Trial Outcomes & Findings for BRAVO Study: Laquinimod Double-blind Placebo-controlled Study in Participants With Relapsing-Remitting Multiple Sclerosis (RRMS) With a Rater Blinded Reference Arm of Interferon β-1a (Avonex®) (NCT NCT00605215)

Last Updated: 2022-04-21

Results Overview

A relapse was defined as the appearance of new neurological abnormalities or the reappearance of previously observed neurological abnormalities; lasting at least 48 hours and immediately preceded by an improved neurological state of ≥30 days from onset of previous relapse, accompanied by observed objective neurological changes (an increase of ≥0.5 in Expanded Disability Status Scale \[EDSS\] score, or an increase of 1 grade in the score of 2 or more of the 7 Functional Systems \[FS\], or an increase of 2 grades in the score of 1 FS as compared to the previous evaluation). Total number of confirmed relapses during the treatment period was divided by the sum of number of days on study in the treatment period and then multiplied by the number of days in the year to calculate the annualized relapse rate. Annualized relapse rate was derived from a baseline-adjusted negative binomial regression.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1331 participants

Primary outcome timeframe

Baseline up to Month 24

Results posted on

2022-04-21

Participant Flow

Participant milestones

Participant milestones
Measure	Placebo Participants received 1 capsule of placebo matched to laquinimod orally once daily for 24 months.	Laquinimod Participants received 1 capsule of laquinimod 0.6 millograms (mg) orally once daily for 24 months.	Avonex® Participants received an injection of Avonex® 30 micrograms (mcg) given intramuscularly (IM) once weekly for 24 months.
Overall Study STARTED	450	434	447
Overall Study Received at Least 1 Dose of Study Drug	449	433	442
Overall Study COMPLETED	359	353	378
Overall Study NOT COMPLETED	91	81	69

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants received 1 capsule of placebo matched to laquinimod orally once daily for 24 months.	Laquinimod Participants received 1 capsule of laquinimod 0.6 millograms (mg) orally once daily for 24 months.	Avonex® Participants received an injection of Avonex® 30 micrograms (mcg) given intramuscularly (IM) once weekly for 24 months.
Overall Study Death	0	0	1
Overall Study Adverse Event	19	21	26
Overall Study Refusal to sign the re-consent form	8	3	3
Overall Study Withdrawal by Subject	39	37	27
Overall Study Request of Primary Care Physician or Investigator	6	4	4
Overall Study Protocol Violation	3	4	1
Overall Study Pregnancy	8	5	4
Overall Study Lost to Follow-up	8	5	2
Overall Study Other than specified	0	2	1

Baseline Characteristics

BRAVO Study: Laquinimod Double-blind Placebo-controlled Study in Participants With Relapsing-Remitting Multiple Sclerosis (RRMS) With a Rater Blinded Reference Arm of Interferon β-1a (Avonex®)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=450 Participants Participants received 1 capsule of placebo matched to laquinimod orally once daily for 24 months.	Laquinimod n=434 Participants Participants received 1 capsule of laquinimod 0.6 mg orally once daily for 24 months.	Avonex® n=447 Participants Participants received an injection of Avonex® 30 mcg given IM once weekly for 24 months.	Total n=1331 Participants Total of all reporting groups
Age, Continuous	37.5 years STANDARD_DEVIATION 9.5 • n=5 Participants	37.0 years STANDARD_DEVIATION 9.3 • n=7 Participants	38.2 years STANDARD_DEVIATION 9.5 • n=5 Participants	37.6 years STANDARD_DEVIATION 9.5 • n=4 Participants
Sex: Female, Male Female	321 Participants n=5 Participants	282 Participants n=7 Participants	307 Participants n=5 Participants	910 Participants n=4 Participants
Sex: Female, Male Male	129 Participants n=5 Participants	152 Participants n=7 Participants	140 Participants n=5 Participants	421 Participants n=4 Participants
Race/Ethnicity, Customized Asian	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants
Race/Ethnicity, Customized Black of African Heritage	1 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants
Race/Ethnicity, Customized Black/African American	2 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants	7 Participants n=4 Participants
Race/Ethnicity, Customized White	443 Participants n=5 Participants	426 Participants n=7 Participants	440 Participants n=5 Participants	1309 Participants n=4 Participants
Race/Ethnicity, Customized Hispanic	3 Participants n=5 Participants	3 Participants n=7 Participants	1 Participants n=5 Participants	7 Participants n=4 Participants
Race/Ethnicity, Customized Other	1 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants	4 Participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline up to Month 24

Population: ITT analysis set included all randomized participants.

Outcome measures

Outcome measures
Measure	Placebo n=450 Participants Participants received 1 capsule of placebo matched to laquinimod orally once daily for 24 months.	Laquinimod n=434 Participants Participants received 1 capsule of laquinimod 0.6 mg orally once daily for 24 months.	Avonex® n=447 Participants Participants received an injection of Avonex® 30 mcg given IM once weekly for 24 months.
Annualized Rate of Confirmed Relapses	0.344 relapse per year Interval 0.291 to 0.406	0.283 relapse per year Interval 0.237 to 0.337	0.255 relapse per year Interval 0.213 to 0.304

SECONDARY outcome

Timeframe: Baseline, Month 24

Population: ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.

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	Placebo n=358 Participants Participants received 1 capsule of placebo matched to laquinimod orally once daily for 24 months.	Laquinimod n=351 Participants Participants received 1 capsule of laquinimod 0.6 mg orally once daily for 24 months.	Avonex® n=377 Participants Participants received an injection of Avonex® 30 mcg given IM once weekly for 24 months.
Change From Baseline in Disability as Assessed by the Multiple Sclerosis Functional Composite (MSFC) Score	-0.5 Z score Standard Deviation 0.85	-0.00 Z score Standard Deviation 0.85	-0.01 Z score Standard Deviation 0.75

SECONDARY outcome

Timeframe: Baseline, Month 24

Population: ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.

Change in brain volume was derived from MRI scans obtained at baseline and at Month 24.

Outcome measures

Outcome measures
Measure	Placebo n=341 Participants Participants received 1 capsule of placebo matched to laquinimod orally once daily for 24 months.	Laquinimod n=332 Participants Participants received 1 capsule of laquinimod 0.6 mg orally once daily for 24 months.	Avonex® n=361 Participants Participants received an injection of Avonex® 30 mcg given IM once weekly for 24 months.
Percent Change From Baseline in Brain Volume	-0.53 Percent Change Standard Deviation 0.65	-0.51 Percent Change Standard Deviation 0.65	-0.53 Percent Change Standard Deviation 0.65

SECONDARY outcome

Timeframe: Baseline up to Month 24

Population: ITT analysis set included all randomized participants.

A confirmed progression of EDSS was defined as a 1 point increase from baseline on EDSS score if baseline EDSS was between 0 and 5.0, or a 0.5 point increase if baseline EDSS was 5.5, confirmed 3 months later. 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 confirmed progression (number of participants with confirmed progression of EDSS) sustained for 3 months. Progression could not be confirmed during a relapse.

Outcome measures

Outcome measures
Measure	Placebo n=450 Participants Participants received 1 capsule of placebo matched to laquinimod orally once daily for 24 months.	Laquinimod n=434 Participants Participants received 1 capsule of laquinimod 0.6 mg orally once daily for 24 months.	Avonex® n=447 Participants Participants received an injection of Avonex® 30 mcg given IM once weekly for 24 months.
Accumulation of Physical Disability Measured by the Number of Participants With Confirmed Progression of EDSS	60 Participants	42 Participants	47 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, Month 6, Month 12, Month 18, Month 24

Population: ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.

