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

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ClinicalTrials.gov Identifier: NCT01707992
Recruitment Status : Completed
First Posted : October 16, 2012
Results First Posted : March 13, 2019
Last Update Posted : March 13, 2019
Sponsor:
Information provided by (Responsible Party):
Teva Pharmaceutical Industries ( Teva Branded Pharmaceutical Products, R&D Inc. )

Tracking Information
First Submitted Date  ICMJE September 28, 2012
First Posted Date  ICMJE October 16, 2012
Results First Submitted Date  ICMJE February 20, 2019
Results First Posted Date  ICMJE March 13, 2019
Last Update Posted Date March 13, 2019
Actual Study Start Date  ICMJE February 20, 2013
Actual Primary Completion Date April 13, 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 20, 2019)
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 Frame: Baseline to Month 24 ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: October 15, 2012)
Time to Confirmed Disease Progression (CDP) in Period 1 [ Time Frame: 24 months (Period 1) ]
CDP is defined as an increase in Kurtzke's Expanded Disability Status Scale (EDSS) of 1 point or more from baseline for subjects with baseline EDSS of ≤5.0, or an increase 0.5 points or more from baseline for subjects with baseline EDSS of 5.5. The EDSS rates a person's disability due to multiple sclerosis severity, ranging from 0 (normal neurological exam) to 10 (death due to MS). The higher score represents more severe disability. The outcome measure is the time recorded from Baseline until the subject meets this definition of CDP.
Change History Complete list of historical versions of study NCT01707992 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 20, 2019)
  • Placebo-Controlled Phase: Percent Change From Baseline in Brain Volume at Month 15 [ Time Frame: Baseline, 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.
  • Placebo-Controlled Phase: Time to First Confirmed Relapse (Number of Participants With Confirmed Relapse) [ Time Frame: Baseline to Month 24 ]
    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).
  • Placebo-Controlled Phase: Time to CDP Confirmed After At Least 6 Months (Number of Participants With CDP After At Least 6 Months) [ Time Frame: Baseline to Month 24 ]
    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.
  • Placebo-Controlled Phase: Time to CDP Confirmed After At Least 9 Months (Number of Participants With Confirmed Relapse After At Least 9 Months) [ Time Frame: Baseline to Month 24 ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 15, 2012)
Percent change in brain volume [ Time Frame: Change from Baseline to 15 Months ]
This is a measure of brain volume and will be assessed by an MRI. Brain atrophy is defined as the percent change in brain volume from baseline to month 15
Current Other Pre-specified Outcome Measures
 (submitted: February 20, 2019)
  • Placebo-Controlled Phase: Number of Participants With Adverse Events (AEs) [ Time Frame: Baseline up to Month 24 ]
    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs.
  • Active-Treatment Phase: Number of Participants With AEs [ Time Frame: Baseline (Month 0 of active-treatment phase/Month 24 of placebo-controlled phase) up to Month 24 of active-treatment phase ]
    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs.
  • Placebo-Controlled Phase: Number of Participants With Clinically Significant Vital Signs Abnormalities [ Time Frame: Baseline up to Week 24 ]
    Clinically significant vital signs abnormalities included: Pulse rate: greater than or equal to (>=) 120 beats per minute (bpm) and increase from baseline of >=30 bpm, <=45 bpm and decrease from baseline of >=30 bpm; Systolic blood pressure: >=180 millimeters of mercury (mmHg) and increase from baseline of >=30 mmHg, <=90 and decrease from baseline of >=30 mmHg; Diastolic blood pressure: >=100 mmHg and increase from baseline of >=20 mmHg, <=50 mmHg and decrease from baseline of >=20 mmHg.
  • Active-Treatment Phase: Number of Participants With Clinically Significant Vital Signs Abnormalities [ Time Frame: Baseline (Month 0 of active-treatment phase/Month 24 of placebo-controlled phase) up to Month 24 of active-treatment phase ]
    Clinically significant vital signs abnormalities included: Pulse rate: >=120 bpm and increase from baseline of >=30 bpm, <=45 bpm and decrease from baseline of >=30 bpm; Systolic blood pressure: >=180 mmHg and increase from baseline of >=30 mmHg, <=90 and decrease from baseline of >=30 mmHg; Diastolic blood pressure: >=100 mmHg and increase from baseline of >=20 mmHg, <=50 mmHg and decrease from baseline of >=20 mmHg.
  • Placebo-Controlled Phase: Number of Participants With Shift From Baseline to Endpoint in Electrocardiogram (ECG) Parameters [ Time Frame: Baseline, Endpoint (Month 24) ]
    ECG parameters included: PR interval, QRS interval, QT interval corrected using the Fridericia formula (QTcF) and QT interval corrected using the Bazett's formula (QTcB). Shifts represented as Baseline - endpoint value (last observed post-baseline value). Abnormal NCS indicated an abnormal but not clinically significant finding. Abnormal CS indicated an abnormal and clinically significant finding.
  • Active Treatment Phase: Number of Participants With Shift From Baseline to Endpoint in ECG Parameters [ Time Frame: Baseline (Month 0 of active-treatment phase/Month 24 of placebo-controlled phase), endpoint (Month 24 of active-treatment phase) ]
    ECG parameters included: PR interval, QRS interval, QTcF and QTcB. Shifts represented as Baseline - endpoint value (last observed post-baseline value). Abnormal NCS indicated an abnormal but not clinically significant finding. Abnormal CS indicated an abnormal and clinically significant finding.
  • Placebo-Controlled Phase: Number of Participants With Potentially Clinically Significant Abnormal Serum Chemistry [ Time Frame: Baseline up to Month 24 ]
    Potentially clinically significant serum chemistry abnormalities included: Glucose <=3 and >=13.88 millimoles per liter (mmol/L); Alanine aminotransferase (ALT) (in units per liter [U/L]), aspartate aminotransferase (AST) (in U/L), alkaline phosphatase (in U/L), gamma-glutamyltransferase (GGT) (in U/L), creatine phosphokinase (CPK) (in U/L), C-reactive protein (CRP) (in milligrams per liter [mg/L]), pancreatic amylase (in U/L)>=3 * upper limit of normal (ULN); Fibrinogen >=6 grams per liter (gm/L); Sodium <=130 and >=150 mmol/L; Potassium <=3.2 and >=5.5 mmol/L; Calcium <=1.87 and >=2.75 mmol/L; Phosphate <=0.65 and >=1.61 mmol/L.
  • Active Treatment Phase: Number of Participants With Potentially Clinically Significant Abnormal Serum Chemistry [ Time Frame: Baseline (Month 0 of active-treatment phase/Month 24 of placebo-controlled phase) up to Month 24 of active-treatment phase ]
    Potentially clinically significant serum chemistry abnormalities included: Glucose <=3 and >=13.88 mmol/L; ALT (in U/L), AST (in U/L), alkaline phosphatase (in U/L), GGT (in U/L), CPK (in U/L), CRP (in mg/L), pancreatic amylase (in U/L)>=3 * ULN; Fibrinogen >=6 gm/L; Sodium <=130 and >=150 mmol/L; Potassium <=3.2 and >=5.5 mmol/L; Calcium <=1.87 and >=2.75 mmol/L; Phosphate <=0.65 and >=1.61 mmol/L; Blood urea nitrogen (in mmol/L); Total bilirubin >=28 micromols per liter (micromols/L); Creatinine >=117 micromols/L; Albumin <=25 gm/L.
  • Placebo-Controlled Phase: Number of Participants With Potentially Clinically Significant Abnormal Hematology Values [ Time Frame: Baseline up to Month 24 ]
    Potentially clinically significant hematological abnormalities included: Hemoglobin <=11.5 grams per deciliter (gm/dL) in males and <=10 gm/dL in females; White blood cells (WBCs) count <=2.5 and >=21*10^9 per liter (L); Absolute neutrophil count (ANC) <=1.49*10^9 per L; Platelet count <=100 and >=600*10^9 per L.
  • Active Treatment Phase: Number of Participants With Potentially Clinically Significant Abnormal Hematology Values [ Time Frame: Baseline (Month 0 of active-treatment phase/Month 24 of placebo-controlled phase) up to Month 24 of active-treatment phase ]
    Potentially clinically significant hematological abnormalities included: Hemoglobin <=11.5, >=20 gm/dL in males, and <=10, >=18.5 gm/dL in females; WBCs count <=2.5 and >=21*10^9 per L; ANC <=1.49*10^9 per L; Platelet count <=100 and >=600*10^9 per L.
Original Other Pre-specified Outcome Measures
 (submitted: October 15, 2012)
  • Number of Participants with Adverse Events [ Time Frame: 24 months (Period 1) ]
  • Number of Participants with Abnormal Vital Signs [ Time Frame: 24 months (Period 1) ]
  • Number of Participants with Abnormal ECG Findings [ Time Frame: 24 months (Period 1) ]
  • Number of Participants with Abnormal Clinical Laboratory Parameters [ Time Frame: 24 months (Period 1) ]
 
