E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10039073 |
E.1.2 | Term | Rheumatoid arthritis |
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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 |
To compare the efficacy of SMP-114 (120 mg and 240 mg) versus placebo in terms of the percentage of patients meeting the American College of Rheumatology criteria for 20% improvement in Rheumatoid arthritis (ACR20) at Week 24. |
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E.2.2 | Secondary objectives of the trial |
To compare the efficacy of SMP-114 (120 mg and 240 mg) versus placebo in terms of the % of patients who: - Meet the ACR criteria for 50% and 70% improvement in RA at Week 24 - Obtain ‘good’ or ‘moderate’ or ‘none’ response according to the EULAR criteria using a calculation of DAS at Week 24 To compare the efficacy of SMP-114 (120 mg and 240 mg) versus placebo with respect to: - The mean change and the mean % change from baseline in core set variable results, the mean change from baseline in Quality of Life (short form - 36) measure and in DAS28 at Week 24 - The mean time to first response (time to ACR20, EULAR and DAS28 responses) - The actual change in radiological joint damage as assessed by x-ray: from Week 24 to Week 48 and from baseline at Week 24 and at Week 48 To assess safety and tolerability of each regimen during the study To describe the PK profile of SMP-114 and the metabolite flurbiprofen To explore the relationship of SMP-114 drug concentration with PD effect |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Is at least 18 years of age 2. Has given his/her written informed consent to participate in the study 3. Has had a diagnosis of RA (based on the ACR criteria) for at least 6 months 4. Has RA disease classified as ACR functional class I, II or III 5. Has active RA disease as defined by: · >= 6 swollen joints (using 28-joint counts) · >= 6 tender joints (using 28-joint counts) · and at least one of the following: ESR >= 28 mm/hr, CRP >= 10 mg/L 6. Has been receiving methotrexate at weekly doses of 10 to 25 mg for >= 12 weeks prior to study drug administration. Methotrexate use must have been in accordance with its product labelling (SmPC) 7. The dose of methotrexate has been stable for at least 8 weeks prior to randomisation and is anticipated to remain constant during the study period Individuals previously treated with methotrexate can be enrolled provided they have not had clinically significant toxic effects or lack of response, at the discretion of the Investigator 8. Has been on a stable dose of folate (or leucovorin) for at least 4 weeks prior to randomisation and the dose of folate (or leucovorin) is anticipated to remain constant during the study period. If not currently prescribed, is willing to start receiving folate (or leucovorin) at screening 9. If on a stable dose of NSAID and/or COX-2 inhibitor, the doses of these concomitant medications must have been stable for at least 2 weeks prior to randomisation. The dose(s) must be anticipated to remain constant during the study 10. If taking oral corticosteroid at a permissible dose (eg <= 10 mg prednisolone) then the dose of the oral corticosteroid must have been stable for at least 4 weeks prior to randomisation and must be anticipated to remain constant during the study
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E.4 | Principal exclusion criteria |
Patients are not eligible for this study if they fulfil any of the following criteria:
1. Is a pregnant or lactating woman 2. Is a woman of childbearing potential not prepared to use a reliable form of contraception during the study. An effective form of birth control includes contraception such as a barrier method (condom with spermicidal) in conjunction with hormone-based contraceptives or certain intra-uterine devices, or alternatively abstinence or surgical methods. 3. Has previously discontinued DMARD therapy due to hepatic intolerance. 4. Has received any DMARD in addition to methotrexate during the 4 weeks prior to randomisation. All DMARD’s, with the exception of methotrexate must have been discontinued at least 4 weeks before randomisation, unless requiring a longer washout period 5. Is receiving more than 2 DMARDs in addition to methotrexate at the time of screening 6. Is receiving or has received Gold, leflunomide or biological agents including TNF/IL-1 inhibitors within the 8 weeks prior to randomisation. Leflunomide washout can be completed with colestyramine according to the manufacturer’s instructions 7. Has previously failed >= 2 DMARDS. Failure is defined as removal of the administration of a DMARD due to inadequate efficacy response rather than discontinuation of DMARD therapy due to intolerance. A patient who has been removed from biological DMARD therapy due to non-clinical reasons can enter the study 8. Will require any treatments contraindicated for methotrexate 9. Is currently taking flurbiprofen 10. Has used intra-articular, intra-muscular or intravenous corticosteroids within 8 weeks prior to randomisation 11. Requires ongoing treatment with warfarin, cimetidine, phenytoin, trimethoprim, quinolones or dextropropoxyphenes (including co-proxamol) during the study 12. Persistent or severe infections within 3 months before randomisation 13. Has any known or suspected hypersensitivity to leflunomide or any other isoxazole compounds or any ingredients contained within the study drug (mannitol, corn starch, croscarmellose sodium, hypromellose, magnesium stearate, titanium dioxide, macrogol, carnuba wax, gelatine, sodium metabisulphite) 14. Has pre-existing hepatic disease, or co morbid illness predisposing to hepatic complications and/or the following laboratory parameters at screening: · AST >= 2 X ULN on two consecutive occasions and/or · ALT >= 2 X ULN on two consecutive occasions 15. Has any pre-existing renal disease, or co morbid illness predisposing to renal complications, or the following laboratory parameter at screening: · Serum creatinine >= 1.5 mg/dL 16. Has current blood dyscrasias such as bone marrow hypoplasia, leukopenia, thrombocytopenia or significant anaemia including Haemoglobin <10 g/dL at screening 17. Has any other significant systemic, cardiac, neurological, psychiatric or other illness that in the Investigator’s opinion would preclude the patient from participating in the study 18. Has a known or had a known malignancy of any type in the previous 5 years with the exception of basal or squamous cell carcinoma of the skin if no recurrence during the 1 year prior to screening 19. Has a current history of known or in the opinion of the Principal Investigator, suspected drug and/or alcohol abuse 20. Has participated in another clinical trial with an investigational agent (including named patient or compassionate use protocols) 8 weeks prior to randomisation (or longer if 8 weeks does not provide a reasonable wash-out period for the drug) 21. Has previously participated in a clinical trial of SMP-114
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E.5 End points |
E.5.1 | Primary end point(s) |
A patient will be classified as a responder as per ACR20 if all of the following criteria are met after 24 weeks of treatment, when compared to baseline: >=20% improvement in tender joint count (TJC) AND >=20% improvement in swollen joint count (SJC) AND >=20% improvement in three of the five following ACR core set measures: 1. Patient assessment of pain (Visual Analogue Scale[VAS]) 2. Patient global assessment of disease activity (VAS) 3. Physician global assessment of disease activity (VAS) 4. Patient self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]) 5. Acute phase reactant C-reactive protein (CRP) or ESR
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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 | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
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.8.3 |
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 | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 49 |
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 | Information not present in EudraCT |
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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last visit of the last patient 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 | 25 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 25 |