| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| 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 |
| The primary objective is to characterize the dose-response of CP-690-550 over the range of 1-15 mg BID on ACR-20 response criteria at 12 weeks. |
|
| E.2.2 | Secondary objectives of the trial |
1. To examine the durability of the response of 5 dose levels of oral CP-690,550 (15 mg, 10 mg, 5 mg, 3 mg and 1 mg BID) versus placebo, administered over 6 months for the treatment of the signs and symptoms in subjects with active RA.
2. To compare the efficacy of adalimumab 40 mg subcutaneous (sc) every other week (QOW), administered over 12 weeks, versus placebo for the treatment of signs and symptoms in subjects with active RA.
3. To evaluate the safety and tolerability of 5 dose levels of oral CP-690,550 (15 mg, 10 mg, 5 mg, 3 mg and 1 mg BID) administered over 6 months versus placebo to subjects with active RA.
4. To evaluate the safety of switching from adalimumab to CP-690,550.
5. To evaluate health status and functional status in these subjects.
6. To characterize the relationship among doses, plasma concentrations of CP-690,550 and efficacy and safety outcome measures in subjects with active RA.
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|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Evidence of a signed and dated informed consent document(s) indicating that the subject has been informed of all pertinent aspects of the study.
2) Subjects must be at least 18 years of age.
3) If the subject is a sexually active woman of childbearing potential, she and any male partner are required to simultaneously use 2 effective contraceptive methods, from the list of effective contraceptives found in Section 4.4.2
4) Non vasectomized men must be willing to abstain from sexual intercourse or willing to use a condom in addition to having their female partner use another form of contraception such as an IUD, barrier method with spermicide, oral contraceptive, injectable progesterone, sub dermal implant, or a tubal ligation, if the woman could become pregnant from the time of the first dose of study medication until completion of follow up procedures.
5) The subject has a diagnosis of RA based upon the American College of Rheumatology (ACR; formerly American Rheumatism Association) 1987 Revised Criteria,5 ie, fulfilling at least 4 of the following 7 criteria for at least 6 consecutive months preceding randomization:
a. morning stiffness in and around any joint for more than 1 hour;
b. soft tissue swelling of 3 or more joint areas;
c. swelling of the proximal interphalangeal (PIP), metacarpophalangeal (MCP) or wrist joints;
d. symmetrical joint swelling;
e. rheumatoid nodules;
f. serum rheumatoid factor positive;
g. radiographic erosions and/or periarticular osteopenia in hand and/or wrist joints.
6) The subject 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:
i. Erythrocyte sedimentation rate (ESR) (Westergren method) above the upper limit of normal in the local laboratory
ii. C reactive protein (CRP) >7 mg/L in the central laboratory
7) The subject meets ACR 1991 Revised Criteria for Global Functional Status in RA, Class I, II or III (Appendix 1).
8) Subjects 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, or as defined in Concomitant Medications (Section 5.5).
9) Subjects must have failed an adequate study of therapy with at least 1 DMARD due to lack of efficacy or toxicity. See inclusion criteria 10 and exclusion criteria 1 and 12.
10) Subjects having received the following treatment regimens are eligible, provided the following discontinuation periods are observed. Note that none of these therapies should be discontinued by a subject to allow participation in this study if they are currently effective and tolerated.
a. Within 4 weeks of first dose of study drug:
DMARDS –
leflunomide (Arava® ) (see additional washout information for leflunomide in Appendix 10), methotrexate, sulfasalazine, and d penicillamine, minocycline; etanercept (Enbrel®); anakinra (Kineret®);
Immunosuppressive/Immunomodulatory therapies azathioprine, cyclosporine, and PROSORBA® device/column;
NSAIDs any experimental NSAIDs or experimental selective COX 2 inhibitors;
Other herbal medications, immunization with any live virus vaccination (eg, FluMist™) other than oral polio vaccine , intra articular, intramuscular, or intravenous corticosteroids;
b. Within 8 weeks of first dose:
infliximab (Remicade®), auranofin (Ridaura®); injectable gold (aurothioglucose or aurothiomalate); immunization with oral polio vaccine;
c. Within 3 months of first dose:
abatacept (Orencia®);
d. Within 6 months of first dose:
any experimental therapy for RA (other than experimental NSAIDs, selective COX 2 inhibitors and selective B lymphocyte depleting agents).
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|
| E.4 | Principal exclusion criteria |
1) Subjects who discontinued any previous TNFi therapy. Subjects who previously received adalimumab therapy are not allowed in the study.
2) Subjects with evidence of hematopoietic disorders:
a. Hemoglobin levels <9.0 gm/dL or hematocrit <30% at screening visit or within the 3 months prior to first study dose.
b. An absolute white blood cell (WBC) count of <3.0 x 109/L or absolute neutrophil count of <1.2 X 109/L at screening visit or within the 3 months prior to first study dose.
c. Thrombocytopenia at screening visit or within the 3 months prior to first study dose.
3) Estimated GFR ≤50 ml/min based on Cockcroft Gault calculation
4) Pregnant or lactating women.
5) Total bilirubin, AST or ALT more than 2 times the upper limit of normal at screening visit.
6) Current or recent history of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, metabolic, endocrine, pulmonary, cardiac, or neurological disease.
Note that for the purposes of this protocol New York Heart Association Class III and Class IV Congestive Heart failure will both be considered severe.
7) History of an infected joint prosthesis at any time, with the prosthesis still in situ.
8) Current routine household contact with individuals who have received either varicella or FluMist® (within 4 weeks) or oral polio vaccine (within 8 weeks), prior to first study dose.
9) History of any lymphoproliferative disorder, history of lymphoma, leukemia, myeloproliferative disorders, multiple myeloma, or signs and symptoms suggestive of current lymphatic disease.
10) Evidence of active or latent infection with Mycobacterium tuberculosis (TB), as defined by any of the following:
a. A subject has a positive Mantoux Purified Protein Derivative (PPD) skin test within the 3 months prior to screening, OR
b. A subject is immunoreactive for TB using an ex vivo method, OR
c. A subject has a chest radiograph (taken within the 3 months prior to screening) that has changes suggestive of active TB infection.
If a subject has a positive PPD or is immunoreactive for TB using an ex vivo method, (s)he may be eligible if (s)he has completed an appropriate treatment regimen for TB and has a chest radiograph within the 3 months prior to Screening that has no evidence of active TB. A subject who is currently being treated for TB infection can only be enrolled with prior approval by the Sponsor.
11) Subjects with clinically significant infections currently or within 6 months of first dose of study drug (eg, those requiring hospitalization or parenteral antimicrobial therapy or opportunistic infections), or those with a history of more than one episode of herpes simplex or zoster, a history of disseminated zoster, a history of any infection otherwise judged by the investigator to have the potential for exacerbation by participation in the study or any infection requiring antimicrobial therapy within 2 weeks of screening.
12) Any prior treatment with lymphocyte depleting agents/therapies (such as CamPath®[alemtuzab], alkylating agents [eg, cyclophosphamide or chlorambucil], total lymphoid irradiation, etc). Subjects who have received rituximab or other selective B lymphocyte depleting agents are eligible if they have not received such therapy for at least 1 year prior to first dose
13) Subjects with any condition possibly affecting oral drug absorption, gastrectomy, or clinically significant diabetic gastroenteropathy.
14) History of alcohol or drug abuse with less than 6 months of abstinence prior to first dose of study drug.
15) Screening 12 lead ECG that demonstrates clinically relevant abnormalities which may affect subject safety or interpretation of study results.
16) Donation of blood in excess of 500 mL within 2 months prior to first study dose.
17) Subjects with an oral or tympanic temperature of 38°C or higher at Screening.
18) Subjects with a first degree relative with a hereditary immunodeficiency.
19) Subjects with malignancies or with a history of malignancies 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 4 weeks of screening visit.
21) Subjects requiring prohibited concomitant medications listed in Appendix 5.
22) Subjects infected with human immunodeficiency virus (HIV) or hepatitis B or C viruses.
23) Subjects who have previously participated in any study of CP 690,550.
24) Subjects who, in the opinion of the investigator or Pfizer, will be uncooperative or unable to comply with study procedures.
25) Subjects in violation of the local label requirements for adalimumab.
26) Any other condition which would make the subject unsuitable for inclusion in the study. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary:
• American College of Rheumatology 20 (ACR 20) responder rate at the Week
12 visit.
|
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| 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 |
|
| 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) | 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 | Yes |
| 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 | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 43 |
| 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 | No |
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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