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 | 21.0 |
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 |
• To evaluate the long term safety and tolerability of treatment with tofacitinib (5 mg twice daily [BID] and 10 mg BID) in adult subjects with active Psoriatic Arthritis (PsA). |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the long term efficacy of treatment with tofacitinib (5 mg BID and 10 mg BID) in adult subjects with active Psoriatic Arthritis (PsA). |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Methotrexate Withdrawal Sub-Study - 12April2017
Primary Objective:
To assess the efficacy of tofacitinib 5 mg BID monotherapy as compared to tofacitinib 5 mg BID with background MTX in subjects who have received prior treatment of tofacitinib in combination with MTX. Secondary Objective:
To assess the safety and tolerability of tofacitinib 5 mg BID monotherapy as compared to tofacitinib 5 mg BID with background MTX in subjects who had received prior treatment of tofacitinib in combination with MTX.
Subjects who have completed at least 24 months of participation in the long term extension study A3921092 and are currently receiving methotrexate may be included. Not all countries participating in the LTE will be included in this sub-study.
Subjects will be randomized to the 2 treatment arms in a 1:1 ratio, one in which they will receive open label tofacitinib 5 mg tablets BID and blinded methotrexate capsules (oral dose range from 7.5 mg to 20 mg per week) and the second in which they will receive open label tofacitinib 5 mg tablets BID and blinded MTX placebo capsules. The sub-study will be approximately 12 (standardized 4-week) months in duration and visits will occur at Baseline, Months 1, 3, 6, 9 and 12. The sub-study baseline will occur at the same time as a scheduled study visit at or after Month 24 of A3921092. |
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E.3 | Principal inclusion criteria |
1. Subjects must have a diagnosis of PsA and previously completed participation in a qualifying study of tofacitinib for the treatment of PsA or have required earlier discontinuation of treatment in a qualifying study for reasons other than treatment-related adverse events (exception being injection-related AEs) with the written approval of the Pfizer Clinician.
2. Subject must be at least 18 years of age (20 years old for subjects in Taiwan) or older at the Screening visit.
3. Subjects receiving permitted traditional non-biologic background DMARDs, eg, methotrexate, sulfasalazine or leflunomide, must be dosed in accordance with the local regulatory label. All local standard of care practices for administration of non-biologic background DMARD therapy, including laboratory testing, contraceptive requirements, follow-up care and contraindications, should be performed according to the local standards of care throughout the study (Background DMARDs as per protocol).
• Other traditional non-biologic DMARDs not listed as a prohibited concomitant medication may be considered after discussion with the Sponsor.
4. Subjects who are already taking oral corticosteroids (but not injectable) may participate in the study:
• Oral corticosteroids: Subjects who are already receiving oral corticosteroids must be on a stable dose of ≤10 mg/day of prednisone or equivalent for 4 weeks prior to first dose of study drug.
• Injected (eg, intraarticular, intramuscular or intravenous) corticosteroids: Discontinued 4 weeks prior to the first dose of study drug.
5. Subjects who are already taking NSAIDs/COX-2 inhibitors may participate in the study provided that that the dose is stable for one week prior to first dose of study drug.
Inclusion Criteria That Apply to Subjects Who Enroll Into This Study After the 14 Day Window From the End of Study Visit of the Qualifying Study
1. Time from End of Study visit of qualifying study must be ≤3 months.
2. In the opinion of the investigator, the subject must have sufficient evidence of PsA disease activity to warrant use of tofacitinib as a DMARD.
3. Subject has discontinued all disallowed concomitant medications for the required time prior to the first dose of study medication and is taking only those concomitant medications in doses and frequency allowed by the protocol. Subjects who are receiving any investigational or marketed treatment for PsA or psoriasis not mentioned elsewhere must have that treatment discontinued for 4 weeks or 5 half-lives, whichever is longer. Discontinuation criteria for biologics not otherwise mentioned must be discussed with the Pfizer Study Clinician.
4.Screening 12-lead electrocardiogram (ECG) that does not
demonstrate clinically relevant abnormalities which may affect subject
safety.
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-Gold®
• In-Tube test performed within the 3 months prior to screening. A negative PPD test can be substituted for the QuantiFERON Gold (QFT-G) In-Tube test only if the central laboratory is unable to perform the test or cannot determine the results to be positive or negative and the Pfizer Study Clinician approves it, on a case by case basis. Subjects with a history of Bacille Calmette Guérin (BCG) vaccination will be tested with the QFT-G test.
