E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with active Rheumatoid Arthritis (RA), despite treatment with methotrexate, who have had an inadequate response to a single TNF-alfa antagonist. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10039073 |
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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 primary objective of this study is to evaluate the efficacy of 2 oral dosing regimens of fostamatinib disodium (FosD) (Regimen A - 100 mg twice daily (bid); Regimen B - induction with 100 mg bid for the first 4 weeks, 150 mg once daily (qd) maintenance thereafter) taken in combination with methotrexate, compared with placebo plus methotrexate, in patients with active rheumatoid arthritis (RA) who have had inadequate response to a single tumour necrosis factor-alpha (TNF-alfa) antagonist. |
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E.2.2 | Secondary objectives of the trial |
• To further assess the efficacy of FosD measured by ACR20, ACR 50% response criteria (ACR50), ACR 70% response criteria (ACR70), ACR-N and the individual components of the ACR score. • To assess physical function status of patients after administration of FosD using the Health Assessment Questionnaire - Disability Index (HAQ-DI). • To evaluate the efficacy of FosD as measured by Disease Activity Score based on a 28 joint count (DAS28) and DAS28 European League Against Rheumatism (EULAR) response criteria. • To investigate the effects of FosD on patient reported health outcomes measures. • To assess the efficacy of FosD in the prevention of structural joint damage, as measured by change in radiographic modified total Sharp score (mTSS) and the components of mTSS at Week 24. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Provision of informed consent, prior to any study-specific procedures. NB: Patients agreeing to participate in the optional exploratory biomarker and/or exploratory genetic research must provide a separate informed consent. 2. Male or female aged 18 and over with a diagnosis of RA after the age of 16 according to the revised (1987) criteria of the American College of Rheumatology (see Appendix E for criteria). NB: Women of childbearing potential may be included only if using acceptable contraceptive methods (see Appendix H for definitions). All females must have 2 negative pregnancy tests, at least 14 days apart, prior to randomisation. 3. Active RA defined as: 6 swollen joints and 6 tender/painful joints (from 28 joint count) and either: ESR ≥28 mm/h, or CRP ≥10 mg/L. 4. At least 1 of the following: Documented history of positive rheumatoid factor Current presence of rheumatoid factor Radiographic erosion within 12 months prior to enrolment Presence of serum anti-cyclic citrullinated peptide antibodies (anti CCP). 5. Treatment with oral, subcutaneous or intramuscular methotrexate for at least 6 months prior to randomisation. The dose and means of administering methotrexate must have been stable between 7.5 mg and 25 mg per week for at least 6 weeks prior to randomisation. Patients receiving the lower doses of methotrexate (7.5 mg and 10 mg) should be doing so as a result of a documented history of intolerance to higher doses of methotrexate. 6. Currently receiving, or have previously received, a single TNF- antagonist for the treatment of RA at a label approved dose for at least 12 weeks, unless discontinued for tolerability and safety reasons, and designated as a treatment failure due to lack of efficacy, safety, or tolerability. NB: TNF- antagonists are subject to a washout period prior to randomisation as follows: etanercept, 4 weeks; adalimumab, certolizumab, infliximab, golimumab 8 weeks. |
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E.4 | Principal exclusion criteria |
1. Females who are pregnant or lactating. 2. Any systemic inflammatory conditions (other than RA), connective tissue disease or chronic pain disorders that may interfere with the interpretation of the outcome data. Examples include psoriatic arthritis, reactive arthritis, gout, systemic lupus erythematosus (SLE), polymyalgia rheumatic and/or temporal arteritis, Lyme’s disease, fibromyalgia and chronic fatigue syndromes. 3. American College of Rheumatology functional Class IV (see Appendix F) or wheelchair/bed-bound. 4. Uncontrolled or poorly controlled hypertension defined as ≥140 mmHg systolic and/or ≥90 mmHg diastolic at baseline (Visit 2) with or without current anti hypertensive treatment. 5. Absolute neutrophil count (ANC) <1500/mm3 or 1.5 x 109/L. If a patient has findings marginally below this limit, re-screening is allowed, at the investigator’s discretion, within the 28 day period between Visit 1 and 2. 6. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.2 x upper limit of normal (ULN), or bilirubin >1.2 x ULN. If a patient has AST or ALT >1.2 x ULN but <2 x ULN, re-screening is allowed, at the investigator’s discretion, within the 28 day period between Visit 1 and 2. 7. History of liver function abnormality requiring investigation, drug induced liver injury, chronic liver disease, excessive alcohol consumption or chronic alcohol induced disease. 8. Evidence of recent or significant CV disease defined as: Any major CV event within the previous 6 months including myocardial infarction, unstable angina, cerebrovascular accident, pulmonary embolism, or heart failure New York Heart Association Class III or IV (see Appendix P). 9. Evidence of active or recent infection including: Positive serological test for hepatitis B or hepatitis C (patients may be included if confirmed hepatitis C recombinant immunoblot assay negative or hepatitis C virus RNA negative [qualitative]), or patients with suspected human immunodeficiency virus (HIV). Treatment with intravenous antibiotics within previous month prior to randomisation, oral antibiotics within 2 weeks prior to randomisation or current evidence of a clinically significant active infection. 10. Evidence of tuberculosis (TB) infection. 11. Patients who have failed to respond to treatment with anakinra. Patients who responded to treatment but where treatment was stopped for other reasons are allowed. Patients who have used anakinra should have a minimum washout of 8 weeks prior to randomisation. 12. Patients who have previously been treated with biologic agents other than TNF- antagonists including rituximab, abatacept and tocilizumab. 13. Use of any DMARDs other than methotrexate within 28 days prior to Visit 1, eg, leflunomide, sulfasalazine, azathioprine, cyclosporine, hydroxychloroquine, chloroquine, gold, penacillamine, minocycline or doxycycline. Any patient that has received leflunomide within 12 weeks prior to randomisation must have completed a cholestyramine washout prior to study randomisation. 14. Intramuscular, intravenous or intra-articular steroid injection within 6 weeks prior to randomisation. 15. Patients requiring doses of oral steroids >10 mg/day prednisolone (or equivalent). NB: Patients on doses ≤10 mg/day are permitted but should have a stable dose for at least 6 weeks prior to randomisation. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint in this study is the proportion of patients achieving ACR20 response at Week 24. This will be assessed for each dose regimen versus placebo. |
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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 | No |
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 | No |
E.6.10 | Pharmacogenetic | Yes |
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) | 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 | Yes |
E.8.2.3.1 | Comparator description |
stesso farmaco, due diversi regimi posologici |
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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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 53 |
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 | Information not present in EudraCT |
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 |
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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 | 6 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |