E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with active Rheumatoid Arthritis despite current treatment with a DMARD. |
|
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 |
|
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 a disease-modifying anti-rheumatic drug (DMARD), compared with placebo plus a DMARD, in patients with active rheumatoid arthritis (RA) |
|
E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study assessed over the 52-week study period are: • 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 and Week 52. • To further assess the efficacy of FosD measured by ACR20, ACR 50% response criteria (ACR50), ACR 70% response criteria (ACR70), major clinical response, 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. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
For inclusion in the study subjects should fulfil the following 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: 4 swollen joints and 4 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 1 of the following traditional DMARDs: methotrexate, sulfasalazine, hydroxychloroquine or chloroquine. NB: Those patients taking methotrexate should have been treated for at least 6 months prior to randomisation and with a stable dose between 7.5 mg and 25 mg per week for at least 6 weeks prior to randomisation. Those patients taking sulfasalazine should have had a stable dose for at least 6 weeks prior to randomisation. Those patients taking hydroxychloroquine or chloroquine should have had a stable dose for at least 12 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. |
|
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. 3. American College of Rheumatology functional Class IV 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. 6. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.2 x upper limit of normal (ULN), or bilirubin >1.2 x ULN. 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 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 a TNF- antagonist (including etanercept, certolizumab, adalimumab, infliximab, golimumab) or anakinra. Patients who responded to treatment but where treatment was stopped for other reasons are allowed. Patients who have used anakinra or a TNF- antagonist should have a minimum washout of 8 weeks prior to randomisation. 12. Patients who have previously been treated with other biologic agents including rituximab, abatacept and tocilizumab. 13. Use of any DMARDs other than methotrexate, sulfasalazine, hydroxychloroquine or chloroquine within 28 days prior to Visit 1, eg, leflunomide, azathioprine, cyclosporine, 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. 16. Administration of a live vaccine in the 4 weeks prior to randomisation. 17. History of malignancy or neoplastic disease, except successfully treated basal or squamous cell carcinoma of the skin >5 years ago. 18. Severely impaired renal function (estimated glomerular filtration rate ≤30 mL/min according to the Cockcroft-Gault formula). 19. Any other clinically significant disease or disorder, which in the opinion of the investigator (by its nature or by being inadequately controlled) might put the patient at risk due to participation in the study, or may influence the results of the study, or the patient’s ability to participate in the study. |
|
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 |
|
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 |
|
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 | 50 |
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 |
|
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 | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
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 | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |