| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Psoriatic arthritis (PsA) |
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| E.1.1.1 | Medical condition in easily understood language |
Psoriatic arthritis is a chronic inflammatory autoimmune disease
characterized by joint inflammation, psoriatic skin lesions, enthesitis, dactylitis, spondylitis, and progressive disability. |
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| 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 | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10037160 |
| E.1.2 | Term | Psoriatic arthritis |
| E.1.2 | System Organ Class | 100000004859 |
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| 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 the efficacy of tofacitinib at doses of 5 mg BID and 10 mg BID versus placebo for the treatment of rheumatological signs and symptoms of PsA, in subjects with active PsA who have had an inadequate response to a traditional non biologic Disease Modifying Anti Rheumatic Drug (DMARD).
2. To compare physical function status of subjects with active PsA who have had an inadequate response to a traditional non biologic Disease Modifying Anti Rheumatic Drug (DMARD) after administration of tofacitinib at doses of 5 mg BID and 10 mg BID versus placebo.
3. To compare the safety and tolerability of two doses (5 mg BID and 10 mg BID) of tofacitinib versus placebo in subjects with active PsA who have had an inadequate response to a traditional non biologic Disease Modifying Anti Rheumatic Drug (DMARD).
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| E.2.2 | Secondary objectives of the trial |
1. To estimate the difference between tofacitinib and adalimumab at Month 12 in the mean change from baseline in modified Total Sharp Score (ΔmTSS).
2. To estimate the difference in the rate of progressors (defined as ΔmTSS >0.5) between tofacitinib and adalimumab at Month 12.
3. To compare efficacy of tofacitinib at doses of 5 mg BID and 10 mg BID versus placebo on all health outcomes measures as appropriate for the specific outcome.
4. To compare the efficacy of tofacitinib at doses of 5 mg BID and 10 mg BID versus placebo for the treatment of dermatological signs and symptoms of PsA in subjects with active PsA.
5. To compare the efficacy of adalimumab 40 mg SC q 2 weeks versus placebo for the treatment of rheumatologic and dermatologic signs and symptoms of PsA, in subjects with active PsA.
Please see the Protocol for the full list of the secondary objectives. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
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. The subject has a diagnosis of PsA based upon the CASPAR Criteria for at least 6 months and evidence of active arthritis based upon number of tender/painful and swollen joints detailed in the Active Psoriatic Arthritis section of the Protocol.
4. Ongoing treatment with a stable dose of traditional DMARDs (eg, methotrexate, sulfasalazine or leflunomide) (Background DMARDs section, as per protocol).
5. Meet all other eligibility criteria described in Sections A3921091 Specific PsA Patient Population, and the Other Inclusion Criteria section, in the Protocol.
6. Must have inadequate response to a traditional oral DMARD.
7. Must be naive to tumour-necrosis factor inhibitor.
Please see the Protocol for the full list of the inclusion criteria. |
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| E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the study:
1. Currently have non plaque forms of psoriasis, eg erythrodermic, guttate or pustular, with the exception of nail psoriasis, which is allowed.
2. Subjects who are investigational site staff members directly involved in the conduct of the trial and their family members, site staff members otherwise supervised by the Investigator, or subjects who are Pfizer employees directly involved in the conduct of the trial.
3. Participation in other studies involving investigational drug(s) (Phases 1-4) within 4 weeks before the current study begins and/or during study participation. Participation in any observational studies during study participation.
4. Pregnant females, breastfeeding females, females of child bearing potential not using highly effective contraception or not agreeing to continue highly effective contraception for at least one ovulatory cycle after last dose of investigational product or females planning pregnancy. Women of childbearing potential must test negative for pregnancy prior to enrollment in this study. (Further description of the requirements and a list of contraceptives considered highly effective and acceptable for use in this study).
5. Current or recent history of a severe, progressive or uncontrolled renal, hepatic, hematological, gastrointestinal, metabolic (including hypercholersterolemia), endocrine, pulmonary, cardiovascular, or neurologic disease.
6. Blood dyscrasias within 3 months prior to the first dose of study drug including confirmed:
a. Hemoglobin <10 g/dL;
b. White blood cell count <3.0 x 10x9/L (<3000/mm3);
c. Absolute neutrophil count ≤1.5 x 10x9/L(<1500/mm3);
d. Absolute lymphocyte count <1.0x10x9/L (<1000/mm3)
e. Platelet count <100 x 10x9/L (<100,000/mm3).
7. Estimated Creatinine Clearance <40 ml/min based on Cockcroft Gault equation (see Appendix 2).
8. Total bilirubin, AST or ALT more than 1.5 times the upper limit of normal at screening visit.
9. Have a known immunodeficiency or a first degree relative with a hereditary immunodefiency.
10. Also excluded are subjects with history of any autoimmune rheumatic disease other than PsA (including systemic lupus erythematosis, mixed connective tissue disease, scleroderma, polymyositis) or known diagnosis of fibromyalgia, without approval by Sponsor. Prior history of, or current rheumatic inflammatory disease other than PsA (eg, gout, reactive arthritis, chronic Lyme disease) without approval by Sponsor.
11. Functional Class IV as defined by the American College of Rheumatology classification of functional status for RA, ie, limited in ability to perform usual self care, vocational and avocational activities.
12. History of an infected joint prosthesis at any time, with the prosthesis still in situ.
13. History of any lymphoproliferative disorder, such as Epstein Barr Virus (EBV) related lymphoproliferative disorder, history of lymphoma, leukemia, or signs and symptoms suggestive of current lymphatic disease.
