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

Primary Purpose

Relapsing Remitting Multiple Sclerosis

Status

Terminated

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Laquinimod

Placebo

About this trial

This is an interventional treatment trial for Relapsing Remitting Multiple Sclerosis

Eligibility Criteria

18 Years - 50 Years (Adult)All SexesDoes not accept healthy volunteers

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.

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Arm Label

Double-Blind: Laquinimod 0.3 mg

Double-Blind: Laquinimod 0.6 mg

Double-Blind: Placebo/Laquinimod 0.3 mg

Double-Blind: Placebo/Laquinimod 0.6 mg

Open-Label: Laquinimod 0.3 mg/Laquinimod 0.6 mg

Open Label: Laquinimod 0.6 mg

Arm Description

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.

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.

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.

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.

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).

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).

Outcomes

Primary Outcome Measures

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'.

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'.

Double-Blind Period: Number of Participants Who Prematurely Discontinued From the Study Due to Any Reason and Due to AEs

Open-Label Period: Number of Participants Who Prematurely Discontinued From the Study Due to Any Reason and Due to AEs

Secondary Outcome Measures

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]).

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).

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).

Double-Blind Period: Number of New T2 Lesions

Inflammatory disease activity was assessed by MRI measurement of the number of new T2 lesions.

Double-Blind Period: Volume of T2 Lesions

Volume of T2 lesion was assessed by magnetic MRI.

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.

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.

Full Information

NCT ID

NCT00745615

First Posted

September 2, 2008

Last Updated

March 4, 2019

Sponsor

Teva Pharmaceutical Industries, Ltd.

1. Study Identification

Unique Protocol Identification Number

NCT00745615

Brief Title

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

Official Title

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)

Study Type

Interventional

2. Study Status

Record Verification Date

March 2019

Overall Recruitment Status

Terminated

Why Stopped

Sponsor terminated RRMS studies as sufficient long term clinical data was collected for the study drug in the relevant dose.

Study Start Date

December 7, 2005 (Actual)

Primary Completion Date

July 23, 2017 (Actual)

Study Completion Date

July 23, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Teva Pharmaceutical Industries, Ltd.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Relapsing Remitting Multiple Sclerosis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Masking Description

Blinding performed by interactive voice response system (IVRS) and relevant only to the first period of the extension. General medical evaluations will be assessed separately from neurological assessment evaluations by two different neurologists/ physicians. Magnetic resonance imaging (MRI) scan evaluation will be performed at a central reading center by staff that does not have access to the clinical data.

Allocation

Randomized

Enrollment

257 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Double-Blind: Laquinimod 0.3 mg

Arm Type

Experimental

Arm Description

Arm Title

Double-Blind: Laquinimod 0.6 mg

Arm Type

Experimental

Arm Description

Arm Title

Double-Blind: Placebo/Laquinimod 0.3 mg

Arm Type

Experimental

Arm Description

Arm Title

Double-Blind: Placebo/Laquinimod 0.6 mg

Arm Type

Experimental

Arm Description

Arm Title

Open-Label: Laquinimod 0.3 mg/Laquinimod 0.6 mg

Arm Type

Experimental

Arm Description

Arm Title

Open Label: Laquinimod 0.6 mg

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Laquinimod

Other Intervention Name(s)

TV-5600

Intervention Description

Laquinimod tablets/capsules will be administered as per the dose and schedule specified in the respective arms.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Placebo matching to laquinimod will be administered as per the dose and schedule specified in the respective arms.

Primary Outcome Measure Information:

Title

Double-Blind Extension Period: Number of Participants With Adverse Events (AEs)

Description

Time Frame

Baseline (Week 0) to Week 36

Title

Open-label Extension Period: Number of Participants With AEs

Description

Time Frame

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)

Title

Double-Blind Period: Number of Participants Who Prematurely Discontinued From the Study Due to Any Reason and Due to AEs

Description

Time Frame

Baseline (Week 0) to Week 36

Title

Open-Label Period: Number of Participants Who Prematurely Discontinued From the Study Due to Any Reason and Due to AEs

Description

Time Frame

Secondary Outcome Measure Information:

Title

Double-Blind Period: Relapse Rate: Total Number of Confirmed Relapses

Description

Time Frame

Baseline (Week 0) up to end of active double-blind phase or termination/early termination visit (up to Week 36)

Title

Double-Blind Period: Percentage of Relapse-Free Participants

Description

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).

Time Frame

Baseline (Week 0) up to end of active double-blind phase or termination/early termination visit (up to Week 36)

Title

Double-Blind Period: Number of Enhancing Lesions on T1-Weighted Images

Description

Time Frame