The Efficacy, Safety, and Tolerability of Laquinimod in Participants With Relapsing Remitting Multiple Sclerosis (RRMS)

Study Overview
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Brief Summary
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This is a multinational, multicenter, randomized, double-blind, parallel-group, placebo-controlled study followed by active treatment, to evaluate the efficacy, safety and tolerability of two doses of oral administration of laquinimod in participants with RRMS. The study has 2 periods: Period 1, the double-blind, placebo-controlled period (up to 24 months) and Period 2, the active treatment period (24 months).

Official Title
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A Multinational, Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study Followed by an Active Treatment Period, to Evaluate the Efficacy, Safety and Tolerability of Two Doses of Oral Administration of Laquinimod (0.6 mg/Day or 1.2 mg/Day) in Patients With Relapsing Remitting Multiple Sclerosis (RRMS)

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: Laquinimod
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must have a confirmed and documented multiple sclerosis (MS) diagnosis as defined by the Revised McDonald criteria, with relapse onset disease or a relapsing-remitting disease course. Participants must be ambulatory with Kurtzke's expanded disability status scale (EDSS) score of 0 to 5.5 in both screening and randomization visits. Participants must be in a stable neurological condition, relapse-free and free of any corticosteroid treatment [intravenous (IV), intramuscular (IM) and/or per os (PO)/oral] or adrenocorticotrophic hormone, 60 days prior to randomization. Participants must have experienced at least one documented relapse in the 12 months prior to randomization. Participants must have disease duration of not more than 15 years. Women of child-bearing potential (for example, women who are not postmenopausal or surgically sterilized) 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. Additional criteria apply, please contact the investigator for more information. Exclusion Criteria: Participants with progressive forms of MS. Participants with neuromyelitis optica. Use of experimental or investigational drugs and/or participation in drug clinical studies within the 6 months prior to randomization. Use of immunosuppressive agents or cytotoxic agents, including cyclophosphamide, within 6 months prior to randomization. Use of either of the following within 2 years prior to randomization visit: natalizumab (Tysabri®), rituximab, ocrelizumab, atacicept, belimumab, or ofatumumab. 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. Previous treatment with glatiramer acetate (Copaxone®) Interferon β (either 1a or 1b), fingolimod (Gilenya®), dimethyl fumarate (Tecfidera®) or intravenous immunoglobulins within 2 months prior to randomization. Chronic (more than 30 consecutive days) systemic (IV, IM or PO) corticosteroid treatment within 2 months prior to randomization. Previous use of mitoxantrone (Novantrone®), cladribine, or alemtuzumab (Lemtrada®). Previous use of laquinimod. Previous total body irradiation or total lymphoid irradiation. Previous stem cell treatment, autologous bone marrow transplantation or allogenic bone marrow transplantation. Use of moderate/strong inhibitors of cytochrome P450 (CYP) 3A4 within 2 weeks prior to randomization. Use of inducers of CYP3A4 within 2 weeks prior to randomization visit. Pregnancy or breastfeeding. A known history of sensitivity to gadolinium (Gd). Inability to successfully undergo magnetic resonance imaging (MRI) scanning. Participants who underwent endovascular treatment for chronic cerebrospinal venous insufficiency within 3 months prior to randomization. Additional criteria apply, please contact the investigator for more information.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo-Controlled Phase: Placebo<br>Participants will receive 2 capsules of placebo (matching to laquinimod 0.6 milligrams [mg]) once daily orally for up to 24 months. | Drug: Placebo<br>* Placebo matching to laquinimod will be administered as per the schedule specified in the respective arms.<br>|
| Experimental: Placebo-Controlled Phase: Laquinimod 0.6 mg<br>Participants will receive 1 capsule of laquinimod 0.6 mg and 1 capsule of matching placebo once daily orally for up to 24 months. | Drug: Laquinimod<br>* Laquinimod will be administered as per the dose and schedule specified in the respective arms.<br>Drug: Placebo<br>* Placebo matching to laquinimod will be administered as per the schedule specified in the respective arms.<br>|
| Experimental: Placebo-Controlled Phase: Laquinimod 1.2 mg<br>Participants will receive laquinimod 1.2 mg (2 capsules of laquinimod 0.6 mg each) once daily orally for up to 24 months. | Drug: Laquinimod<br>* Laquinimod will be administered as per the dose and schedule specified in the respective arms.<br>|
| Experimental: Active Treatment Phase: Laquinimod 0.6 mg<br>Participants who completed the placebo-controlled phase on placebo and on laquinimod 0.6 mg treatment group after 01 January 2016, will receive 1 capsule of laquinimod 0.6 mg and 1 capsule of matching placebo once daily orally for 24 months. | Drug: Laquinimod<br>* Laquinimod will be administered as per the dose and schedule specified in the respective arms.<br>Drug: Placebo<br>* Placebo matching to laquinimod will be administered as per the schedule specified in the respective arms.<br>|
| Experimental: Active Treatment Phase: Laquinimod 1.2 mg<br>Participants who completed the placebo-controlled phase on placebo and on laquinimod 1.2 mg treatment group prior to 01 January 2016, will receive laquinimod 1.2 mg (2 capsules of laquinimod 0.6 mg each) once daily orally for 24 months. | Drug: Laquinimod<br>* Laquinimod will be administered as per the dose and schedule specified in the respective arms.<br>|
| No Intervention: Active Treatment Phase: Off Drug<br>Participants who were discontinued from treatment with laquinimod 1.2 mg during the placebo-controlled phase due to sponsor decision after 01 January 2016 will continue the active-treatment phase off drug for 24 months. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Placebo-Controlled Phase: Time to Confirmed Disease Progression (CDP) Confirmed After At Least 3 Months (Number of Participants With CDP After At Least 3 Months) | Time to CDP was defined as the time to a sustained increase in Kurtzke's Expanded Disability Status Scale (EDSS) score of at least 1 point if baseline EDSS score was less than or equal to 5.0, or at least 0.5 point if the baseline EDSS score was 5.5, over a period of at least three months. EDSS assesses disability in 8 functional systems with an overall score ranging from 0 (normal) to 10 (death due to multiple sclerosis [MS]). Data is presented as distribution of CDP (number of participants with CDP) sustained for 3 months. | Baseline to Month 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Placebo-Controlled Phase: Percent Change From Baseline in Brain Volume at Month 15 | Brain atrophy was defined by the percent change in brain volume from baseline to Month 15. For participants who prematurely discontinued treatment or completed the placebo-controlled phase before Month 15, the last available measurement was used, provided it was performed at least 9 months following the initiation of study drug. | Baseline, Month 15 | 
| Placebo-Controlled Phase: Time to First Confirmed Relapse (Number of Participants With Confirmed Relapse) | Relapse was defined as appearance of one or more new neurological abnormalities or reappearance or worsening of one or more previously observed neurological abnormalities, lasting for at least 48 hours (in absence of fever or any infection) and immediately preceded by an improving neurological state of at least 30 days from onset of previous relapse. An event was counted as a relapse only when the participant's symptoms were accompanied by observed objective neurological changes, consistent with an increase of at least 0.5 in EDSS; or one grade in score of 2 or more of 7 Functional Systems (FS) (excluding changes in bowel or bladder function or cognition); or 2 grades in score of one of the FS as compared to previous evaluation. EDSS assesses disability in 8 FS with an overall score ranging from 0 (normal) to 10 (death due to MS). Data is presented as distribution of relapsing participants (number of participants with confirmed relapse). | Baseline to Month 24 | 
| Placebo-Controlled Phase: Time to CDP Confirmed After At Least 6 Months (Number of Participants With CDP After At Least 6 Months) | Time to CDP was defined as the time to a sustained increase in Kurtzke's EDSS score of at least 1 point if baseline EDSS score was less than or equal to 5.0, or at least 0.5 point if the baseline EDSS score was 5.5, over a period of at least 6 months. EDSS assesses disability in 8 functional systems with an overall score ranging from 0 (normal) to 10 (death due to MS). Data is presented as distribution of CDP (number of participants with CDP) sustained for 6 months. | Baseline to Month 24 | 
| Placebo-Controlled Phase: Time to CDP Confirmed After At Least 9 Months (Number of Participants With Confirmed Relapse After At Least 9 Months) | Time to CDP was defined as the time to a sustained increase in Kurtzke's EDSS score of at least 1 point if baseline EDSS score was less than or equal to 5.0, or at least 0.5 point if the baseline EDSS score was 5.5, over a period of at least 9 months. EDSS assesses disability in 8 functional systems with an overall score ranging from 0 (normal) to 10 (death due to MS). Data is presented as distribution of CDP (number of participants with CDP) sustained for 9 months. | Baseline to Month 24 |