An Extension Study of LAQ/5062 Exploring the Long Term Safety, Tolerability and Clinical Effect Parameters During the Disease

An Active Extension of LAQ/5062 Study. A Multinational, Multicenter, Randomized, Double-Blind, Parallel-Group Study to Evaluate the Safety, Tolerability and Efficacy of Two Doses (0.3 mg and 0.6 mg) of Laquinimod, Orally Administered in Relapsing Remitting (R-R) Multiple Sclerosis (MS) Subjects (Study LAQ/5063 Active Double-Blind Phase) Followed by an Open Label Phase of Laquinimod 0.6 mg Daily (LAQ/5063 OL)

This is a multinational, multicenter, randomized, double-blind, parallel-group active extension of LAQ/5062 study (NCT00349193), assessing the tolerability, safety and efficacy of two doses (0.3 mg and 0.6 mg) of laquinimod, orally administered in participants with relapsing remitting multiple sclerosis (RRMS), followed by an open-label phase of laquinimod 0.6 mg daily. This study is LAQ/5063 (i.e., double-blind extension) and LAQ/5063 OL (i.e., subsequent open-label extension). - The first period of the extension study is an active, double-blind period. Participants from the active treatment arms in LAQ/5062 continue their assigned treatment in blinded fashion. Participants who were assigned to placebo treatment in LAQ/5062 are equally randomized in blinded-fashion to laquinimod 0.6 mg or laquinimod 0.3 mg. - Once termination visit of LAQ/5063 active double-blind phase (completion of the full 36 weeks or as requested by the Sponsor) is performed, all participants continue on laquinimod 0.6 mg daily as an open-label intervention. The open-label period continues as long as the Sponsor continues the development of laquinimod 0.6 mg for RRMS or early discontinuation.

Study Overview

• Status: Terminated
• Conditions: Relapsing Remitting Multiple Sclerosis
• Intervention / Treatment: Drug: Laquinimod; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 257
• Phase: Phase 2

Contacts and Locations

Study Locations

• Czechia
  • Hradec Kralove 3, Czechia
    • Teva Investigational Site 382
  • Praha 2, Czechia
    • Teva Investigational Site 380
  • Praha 5- Motol, Czechia
    • Teva Investigational Site 384
• Germany
  • Berlin, Germany
    • Teva Investigational Site 681
  • Erfurt, Germany
    • Teva Investigational Site 684
  • Hamburg, Germany
    • Teva Investigational Site 687
  • Mainz, Germany
    • Teva Investigational Site 683
  • Ulm, Germany
    • Teva Investigational Site 686
  • Wuerzburg, Germany
    • Teva Investigational Site 685
• Hungary
  • Debrecen, Hungary
    • Teva Investigational Site 580
  • Gyula, Hungary
    • Teva Investigational Site 581
  • Miskolc, Hungary
    • Teva Investigational Site 583
  • Veszprem, Hungary
    • Teva Investigational Site 584
• Israel
  • Haifa, Israel
    • Teva Investigational Site 982
  • Jerusalem, Israel
    • Teva Investigational Site 980
  • IL
    • Ramat -Gan, IL, Israel
      • Teva Investigational Site 981
• Italy
  • Cagliari, Italy
    • Teva Investigational Site 483
  • Milano, Italy
    • Teva Investigational Site 484
  • Milano, Italy
    • Teva Investigational Site 486
  • Siena, Italy
    • Teva Investigational Site 488
• Poland
  • Bydgoszcz, Poland
    • Teva Investigational Site 281
  • Katowice, Poland
    • Teva Investigational Site 280
  • Katowice, Poland
    • Teva Investigational Site 285
  • Lodz, Poland
    • Teva Investigational Site 283
  • Lublin, Poland
    • Teva Investigational Site 284
  • Wroclaw, Poland
    • Teva Investigational Site 282
• Russian Federation
  • Moscow, Russian Federation
    • Teva Investigational Site 186
  • Moscow, Russian Federation
    • Teva Investigational Site 187
  • Moscow, Russian Federation
    • Teva Investigational Site 188
  • Moscow, Russian Federation
    • Teva Investigational Site 189
  • Saint Petersburg, Russian Federation
    • Teva Investigational Site 180
  • St. Petersburg, Russian Federation
    • Teva Investigational Site 181
  • St. Petersburg, Russian Federation
    • Teva Investigational Site 182
  • St. Petersburg, Russian Federation
    • Teva Investigational Site 184
  • St. Petersburg, Russian Federation
    • Teva Investigational Site 185
• Spain
  • Barakaldo, Spain
    • Teva Investigational Site 782
  • Barcelona, Spain
    • Teva Investigational Site 785
  • Bilbao, Spain
    • Teva Investigational Site 781
  • L'Hospitalet de Llobregat, Spain
    • Teva Investigational Site 784
  • Madrid, Spain
    • Teva Investigational Site 780
  • Sevilla, Spain
    • Teva Investigational Site 783
• United Kingdom
  • Liverpool, United Kingdom
    • Teva Investigational Site 884
  • London, United Kingdom
    • Teva Investigational Site 882
  • Sheffield, United Kingdom
    • Teva Investigational Site 881
  • Stoke on Trent, United Kingdom
    • Teva Investigational Site 883