14. History of recurrent (more than one episode) herpes zoster or disseminated (a single episode) herpes zoster or disseminated (a single episode) herpes simplex.
15. History of 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 medication.
• Oral antimicrobial therapy within 2 weeks prior to the first dose of study medication.
16. Any prior treatment with non B cell specific lymphocyte depleting agents/therapies [eg, alemtuzumab (Campath®), efalizumab (Raptiva®)], alkylating agents (eg, cyclophosphamide or chlorambucil), or total lymphoid irradiation. Subjects 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 first dose of study drug and have normal CD19/20+ counts by FACS analysis.
17. Any subject who has been vaccinated with live or attenuated vaccines within the 6 weeks prior to the first dose of study medication or is to be vaccinated with these vaccines at any time during treatment or within 6 weeks following discontinuation of study medication. (See Vaccine Guidelines for further information regarding avoidance of household contacts who may be vaccinated in the Protocol).
18. A subject 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.
19. History of alcohol or drug abuse unless in full remission for greater than 6 months prior to first dose of study medication.
Please see the Protocol for the full list of the exclusion criterion. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoints:
• ACR20 responder rates at 3 months;
• HAQ DI at 3 months
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints:
Radiographic Changes
• Total Sharp Score (ΔmTSS) at Month 12
• Progressor rates (defined as ΔmTSS >0.5) at Month 12
Signs and Symptoms
• ACR (American College of Rheumatology) 50 (ACR50) and ACR70 responder rates at all timepoints;
• ACR20 responder rates at all timepoints other than Month 3;
• ACR response criteria components (Health Assessment Questionnaire-Disability Index (HAQ DI), C-reactive Protein (CRP), Patient assessment of Arthritis Pain, Patient Global Assessment of Arthritis, Physcian’s Global Assessment of Arthritis; swollen joint count, tender/painful joint count) at Month 3;
• Psoriatic Arthritis Response Criteria (PsARC) at all timepoints
• Physician’s Global Assessment of Psoriasis (PGA PsO) response at Months 1, 3, 6, 9, and 12;
• Psoriasis Area and Severity Index 75 (PASI75) response at Months 1, 3, 6, 9, and 12;
• Dactylitis severity score at Months 1, 3, 6, 9, and 12;
• Enthesitis (using the Spondyloarthritis Research Consortium of Canada (SPARCC) enthesitis index and Leeds index) at Months 1, 3, 6, 9, and 12.
Secondary Physical Function and Health Outcome Measures
Assessed at Baseline, Months 1, 3, 6, 9, and 12
• Short Form 36 Health Survey (SF 36) Version 2, Acute;
• EuroQol 5 Dimension Health State Profile (EQ5D);
• Functional Assessment of Chronic Illness Therapy Fatigue (FACIT F);
• Evaluation of spondylitis using Bath Anklyosing Spondylitis Disease Assessment Index (BASDAI) and Ankylosing Spondylitis Quaility of Life (ASQOL) questionnaire.
Secondary Safety Endpoints
• Incidence and severity of adverse events;
Other Endpoints
Other Efficacy Endpoints for Signs and Symptoms
• American College of Rheumatology (ACR) response criteria components (Health Assessment Questionnaire-Disability Index (HAQ DI), C-reactive Protein (CRP), Patient assessment of Arthritis Pain, Patient Global Assessment of Arthritis, Physcian’s Global Assessment of Arthritis; swollen joint count, tender/painful joint count) at all timepoints except Month 3;
• DAS28 3(CRP) at all timepoints;
• Psoriatic Arthritis Joint Activity Index (PsAJAI) and Disease Activity Index for Reactive Arthritis/Psoriatic Arthritis (DAREA/DAPSA), Psoriatic Arthritis Disease Severity Score (PASDAS), Composite Psoriasis Disease Activity Index in Psoriatic Arthritis (CPDAI), Minimal Disease Activity (MDA) , and their components at Months 1, 3, 6, 9, and 12;
• PASI and PASI component scores at Months 1, 3, 6, 9, and 12;
• NAPSI at Months 1, 3, 6, 9, and 12;
• Presence of dactylitis at Months 1, 3, 6, 9, and 12;
Physical Function and Health Outcome Measures
Assessed at Baseline, Months 1, 3, 6, 9, and 12
• Patient’s Global Joint and Skin Assessment (PGJS VAS);
• Dermatology Life Quality Index (DLQI);
• Itch Severity Index (ISI);
• Ankylosing Spondylitis Quaility of Life (ASQOL) questionnaire.
Assessed at Baseline, Months 3, 6, 9, and 12:
• PsA Healthcare Resource Utilization Questionnaire (PsA HCRU);
• Work Limitations Questionnaire (WLQ).
Other Safety Endpoints
• Laboratory safety data (clinical chemistry, hematology, etc);
• Physical examinations;
• ECG measurements;
• Vital sign measurements (blood pressure, pulse rate and temperature);
Pharmacokinetic Endpoint
• Oral clearance (CL/F) and other PK parameters calculated from plasma tofacitinib concentrations, if applicable.
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| 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 | 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) | 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 | 5 |
| 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 | 72 |
| 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 |
| Australia |
| Belgium |
| Bulgaria |
| Canada |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Mexico |
| Poland |
| Russian Federation |
| Slovakia |
| Spain |
| Taiwan |
| United Kingdom |
| United States |
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| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 8 |
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