| 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 | 12.0 |
| 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 |
| To determine the efficacy of PF-04171327 (high and low dose) compared to placebo as assessed by DAS28-4 (CRP) at Week 2 |
|
| E.2.2 | Secondary objectives of the trial |
To determine the efficacy of 5 mg prednisone compared to placebo as assessed by DAS28-4 (CRP) at Week 2.
To assess the safety and tolerability of PF-04171327 and prednisone 5 mg when administered to RA patients for 2 weeks.
To evaluate PF-00251802 pharmacokinetics and biomarker responses in RA patients.
To evaluate the pharmacokinetics of MTX in the presence of PF 00251802. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study.
2. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3. Males and females ≥18 years of age.
4. Subject should have RA (ACR criteria, 1987 revised criteria) with a minimum duration of 3 months and fulfilled 4/7 criteria for the diagnosis of RA.
5. Subject must have minimum disease activity level of at least :
≥6 swollen joints and ≥6 tender joints at screening and baseline (28 joint count);
CRP ≥0.7 mg/dL (≥7.0 mg/L) at screening.
6. Has observed the following washout periods, if treated with any of the following therapies:
4 weeks of the first dose:
Biologics−anakinra (Kineret®), etanercept (Enbrel®).
DMARDs−leflunomide (Arava®), auranofin (oral gold) injectible gold (aurothioglucose or aurothiomalate), sulfasalazine, d-penicillamine, minocycline, cyclosporine, and azathioprine.
Note: In addition to a washout period of 4 weeks for leflunomide, one of the following elimination procedures must have been adhered to for a minimum of 11 days:
cholestyramine at a dose of 8 grams 3 times daily for at least 24 hours, or
activated powdered charcoal at a dosage of 50 grams 4 times a day for at least 24 hours.
Experimental NSAIDs−any experimental non-selective NSAID or experimental selective NSAID (COX-2 inhibitor).
Other−herbal medications, immunization with any live or live attenuated virus vaccination (eg, FluMist™).
6 weeks of the first dose:
Glucocorticoids by any route (oral, intra-articular, intramuscular or intravenous) that may result in significant systemic exposure.
8 weeks of first dose:
infliximab (Remicade®), adalimumab (Humira®), certolizumab pegol (Cimzia®).
12 weeks of first dose:
abatacept (Orencia®)
12 months of first dose:
rituximab(Rituxan®) or other selective B lymphocyte depleting agents—however, a B lymphocyte count is recommended to consider the subject sufficiently washed off before treatment with study drug.
7. Meet the ACR 1991 Revised Criteria for Global Functional Status in RA, Class I, II or III.
8. Subject must have been on MTX or allowed MTX-DMARD combination (eg, MTX + hydroxychloroquine or MTX+ chloroquine) for at least 3 months, and be on a stable dose of MTX for at least 6 weeks (8 weeks for antimalarials) prior to screening. In addition, MTX or allowed DMARD combination as well as any concomitant medication(s) dose will remain unchanged during treatment period. In addition:
Subjects should not be removed from ongoing glucocorticoid therapy and complete a wash out period for the purpose of qualification for this study.
9. Subject must be on a MTX of dose ≥7.5 mg weekly (po/sc/im) and ≤25 mg weekly unless documented intolerance requires a lower dose. MTX should be administered as a single dose for a minimum of 28 days prior to randomization. If the proportion of enrolled subjects receiving a parenteral formulation (sc or im) exceeds 10% of the total, the sponsor may at its discretion limit further subsequent enrollment to subjects receiving oral MTX.
10. For subjects on chronic topical or inhaled glucocorticoids, the treatment must be stable for ≥4 weeks prior to entry and remain unchanged through the 2-week treatment period.
11. If of childbearing potential, agrees that when sexually active, to use 2 effective contraceptive methods and abide by the timeframes as noted in the Contraception section of the Lifestyle Guidelines.
12. Women of childbearing potential must test negative for pregnancy prior to enrollment in this study.
13. No evidence or history 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, a Mantoux Purified Protein Derivative skin test using 5 tuberculin units per 0.1 mL (5 TU PPD) result of <5 mm of induration, performed within the 3 months prior to screening. [It is strongly recommended that patients with a history of Bacille Calmette Guérin (BCG) vaccination be tested with the QuantiFERON®-TB Gold In Tube test.];
A chest radiograph taken within the 3 months prior to screening without changes suggestive of active TB infection. |
|
| E.4 | Principal exclusion criteria |
1. Diagnosis of any other arthritidies (inflammatory or non-inflammatory) or chronic pain condition (fibromyalgia, neuropathy) that, in the opinion of the investigator would interfere with disease activity assessments.
2. Severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, metabolic, endocrine, pulmonary, cardiac, neurological disease, or any other condition which would make the subject unsuitable for the study.
3. Any lymphoproliferative disorder, such as Epstein-Barr Virus (EBV), history of lymphoma, leukemia, myeloproliferative disorders, multiple myleoma or signs and symptoms suggestive of current lymphatic disease.
4. Active TB or currently undergoing treatment for active or latent TB.
5. Any solid malignancy that has been in remission for less than 10 years, excluding subjects with nonmetastic basal cell or squamous cell carcinoma of the skin or cervical carcinoma in situ, who are eligible immediately after adequate treatment.
6. Blood dyscrasis including confirmed:
Hemoglobin <9 g/dL or Hematocrit <30%;
Absolute white blood cell (WBC) count <3.0 x 10 to the power 9/L;
Absolute neutrophils count <1.2 x 10 to the power 9/L;
Platelet count<100 x 10 to the power 9/L.
7. Hepatic transaminase elevations (AST or ALT) >1.5 ULN, confirmed at the screening visit.
8. Subject diagnosed with insulin dependent diabetes mellitus or poorly controlled noninsulin dependent diabetes mellitus (HgbA1c value of >7.0% [ADA recommendation of poorly controlled]).
9. Drug or alcohol abuse with less than 6 months of continued abstinence prior to the screening visit.
10. Clinically significant infections (those requiring hospitalization or requiring parenteral antimicrobial therapy) within 6 months of the screening visit.
11. A body temperature of 38 degrees Celcius or higher at the baseline visit or a febrile illness within 14 days prior to the first dose.
12. An infection with human immunodeficiency virus (HIV) or Hepatitis B or C.
13. Any condition possibly affecting oral drug absorption (eg, gastrectomy or clinically significant diabetic gastroenteropathy).
14. Significant trauma, blood loss or major surgery (involving anesthesia or respiratory assistance within 4 weeks of the screening visit).
15. Bone fracture and/or immobility/immobilization within 3 months of the screening visit.
16. A standard 12-lead ECG demonstrating a QTc>460 ms for males and QTc>480 ms for females or other clinically significant abnormality at the screening visit. If the QTc is greater than 460 ms (for males) or 480 ms (for females), the ECG should be repeated two more times and the average of the three QTc values should be used to determine the subject’s eligibility.
17. Treatment with an investigational drug within 30 days (or as determined by the local requirement, whichever is longer) or 5 half-lives preceding the first dose of study medication.
18. Blood donation of approximately 1 pint (500 mL) within 60 days of the screening visit.
19. Subjects with a previous or current history of glaucoma or ocular herpetic infections.
20. Subjects known to be glucocorticoid ‘non-reponders’ or with a previous history of intolerance or significant adverse effects with glucocorticoid therapy.
21. Documented history of peptic ulcer disease within 5 years.
22. Subjects requiring prohibited concomitant medications listed in Appendix 1. This listing includes CYP3A4 inhibitors, CYP3A4 inducers, selected CYP3A4 substrates and/or other medications.
23. Female subject who is pregnant or lactating.
24. Current household contact with children who have received varicella or oral polio vaccine within 8 weeks of the screening visit.
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 subject inappropriate for entry into this study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| 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 | Yes |
| 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 | No |
| 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) | Yes |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 28 |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 7 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 7 |
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