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] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 15.1 |
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. |
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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.
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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) (Appendix 8) at least 6 months prior to Screening.
4. Subject’s other related medication taken for the treatment of RA at the time of Screening must meet the following stability requirements:
• Non-steroidal anti-inflammatory drugs (NSAIDs), selective cyclooxygenase-2 (COX-2) inhibitors, and oral corticosteroids (≤ 10 mg of prednisone, or equivalent, daily) for the treatment of RA must be stable for at least 28 days prior to the start of study drug.
• Hydroxychloroquine (≤ 400 mg/day) and sulfasalazine (≤ 3 g/day) must have been started at least 60 days prior to the start of study drug and must be stable for at least 28 days prior to the start of study drug.
5. 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.
6. Subject meets the ACR 1991 Revised Criteria for Global Functional Status in RA (Appendix 9), Class I, II or III at Screening.
7. Female subjects of childbearing potential must not be breastfeeding, must have a negative serum or urine pregnancy test at enrollment and must agree to maintain highly effective birth control during the study and for 60 days after the last dose of study drug. A highly effective method of birth control is defined as those which result in a low failure rate (CPMP/ICH/ 286/95 modified) of less than 1% per year when used consistently and correctly such as implants, injectables, combined oral contraceptives, some IUDs, sexual abstinence or vasectomized partner. If female and not of child-bearing potential, the subject must be surgically sterile (documented) and/or post-menopausal (defined as at least one year without menses).
8. Subject, if male, must agree to no sperm donation and/or must be using an adequate method of contraception throughout the study period and for 90 days after the last dose of study drug.
9. Subject must be willing and able to comply with the study requirements.
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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 tuberculin (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 Screening 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 and/or biologic agents within the specified period prior to the first dose of study drug:
• Methotrexate, gold, and penicillamine – 28 days
• Etanercept – 28 days
• Certolizumab, adalimumab, golimumab, infliximab, and tocilizumab – 60 days
• Rituximab or any other CD20 inhibitors – 180 days
• Abatacept – 90 days
• Anakinra – 7 days
• Cyclophosphamide – 180 days
• Leflunomide – 60 days; if the subject has undergone a cholestyramine washout, then the washout is reduced to 30 days prior to Day 1 dosing
9. Subject has taken one of the following oral DMARDs within 28 days prior to the first dose of study drug:
• Methotrexate
• Sulfasalazine
• Hydroxychloroquine
• Gold
• Penicillamine
• Leflunomide
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.
12. Subject has previously received ASP015K.
13. Subject has received any investigational agent within 30 days or 5 half-lives, whichever is longer, prior to the first dose of study drug.
14. 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.
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: alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus 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
• 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/1.73 m2, as measured by the Modification of Diet in Renal Disease (MDRD) method
• CPK > 1.5 x upper limit of normal
17. Subject has a history of heart failure, defined as New York Heart Association (NYHA) grade 3 or greater.
18. Subject has a history of long QT syndrome or prolonged QT interval at Screening.
19. 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.
20. Any condition possibly affecting oral absorption (e.g. gastrectomy 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 and center 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 are the same
H1: The ACR20 response rates at end of treatment for ASP015K and placebo 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.8.4.1 | 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 | 15 |
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 |
Bulgaria |
Czech Republic |
Mexico |
Poland |
Ukraine |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
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 | 0 |