| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| patients with a diagnosis of early active rheumatoid arthritis in the previous 6 months, naïves of previous treatment by a DMARD and who need to be treated by a DMARD |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10039073 |
| E.1.2 | Term | Rheumatoid arthritis |
|
| 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 assess the clinical efficacy response rate using ACR20 criteria as primary endpoint at 3-month in each initial dosing regimen group of treatment. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
- To assess the clinical efficacy at 1-month and 3-month using complementary efficacy criteria (ACR 50, ACR 70, DAS 28, patient and physician RA activity level assessment) in each group of treatment.
- To assess the clinical and biological safety using standard blood monitoring, TEAED and SAE in each group of treatment.
- To evaluate treatment modifications; particularly leflunomide and concomitant use of AINS, corticoids and analgesics.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female* patients, aged over 18 years .
*The inclusion of women of childbearing must strictly respect the following recommendations:
- To demonstrate they are not pregnant at the time of study entry, they agree to undergo urine pregnancy testing at inclusion visit. They also agree to undergo urine pregnancy testing at safety follow-up visit.
- They are demonstrated not to be breast feeding at the time of study entry.
- They agree to maintain adequate means of contraception throughout the study and for 24 months after the discontinuation of treatment or they undergo a washout procedure.
- They agree not to get pregnant for 24 months after discontinuation of treatment with study medication or they undergo a washout procedure. In either case (waiting period of 24 months or washout procedure), the A77 1726 plasma concentration has then to be determined two times at an interval of at least 14 days after treatment discontinuation.
Male patients must consent to practice contraception during the study and as long as they are taking leflunomide and to follow the washout procedure if they wish to father a child after treatment discontinuation (according to the SmPC).
2. Diagnosis of active rheumatoid arthritis in the previous 6 months according to ACR guidelines (in Appendix A).
3. Active disease demonstrated by: clinical (tender and swollen joint count, morning stiffness and pain) and biological (CRP > 2.0mg/dl or ESR>28mm/Hg) criteria, to be initiated by DMARD.
4. Unchanged doses, for at least 4 weeks before entering the study, of:
- NSAIDs
- oral corticosteroids (with a maximum dose of 10 mg prednisolone daily, or the corticosteroid equivalent administered orally).
5. Subjects must be well-orientated, cooperative and willing to comply with the terms of this protocol.
6. Informed consent must be obtained for all subjects before enrollment in the study.
|
|
| E.4 | Principal exclusion criteria |
1. Patient presenting or having a history of other inflammatory joint disease, e.g. mixed connective tissue disease, seronegative spondylarthropathy, arthropathic psoriasis, Reiter’s syndrome, systemic lupus erythematosus, sarcoidosis, history of Felty’s syndrome, or any arthritis with onset prior to 16 years of age.
2. Patients with ongoing or previous Stevens- Johnson syndrome, toxic epidermal necrolysis or erythema multiforme.
3. Patients with significantly impaired bone marrow function or significant anaemia, leucopenia or thrombocytopenia due to causes other than active rheumatoid arthritis.
4. Persistent infection or severe infection within 3 months before enrollment.
5. Uncontrolled hypertension, uncontrolled diabetes, unstable ischemic heart disease, active inflammatory bowel disease, active peptic ulcer disease, terminal illness or other medical condition which, in the opinion of the investigator, would put the patient at risk to participate in the study.
6. Clinically relevant cardiovascular, hepatic, neurological, endocrine, or other major systemic disease making implementation of the protocol or interpretation of the study results difficult.
7. Severe hypoproteinemia (e.g. in case of severe liver disease or nephrotic syndrome) with serum albumin < 3.0 g/dl.
8. Moderate or severe impairment of renal function, as shown by serum creatinine > 133 µmol/L (or 1.5 mg/dL).
9. Patients with a history of recent and clinically significant drug or alcohol abuse.
10. Impairment of liver function or persisting ALT (SGPT) elevations of more than 2-fold the upper limit of normal.
11. Pregnancy.
12. Breastfeeding.
13. Women of childbearing potential, except if they fulfill all conditions described in
section 8.2.
14. Men wishing to father children during the course of the study or within the 24 months thereafter (or 3 months with the washout procedure).
15. Patient with a congenital or acquired severe immunodeficiency, a history of cancer or lymphoproliferative disease, or any patient who has received total lymphoid irradiation.
16. Known HIV positive status.
17. Known positive serology for hepatitis B or C.
18. Patients with hypersensitivity to any of the excipients in the tablets of leflunomide.
19. Previous therapy at any time with:
• any DMARD including leflunomide, methotrexate , oral or injectable gold salts, chloroquine, hydroxychloroquine, ciclosporin, azathioprine, methotrexate, sulfasalazine)
• D penicillamine
• alkylating agents, e.g. cyclophosphamide, chlorambucil, biological agents, e.g. interferon, monoclonal antibodies, growth factor, cytokines
• any investigational drug
• any anti metabolites
• any opiate
20. Therapy within the previous 4 weeks with :
• oral corticosteroids exceeding a prednisolone equivalent of 10 mg/day
• parenteral or intra-articular corticoid injection
21. Any known condition or circumstance which would in the investigator’s opinion prevent compliance or completion of the study
Any concomitant disorder (such as diabetes mellitus, hypertension, heart disease, etc.) should be controlled before entry into the study by appropriate medication which should be, if possible, continued unchanged during the entire study period.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary end point is the efficacy response rate using ACR20 criteria at 3-month in each initial dosing regimen group of treatment |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| 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 | 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) | 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 | Yes |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| 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 | 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 | No |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
Print