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria - Participants must have completed the 36 weeks of treatment (completion of the full 36 weeks or as requested by the Sponsor) of the active double-blind phase. - Women of childbearing potential (for example, women who were not postmenopausal or surgically sterilized) must have practiced 2 acceptable methods of birth control for the duration of the study and until 30 days after the last dose of study medication (acceptable methods of birth control in this open-label extension phase included intrauterine devices, barrier methods [condom or diaphragm with spermicide], and hormonal methods of birth control [for example, oral contraceptive, contraceptive patch, and long-acting injectable contraceptive]). - Participants must have been willing and able to comply with the protocol requirements for the duration of LAQ/5063 OL. - Participants must have given signed, written informed consent prior to entering LAQ/5063 OL. - For the 36 months further extension: Participants must have completed the 24 months of treatment of the first period of the open label phase. Exclusion Criteria - For the 36 month further extension: Premature discontinuation from LAQ/5063 OL phase prior to completion of 24 months of treatment period. - Pregnancy or breastfeeding. - Participants with clinically significant or unstable medical or surgical condition, detected or worsened during the active double-blind phase of LAQ/5063, which would have precluded safe and complete study participation. - Use of experimental drugs, immunosuppressive drugs, and/or participation in clinical studies within the period from termination of LAQ/5063 active double-blind phase to LAQ/5063 OL. - Previous treatment with immunomodulators with the exception of laquinimod (including interferon [IFN] 1a and 1b, glatiramer acetate, and intravenous [IV] immunoglobulin) within 2 months prior to entering the open-label phase for those subjects who had a time gap between termination of LAQ/5063 active double-blind phase to LAQ/5063 OL. - Use of corticosteroids within 30 days prior to entering the open-label phase, except for IV methylprednisolone 1 grams/day for a maximum of 3 days, in the period from termination of LAQ/5063 active double-blind phase to LAQ/5063 OL. - Use of potent inhibitors of cytochrome P3A4 (CYP3A4) within 2 weeks prior to LAQ/5063 OL and/or use of fluoxetine 1 month prior to entering LAQ/5063 OL, in the period from termination of LAQ/5063 active double-blind phase to LAQ/5063 OL. - Use of the following substrates of cytochrome P1A2 (CYP1A2): theophylline and/or warfarin within 2 weeks prior to entering LAQ/5063 OL, in the period from termination of LAQ/5063 active double-blind phase to LAQ/5063 OL. - Use of amiodarone in the period from termination of LAQ/5063 active double-blind phase to LAQ/5063 OL. - Following the switch to new formulation (capsules), hypersensitivity to mannitol, meglumine, or sodium stearyl fumarate.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Double-Blind: Laquinimod 0.3 mg; Participants who will be receiving laquinimod 0.3 milligram (mg) tablet once daily orally in double-blind core study, will continue to receive laquinimod 0.3 mg tablet once daily orally in double-blind extension period of this study for up to Week 36.	Drug: Laquinimod; Laquinimod tablets/capsules will be administered as per the dose and schedule specified in the respective arms.; Other Names: TV-5600
