Trial Outcomes & Findings for Safety and Efficacy of Orally Administered Laquinimod Versus Placebo for Treatment of Relapsing Remitting Multiple Sclerosis (RRMS) (NCT NCT00509145)

Last Updated: 2021-11-02

Results Overview

A relapse was defined as the appearance of at least one new neurological abnormality or the reappearance of at least one previously observed neurological abnormalities lasting greater than or equal to 48 hours and immediately preceded by an improving neurological state of greater than or equal to 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 one or more of the following: An increase of greater than or equal to 0.5 in the Expanded Disability Status Scale (EDSS) score as compared to previous evaluation, an increase of one grade in the actual score of greater than or equal to 2 of the 7 functional systems (FS), as compared to previous evaluation, or an increase of 2 grades in the actual score of one FS as compared to the previous evaluation.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1106 participants

Primary outcome timeframe

Up to Month 24

Results posted on

2021-11-02

Participant Flow

1106 participants were enrolled and randomized in the placebo-controlled (PC) double-blind period. Participants were randomized 1:1 to the treatment arms.

Participant milestones

Participant milestones
Measure	Laquinimod Laquinimod 0.6 mg capsule taken orally once a day	Placebo Matching placebo capsule taken orally once a day
Overall Study STARTED	550	556
Overall Study COMPLETED	437	427
Overall Study NOT COMPLETED	113	129

Reasons for withdrawal

Reasons for withdrawal
Measure	Laquinimod Laquinimod 0.6 mg capsule taken orally once a day	Placebo Matching placebo capsule taken orally once a day
Overall Study Death	0	2
Overall Study Adverse Event	42	28
Overall Study Withdrawal by Subject	32	38
Overall Study Physician Decision	11	14
Overall Study Protocol Violation	1	6
Overall Study Pregnancy	3	8
Overall Study Lost to Follow-up	6	5
Overall Study Withdrawal by participant after confirmed relapse	12	22
Overall Study Other	6	6

Baseline Characteristics

Race not reported for 4 participants.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Laquinimod n=550 Participants Laquinimod 0.6 mg capsule taken orally once a day	Placebo n=556 Participants Matching placebo capsule taken orally once a day	Total n=1106 Participants Total of all reporting groups
Age, Continuous	38.9 years STANDARD_DEVIATION 9.2 • n=550 Participants	38.5 years STANDARD_DEVIATION 9.1 • n=556 Participants	38.7 years STANDARD_DEVIATION 9.1 • n=1106 Participants
Sex: Female, Male Female	391 Participants n=550 Participants	368 Participants n=556 Participants	759 Participants n=1106 Participants
Sex: Female, Male Male	159 Participants n=550 Participants	188 Participants n=556 Participants	347 Participants n=1106 Participants
Race/Ethnicity, Customized Race : Asian	2 Participants n=548 Participants • Race not reported for 4 participants.	1 Participants n=554 Participants • Race not reported for 4 participants.	3 Participants n=1102 Participants • Race not reported for 4 participants.
Race/Ethnicity, Customized Race : Black or African American	1 Participants n=548 Participants • Race not reported for 4 participants.	8 Participants n=554 Participants • Race not reported for 4 participants.	9 Participants n=1102 Participants • Race not reported for 4 participants.
Race/Ethnicity, Customized Race : White	532 Participants n=548 Participants • Race not reported for 4 participants.	532 Participants n=554 Participants • Race not reported for 4 participants.	1064 Participants n=1102 Participants • Race not reported for 4 participants.
Race/Ethnicity, Customized Race : Hispanic	11 Participants n=548 Participants • Race not reported for 4 participants.	9 Participants n=554 Participants • Race not reported for 4 participants.	20 Participants n=1102 Participants • Race not reported for 4 participants.
Race/Ethnicity, Customized Race : Other	2 Participants n=548 Participants • Race not reported for 4 participants.	4 Participants n=554 Participants • Race not reported for 4 participants.	6 Participants n=1102 Participants • Race not reported for 4 participants.

PRIMARY outcome

Timeframe: Up to Month 24

Population: Intent to treat (ITT) analysis set included all randomized participants.

