| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 16.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10042952 |
| E.1.2 | Term | Systemic rheumatoid 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 |
| The objective of this study is to evaluate the safety and efficacy of ASP015K in moderate to severe Rheumatoid Arthritis (RA) subjects who are Methotrexate-Inadequate Responders (MTX-IR). |
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| E.2.2 | Secondary objectives of the trial |
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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 |
There is an optional sub study for Pharmacogenomics. There is no separate protocol, it is included in the main protocol.
The pharmacogenomic research that will be conducted in the future with acquired blood samples is exploratory. The objective of this research is to comprehensively analyze:
• Suspected disease-related genes;
• Genes of relevance to clinical response, pharmacokinetics, and toxicity/safety issues, to be identified in a precautionary/retrospective setting
By analyzing differing genetic polymorphisms, it may be possible to predict genetic influence on an individual subject’s response to ASP015K in terms of efficacy and/or toxicity.
An optional whole blood sample will be collected during the Baseline visit after randomization but prior to the first dose of study drug and at weeks 4 and 12 for exploratory mRNA expression profiling to better understand the pathological mechanisms involved in RA and the effects of ASP015K on whole blood gene expression.
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| E.3 | Principal inclusion criteria |
Subject is eligible for the study if all of the following apply:
1. Institutional Review Board (IRB) / Independent Ethics Committee (IEC) approved written Informed Consent and privacy language as per national regulations (e.g., HIPAA Authorization for U.S. sites) must be obtained from the Subject or legally authorized representative prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).
2. Male or female subject is at least 18 years of age at the time of Informed Consent.
3. Subject has RA that was diagnosed according to the 1987 revised criteria of the American College of Rheumatology (ACR) at least 6 months prior to Screening.
4. Subject has been treated with oral MTX:
• for a minimum of 90 days
• at a stable dose (single, unchanging dose) of 15 - 25 mg/week for a minimum of 28 days prior to the first dose of study drug
NOTE: A lower dosage of MTX (but at least 7.5 mg/week) may be allowed only if there is an intolerance to doses ≥ 15 mg/week, as determined by the investigator.
5. Subject’s other related medication taken for the treatment of RA at the time of Screening must meet the noted stability requirements as follows:
• Non-steroidal anti-inflammatory drugs (NSAIDs), selective cyclo-oxygenase-2 (COX-2) inhibitors, and oral corticosteroids (≤ 10 mg
of prednisone, or equivalent, daily) must be stable for at least 28 days prior to the start of study drug
• Hydroxychloroquine (≤ 400 mg/day), chloroquine (≤ 250 mg/day) and sulfasalazine (≤ 3 g/day) must have been started at least 60 days prior to start of study drug and must be stable for at least 28 days prior to the start of study drug.
6. Subject has active rheumatoid arthritis as evidenced by the following:
• ≥ 6 tender/painful joints (using 68-joint assessment);
• ≥ 6 swollen joints (using 66-joint assessment); and
• C-Reactive Protein (CRP) of ≥ 0.8 mg/dL or Erythrocyte Sedimentation Rate (ESR) of ≥ 28 mm/hr at Screening.
Subjects must continue to meet both joint count criteria at the Baseline visit prior to being randomized.
7. Subject meets the ACR 1991 Revised Criteria for Global Functional Status in RA, Class I, II or III at Screening. and Baseline.
8. Female subject must be either:
• Of non child bearing potential:
post-menopausal (defined as at least 1 year without any menses) prior to Screening, or
documented surgically sterile or status post hysterectomy (at least 1 month prior to Screening)
• Or, of childbearing potential,
must agree to have a negative serum pregnancy test at Screening, and/
must use use two forms of birth control* (at least one of which must be a barrier method) starting at Screening and throughout the study period and for 60 days after the final study drug administration.
9. Female subject must not be breastfeeding at Screening or during the study period, and for 60 days after the final study drug administration.
10. Female subject must not donate ova starting at Screening and throughout the study period, and for 60 days after the final study drug administration.
11. Male subject and their female spouse/partners who are of childbearing potential must be using highly effective contraception consisting of two forms of birth control* (one of which must be a barrier method) starting at Screening and continue throughout the study period and for 90 days after the final study drug administration.
12. Male subject must not donate sperm starting at Screening and throughout the study period and for 90 days after the final study drug administration.
13. Subject must be willing and able to comply with the study requirements.
14. Subject agrees not to participate in another interventional study while on treatment.
*Acceptable forms of birth control include:
Established use of oral, injected or implanted hormonal methods of contraception.
Placement of an intrauterine device (IUD) or intrauterine system (IUS).
Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository
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| E.4 | Principal exclusion criteria |
Subject will be excluded from participation if any of the following apply:
1. Subject currently has or has a history of a positive Mycobacterium tuberculosis (TB) test and does not have documentation of completion of a recommended course of antimicrobial therapy per local guidelines.