Experimental: Double-Blind: Laquinimod 0.6 mg; Participants who will be receiving laquinimod 0.6 mg (2 tablets of 0.3 mg each) once daily orally in double-blind core study, will continue to receive laquinimod 0.6 mg once daily orally in double-blind extension period of this study for up to Week 36.	Drug: Laquinimod; Laquinimod tablets/capsules will be administered as per the dose and schedule specified in the respective arms.; Other Names: TV-5600
Experimental: Double-Blind: Placebo/Laquinimod 0.3 mg; Participants who will be receiving placebo matching to laquinimod 0.3 mg tablet once daily orally in double-blind core study, will receive laquinimod 0.3 mg tablet once daily orally in double-blind extension period of this study for up to Week 36.	Drug: Laquinimod; Laquinimod tablets/capsules will be administered as per the dose and schedule specified in the respective arms.; Other Names: TV-5600; Drug: Placebo; Placebo matching to laquinimod will be administered as per the dose and schedule specified in the respective arms.
Experimental: Double-Blind: Placebo/Laquinimod 0.6 mg; Participants who will be receiving placebo matching to laquinimod 0.6 mg (2 tablets of placebo) once daily orally in double-blind core study, will receive laquinimod 0.6 mg once daily orally in double-blind extension period of this study for up to Week 36.	Drug: Laquinimod; Laquinimod tablets/capsules will be administered as per the dose and schedule specified in the respective arms.; Other Names: TV-5600; Drug: Placebo; Placebo matching to laquinimod will be administered as per the dose and schedule specified in the respective arms.
Experimental: Open-Label: Laquinimod 0.3 mg/Laquinimod 0.6 mg; Participants who will be receiving laquinimod 0.3 mg tablet once daily orally either in double-blind core study or double-blind extension period, will receive laquinimod 0.6 mg capsule once daily orally in open-label extension period of this study until termination (as long as the Sponsor will continue the development of laquinimod 0.6 mg for RRMS) or early discontinuation (up to approximately 10.5 years).	Drug: Laquinimod; Laquinimod tablets/capsules will be administered as per the dose and schedule specified in the respective arms.; Other Names: TV-5600
Experimental: Open Label: Laquinimod 0.6 mg; Participants who will be receiving laquinimod 0.6 mg (2 tablets of 0.3 mg each) once daily orally either in double-blind core study or double-blind extension period, will receive laquinimod 0.6 mg capsule once daily orally in open-label extension period of this study until termination (as long as the Sponsor will continue the development of laquinimod 0.6 mg for RRMS) or early discontinuation (up to approximately 10.5 years).	Drug: Laquinimod; Laquinimod tablets/capsules will be administered as per the dose and schedule specified in the respective arms.; Other Names: TV-5600

