E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsing Remitting Multiple Sclerosis (RRMS) |
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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 | LLT |
E.1.2 | Classification code | 10063399 |
E.1.2 | Term | Relapsing-remitting multiple sclerosis |
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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 assess the efficacy of 0.6 mg daily dose of laquinimod in patients with RRMS, as measured by the number of confirmed relapses during the treatment period. |
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E.2.2 | Secondary objectives of the trial |
To assess the effect of 0.6 mg daily dose of laquinimod on the development of brain atrophy as defined by the percent brain volume change from baseline at the end of the treatment period. To assess the effect of 0.6 mg daily dose of laquinimod on the accumulation of physical disability as measured by the time to confirmed progression of EDSS during the treatment period. To assess the effect of 0.6 mg daily dose of laquinimod on the accumulation of disability, as assessed by the MSFC score at the end of the treatment period. |
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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 |
Pharmacogenetic (PGt) ancillary study: This ancillary study is planned to be performed in all sites. Ojective: Relationship between PGt and response to laquinimod or to Avonex® in terms of clinical, MRI and safety parameters. Pharmacogenetic (PGt) assessment: Blood samples for PGt parameters will be collected from all subjects at month -1 (screening).
Second ancillary study which will be performed in all subjects from US sites only:
The effect of general health and symptom severity on work will be assessed by the work productivity and activities impairment General Health (WPAI-GH) questionnaire (Appendix 16) at months 0 (baseline) and every 3 months thereafter, until month 24 (termination/ early discontinuation) visit (this assessment will be performed in all subjects from US sites only). |
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E.3 | Principal inclusion criteria |
1.Subjects must have a confirmed and documented MS diagnosis as defined by the Revised McDonald criteria [Ann Neurol 2005: 58:840-846], with a relapsing-remitting disease course. 2.Subjects must be ambulatory with Converted EDSS score of 0-5.5 in both screening and baseline visits. 3.Subjects must be in a stable neurological condition and free of corticosteroid treatment [intravenous (IV), intramuscular (IM) and/or per os (PO)] 30 days prior to screening (month -1) and between screening (month -1) and baseline (month 0) visits. 4.Subjects must have had experienced one of the following: At least one documented relapse in the 12 months prior to screening, or At least two documented relapses in the 24 months prior to screening or One documented relapse between 12 and 24 months prior to screening with at least one documented T1-Gd enhancing lesion in an MRI performed within 12 months prior to screening. 5.Subjects must be between 18 and 55 years of age, inclusive. 6.Women of child-bearing potential must practice an acceptable method of birth control [acceptable methods of birth control in this study include: surgical sterilization, intrauterine devices, oral contraceptive, contraceptive patch, long-acting injectable contraceptive, partner’s vasectomy or a double-protection method (condom or diaphragm with spermicide)]. 7.Subjects must be able to sign and date a written informed consent prior to entering the study. 8.Subjects must be willing and able to comply with the protocol requirements for the duration of the study.
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E.4 | Principal exclusion criteria |
1. An onset of relapse or any treatment with corticosteroids [intravenous (IV), intramuscular (IM) and/or per os (PO)] or ACTH between month -1 (screening) and 0 (baseline). 2. Subjects with progressive forms of MS. 3. Use of experimental or investigational drugs, and/or participation in drug clinical studies within the 6 months prior to screening visit. 4. Use of immunosuppressive (including Mitoxantrone (Novantrone®) or cytotoxic agents within 6 months prior to the screening visit. 5. Previous use of either of the following: natalizumab (Tysabri®), cladribine, laquinimod, Interferon beta-1a (Avonex® or Rebif®), Interferon beta-1b (Betaseron®/Betaferon®) or any other experimental Interferon-beta for MS. 6. Previous treatment with glatiramer acetate (Copaxone®) or IVIG within 2 months prior to screening visit. 7. Chronic (more than 30 consecutive days) systemic (IV, PO or IM) corticosteroid treatment within 2 months prior to screening visit. 8. Previous total body irradiation or total lymphoid irradiation. 9. Previous stem cell treatment, autologous bone marrow transplantation or allogenic bone marrow transplantation. 10. A known history of tuberculosis. 11. Acute infection within two weeks prior to baseline visit. 12. Major trauma or surgery within two weeks prior to baseline visit. 13. Known human immunodeficiency virus (HIV) positive status. 14. Use of inhibitors of CYP3A4 within 2 weeks prior to baseline visit (see Appendix 5) 15. Use of amiodarone within 2 years prior to screening visit. 16. Pregnancy or breastfeeding. 17. A ≥3xULN serum elevation of either ALT or AST at screening. 18. Serum direct bilirubin which is ≥2xULN at screening 19. A QTc interval which is > 450 msec (according to machine output), obtained from: -Two ECG recordings at screening visit OR - The mean value calculated from 3 baseline ECG recordings 20. Subjects with a clinically significant or unstable medical or surgical condition that, in the Investigator's opinion, would preclude safe and complete study participation, as determined by medical history, physical examinations, ECG, laboratory tests or chest X-ray. Such conditions may include: - A cardiovascular or pulmonary disorder that cannot be well-controlled by standard treatment permitted by the study protocol. - A gastrointestinal disorder that may affect the absorption of study medication. - Renal, metabolic or hematological diseases. - Thyroid disease: A subject with hyperthyroidism is not permitted to participate in the study. A subject with hypothyroidism may be permitted to participate in the study provided that he/she is clinically euthyroid and considered stable. - Liver disease, such as cirrhosis. - A family history of Long-QT syndrome. - A history of drug and/or alcohol abuse. - A current major psychiatric disorder, including schizophrenia or severe depression, with or without suicidal ideation. - A history of seizure disorder, with the last convulsive episode occurring within 12 months prior to screening visit. 21. A known history of sensitivity to Gadolinium. 22. Inability to successfully undergo MRI scanning. 23. A known drug hypersensitivity that would preclude administration of laquinimod, such as hypersensitivity to: mannitol, meglumine or sodium stearyl fumarate. 24. A known history of hypersensitivity to natural or recombinant interferon beta, human albumin, or any other component of the formulation of Avonex®. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The number of confirmed relapses during the treatment period. |
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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 | No |
E.6.7 | Pharmacodynamic | No |
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 | Yes |
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 | Yes |
E.8.1.7.1 | Other trial design description |
Third arm comparator, rater-blinded |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Avonex 30 microgram/0.5 ml Solution for Injection |
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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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 77 |
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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Last visit of the three-arm phase will be visit 12 (month 24).
Subjects successfully completing the study will be offered the opportunity to enter into a 1-year open-label extension in which laquinimod 0.6 mg/d will be administered. |
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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 | 3 |
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 | 4 |
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 |