Descriptive Information
Brief Title  ICMJE The Efficacy, Safety, and Tolerability of Laquinimod in Participants With Relapsing Remitting Multiple Sclerosis (RRMS)
Official Title  ICMJE 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)
Brief Summary 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).
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Multiple Sclerosis
Intervention  ICMJE
  • Drug: Laquinimod
    Laquinimod will be administered as per the dose and schedule specified in the respective arms.
  • Drug: Placebo
    Placebo matching to laquinimod will be administered as per the schedule specified in the respective arms.
Study Arms  ICMJE
  • Placebo Comparator: Placebo-Controlled Phase: Placebo
    Participants will receive 2 capsules of placebo (matching to laquinimod 0.6 milligrams [mg]) once daily orally for up to 24 months.
    Intervention: Drug: Placebo
  • Experimental: Placebo-Controlled Phase: Laquinimod 0.6 mg
    Participants will receive 1 capsule of laquinimod 0.6 mg and 1 capsule of matching placebo once daily orally for up to 24 months.
    Interventions:
    • Drug: Laquinimod
    • Drug: Placebo
  • Experimental: Placebo-Controlled Phase: Laquinimod 1.2 mg
    Participants will receive laquinimod 1.2 mg (2 capsules of laquinimod 0.6 mg each) once daily orally for up to 24 months.
    Intervention: Drug: Laquinimod
  • Experimental: Active Treatment Phase: Laquinimod 0.6 mg
    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.
    Interventions:
    • Drug: Laquinimod
    • Drug: Placebo
  • Experimental: Active Treatment Phase: Laquinimod 1.2 mg
    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.
    Intervention: Drug: Laquinimod
  • No Intervention: Active Treatment Phase: Off Drug
    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.
Publications * Not Provided

*   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: July 2, 2015)
2199
Original Estimated Enrollment  ICMJE
 (submitted: October 15, 2012)
1800
Actual Study Completion Date  ICMJE July 4, 2017
Actual Primary Completion Date April 13, 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 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 Austria,   Belarus,   Belgium,   Bosnia and Herzegovina,   Bulgaria,   Canada,   Croatia,   Czechia,   Estonia,   France,   Georgia,   Germany,   Greece,   Hungary,   Israel,   Italy,   Korea, Republic of,   Latvia,   Macedonia, The Former Yugoslav Republic of,   Moldova, Republic of,   Montenegro,   Poland,   Romania,   Russian Federation,   Serbia,   Slovakia,   Spain,   Ukraine,   United Kingdom,   United States
Removed Location Countries Czech Republic,   Kazakhstan,   Mexico,   Portugal
 
Administrative Information
NCT Number  ICMJE NCT01707992
Other Study ID Numbers  ICMJE LAQ-MS-305
2012-003647-30 ( 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 February 2019

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