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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 (ARPEGGIO)

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ClinicalTrials.gov Identifier: NCT02284568
Recruitment Status : Completed
First Posted : November 6, 2014
Results First Posted : November 2, 2018
Last Update Posted : November 2, 2018
Sponsor:
Information provided by (Responsible Party):
Teva Pharmaceutical Industries ( Teva Branded Pharmaceutical Products R&D, Inc. )

Tracking Information
First Submitted Date  ICMJE October 31, 2014
First Posted Date  ICMJE November 6, 2014
Results First Submitted Date  ICMJE August 16, 2018
Results First Posted Date  ICMJE November 2, 2018
Last Update Posted Date November 2, 2018
Actual Study Start Date  ICMJE January 12, 2015
Actual Primary Completion Date May 4, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 2, 2018)
  • Percent Brain Volume Change (PBVC) From Baseline to Week 48 Using a Repeated Measures ANCOVA Model [ Time Frame: Baseline (at least 14 days but not more than 6 weeks prior to Day 1), Weeks 24, 48 and including early termination visits ]
    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.
  • Percent Brain Volume Change (PBVC) From Baseline to Weeks 24 and 48 [ Time Frame: Baseline (at least 14 days but not more than 6 weeks prior to Day 1), Weeks 24, 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.
Original Primary Outcome Measures  ICMJE
 (submitted: November 3, 2014)
Percent brain volume change (PBVC) [ Time Frame: 48 weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 2, 2018)
  • Percentage of Participants With 12-Week Confirmed Disability Progression (CDP) As Measured by Expanded Disability Status Scale (EDSS) up to Week 48 [ Time Frame: Baseline (Week 0), Weeks 12, 24, 36, 48 (end if treatment if < 48 weeks) ]
    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.
  • 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 [ Time Frame: Baseline (Week 0), Weeks 12, 24, 36, 48 (end if treatment if < 48 weeks) ]
    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.
  • Change From Baseline for the Timed 25-foot Walk (T25FW) Score at Weeks 12, 24, 36 and 48 [ Time Frame: Baseline (Week 0), Weeks 12, 24, 36, 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.
  • Number of New T2 Brain Lesions at Week 48 [ Time Frame: Baseline (Week 0), 48 weeks ]
    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.
  • Participants With Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: Day 1 up to Week 130 (longest duration of treatment) ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 3, 2014)
  • Time to confirmed disability progression (CDP) [ Time Frame: 48 weeks ]
    Time to event
  • Number of new T2 brain lesions [ Time Frame: 48 weeks ]
  • Change in the Brief International Cognitive Assessment for Multiple Sclerosis score (BICAMS) [ Time Frame: 48 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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
Official Title  ICMJE 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)
Brief Summary 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

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
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Primary Progressive Multiple Sclerosis
Intervention  ICMJE
  • Drug: Placebo
    Placebo
  • Drug: Laquinimod
    Laquinimod capsules in 0.5 mg and 0.6 mg strengths
    Other Name: TV-5600
  • Drug: Placebo
    Placebo capsules
Study Arms  ICMJE
  • Placebo Comparator: Placebo
    once daily oral dose
    Intervention: Drug: Placebo
  • Experimental: Laquinimod 0.6 mg
    1 capsule containing 0.6 mg laquinimod and 2 capsules containing placebo were administered orally once daily for at least 48 weeks.
    Interventions:
    • Drug: Laquinimod
    • Drug: Placebo
  • Experimental: Laquinimod 1.5 mg
    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.
    Intervention: Drug: Laquinimod
Publications * Giovannoni G, Knappertz V, Steinerman JR, Tansy AP, Li T, Krieger S, Uccelli A, Uitdehaag BMJ, Montalban X, Hartung HP, Pia Sormani M, Cree BAC, Lublin F, Barkhof F. A randomized, placebo-controlled, phase 2 trial of laquinimod in primary progressive multiple sclerosis. Neurology. 2020 Aug 25;95(8):e1027-e1040. doi: 10.1212/WNL.0000000000010284. Epub 2020 Jul 10.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: October 7, 2016)
374
Original Estimated Enrollment  ICMJE
 (submitted: November 3, 2014)
375
Actual Study Completion Date  ICMJE October 1, 2017
Actual Primary Completion Date May 4, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Patients must have a confirmed and documented PPMS diagnosis as defined by the 2010 Revised McDonald criteria
  2. Baseline magnetic resonance imaging (MRI) showing lesions consistent with PPMS in either or both brain and spinal cord
  3. Patients must have an Expanded Disability Status Scale (EDSS) score of 3 to 6.5, inclusive, at both screening and baseline visits
  4. Documented evidence of clinical disability progression in the 2 years prior to screening.
  5. Functional System Score (FSS) of > or equal 2 for the pyramidal system or gait impairment due to lower extremity dysfunction
  6. Patients must be between 25 to 55 years of age, inclusive
  7. 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.
  8. Patients must sign and date a written informed consent prior to entering the study.
  9. Patients must be willing and able to comply with the protocol requirements for the duration of the study.

Exclusion Criteria:

  1. Patients with history of any multiple sclerosis (MS) exacerbations or relapses, including any episodes of optic neuritis.
  2. Progressive neurological disorder other than PPMS.
  3. Any MRI record showing presence of cervical cord compression.
  4. Baseline MRI showing other findings (including lesions that are atypical for PPMS) that may explain the clinical signs and symptoms.
  5. Relevant history of vitamin B12 deficiency.
  6. Positive human T-lymphotropic virus Type I and II (HTLV-I/II) serology.
  7. 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.
  8. Use of immunosuppressive agents, or cytotoxic agents, including cyclophosphamide and azathioprine within 48 weeks prior to baseline.
  9. 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.
  10. 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.
  11. Prior use of monoclonal antibodies ever, except for:

    1. 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)
    2. rituximab, ocrelizumab, or ofatumumab, if B cell count (CD19, as per medical history) is higher than 80 cells/μL
  12. 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.
  13. Previous use of laquinimod.
  14. 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.
  15. Previous use of cladribine or alemtuzumab (LEMTRADA®, Sanofi).
  16. Previous total body irradiation or total lymphoid irradiation.
  17. Previous stem cell treatment, cell-based treatment, or bone marrow transplantation of any kind.
  18. Patients who underwent endovascular treatment for chronic cerebrospinal venous insufficiency (CCSVI) within 12 weeks prior to baseline.
  19. Use of moderate/strong inhibitors of cytochrome P450 (CYP) 3A4 within 2 weeks prior to baseline.
  20. Use of inducers of CYP3A4 within 2 weeks prior to baseline.
  21. Pregnancy or breastfeeding.
  22. Serum levels ≥3× upper limit of the normal range (ULN) of either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) at screening.
  23. Serum direct bilirubin which is ≥2×ULN at screening.
  24. 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.
  25. A known history of hypersensitivity to gadolinium (Gd).
  26. Glomerular filtration rate (GFR) < or equal 60 mL/min at screening visit.
  27. Inability to successfully undergo MRI scanning, including claustrophobia.
  28. Known drug hypersensitivity that would preclude administration of laquinimod, such as hypersensitivity to mannitol, meglumine or sodium stearyl fumarate.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 25 Years to 55 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   Germany,   Italy,   Netherlands,   Poland,   Russian Federation,   Spain,   Ukraine,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02284568
Other Study ID Numbers  ICMJE TV5600-CNS-20006
2014-001579-30 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Teva Pharmaceutical Industries ( Teva Branded Pharmaceutical Products R&D, Inc. )
Study Sponsor  ICMJE Teva Branded Pharmaceutical Products R&D, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Teva Medical Expert, MD Teva Pharmaceuticals USA
PRS Account Teva Pharmaceutical Industries
Verification Date October 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP