E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsing remitting multiple sclerosis |
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E.1.1.1 | Medical condition in easily understood language |
Relapsing-remitting multiple sclerosis, is a chronic inflammatory disease that affects the central nervous system |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10063399 |
E.1.2 | Term | Relapsing-remitting multiple sclerosis |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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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, safety and tolerability of a daily dose of 0.6 mg and 1.2 mg of laquinimod as compared to placebo in subjects with relapsing remitting multiple sclerosis (RRMS). |
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E.2.2 | Secondary objectives of the trial |
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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 |
Ancillary-studies (sub-studies) are included in the main study protocol LAQ-MS-305, dated 15 August 2012 (final version)
GENETIC MARKERS SUB-STUDY (Pharmacogenetic (PGx))
To explore the association between genetic polymorphism and response to laquinimod in terms of clinical, MRI and safety parameters.
IMMUNOLOGICAL SUB-STUDY
to evaluate the immunological response to treatment with laquinimod and further investigation of the potential mechanism of action
CERVICAL CORD MRI SUB-SUDY
to evaluate the percent change in cervical cord volume to be used as an exploratory endpoint
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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, with relapse onset disease or a relapsing-remitting disease course.
2. Subjects must be ambulatory with Kurtzke EDSS score of 0-5.5 in both screening and randomization visits.
3.Subjects must be in a stable neurological condition, relapse-free and free of any corticosteroid treatment [intravenous (IV), intramuscular (IM) and/or per os (PO)] or adrenocorticotrophic hormone (ACTH), 60 days prior to randomization.
4. Subjects must have experienced at least one documented relapse in the 12 months prior to randomization.
5. Subjects must be between 18 and 55 years of age at screening, inclusive.
6. Subjects must have disease duration of not more than 15 years.
7. Women of child-bearing potential must practice an acceptable method of birth control for 30 days before taking the study drug and two acceptable methods of birth control during the duration of the study and
until 30 days after the last dose of study medication.
8. Subjects must be able to sign and date a written informed consent prior to entering the study.
9. 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. Subjects with progressive forms of MS.
2. Subjects with Neuromyelitis Optica (NMO).
3.Use of experimental or investigational drugs and/or participation in drug clinical studies within 6 months prior to randomization.
4.Use of immunosuppressive agents or cytotoxic agents, including Cyclophosphamide within 6 months prior to randomization.
5.Use of either of the following within 2 years prior to randomization: natalizumab (Tysabri®), rituximab, ocrelizumab, atacicept, belimumab, or ofatumumab.
6.Use of teriflunomide (Aubagio®) within 2 years prior to randomization, except if active washout (with either cholestyramine or activated charcoal) was done 2 months or more prior to randomization.
7.Previous treatment with glatiramer acetate (Copaxone®) Interferon β
(either 1a or 1b), fingolimod (Gilenya®), dimethyl fumarate
(Tecfidera®) or intravenous immunoglobulin (IVIG) within 2 months
prior to randomization.
8.Chronic (more than 30 consecutive days) systemic (IV, IM or PO) corticosteroid treatment within 2 months prior to randomization.
9.Previous use of Mitoxantrone (Novantrone®), Cladribine, or
alemtuzumab (Lemtrada®).
10.Previous use of laquinimod.
11.Previous total body irradiation or total lymphoid irradiation.
12.Previous stem cell treatment, autologous bone marrow transplantation or allogenic bone marrow transplantation.
13.Use of moderate/strong inhibitors of CYP3A4 within 2 weeks prior to randomization.
14.Use of inducers of CYP3A4 within 2 weeks prior to randomization.
15.Pregnancy or breastfeeding.
16.Serum levels ≥3x upper limit of the normal range (ULN) of either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) at screening.
17.Serum direct bilirubin which is ≥2xULN at screening.
18.Subjects with a clinically significant or unstable medical or surgical condition or any other condition that cannot be well-controlled by the allowed medications permitted in the study protocol that would preclude safe and complete study participation, as determined by medical history, physical examinations, ECG, laboratory tests MRI or chest X-ray.
19.A known history of sensitivity to gadolinium (Gd).
20.GFR ≤ 60 mL/min at the screening visit.
21.Inability to successfully undergo MRI scanning.
22.Subjects who underwent endovascular treatment for Chronic Cerebrospinal Venous Insufficiency (CCSVI) within 3 months prior to randomization.
23.Known hypersensitivity that would preclude administration of laquinimod capsule, such as hypersensitivity to: mannitol, meglumine or sodium stearyl fumarate. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Time to Confirmed Disease Progression (CDP) during Period 1.
CDP is defined as an increase in EDSS of ≥1 point from baseline for subjects with baseline EDSS of ≤5.0, or an increase in EDSS of ≥ 0.5 points from baseline for subjects with baseline EDSS of 5.5. Analysis will be performed at the completion of Period 1. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Evaluation will be performed at months -1 (screening), 0 (baseline) and every 3 months thereafter and until completion visit of Period 1 |
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E.5.2 | Secondary end point(s) |
-Brain atrophy as defined by the percent change in brain volume from baseline to month 15
-The time to first confirmed relapse during Period 1.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
In terms of brain atrophy:
evaulation at baseline and at month 15
In terms relapse evaluation:
Evaluation will be done at each timepoint during the study once any symptoms suggestive of a relapse appear / are reported by any subject.
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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 | 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 | 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 | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 142 |
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 | No |
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 |
Belarus |
Bosnia and Herzegovina |
Chile |
Croatia |
Georgia |
Israel |
Korea, Republic of |
Macedonia, the former Yugoslav Republic of |
Moldova, Republic of |
Montenegro |
Russian Federation |
Serbia |
Ukraine |
United States |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |