A Phase 2 Clinical Study in Subjects With Primary Progressive Multiple Sclerosis to Assess the Efficacy, Safety and Tolerability of Two Oral Doses of Laquinimod Either of 0.6 mg/Day or 1.5mg/Day (Experimental Drug) as Compared to Placebo

Study Overview
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Brief Summary
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This Phase 2 study is intended to serve as a proof of concept for potential treatment with laquinimod in patients with PPMS. The study is also aimed at evaluating 2 doses of laquinimod in this population.

Detailed Description
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Due to serious cardiovascular adverse events, Data Monitoring Committee (DMC) made a recommendation to stop all laquinimod treatment arms above 0.6 mg in the multiple sclerosis (MS) trials; therefore the 1.5 mg treatment arm in the ARPEGGIO study was discontinued as of 01 January 2016. The DMC did not identify any definite cardiovascular risk in the 0.6 mg treatment arm, but felt that long term monitoring for emergence of any potential signal was necessary. Therefore, the 0.6 mg treatment arm was continued while the sponsor closely monitored cardiovascular events in all laquinimod studies. Prior to 01 January 2016, eligible patients were randomized in a 1:1:1 ratio into 1 of the following treatment arms (a total of 286 patients were randomized 1:1:1 prior to 01 January 2016): Laquinimod 0.6 mg daily Laquinimod 1.5 mg daily Daily placebo As of 01 January 2016, following the decision to discontinue the laquinimod 1.5 mg dose arm, additional eligible patients (87 patients) who were enrolled were randomized in a 1:1 ratio into one of the following treatment arms: Laquinimod 0.6 mg daily Daily placebo

Official Title
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A Multinational, Multicenter, Randomized, Double Blind, Parallel Group, Placebo Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Once Daily Oral Administration of Laquinimod (0.6 or 1.5 mg) in Patients With Primary Progressive Multiple Sclerosis (PPMS)

Conditions
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Primary Progressive Multiple Sclerosis

Intervention / Treatment
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* Drug: Placebo
* Drug: Laquinimod
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have a confirmed and documented PPMS diagnosis as defined by the 2010 Revised McDonald criteria Baseline magnetic resonance imaging (MRI) showing lesions consistent with PPMS in either or both brain and spinal cord Patients must have an Expanded Disability Status Scale (EDSS) score of 3 to 6.5, inclusive, at both screening and baseline visits Documented evidence of clinical disability progression in the 2 years prior to screening. Functional System Score (FSS) of > or equal 2 for the pyramidal system or gait impairment due to lower extremity dysfunction Patients must be between 25 to 55 years of age, inclusive Women of child-bearing potential must practice an acceptable method of birth control for 30 days before taking the study drug, and 2 acceptable methods of birth control during all study duration and until 30 days after the last dose of treatment is administered. Patients must sign and date a written informed consent prior to entering the study. Patients must be willing and able to comply with the protocol requirements for the duration of the study. Exclusion Criteria: Patients with history of any multiple sclerosis (MS) exacerbations or relapses, including any episodes of optic neuritis. Progressive neurological disorder other than PPMS. Any MRI record showing presence of cervical cord compression. Baseline MRI showing other findings (including lesions that are atypical for PPMS) that may explain the clinical signs and symptoms. Relevant history of vitamin B12 deficiency. Positive human T-lymphotropic virus Type I and II (HTLV-I/II) serology. Use of experimental or investigational drugs in a clinical study within 24 weeks prior to baseline. Use of a currently marketed drug in a clinical study within 24 weeks prior to baseline would not be exclusionary, provided no other exclusion criteria are met. Use of immunosuppressive agents, or cytotoxic agents, including cyclophosphamide and azathioprine within 48 weeks prior to baseline. Previous treatment with fingolimod (GILENYA®, Novartis), dimethyl fumarate (TECFIDERA®, Biogen Idec Inc), glatiramer acetate (COPAXONE®, Teva), interferon-β (either 1a or 1b), intravenous immunoglobulin, or plasmapheresis within 8 weeks prior to baseline. Use of teriflunomide (AUBAGIO®, Sanofi) within 2 years prior to baseline, except if active washout (with either cholestyramine or activated charcoal) was done 2 months or more prior to baseline. Prior use of monoclonal antibodies ever, except for: natalizumab (TYSABRI®, Biogen Idec Inc), if given more than 24 weeks prior to baseline AND the patient is John Cunningham (JC) virus antibody test negative (as per medical history) rituximab, ocrelizumab, or ofatumumab, if B cell count (CD19, as per medical history) is higher than 80 cells/μL Use of mitoxantrone (NOVANTRONE®, Immunex) within 5 years prior to screening. Use of mitoxantrone >5 years before screening is allowed in patients with normal ejection fraction and who did not exceed the total lifetime maximal dose. Previous use of laquinimod. Chronic (eg, more than 30 consecutive days or monthly dosing, with the intent of MS disease modification) systemic (intravenous, intramuscular or oral) corticosteroid treatment within 8 weeks prior to baseline. Previous use of cladribine or alemtuzumab (LEMTRADA®, Sanofi). Previous total body irradiation or total lymphoid irradiation. Previous stem cell treatment, cell-based treatment, or bone marrow transplantation of any kind. Patients who underwent endovascular treatment for chronic cerebrospinal venous insufficiency (CCSVI) within 12 weeks prior to baseline. Use of moderate/strong inhibitors of cytochrome P450 (CYP) 3A4 within 2 weeks prior to baseline. Use of inducers of CYP3A4 within 2 weeks prior to baseline. Pregnancy or breastfeeding. Serum levels ≥3× upper limit of the normal range (ULN) of either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) at screening. Serum direct bilirubin which is ≥2×ULN at screening. Patients with a clinically significant or unstable medical or surgical condition that (in the opinion of the Investigator) would preclude safe and complete study participation, as determined by medical history, physical examinations, electrocardiogram (ECG), laboratory tests or chest X-ray. A known history of hypersensitivity to gadolinium (Gd). Glomerular filtration rate (GFR) < or equal 60 mL/min at screening visit. Inability to successfully undergo MRI scanning, including claustrophobia. Known drug hypersensitivity that would preclude administration of laquinimod, such as hypersensitivity to mannitol, meglumine or sodium stearyl fumarate.

Ages Eligible for Study
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Minimum Age: 25 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>once daily oral dose | Drug: Placebo<br>* Placebo<br>|
| Experimental: Laquinimod 0.6 mg<br>1 capsule containing 0.6 mg laquinimod and 2 capsules containing placebo were administered orally once daily for at least 48 weeks. | Drug: Laquinimod<br>* Laquinimod capsules in 0.5 mg and 0.6 mg strengths<br>* Other names: TV-5600;Drug: Placebo<br>* Placebo capsules<br>|
| Experimental: Laquinimod 1.5 mg<br>3 capsules containing 0.5 mg laquinimod were administered orally once daily for at least 48 weeks. However this arm was discontinued as of 01 January 2016 and no participants reached the 48 week timeframe. | Drug: Laquinimod<br>* Laquinimod capsules in 0.5 mg and 0.6 mg strengths<br>* Other names: TV-5600;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Brain Volume Change (PBVC) From Baseline to Week 48 Using a Repeated Measures ANCOVA Model | Brain atrophy (BA) was measured using magnetic resonance imaging (MRI) scans of the brain. BA was analyzed using baseline-adjusted repeated measures analysis of covariance (ANCOVA- SAS® PROC MIXED) in which 1 contrast was constructed in order to compare between laquinimod 0.6 mg and placebo. The statistical model was a repeated measures analysis of covariance with treatment group, week, treatment group by week interaction, normalized brain volume at baseline, natural logarithm of T2 lesion volume at baseline, and country as fixed effects. Only on-treatment observations (include all the assessments done up to one month after the last dose of the study drug) were included. Values are adjusted means. The cancelled laquinimod 1.5 mg treatment arm was not included in the repeated measures ANCOVA model analysis. However PBVC by visit data are offered in outcome #2. | Baseline (at least 14 days but not more than 6 weeks prior to Day 1), Weeks 24, 48 and including early termination visits | 
| Percent Brain Volume Change (PBVC) From Baseline to Weeks 24 and 48 | Brain atrophy (BA) was measured using magnetic resonance imaging (MRI) scans of the brain. Early termination scans of participants who discontinued the study after week 36 are considered scans at week 48. | Baseline (at least 14 days but not more than 6 weeks prior to Day 1), Weeks 24, 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With 12-Week Confirmed Disability Progression (CDP) As Measured by Expanded Disability Status Scale (EDSS) up to Week 48 | CDP was defined as increase in EDSS of >=1 point from baseline EDSS, if EDSS at entry is ≤5.0 or increase of >=0.5 point, if EDSS at entry is >=5.5. This increase should be confirmed after at least 12 weeks. Progression cannot be confirmed during a protocol defined relapse. EDSS is a method of quantifying disability in multiple sclerosis and monitoring changes in the level of disability over time. The EDSS scale ranges from 0 to 10 in 0.5 unit increments with 0=no disability and 10=death due to MS. Only an Examining Neurologist administered the EDSS. The Examining Neurologist did not have access to the patient's medical records or source documents, including previous EDSS forms or adverse events. If a patient died due to MS disease progression, the patient was analyzed as having CDP with the time to CDP as the onset date of progression. If a patient died due to MS before having progression, then the time to disability progression was censored using the date of death. | Baseline (Week 0), Weeks 12, 24, 36, 48 (end if treatment if < 48 weeks) | 
| Percentage of Participants With 12-Week Confirmed Disability Progression (CDP) As Measured by Expanded Disability Status Scale (EDSS) or the Timed 25-foot Walk (T25FW) Test up to Week 48 | CDP was defined as increase in EDSS of >=1 point from baseline EDSS, if EDSS at entry is ≤5.0 or increase of >=0.5 point, if EDSS at entry is >=5.5 confirmed after at least 12 weeks, OR increase of >= 20% from baseline in the T25FW test, confirmed after at least 12 weeks. EDSS quantifies disability in MS and monitors changes in the level of disability over time. The EDSS scale is 0-10 in 0.5 unit increments with 0=no disability and 10=death due to MS. The T25-FW is a quantitative mobility and leg function performance test based on the average time of two trials in which participants walk 25 feet as quickly as possible. Increasing time scores indicate increasing impairment. If a patient died due to MS disease progression, the patient was analyzed as having CDP with the time to CDP as the onset date of progression. If a patient died due to MS before having progression, then the time to disability progression was censored using the date of death. | Baseline (Week 0), Weeks 12, 24, 36, 48 (end if treatment if < 48 weeks) | 
| Change From Baseline for the Timed 25-foot Walk (T25FW) Score at Weeks 12, 24, 36 and 48 | The T25FW is a quantitative mobility and leg function performance test based on the average time of two trials in which participants walk 25 feet as quickly as possible. In cases when a patient could not complete a T25FW trial due to the physical limitations, a value of 180 seconds was assigned for that trial (this is the maximal possible value for the T25FW test). Increasing time scores indicate increasing impairment. Baseline values are summaries of observed values. Week values are change from baseline values. | Baseline (Week 0), Weeks 12, 24, 36, 48 | 
| Number of New T2 Brain Lesions at Week 48 | Inflammatory disease activity was assessed by magnetic resonance imaging (MRI) measurement of the number of new T2 lesions at week 48 as compared to baseline. Scans of patients who discontinued the study after week 36 are considered scans at week 48, and are included in week 48. | Baseline (Week 0), 48 weeks | 
| Participants With Treatment-Emergent Adverse Events (TEAEs) | An adverse event (AE) was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents usual activities. Relationship of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes. | Day 1 up to Week 130 (longest duration of treatment) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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multiple sclerosis, primary progressive multiple sclerosis, oral immunomodulator