| 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 |
|
| 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 | 15.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066578 |
| E.1.2 | Term | Progression of 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 compare efficacy and safety of PF 04171327 (1, 5, 10 mg, 15 mg once daily) to 5 mg daily prednisone, 10 mg daily prednisone and placebo given over 8 weeks, in subjects with active RA on a stable background of MTX;
Determine comparative therapeutic window of PF 04171327 using ACR 20 responses and change from baseline in P1NP and UNTx/uCr, (primary set of biomarkers) ie, determining a dose, or a range of doses, in which there is sufficient efficacy on the ACR20 and minor changes in P1NP and UNTx/uCr.
|
|
| E.2.2 | Secondary objectives of the trial |
To characterize the dose effect and concentration effects for efficacy, safety and biomarker outcome measures;
To characterize the effects of PF 04171327 on the bone and carbohydrate biomarkers compared to prednisone 5 mg, 10 mg, and placebo;
To examine the durability of the response to PF 04171327;
To evaluate the tapering of PF 04171327;
To evaluate the safety and tolerability of PF 04171327;
To evaluate health and functional status of study subjects.
|
|
| 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 legal 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. Male and female subjects of childbearing potential must agree to use a highly effective method of contraception throughout the study and for at least 28 days after the last dose of assigned treatment. A subject is of childbearing if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active.
5. Women of child bearing potential must have a negative pregnancy test prior to nrollment in this study. Women are considered to be of child-bearing potential unless they are either post menopausal (documented by elevated FSH at screening), surgically sterile, or have had a hysterectomy and/or bilateral salpingo oophorectomy.
6. If of child bearing potential, the subject 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.
7. 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.
8. 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.
9. Meet the ACR 1991 Revised Criteria for Global Functional Status in RA, Class I, II or III.
10. Subject must have been on MTX or allowed MTX DMARD combination (eg, MTX + hydroxychloroquine or MTX + chloroquine or MTX + sulfasalazine) for at least 3 months, and be on a stable dose of MTX for at least 8 weeks prior to randomization. MTX or allowed DMARD combination, as well as any concomitant medication(s) dose, will remain unchanged during the treatment period.
11. Subject must be on a stable MTX of dose ≤25 mg weekly (po/sc/IM). Stable MTX doses should be administered as a weekly single dose for a minimum of 8 weeks prior to randomization.
12. For subjects on chronic topical or inhaled glucocorticoids, the treatment must be stable for ≥4 weeks prior to entry and remain unchanged throughout the study period.
13. No evidence of active or latent 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 (PPD) 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;
• No history of previously untreated infection with TB, and not currently receiving treatment for active TB;
• A chest radiograph taken within the 3 months prior to screening without changes suggestive of active TB infection.
• If a patient has a positive QFT Gold or PPD test, he/she may be eligible if he/she has completed an appropriate treatment regimen for TB and has a chest radiograph within the 3 months prior to Screening that shows no evidence of active TB. A subject who is currently being treated for latent TB infection can only be enrolled with documentation of an adequate treatment regimen, a chest radiograph within the 3 months prior to Screening that shows no evidence of active TB, and the approval by the Sponsor. In addition, patients must have maintained normal ALT and AST levels following initiation of treatment for latent TB (minimum of 1 month) duration of latent TB treatment prior to PF 04171327 dosing. |
|
| 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 conditions 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 myeloma or signs andsymptoms suggestive of current lymphatic disease. 4. A prior history of malignancy, excluding subjects with non-metastic basal cell or squamous cell carcinoma of the skin or cervical carcinoma in situ, who are eligible immediately after adequate treatment. 5. Blood dyscrasis including confirmed:Hemoglobin <9 g/dL or Hematocrit <30%; Absolute white blood cell (WBC) count <3.0 x 10 to the power of 9/L; Absolute neutrophils count <1.2 x 10 to the power of 9/L; Platelet count<100 x 10 to the power of 9/L. 6. Subjects treated with the following who did not observe the protocol specified wash out period before baseline: CYP3A4 inducers or inhibitors, Experimental NSAIDs,herbal medications, Immunization with any live or live attenuated virus vaccination (egg, FluMist™), Glucocorticoids by any route that may result in significant systemic exposure, Biologic DMARDs, Anakinra (Kineret®), etanercept (Enbrel®), Adalimumab (Humira®), Infliximab (Remicade®), Golimumab (Simponi TM), Abatacept (Orencia®), tocilizumab (Actemra), certolizumab pegol (Cimzia®), rituximab(Rituxan®) or other selective B lymphocyte depleting agents, DMARDs, d-penicillamine, azathioprine, cyclosporine, tacrolimus, and staphylococcal protein. Immuno-absorbant pheresis columns (eg, PROSORBA device/column), Tetracyclines, unless prescribed for the treatment of acne or other dermatologic disorders, Auranofin (oral gold), aurothioglucose (injectable gold), aurothiomalate (injectable gold), Leflunomide (Arava®). 7. 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 other clinical studies at any time during their participation in this study. Prior exposure to investigational biologics should be discussed with the Pfizer Medical Monitor, as these agents may require extended washout periods.
8. Hepatic enzyme elevations (ALT or ALP) >1.3 ULN. 9. Subject diagnosed with insulin dependent diabetes mellitus or poorly controlled noninsulin dependent diabetes mellitus (HgbA1c value of >8.0%). 10. Drug or alcohol abuse with less than 6 months of continued abstinence prior to the screening visit. 11. Clinically significant infections (those requiring hospitalization or requiring parenteral antimicrobial therapy) within 6 months of the screening visit. 12. A body temperature of 38◦C or higher at the baseline visit or a febrile illness within 14 days prior to the first dose. 13. An infection with human immunodeficiency virus (HIV) or Hepatitis B or C. 14. Any condition possibly affecting oral drug absorption 15. Significant trauma, blood loss or major surgery (involving anesthesia or respiratory assistance within 4 weeks of the screening visit). 16. Bone fracture and/or immobility/immobilization within 3 months of the screening visit. 17. A standard 12-lead ECG demonstrating a QTcF >450 ms for males and QTcF >480 ms for females or other clinically significant abnormality at the screening visit. If the QTcF is greater than 450 ms (for males) or 480 ms (for females), the ECG should be repeated two more times and the average of the three QTcF values should be used to determine the subject’s eligibility. 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-responders’ 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. Ongoing treatment with an NSAID or selective COX inhibitor that is not stable (dose and duration) for at least six weeks prior to screening. 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 abnormalities 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) |
Efficacy: ACR20 at week 8;
Primary set of dissociation biomarkers: P1NP, and UNTx/Ucr at week 8. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Efficacy:
ACR20 at 2, 4 and 12 weeks; ACR50, ACR70, Hybrid ACR response, Individual ACR components, all at Week 2, 4, 6, 8 &12;
DAS 28 3 (CRP), DAS28 4 (CRP) at Week 2, 4, 6, 8 and 12;
SF 36 v 2 (Quality of Life) at Week 4, 8, and 12.
Pharmacokinetic and Pharmacodynamic endpoints:
Plasma concentrations of PF 00251802 and its N Oxide metabolite PF 04015475 (baseline, Week 2, 4, 6, 8, 10 and 12);
Pharmacodynamic effects will be assessed by several biomarkers, such as serum CTx, osteocalcin, P1NP, UNTx/UCr (baseline, Week 2, 4, 6, 8, 10, 12 and 13) and PTH and adiponectin (baseline, Week 4, 8, and 12).
Safety endpoints:
Biomarkers: plasma cortisol, CRP, will be obtained at baseline, Week 2, 4, 6, 8, 10, 12 and 13;
Circulating lymphocytes, neutrophils, and eosinophil counts will be obtained at 4, 8 and 12 weeks;
HbA1C (baseline Week 8 and 12), and fasting glucose at Week 0, 4, 8 and 12;
Safety outcomes: Assessment of taper period, HPA axis labs (ACTH stimulation test (Week 13 after one week of study drug discontinuation), vital signs, telephone follow up (taper period), AE reports, routine labs (including liver tests), concomitant meds (esp. diabetes meds, glucocorticoids other than study drug).
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Study Weeks 2, 4, 6, 8 and 12 |
|
| 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 | No |
| 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.8.2.4 | Number of treatment arms in the trial | 7 |
| 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 | 50 |
| 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 |
| Bulgaria |
| Canada |
| Colombia |
| Czech Republic |
| Germany |
| Hungary |
| India |
| Korea, Republic of |
| Malaysia |
| Mexico |
| Poland |
| Romania |
| Russian Federation |
| Serbia |
| Slovakia |
| South Africa |
| Spain |
| 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
|
|
| 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 | 8 |
| 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 | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
