| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| psoriatic arthritis |
| artritis psoriatica |
|
| E.1.1.1 | Medical condition in easily understood language |
| psoriatic arthritis |
| artritis psoriatica |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| 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 |
| Identify pre-treatment profiles with integrated clinical, transcriptomic, metabolomic, proteomic, flow cytometric, and imaging data that predict response to treatment with tofacitinib in DMARD-naïve and DMARD non-responsive PsA patients |
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| E.2.2 | Secondary objectives of the trial |
● Compare clinical efficacy of treatment with tofacitinib, methotrexate and etanercept in DMARD-naïve and DMARD-non responsive patients with active PsA
● Determine (medication specific) molecular mechanisms predicting and underlying clinical response to tofacitinib in comparison to methotrexate and etanercept in active PsA
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|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
In order to be eligible to participate in this study, a subject must meet all of the following criteria:
• Age 18-75 years old
• Meets CASPAR criteria for psoriatic arthritis
• Disease duration of at least 8 weeks
• Evidence of active arthritis based upon ≥2 swollen joints and ≥2 tender joints
• No evidence of active or latent or inadequately treated infection with Mycobacterium tuberculosis (TB) as defined by all of the following:
o A negative QuantiFERON-TB Gold (QFT-G) In-Tube test performed at or within 3 months prior to a given Screening visit. Subjects with a history of Bacille Calmette Guerin (BCG) vaccination will be tested with the QFT-G test.
o A chest radiograph taken at or within the 3 months prior to screening without changes
o suggestive of active TB infection as determined (and documented) by a qualified radiologist or pulmonologist as per local standard of care.
o No history of either untreated or inadequately treated latent or active TB infection.
o 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- TB Gold In-TubeR™ (QFT Gold test) need be obtained, but a chest radiograph must still be obtained if not done so within the prior 3 months.
• Subjects who are already taking oral corticosteroids (but not injectable) may participate in the study:
o 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.
o Injected (eg, intraarticular, intramuscular or intravenous) corticosteroids: Discontinued 4 weeks prior to the first dose of study drug.
• 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.
• Subjects are to discontinue active psoriasis treatment prior to being enrolled in the study.
o Topical treatments that could affect psoriasis including: corticosteroids, tars, keratolytics, anthralin, vitamin D analogs, and retinoids must be discontinued for at least 2 weeks prior to the first dose of study drug.
o Exceptions: the following topical treatments are allowed: non-medicated emollients for use over the whole body; topical steroids including hydrocortisone and hydrocortisone acetate £1% for the palms, soles, face, and intertriginous areas only; tar and salicylic acid preparations for the scalp only and shampoos free of corticosteroid for the scalp only.
o UVB (narrowband or broadband) phototherapy must be discontinued at least 2 weeks prior to the first dose of study drug. Psoralens + UVA phototherapy (PUVA) must be discontinued for at least 4 weeks prior to the first dose of study drug.
Inclusion criteria for the csDMARD-naïve group (Arm 1):
• No history of csDMARD use or bDMARD therapy use
Inclusion criteria for the csDMARD-IR group (Arm 2):
• Current use of methotrexate, sulfasalazine or leflunomide on the highest tolerated and on a stable dosage for at least 4 weeks prior to randomization. Highest dosage accepted respectively are max ≤25mg/wk, 20mg/day and 3000mg/day. Subjects on methotrexate should be on an adequate and stable dose of folate supplementation (not less than 5 mg weekly based on folic acid, unless such doses would violate the local label guidelines or standard of care) for at least 4 weeks prior to the first dose of study drug. Subject must not have had previous serious toxicity while on methotrexate and not be expected to require evaluation for possible methotrexate toxicity (eg, require a liver biopsy for methotrexate toxicity) during the study.
• “History of use of max. 1 bDMARD prior to inclusion is allowed, except:
o Prior use of etanercept
o Primary failure (total non-response at start) on other TNFi (adalimumab, golimumab, infliximab, certolizumab). Patients that have had a loss of response on their first TNFi are allowed to participate.
• No history of tsDMARD therapy use (JAKi, abatacept)
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|
| E.4 | Principal exclusion criteria |
• Currently have pustular psoriasis only
• 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.
• 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.
• Current or recent history of a severe, progressive or uncontrolled renal, hepatic, hematological, gastrointestinal, metabolic, endocrine, pulmonary, cardiovascular, or neurologic disease.
• Blood dyscrasias within 3 months prior to the first dose of study drug including confirmed:
o Hemoglobin <10 g/dL; White blood cell count <3.0 x 109/L; Absolute neutrophil count ≤1.5 x 109/L);
o Absolute lymphocyte count <1.0x109/L; Platelet count <100 x 109/L.
• Estimated Creatinine Clearance <40 ml/min based on Cockcroft formula.
• Total bilirubin, AST or ALT more than 2.0 times the upper limit of normal at screening visit.
• a known immunodeficiency or a first-degree relative with a hereditary immunodefiency.
• 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
• History of an infected joint prosthesis at any time, with the prosthesis still in situ.
• 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.
• History of recurrent (more than one episode) herpes zoster or disseminated (a single episode) herpes zoster or disseminated (a single episode) herpes simplex.
• History of active infection (including localized infection) requiring:
o 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.
o Oral antimicrobial therapy within 2 weeks prior to the first dose of study medication.
• Any prior treatment with non-B cell-specific lymphocyte depleting agents/therapies, alkylating agents, 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.
• 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.
• Any condition possibly affecting oral drug absorption, e.g. gastrectomy, clinically significant diabetic gastroenteropathy, or certain types of bariatric surgery such as gastric bypass.
• History of alcohol or drug abuse unless in full remission for greater than 6 months prior to first dose of study medication.
• A subject with a malignancy may be included only in the following cases:
o adequately treated or excised non-metastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in situ.
o Adequately treated other malignancies with a minimal follow-up period of 10 years with no recurrence of the disease.
o patients with a history of lymphoma are to be excluded
• Significant trauma or surgery procedure within 1 month prior to first dose of study medication, or any planned elective surgery during the study period.
• A subject requiring prohibited concomitant medications.
• 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 for HBsAb to be considered for enrollment. If HBsAb+, subject may enroll; if HBsAb-, subject is excluded. Subjects who are HCV Ab+ must undergo further testing for HCV RNA. Subjects who are HCV RNA- may enroll.
• evidence of skin conditions (eg, eczema) at the time of the screening or baseline visit that would interfere with evaluation of psoriasis.
• considered at increased risk for gastrointestinal perforation (eg, patients with diverticulitis)
• 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.
• previously participated in any study of tofacitinib. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
-Minimal Disease Activity (MDA) at week 16
-Baseline molecular network profile (based on the composite systems medicine analysis)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
-change (50%) in the molecular network before treatment as compared to after (week 4 and 16) treatment
-change in composite clinical disease activity scores (MDA, ACR(20,50,70) response, DAS28) at week 16.
-change in individual clinical parameters that make up the composite scores (i.e. PASI score (reduction of 50%, 75%, 90%), joint count, CRP, ESR, QOL-measures) at week 16. |
|
| 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 | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| 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 | No |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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 | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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