2. Subject has an abnormal chest x-ray within 90 days of or at Screening indicative of an acute or chronic infectious process or malignancy.
3. Subject has received live or live attenuated virus vaccination within 30 days prior to the first dose of study drug.
4. Subject has a known history of positive test for hepatitis B surface antigen (HBsAg) or hepatitis C antibody or history of a positive test for human immunodeficiency virus (HIV) infection.
5. Subject has a history of any other autoimmune rheumatic disease, other than Sjogren’s syndrome.
6. Subject has a previous history of clinically significant infections or illness (requiring hospitalization or requiring parenteral therapy) within 90 days of the Baseline visit, or a history of any illness that in the investigator’s opinion would preclude participation in the study.
7. Subject has a history of any malignancy, except for successfully treated basal or squamous cell carcinoma of the skin or in-situ carcinoma of the cervix.
8. Subject has taken any of the following DMARDs or biologic agents within the following period prior to the first dose of study drug:
• Gold, azathioprine, minocycline, and penicillamine – 28 days
• Etanercept – 28 days
• Certolizumab, adalimumab, golimumab and infliximab – 60 days
• Cyclophosphamide – 180 days
• Leflunomide – 60 days; if the patient has undergone a cholestyramine washout, then the period is reduced to 30 days prior to Day 1 dosing
9. Subject has previously used a non anti-TNF biologic DMARD (e.g., anakinra, abatacept, rituximab or any other CD20 inhibitors, tocilizumab).
10. Subject has a previous intolerance to JAK inhibitors.
11. Subject has received intra-articular or parenteral (intravenous [IV], subcutaneous, intramuscular) corticosteroid within 28 days prior to the first dose of study drug or is currently taking > 30 mg oral morphine (or narcotic equivalent) per day.
12. Subject has received plasma exchange therapy within 60 days prior to the start of study drug.
13. Subject has previously received ASP015K.
14. Subject has received any investigational agent within 30 days or 5 half-lives, whichever is longer, prior to the first dose of study drug.
15. Subject has received medications that are CYP3A substrates with narrow therapeutic range within 14 days prior to first dose of study drug. These medications include but are not limited to: alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, and terfenadine.
16. Subject has any of the following laboratory values at Screening:
• Hemoglobin < 10 g/dL
• White blood cell count < 3000/mm3
• Absolute neutrophil count (ANC) < 2000/mm3
• Absolute lymphoctye count (ALC) < 750/mm3
• Platelet count < 100,000/mm3
• ALT ≥ 2 x upper limit of normal
• AST ≥ 2 x upper limit of normal
• Total bilirubin ≥ 1.5 x upper limit of normal
• Estimated GFR ≤ 40 mL/min/1.73m2, as measured by the Modification of Diet in Renal Disease (MDRD) method
• CPK > 1.5 x upper limit of normal
25. Subject has a history of heart failure, defined as New York Heart Association (NYHA) grade 3 or greater.
26. Subject has a history of long QT syndrome or prolonged QT interval at Screening.
27. Subject has any ongoing severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, metabolic, endocrine, pulmonary, cardiac, neurological, or infectious disease, or any ongoing illness which would make the subject unsuitable for the study as determined by the investigator. This includes stomatitis, gastrointestinal ulcers, or any other condition that would preclude continued treatment with methotrexate.
28. Any condition possibly affecting oral absorption (e.g., gastrectomy, other malabsorption syndromes or clinically significant diabetic gastroenteropathy).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint, ACR20 response rate at Week 12, will be analyzed using a logistic regression model including treatment group, center and TNF past use (yes or no) as explanatory variables. Subjects who withdraw before Week 12 will be counted as non-responders.
The hypothesis for comparisons is given as follows:
H0: The ACR20 response rates at end of treatment for ASP015K and placebo with concomitant methotrexate are the same
H1: The ACR20 response rates at end of treatment for ASP015K and placebo with concomitant methotrexate are not the same
Comparisons to placebo will be performed at each ASP015K dose level. This study will not consider adjustments for multiplicity, since it is not a pivotal study. The primary analysis will be conducted using the FAS.
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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) |
| For secondary efficacy endpoints, the binary variables ACR50 and ACR70 response rates at Week 12 will be analyzed with a model similar to the primary analysis, and the continuous variable Change from Baseline/Day 1 to Week 12/ET in DAS28-CRP score will be analyzed using a three-way ANOVA model with the same factors as in the primary analysis, as well as interaction terms, as appropriate. |
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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) | 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 | 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 | 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 |
| Mexico |
| Ukraine |
| United States |
| Czech Republic |
| Belgium |
| Bulgaria |
| Colombia |
| Poland |
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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 | 4 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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