| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Psoriatic arthritis (PsA) |
|
| 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 efficacy of tofacitinib at doses of 5 mg BID (twice a day) and 10 mg BID versus placebo for treatment of rheumatological signs and symptoms of active PsA in subjects who have had an inadequate response in PsA to at least one TNF inhibitor.
2. To compare physical function status after administration of tofacitinib at doses of 5 mg BID and 10 mg BID versus placebo in subjects with active PsA who have had an inadequate response in PsA to at least one TNF inhibitor.
3. To compare the safety and tolerability of tofacitinib at doses of 5 mg BID and 10 mg BID versus placebo in subjects with active PsA who have had an inadequate response in PsA to at least one TNF inhibitor. |
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| E.2.2 | Secondary objectives of the trial |
1. To compare the effects of tofacitinib at doses of 5 mg BID and 10 mg BID versus placebo on all health outcomes measures in subjects with active PsA who have had an inadequate response to at least one TNF inhibitor as appropriate for the specific outcome.
2. To compare the efficacy of tofacitinib at doses of 5 mg BIDand 10 mg BID versus placebo for the treatment of dermatological signs and symptoms of PsA in subjects who have had an inadequate response to at least one TNF inhibitor. |
|
| 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. The subject has signs and symptoms consistent with the diagnosis of PsA for at least 6 months and fulfills CASPAR (ClASsification criteria for Psoriatic ARthritis) Criteria and has evidence of active arthritis based upon having both ≥3 tender/painful joints and ≥ 3 swollen joints at screening and baseline.
2. Ongoing treatment with a stable dose of a traditional non-biologic DMARD (eg, methotrexate, sulfasalazine or leflunomide) (Background DMARDs, as per protocol).
3.The subject has signs and symptoms consistent with the diagnosis of PsA for at least 6 months and fulfills CASPAR Criteria at screening and has evidence of active arthritis based upon number of tender/painful and swollen joints.
4. PsA Patient Population
• Subjects must have received at least one approved TNF inhibiting biologic agent that was administered in accordance with its labeling recommendations and was inadequately effective and/or not tolerated as follows:
An inadequate response to TNF inhibitor treatment due to lack of efficacy as evident by active PsA at screening, as defined above, and prior treatment according to local label and after minimum treatment duration based upon the agent received:
• At least 3 months of adalimumab treatment.
• At least 3 months of etanercept treatment.
• At least 4 infusions of infliximab.
• At least 3 injections of golimumab.
• At least 3 months of certoluzimab.
An inadequate response to TNF inhibitor treatment due to intolerance is defined as a treatment-related adverse event (eg, infusion/injection reactions, infections, laboratory test
changes, etc).
5. 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. All biologic agents not
otherwise mentioned (eg, exclusion criteria #16) must be discontinued for a minimum of 6 months prior to the first dose of study drug.
6. Subjects must not be receiving TNF inhibitors. Subjects on TNF inhibitors must discontinue according to the following criteria:
• Etanercept (Enbrel®): Discontinued at least 4 weeks prior to the first dose of study drug;
• Adalimumab (Humira®): Discontinued at least 10 weeks prior to first dose of study drug;
• Infliximab (Remicade®): Discontinued at least 8 weeks prior to the first dose of study drug;
• Golimumab (Simponi®): Discontinued at least 10 weeks prior to the first dose of study drug.
• Certoluzimab (Cimzia®): Discontinued at least 10 weeks prior to first dose of study drug.
7. Meet all other eligibility criteria described in the PsA Patient Population, as per Protocol and the Other Inclusion Criteria, as per protocol.
Please see the Protocol for the full list of 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. Pregnant females, breastfeeding females, females of child-bearing potential who are 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 will be found in the Contraceptive Methods in Women of Childbearing Potential section of the protocol).
3. Blood dyscrasias within 3 months prior to the first dose of study drug including confirmed:
a. Hemoglobin <10 g/dL (<100 g/L);
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 of <1.0 x 10x9/L (<1000/mm3);
e. Platelet count <100 x 10x9/L (<100,000/mm3).
4. Estimated Creatinine Clearance <40 ml/min based on Cockcroft Gault equation (Appendix 2).
5. Total bilirubin, AST or ALT more than 1.5 times the upper limit of normal at screening visit.
6. Current or recent history of uncontrolled renal, hepatic, hematological, gastrointestinal, metabolic (including hypercholesterolemia), endocrine, pulmonary, cardiovascular, or neurologic disease.
