as measured by ACR20, 50 and 70 and DAS 28 response rates at all time points.
2. To compare physical function status of patients at each visit.
3. To compare the durability of ACR20, ACR50, and ACR70 and DAS 28 response rates at each visit.
4. To compare the incidence of DAS28 <2.6 and DAS28 ≤3.2 at each visit after administration of CP-690,550 in doses of 5 mg BID and 10 mg BID versus MTX alone in MTX-naïve patients with active RA.
5. To compare the incidence of major clinical response as defined in the protocol.
6. To compare effects on all health outcomes measures in the study at each visit,
7. To characterize the pharmacokinetics of CP-690,550 in patients who are MTX-naïve. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Active, moderate to severe, rheumatoid arthritis with joint erosions or positive IgM Rheumatoid Factor (RF) or antibodies to cyclic citrullinated peptide (anti-CCP).
2. Meet all eligibility criteria outlined below.
Active Rheumatoid Arthritis
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 (ACR) classification criteria for the diagnosis of rheumatoid arthritis (RA) by satisfying at least four of the seven criteria.
2. Evidence of at least three distinct joint erosions on posteroanterior (PA) hand and wrist or anteroposterior (AP) foot radiographs (locally read) OR if radiographic evidence of joint erosion is not available, patient must have a positive IgM rheumatoid factor (RF+), as determined by an acceptable laboratory method, OR antibodies to cyclic citrullinated peptide (anti-CCP+), as determined by an acceptable laboratory method.
3. The patient must have active disease at both screening and baseline, as defined by having both:
a. ≥6 tender/painful joints on motion, and;
b. ≥6 swollen joints.
4. The patient must have one of the following criteria at screening:
• Erythrocyte sedimentation rate (ESR) (Westergren method) >28 mm/hr, or;
• C-reactive protein (CRP) >7 mg/L in the central laboratory
5. The patient must meet Class I, II or III of the ACR 1991 Revised Criteria for Global Functional Status in RA.
Other Inclusion Criteria
Patient eligibility should be reviewed and documented by an appropriately qualified member of the investigator’s study team before patients are included in the study.
• Evidence of a personally 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.
• Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
A patient with a diagnosis of rheumatoid arthritis must also meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Patient must be at least 18 years of age or older;
2. 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;
3. Women of childbearing potential must test negative for pregnancy prior to enrollment in this study;
4. 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, as required for men and women on methotrexate therapy.
5. No evidence of active or latent or inadequately treated infection with Mycobacterium tuberculosis (TB) as defined by all of the following:
• A negative QuantiFERON®-TB Gold In-Tube test or, if unavailable or indeterminate
upon retest, a Mantoux Purified Protein Derivative skin test result of <5 mm of induration, performed according to local standards within the 3 months prior to screening. [Patients with a history of Bacille Calmette Guérin (BCG) vaccination will be tested with the QuantiFERON®-TB Gold In-Tube test];
• A chest radiograph taken at the Screening visit or 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;
• If a patient has previously received an adequate course of therapy for either latent (9 months of isoniazid in a locale where rates of primary multi-drug resistant TB infection are <5% or an acceptable alternative regimen) or active (acceptable multi- drug regimen) TB infection, neither a PPD test nor a QuantiFERON®-TB Gold In-Tube test need be obtained, but a chest radiograph must still be obtained if not done so within the prior 3 months. 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 prior approval of the Sponsor. |
|
| E.4 | Principal exclusion criteria |
Patients presenting with any of the following will not be included in the study:
1. Patients who have received more than 3 weekly doses of MTX or, if 3 or less weekly doses were received, MTX was stopped due to adverse event attributed to methotrexate.
2. Pregnancy or currently lactating.
3. Blood dyscrasias, including confirmed:
a. Hemoglobin <9 g/dL or Hematocrit <30%;
b. White blood cell count <3.0 x 10 to the power 9/L;
c. Absolute neutrophil count <1.2 x 10 to the power 9/L;
d. Platelet count <100 x 10 to the power 9/L
4. Estimated GFR <60 ml/min based on the formula for estimating GFR developed by the Modification of Diet in Renal Disease (MDRD)
5. AST or ALT greater than 1.5 times the upper limit of normal at screening or any uncontrolled clinically significant laboratory abnormality
6. Severe, progressive, or uncontrolled renal, hepatic, hematologic, gastrointestinal, metabolic (including clinically significant hypercholesterolemia), endocrine, pulmonary, cardiac or neurologic disease, including pleural effusions or ascites; and conditions contraindicating treatment with MTX, including presence of severe or significant renal or significant hepatic impairment.
7. Severe, progressive or uncontrolled chronic liver disease including fibrosis, cirrhosis, or recent or active hepatitis.
8. History of any other rheumatic autoimmune disease, other than Sjogren’s syndrome.
9. History of an infected joint prosthesis at any time, with the prosthesis still in situ.
10. History of any lymphoproliferative disorder, history of lymphoma, leukemia, or signs and symptoms suggestive of current lymphatic disease.
11. History of recurrent (more than one episode) herpes zoster or disseminated (a single episode) herpes zoster or disseminated (a single episode) herpes simplex.
12. History of any 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.
13. History of any infection requiring antimicrobial therapy within 2 weeks prior to the first dose of study drug.
14. Any prior treatment with non B cell-specific lymphocyte depleting agents/therapies 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.
15. 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.
16. 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.
17. History of alcohol or substance abuse, unless in full remission for greater than 6 months prior to first dose of study drug.
18. Screening 12-lead electrocardiogram (ECG) that demonstrates clinically relevant abnormalities that may affect patient safety.
19. A patient with a first degree relative with a hereditary immunodeficiency.
20. 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.
21. Significant trauma or surgery procedure within 1 month prior to first dose of study drug.
22. A patient requiring prohibited concomitant medications including prohibited dietary supplements.
23. A patient known to be infected with HIV, hepatitis B or C virus.
24. A patient who has previously participated in any study of CP-690,550.
25. Participation in studies of 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.
26. 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.
27. Any contraindication to MTX listed in the local MTX label which is not listed elsewhere in these exclusion criteria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Structure Preservation
- Scores of PA hand and AP foot radiographs obtained at baseline, Month 6, Month 12, and Month 24, read and scored by a central facility.
- Patients who drop out of the study early will have radiographs obtained at the last study visit, if the previous radiographs were obtained more than 3 months prior to the end of study visit. Additionally, radiographs will be obtained periodically in all patients who discontinue from this study and enroll in the open-label, long-term study, A3921024. Changes in joint structure seen in the long-term study will be scored using a validated method, similar to that used in the current study.
Signs & Symptoms
- ACR70 responder rates analyzed at Month 6 and all other time points; ACR20 and ACR50 responder rates analyzed at all time points;
- DAS 28-3 (CRP) and DAS 28-4 (CRP) at all timepoints;
- DAS 28-3 (ESR) and DAS 28-4 (ESR) at all timepoints 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).
Physical Function and Patient Reported Outcomes
Assessed at Baseline and Months 1, 2, 3, 6, 9, 12, 15, 18, 21 and 24/Early Termination:
- Health Assessment Questionnaire – Disability Index;
- Patient Assessment of Arthritis Pain;
- Patient Global Assessment of Arthritis;
- Physician Global Assessment of Arthritis;
- SF-36 (Version 2, Acute).
Assessed at Baseline and Months 1, 2, 3, 6, 12, 18 and 24/ Early Termination:
- MOS Sleep Scale;
- FACIT – Fatigue Scale.
Assessed at Baseline and Months 3, 6, 12, 18 and 24/ Early Termination:
- Euro Qol EQ-5D;
- RA Healthcare Resource Utilization Questionnaire;
- Work Limitations Questionnaire.
Safety Endpoint
- 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;
- Categorical summary of absolute vital signs and vital sign changes compared to baseline by patient.
Pharmacokinetic Endpoint
- Oral clearance (CL/F) and other PK parameters, if applicable |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Scores of PA hand and AP foot radiographs obtained at baseline, Month 6, Month 12, and Month 24, read and scored by a central facility.
ACR70 responder rates analyzed at Month 6 and all other time points; ACR20 and ACR50 responder rates analyzed at all time points;
DAS 28 3 (CRP) and DAS 28 4 (CRP) at all time points;
DAS 28 3 (ESR) and DAS 28 4 (ESR) at all time points at participating sites
Health Assessment Questionnaire – Disability Index (HAQ DI); all time points;
Patient Assessment of Arthritis Pain; all time points;
Patient Global Assessment of Arthritis; all time points;
Physician Global Assessment of Arthritis; all time points.
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;
Categorical summary of absolute vital signs and vital sign changes compared to baseline by patient. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Months 1,2,3,6,9,12,15,18,21,24 |
|
| 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 | Yes |
| 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 | 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 55 |
| 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 | No |
| 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 |
| Argentina |
| Australia |
| Belgium |
| Brazil |
| Bulgaria |
| Canada |
| Chile |
| Colombia |
| Costa Rica |
| Czech Republic |
| Denmark |
| Dominican Republic |
| Germany |
| Hungary |
| India |
| Korea, Republic of |
| Malaysia |
| Mexico |
| New Zealand |
| Peru |
| Philippines |
| Poland |
| Russian Federation |
| Slovakia |
| Spain |
| Sweden |
| Taiwan |
| Thailand |
| Ukraine |
| United States |
|
| 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
|
| as defined in the protocol |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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