• No local QFT-G testing will be accepted for meeting the inclusion criterion.
• A chest radiograph taken within the 3 months prior to screening and reviewed by a radiologist or pulmonologist as per local standard of care and documented to be without changes suggestive of active TB infection.
• No history of either untreated or inadequately treated latent or active TB infection.
• If a subject 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 PPD test nor a QuantiFERON-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 subject 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 Sponsor.
Please see the Protocol for the full list of the inclusion criteria. |
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E.4 | Principal exclusion criteria |
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. Pregnant females, breastfeeding females and females of child-bearing
potential who are unwilling or unable to use a highly effective method of
contraception as outlined in this protocol for the duration of the study
and 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.
4. Current or recent history of uncontrolled renal, hepatic,
hematological, gastrointestinal, metabolic (including
hypercholesterolemia), endocrine, pulmonary, cardiovascular, or
neurologic disease.
5. 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. Also excluded are subjects with prior
history of, or current, rheumatic inflammatory disease other than PsA
(eg, gout, reactive arthritis, chronic Lyme disease) without approval by
Sponsor.
6. A subject with known immunodeficiency disorder or a first degree
relative with a hereditary immunodeficiency.
7. Functional Class IV status 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.
8. History of an infected joint prosthesis at any time, with the prosthesis
still in situ.
9. 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.
10. History of recurrent (more than one episode) herpes zoster or
disseminated (a single episode) herpes zoster or disseminated (a single
episode) herpes simplex.
11. History of active infection (including localized infection):
• Requiring hospitalization, parenteral antimicrobial therapy, or as
otherwise judged clinically significant by the investigator, within the 3
months prior to the first dose of study medication;
• Requiring oral antimicrobial therapy within 2 weeks prior to the first
dose of study medication.
12. 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.
13. 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.
14. 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.
15. A subject that is considered at increased risk for GI perforation (eg,
patients with diverticulitis) by the Investigator or Sponsor.
16. A subject with a malignancy or with a history of malignancy, with the
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exception of adequately treated or excised non-metastatic basal cell or
squamous cell cancer of the skin or cervical carcinoma in situ.
17. A subject requiring prohibited concomitant medications. Subjects
receiving non-prohibited concomitant medications must be on a stable
regimen which is defined as not starting a new drug or changing dosage
within seven days or 5 half-lives (whichever is longer) prior to the
baseline visit.
18. A subject known to be infected with human immunodeficiency virus
(HIV), hepatitis B virus or hepatitis C virus or any chronic infection.
• HBsAg+ is exclusionary; subjects who are HBsAg- but HBcAb+ must
undergo further testing and be HBsAb+ to be considered for enrollment.
• Subjects who are HCV Ab+ must undergo further testing for HCV RNA
and are allowed to enroll if negative.
19. A subject with evidence of skin conditions (eg, eczema) at the time
of the screening or baseline visit that would interfere with evaluation of
psoriasis.
Please see the Protocol for the full list of the exclusion criteria. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Primary Endpoints
• Incidence and severity of adverse events.
• Incidence of clinical abnormalities and change from baseline (in this and/or prior study) in clinical laboratory values during treatment. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Secondary Endpoints
• ACR20, ACR50 and ACR70 response rate at all timepoints.
• HAQ-DI score at all timepoints.
• Psoriatic Arthritis Response Criteria (PsARC) response at all timepoints.
• Physician’s Global Assessment of Psoriasis (PGA-PsO) response at all timepoints.
• Psoriasis Area and Severity Index 75 (PASI75) response ie, the proportion of subjects achieving at least a 75% reduction in PASI relative to baseline (in this and/or prior study) and PASI/PASI component scores at all time points.
• Dactylitis severity score at all timepoints.
• Enthesitis score (using Spondyloarthritis Research Consortium of Canada (SPARCC)
Enthesitis Index and Leed’s Index) at all time points.
• Bath Ankylosing Spondylitis Disease Assessment Index (BASDAI) at all timepoints.
• Physical function/other patient reported outcomes to be assessed at Month 1, Month 6 (and every 6 months thereafter): Short-Form 36 (version 2, Acute); EQ5D; FACIT-F. |
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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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 | No |
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 | 14 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 99 |
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 |
Brazil |
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 | 6 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 9 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 21 |