7. 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.
8. A subject with known immunodeficiency disorder or a first degree relative with a hereditary immunodeficiency.
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 6 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 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, as per protocol).
13. 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.
14. History of alcohol or drug abuse unless in full remission for greater than 6 months prior to first dose of study medication.
15. A subject with a malignancy or with a history of malignancy, with the exception of adequately treated or excised non metastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in situ.
16. A subject requiring prohibited concomitant medications.
17. 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 HCVAb+ must undergo further testing for HCV RNA and are allowed to enroll if negative.
Please see the Protocol for the full list of exclusion criteria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoints:
• ACR (American College of Rheumatology) 20 responder rate at Month 3;
• HAQ-DI (Health Assessment Questionnaire-Disability Index) at Month 3.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoints:
Secondary Efficacy Endpoints:
• ACR (American College of Rheumatology) 50 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’s Assessment of Arthritis Pain, Patient’s Global Assessment of Arthritis, Physician’s Global Assessment of Arthritis, swollen joint count, tender/painful joint count) at Month 3;
• Psoriatic Arthritis Response Criteria (PsARC) at Month 1, Month 3 and Month 6;
• Physician’s Global Assessment of Psoriasis (PGA-PsO) response at Month 1, Month 3 and Month 6;
• Psoriasis Area and Severity Index 75 (PASI75) response at Month 1, Month 3 and Month 6;
• Dactylitis severity score at Month 1, Month 3 and Month 6;
• Enthesitis score (using the Spondyloarthritis Research Consortium of Canada (SPARCC) enthesitis index and Leeds index) at Month 1, Month 3 and Month 6.
Secondary Physical Function and Health Outcome Measures:
Assessed at Months 1, 3 and 6:
• Short-Form-36 Health Survey (SF-36) Version 2, Acute;
• EuroQol 5-Dimension Health State Profile (EQ-5D);
• Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F);
• Evaluation of spondylitis using Bath Ankylosing Spondylitis Disease Assessment Index (BASDAI).
Safety Endpoints:
Incidence and severity of adverse events.
Other Endpoints:
Other Efficacy Endpoints:
• ACR response criteria components at (HAQ-DI, CRP, Patient’s Assessment of Arthritis Pain, Patient’s Global Assessment of Arthritis, Physician’s Global Assessment of Arthritis, swollen joint count, tender/painful joint count) at all timepoints except Month 3;
• Disease Activity Score (DAS) 28-3(CRP) and at all timepoints;
• Psoriatic Arthritis Joint Activity Index (PsAJAI), Psoriatic Arthritis Disease Activity Score (PASDAS), Disease Activity Index for Reactive Arthritis/PsA (DAREA/DAPSA), Composite Psoriasis Disease Activity Index in Psoriatic Arthritis (CPDAI), Minimal Disease Activity (MDA) and their components, at Month 1, Month 3 and Month 6;
• PASI and PASI component scores at Month 1, Month 3 and Month 6;
• Presence of dactylitis at Month 1, Month 3 and Month 6;
• Nail Psoriasis Severity Index (NAPSI) Score at Month 1, Month 3 and Month 6.
Health Outcome Measures Assessed at Months 1, 3 and 6:
• Patient’s Global Joint and Skin Assessment (PGJS-VAS);
• Dermatology Life Quality Index (DLQI);
• Itch Severity Index (ISI);
• Ankylosing Spondylitis Quality of Life (ASQOL) questionnaire.
Health Outcome Measures Assessed at Months 3 and 6:
• PsA Healthcare Resource Utilization Questionnaire (PsA-HCRU);
• Work Limitations Questionnaire (WLQ).
Other Safety Endpoints:
• Clinical laboratory tests (eg clinical chemistry, hematology);
• Vital sign measurements (blood pressure, pulse rate and temperature);
• Physical examinations;
• ECG measurements.
Pharmacokinetic Endpoints:
• Oral clearance (CL/F) and other PK parameters calculated from plasma tofacitinib concentrations, if applicable. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| 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 |
| Canada |
| Czech Republic |
| France |
| Germany |
| Mexico |
| Poland |
| Russian Federation |
| Slovakia |
| Spain |
| Taiwan |
| United Kingdom |
| 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 | 11 |
| E.8.9.1 | In the Member State concerned days | 4 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 11 |
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