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Double-Blind Extension Period: Number of Participants With Adverse Events (AEs)	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. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'.	Baseline (Week 0) to Week 36
Open-label Extension Period: Number of Participants With AEs	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An 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. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'.	Baseline (Month 0/termination visit of double-blind extension phase [completion of full 36 weeks] until termination (as long as the Sponsor continued the development of laquinimod 0.6 mg for RRMS) or early discontinuation (up to approximately 10.5 years)
Double-Blind Period: Number of Participants Who Prematurely Discontinued From the Study Due to Any Reason and Due to AEs	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An 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.	Baseline (Week 0) to Week 36
Open-Label Period: Number of Participants Who Prematurely Discontinued From the Study Due to Any Reason and Due to AEs	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An 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.	Baseline (Month 0/termination visit of double-blind extension phase [completion of full 36 weeks] until termination (as long as the Sponsor continued the development of laquinimod 0.6 mg for RRMS) or early discontinuation (up to approximately 10.5 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Double-Blind Period: Relapse Rate: Total Number of Confirmed Relapses	Relapse was defined as the appearance of one or more new neurological abnormalities or the reappearance of one or more previously observed neurological abnormalities, lasting for at least 48 hours (in the 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 the Expanded disability status scale (EDSS); or one grade in the score of 2 or more of the 7 Functional Systems (FS) (excluding changes in bowel or bladder function or cognition); or 2 grades in the score of one of the FS as compared to the previous evaluation. EDSS assesses disability in 8 functional systems with an overall score ranging from 0 (normal) to 10 (death due to multiple sclerosis [MS]).	Baseline (Week 0) up to end of active double-blind phase or termination/early termination visit (up to Week 36)
Double-Blind Period: Percentage of Relapse-Free Participants	Relapse was defined as the appearance of one or more new neurological abnormalities or the reappearance of one or more previously observed neurological abnormalities, lasting for at least 48 hours (in the 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 the EDSS; or one grade in the score of 2 or more of the 7 FS (excluding changes in bowel or bladder function or cognition); or 2 grades in the score of one of the FS as compared to the previous evaluation. EDSS assesses disability in 8 functional systems with an overall score ranging from 0 (normal) to 10 (death due to MS).	Baseline (Week 0) up to end of active double-blind phase or termination/early termination visit (up to Week 36)
Double-Blind Period: Number of Enhancing Lesions on T1-Weighted Images	Inflammatory disease activity was assessed by magnetic resonance imaging (MRI) measurement of the number of gadolinium-enhanced T1 lesions. T1-weighted scan was taken after administration of gadolinium-gadopentetic acid (Gd-DTPA).	At the end of active double-blind phase or termination/early termination visit (up to Week 36)
Double-Blind Period: Number of New T2 Lesions	Inflammatory disease activity was assessed by MRI measurement of the number of new T2 lesions.	At the end of active double-blind phase or termination/early termination visit (up to Week 36)
Double-Blind Period: Volume of T2 Lesions	Volume of T2 lesion was assessed by magnetic MRI.	At the end of active double-blind phase or termination/early termination visit (up to Week 36)
Double-Blind Period: Number of New Hypointense T1 Lesion on Enhanced T1 Scans	Inflammatory disease activity was assessed by MRI measurement of the number of new hypointense T1 lesions.	At the end of active double-blind phase or termination/early termination visit (up to Week 36)
Double-Blind Period: Kurtzke's Expanded Disability Status Scale (EDSS) Score	EDSS (developed by John F. Kurtzke) is a scale for assessing disability in 8 functional systems (visual, brain stem, pyramidal, cerebellar, sensory, bowel and bladder, cerebral, and other functions). Each functional system score and an overall score ranges from 0 to 10, where 0 = Normal; 1-1.5 = No disability, but some abnormal neurological signs; 2-2.5 = Minimal disability; 3-4.5 = Moderate disability, affecting daily activities, but can still walk; 5-8 = More severe disability, impairing daily activities and requiring assistance with walking; 8.5-9.5 = Very severe disability, restricting to bed; 10 = Death due to MS. A lower score indicated less disability.	At the end of active double-blind phase or termination/early termination visit (up to Week 36)

Collaborators and Investigators

• Sponsor: Teva Pharmaceutical Industries, Ltd.
• Investigators: Principal Investigator: Giancarlo Comi, Instituto Scientifico Fondazione Centro S. Raffaele, Milan, Italy

Study record dates

Study Major Dates

• Study Start (Actual): December 7, 2005
• Primary Completion (Actual): July 23, 2017
• Study Completion (Actual): July 23, 2017

Study Registration Dates

• First Submitted: September 2, 2008
• First Submitted That Met QC Criteria: September 2, 2008
• First Posted (Estimate): September 3, 2008

Study Record Updates

• Last Update Posted (Actual): March 27, 2019
• Last Update Submitted That Met QC Criteria: March 4, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Multiple Sclerosis, Relapsing-Remitting
• Other Study ID Numbers: LAQ/5063OL; LAQ/5063 (Other Identifier: Sponsor ID); 2005-004334-41 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No