| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Early moderate to severe rheumatoid arthritis |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.0 |
| 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 |
To estimate the effect of CP-690,550 administered as a DMARD monotherapy or in combination with MTX vs MTX alone on changes from baseline in wrist and metacarpophalangeal joints (MCP) bone marrow edema at Month 6 and wrist and MCP synovitis at Month 3, as assessed by utilizing the OMERACT RAMRIS in patients with early RA.
|
|
| E.2.2 | Secondary objectives of the trial |
• Estimate the effect of CP-690,550 administered as monotherapy or in combination with MTX vs MTX alone on wrist and MCP synovitis (except at Month 3), bone edema (except at Month 6), & erosions by OMERACT RAMRIS at all assessed time points in patients with early RA
• Estimate preservation of joint structure by a validated radiographic method (eg, vdHSS) at Month 6 & Month 12
• Estimate the efficacy for treatment of signs & symptoms of RA measured by ACR response rates
• Estimate the rate of achieving DAS28-4 ESR <2.6 at all time points
• Estimate the rate of achieving DAS28-4 ESR ≤3.2 at all time points
• Investigate correlation between clinical signs & symptoms measured by the various versions of DAS28 and changes in imaging at all time points
• Investigate relationship between wrist & MCP synovitis, bone edema, & erosions by OMERACT RAMRIS at all assessed time points & radiographic changes at Month 6 & Month 12
• Evaluate the safety & tolerability of CP-690,550 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. ACR classification criteria for the diagnosis of RA by satisfying at least four of the seven criteria.
2. Early RA, as defined by ≤2 years duration since diagnosis.
3. Unequivocal evidence of at least one joint erosion on hand and wrist radiographs at Screening.
4. Evidence of clinical synovitis (tenderness/pain or swelling or both) of an index wrist or MCP joints and evidence of synovitis in the index wrist or MCP joints on MRI at the Screening visit. The index hand will be chosen as follows:
a. If only one hand (wrist/MCP) shows clinical synovitis it will be the index hand (if evidence of synovitis is confirmed by MRI).
b. If both hands show clinical synovitis at the time of randomization, the hand with the evidence of erosions will be selected.
c. If both hands show erosions then the hand with the greater burden of synovitis will be selected as the index hand.
d. If the hands are equally affected, then the dominant side will be chosen as the index hand.
The index hand will not change during the course of the study.
5. Active disease at both screening and baseline, as defined by having both:
a. >6 tender/painful joints on motion (out of 68 joints assessed, also see 7.1.1 of the protocol), and;
b. >6 swollen joints (out of 66 joints assessed, also see Section 7.1.2 of the protocol).
6. At least one of the following acute phase reactant criteria at screening:
a. ESR (Westergren method, performed by the local laboratory) >28 mm/hr, or;
b. CRP >7 mg/L (performed by the central laboratory).
7. Class I, II or III of the ACR 1991 Revised Criteria for Global Functional Status in RA
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 RA 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 two adequate contraceptive methods during participation in this trial, as required for men and women receiving MTX 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
performed according to local standards within the 3 months prior to screening;
- 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 Purified Protein Derivative (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 Pfizer Medical Monitor.
|
|
| E.4 | Principal exclusion criteria |
1. Patients who have received more than 3 weekly doses of MTX; or, if 3 or less weekly doses were received and MTX was stopped due to an AE attributed to MTX.
2. Pregnancy or currently lactating.
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; Absolute lymphocyte count of <0.5 x 10 to the power of 9/L; Platelet count <100 x 10 to the power of 9/L.
4. Estimated GFR <60 mL/min based on the formula for estimating GFR developed by the Modification of Diet in Renal Disease Study Group, or the Abbreviated Modification of Diet in Renal Disease formulae.
5. AST or ALT greater than 1.5 times ULN at Screening or Baseline, or any uncontrolled clinically significant laboratory abnormality that would affect interpretation of study data or the patient’s participation in the study.
6. Severe, progressive, or uncontrolled hematologic, gastrointestinal, metabolic (including clinically significant hypercholesterolemia), endocrine, pulmonary, cardiac or neurologic disease, including pleural effusions or ascites; & conditions contraindicating treatment with MTX, including presence of significant renal or hepatic impairment.
7. 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, such as EBV related lymphoproliferative disorder, history of lymphoma, leukemia, or signs & symptoms suggestive of current lymphatic disease.
11. History of recurrent herpes zoster or disseminated (a single episode) herpes zoster or disseminated (a single episode) herpes simplex.
12. History of any infection requiring hospitalization, intravenous 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. Body weight >300 lbs (136 kg).
15. Joint replacement of an MCP or wrist joint within the index (MRI imaged) wrist/hand.
16. Patients with pacemakers, otic implants, metal in eye or orbit, or an implanted cardiac defibrillator.
17. Any contraindications to MRI such as, but not limited to cardiac pacemaker; implanted cardiac defibrillator; aneurysm clips; carotid artery vascular clamp; neurostimulator; insulin or infusion pumps; implanted drug infusion device; bone growth/fusion stimulator; cochlear, otologic, ear implant; severe claustrophobia. Patients with passive implants that may be weakly ferromagnetic in the vicinity of the RF coil that may cause image artifacts in the index hand.
18. Patients with previous reactions to gadolinium contrast that preclude additional exposure to gadolinium.
19. History of any prior treatment with biologic DMARDs or other selective B lymphocyte depleting agents.
20. 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.
21. 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.
22. History of alcohol or substance abuse, unless in full remission for greater than 6 months prior to first dose of study drug.
23. Screening 12-lead ECG that demonstrates clinically relevant abnormalities.
24. A patient with a first degree relative with a hereditary immunodeficiency.
25. 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.
26. Significant trauma or surgery procedure within 1 month prior to first dose of study drug.
27. A patient requiring prohibited concomitant medications including prohibited dietary supplements.
28. A patient known to be infected with HIV, hepatitis B or hepatitis C virus.
29. A patient who has previously participated in any study of (CP-690,550).
30. Participation in studies of investigational compounds within 4 weeks or 5 half-lives (whichever is longer) prior to the first dose of study drug.
For a full list of Exclusion Criteria see Section 4.2 of the protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoints
• Change from baseline in OMERACT RAMRIS wrist joints and MCP synovitis (range
0-21) at Month 3.
• Change from baseline in OMERACT RAMRIS wrist joints and MCP bone marrow
edema (range 0-69) at Month 6.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary Endoints
Structure Related Endpoints
1. Change from baseline in OMERACT RAMRIS wrist joints and MCP synovitis (range
0-21) at Months 1, 6, and 12.
2. Change from baseline in OMERACT RAMRIS bone marrow edema (range 0 – 69) in
MCP and wrist joints at Months 1, 3, and 12.
3. Change from baseline in OMERACT RAMRIS erosions in MCP and wrist joints,
range (0 - 230) at all assessed time points.
4. Modified total Sharp scores, joint space narrowing and erosion scores as ascertained from PA hand and anteroposterior AP foot radiographs obtained at baseline, 6 and 12 months, scored by a central facility.
Signs and Symptoms
1. Proportion of subjects achieving ACR 20, ACR 50 and ACR 70 at all time points.
2. Actual and change from baseline in disease activity, assessed as DAS28-3 CRP and
DAS28-4 ESR and the categorization of disease activity based on DAS at all time
points.
Safety Endpoints
1. Incidence and severity of AEs.
2. Incidence and severity of clinical laboratory abnormalities.
Exploratory Endpoints
1. Quantitative measurement of erosion volume.
2. Quantitative measurement of synovitis volume.
3. Quantiative measurement of bone marrow edema.
4. Semi-quantitative or quantitative tenosynovitis scoring (MRI).
5. Semi-quantitative or quantitative joint space width.
6. Dynamic gadolinium contrast uptake kinetics in wrist. |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability, 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) | 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 | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 13 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 7 |
Print