Outcome measures

Outcome measures
Measure	Laquinimod n=550 Participants Laquinimod 0.6 mg capsule taken orally once a day	Placebo n=556 Participants Matching placebo capsule taken orally once a day
Relapse Rate: Number of Confirmed Relapses During the Double Blind Study Period	0.54 Confirmed relapses Standard Deviation 0.88	0.67 Confirmed relapses Standard Deviation 0.92

SECONDARY outcome

Timeframe: Month 12, Month 24

Population: ITT analysis set included all randomized participants. Number of participants analyzed included the number of participants evaluable at each time point.

Composite score was calculated as the sum of the number of gadolinium (Gd)-enhanced lesions at Month 12 and the number of gadolinium (Gd)-enhanced lesions at Month 24 on T1-Weighted MRI scans.

Outcome measures

Outcome measures
Measure	Laquinimod n=482 Participants Laquinimod 0.6 mg capsule taken orally once a day	Placebo n=464 Participants Matching placebo capsule taken orally once a day
Composite Endpoint: Sum of the Number of T1 Gadolinium (Gd)-Enhanced Lesions on T1-Weighted MRI Images	1.86 Lesions Standard Deviation 5.02	2.92 Lesions Standard Deviation 7.58

SECONDARY outcome

Timeframe: Month 12, Month 24

Population: ITT analysis set included all randomized participants. Number of participants analyzed included the number of participants evaluable at each time point.

Composite score calculated as the sum of T2 lesions at Months 12 and 24 that are new or enlarged.

Outcome measures

Outcome measures
Measure	Laquinimod n=482 Participants Laquinimod 0.6 mg capsule taken orally once a day	Placebo n=464 Participants Matching placebo capsule taken orally once a day
Composite Endpoint: Sum of the Number of New/Enlarging T2 Lesions	5.26 Lesions Standard Deviation 9.08	7.87 Lesions Standard Deviation 12.56

SECONDARY outcome

Timeframe: Baseline to Month 24

Population: ITT analysis set included all randomized participants.

EDSS assesses disability in 8 functional systems with an overall score ranging from 0 (normal) to 10 (death due to multiple sclerosis \[MS\]). A confirmed progression of EDSS is defined as at least 1 point increase from baseline if baseline EDSS was between 0 and 5.0, or at least 0.5 point increase if baseline EDSS was 5.5 or higher, confirmed 3 months later. Participants were assessed between baseline and month 24 visit. Participants that met these criteria for any 3 consecutive months were counted in the progression category. Progression could not be confirmed during an MS relapse. Data is presented as a distribution of confirmed disease progression (CDP) events (number of participants with CDP).

Outcome measures

Outcome measures
Measure	Laquinimod n=550 Participants Laquinimod 0.6 mg capsule taken orally once a day	Placebo n=556 Participants Matching placebo capsule taken orally once a day
Accumulation of Physical Disability Measured by the Time to Confirmed Progression of Expanded Disability Status Scale (EDSS) Progressed	54 Participants	78 Participants
Accumulation of Physical Disability Measured by the Time to Confirmed Progression of Expanded Disability Status Scale (EDSS) Progression Free	496 Participants	478 Participants

SECONDARY outcome

Timeframe: Baseline, Month 24

Population: ITT analysis set included all randomized participants. Number of participants analyzed included the number of participants evaluable at each time point.

The Multiple Sclerosis Functional Composite is an instrument assessing disability that consists of 3 clinical assessments. The 3 are Timed 25-Foot Walk, 9-Hole Peg Test which measures upper extremity (arm and hand) function, and PASAT (Paced Auditory Serial Addition Test) which is a measure of cognitive function that specifically assesses auditory information processing speed and flexibility, as well as calculation ability. A Z-score is used to define a common metric from the 3 assessments that constitute the MSFC score. The study's population at baseline was used as reference population for the Z-score calculation. A Z-score of 0 represents the population mean at baseline. Higher Z-scores correspond to an improved outcome.

Outcome measures

Outcome measures
Measure	Laquinimod n=424 Participants Laquinimod 0.6 mg capsule taken orally once a day	Placebo n=420 Participants Matching placebo capsule taken orally once a day
Change From Baseline in Disability as Assessed by the Multiple Sclerosis Functional Composite (MSFC) Score	0.0 Z score Standard Deviation 0.4	0.0 Z score Standard Deviation 0.7

Adverse Events

Laquinimod 0.6 mg

Serious events: 61 serious events

Other events: 368 other events

Deaths: 0 deaths

Placebo

Serious events: 53 serious events

Other events: 346 other events

Deaths: 3 deaths

Serious adverse events

Other adverse events

Additional Information

Director, Clinical Research

Teva Branded Pharmaceutical Products R&D, Inc.

Phone: 1-888-483-8279

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Sponsor has the right 60 days before submission for publication to review/provide comments. If the Sponsor's review shows that potentially patentable subject matter would be disclosed, publication or public disclosure shall be delayed for up to 90 additional days in order for the Sponsor, or Sponsor's designees, to file the necessary patent applications. In multicenter trials, each PI will postpone single center publications until after disclosure or publication of multicenter data.
Publication restrictions are in place

Restriction type: OTHER

Measure	Laquinimod 0.6 mg n=550 participants at risk Laquinimod 0.6 mg capsule taken orally once a day	Placebo n=556 participants at risk Matching placebo capsule taken orally once a day
Gastrointestinal disorders Abdominal pain upper	5.1% 28/550 • Number of events 33 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.	5.2% 29/556 • Number of events 34 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.
Gastrointestinal disorders Diarrhoea	7.6% 42/550 • Number of events 49 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.	5.9% 33/556 • Number of events 41 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.
Gastrointestinal disorders Nausea	6.2% 34/550 • Number of events 38 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.	5.8% 32/556 • Number of events 38 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.
General disorders Fatigue	4.5% 25/550 • Number of events 28 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.	5.2% 29/556 • Number of events 36 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.
Infections and infestations Influenza	6.0% 33/550 • Number of events 39 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.	7.9% 44/556 • Number of events 50 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.
Infections and infestations Nasopharyngitis	18.2% 100/550 • Number of events 159 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.	21.4% 119/556 • Number of events 199 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.
Infections and infestations Sinusitis	5.3% 29/550 • Number of events 40 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.	4.5% 25/556 • Number of events 38 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.
Infections and infestations Upper respiratory tract infection	7.6% 42/550 • Number of events 61 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.	8.6% 48/556 • Number of events 62 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.
Infections and infestations Urinary tract infection	7.3% 40/550 • Number of events 60 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.	4.3% 24/556 • Number of events 35 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.
Investigations Alanine aminotransferase increased	6.9% 38/550 • Number of events 49 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.	2.7% 15/556 • Number of events 16 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Arthralgia	8.5% 47/550 • Number of events 61 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.	7.4% 41/556 • Number of events 51 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Back pain	16.2% 89/550 • Number of events 122 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.	9.0% 50/556 • Number of events 73 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Pain in extremity	6.4% 35/550 • Number of events 47 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.	6.8% 38/556 • Number of events 44 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.
Nervous system disorders Headache	22.4% 123/550 • Number of events 225 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.	17.8% 99/556 • Number of events 176 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.
Psychiatric disorders Depression	5.5% 30/550 • Number of events 31 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.	5.8% 32/556 • Number of events 32 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Cough	7.3% 40/550 • Number of events 47 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.	4.5% 25/556 • Number of events 29 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.
Gastrointestinal disorders Abdominal pain	5.6% 31/550 • Number of events 36 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.	2.7% 15/556 • Number of events 16 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.
General disorders Pyrexia	3.6% 20/550 • Number of events 21 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.	5.0% 28/556 • Number of events 34 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.
Nervous system disorders Dizziness	4.9% 27/550 • Number of events 29 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.	5.2% 29/556 • Number of events 33 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.
Psychiatric disorders Insomnia	6.5% 36/550 • Number of events 40 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.	5.6% 31/556 • Number of events 39 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	4.2% 23/550 • Number of events 24 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.	5.2% 29/556 • Number of events 34 • Baseline to 24 months Safety analysis included all participants that received at least one dose of study drug.