The SF-36 questionnaire has 36 questions composing the scale that represent 8 domains: 1) physical functioning, role physical, 2) bodily pain, 3) general health, 4) vitality, 5) social functioning, 6) role, 7) emotional, and 8) mental health. The scores for the 8 domains were combined into two summary scores: the physical component summary (PCS) score and the mental component summary (MCS) score. Items 1 to 4 primarily contribute to the PCS score of the SF-36. Items 5-8 primarily contribute to the MCS score of the SF-36. Scores on each item were summed and averaged (range: 0=worst to 100=best). Higher scores represent better health status and functional ability.

Outcome measures

Outcome measures
Measure	Placebo n=450 Participants Participants received 1 capsule of placebo matched to laquinimod orally once daily for 24 months.	Laquinimod n=434 Participants Participants received 1 capsule of laquinimod 0.6 mg orally once daily for 24 months.	Avonex® n=447 Participants Participants received an injection of Avonex® 30 mcg given IM once weekly for 24 months.
Change From Baseline in General Health Status as Assessed by the Short-Form General Health Survey (SF-36) Patient-Reported Questionnaire For Physical Component Summary (PCS) Scores Month 6	-0.2 units on a scale Standard Deviation 6.3	0.1 units on a scale Standard Deviation 6.3	-0.1 units on a scale Standard Deviation 6.3
Change From Baseline in General Health Status as Assessed by the Short-Form General Health Survey (SF-36) Patient-Reported Questionnaire For Physical Component Summary (PCS) Scores Month 12	-0.3 units on a scale Standard Deviation 6.9	-0.1 units on a scale Standard Deviation 6.9	0.0 units on a scale Standard Deviation 6.7
Change From Baseline in General Health Status as Assessed by the Short-Form General Health Survey (SF-36) Patient-Reported Questionnaire For Physical Component Summary (PCS) Scores Month 18	-0.5 units on a scale Standard Deviation 7.0	-0.3 units on a scale Standard Deviation 7.0	0.2 units on a scale Standard Deviation 6.9
Change From Baseline in General Health Status as Assessed by the Short-Form General Health Survey (SF-36) Patient-Reported Questionnaire For Physical Component Summary (PCS) Scores Month 24	-0.6 units on a scale Standard Deviation 7.6	0.1 units on a scale Standard Deviation 6.9	0.2 units on a scale Standard Deviation 7.0

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, Month 6, Month 12, Month 18, Month 24

Population: ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.

Outcome measures

Outcome measures
Measure	Placebo n=450 Participants Participants received 1 capsule of placebo matched to laquinimod orally once daily for 24 months.	Laquinimod n=434 Participants Participants received 1 capsule of laquinimod 0.6 mg orally once daily for 24 months.	Avonex® n=447 Participants Participants received an injection of Avonex® 30 mcg given IM once weekly for 24 months.
Change From Baseline in General Health Status as Assessed by the Short-Form General Health Survey (SF-36) Patient-Reported Questionnaire For Mental Component Summary (MCS) Scores Month 6	-0.4 units on a scale Standard Deviation 8.5	-0.6 units on a scale Standard Deviation 8.2	-0.4 units on a scale Standard Deviation 8.9
Change From Baseline in General Health Status as Assessed by the Short-Form General Health Survey (SF-36) Patient-Reported Questionnaire For Mental Component Summary (MCS) Scores Month 12	-0.7 units on a scale Standard Deviation 9.2	-0.1 units on a scale Standard Deviation 9.8	-0.5 units on a scale Standard Deviation 9.0
Change From Baseline in General Health Status as Assessed by the Short-Form General Health Survey (SF-36) Patient-Reported Questionnaire For Mental Component Summary (MCS) Scores Month 18	-0.9 units on a scale Standard Deviation 9.3	-1.4 units on a scale Standard Deviation 10.4	-0.7 units on a scale Standard Deviation 9.2
Change From Baseline in General Health Status as Assessed by the Short-Form General Health Survey (SF-36) Patient-Reported Questionnaire For Mental Component Summary (MCS) Scores Month 24	-0.5 units on a scale Standard Deviation 9.2	-0.9 units on a scale Standard Deviation 9.6	-0.3 units on a scale Standard Deviation 9.3

OTHER_PRE_SPECIFIED outcome

Timeframe: Months 12 and 24

Population: ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.

The cumulative number of new or enlarging hypointense lesions was calculated as the sum of the numbers of new or enlarging hypointense lesions observed on scans taken at Months 12 and 24.

Outcome measures

Outcome measures
Measure	Placebo n=393 Participants Participants received 1 capsule of placebo matched to laquinimod orally once daily for 24 months.	Laquinimod n=381 Participants Participants received 1 capsule of laquinimod 0.6 mg orally once daily for 24 months.	Avonex® n=403 Participants Participants received an injection of Avonex® 30 mcg given IM once weekly for 24 months.
Cumulative Number of New or Enlarging Hypointense Lesions on Enhanced T1 Scans	7.10 lesions Standard Deviation 10.25	7.33 lesions Standard Deviation 10.87	5.91 lesions Standard Deviation 8.58

OTHER_PRE_SPECIFIED outcome

Timeframe: Months 12 and 24

Population: ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.

The cumulative number of T1 Gadolinium (Gd)-enhancing lesions was calculated as the sum of the numbers of Gd-enhancing lesions observed on scans taken at Months 12 and 24.

Outcome measures

Outcome measures
Measure	Placebo n=393 Participants Participants received 1 capsule of placebo matched to laquinimod orally once daily for 24 months.	Laquinimod n=381 Participants Participants received 1 capsule of laquinimod 0.6 mg orally once daily for 24 months.	Avonex® n=404 Participants Participants received an injection of Avonex® 30 mcg given IM once weekly for 24 months.
Cumulative Number of Enhancing Lesions on T1-Weighted Images	2.70 lesions Standard Deviation 8.00	2.58 lesions Standard Deviation 7.40	1.23 lesions Standard Deviation 3.32

Adverse Events

Placebo

Serious events: 36 serious events

Other events: 146 other events

Deaths: 0 deaths

Laquinimod

Serious events: 31 serious events

Other events: 158 other events

Deaths: 1 deaths

Avonex®

Serious events: 25 serious events

Other events: 286 other events

Deaths: 1 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Placebo n=449 participants at risk Participants received 1 capsule of placebo matched to laquinimod orally once daily for 24 months.	Laquinimod n=433 participants at risk Participants received 1 capsule of laquinimod 0.6 mg orally once daily for 24 months.	Avonex® n=442 participants at risk Participants received an injection of Avonex® 30 mcg given IM once weekly for 24 months.
General disorders Influenza like illness	1.6% 7/449 • Number of events 7 • Baseline up to Month 24 Safety analysis set included all randomized participants who received at least 1 dose of laquinimod.	1.2% 5/433 • Number of events 5 • Baseline up to Month 24 Safety analysis set included all randomized participants who received at least 1 dose of laquinimod.	46.6% 206/442 • Number of events 385 • Baseline up to Month 24 Safety analysis set included all randomized participants who received at least 1 dose of laquinimod.
General disorders Pyrexia	1.6% 7/449 • Number of events 10 • Baseline up to Month 24 Safety analysis set included all randomized participants who received at least 1 dose of laquinimod.	1.4% 6/433 • Number of events 7 • Baseline up to Month 24 Safety analysis set included all randomized participants who received at least 1 dose of laquinimod.	11.8% 52/442 • Number of events 77 • Baseline up to Month 24 Safety analysis set included all randomized participants who received at least 1 dose of laquinimod.
Infections and infestations Influenza	6.2% 28/449 • Number of events 32 • Baseline up to Month 24 Safety analysis set included all randomized participants who received at least 1 dose of laquinimod.	6.2% 27/433 • Number of events 30 • Baseline up to Month 24 Safety analysis set included all randomized participants who received at least 1 dose of laquinimod.	4.5% 20/442 • Number of events 30 • Baseline up to Month 24 Safety analysis set included all randomized participants who received at least 1 dose of laquinimod.
Infections and infestations Nasopharyngitis	7.8% 35/449 • Number of events 45 • Baseline up to Month 24 Safety analysis set included all randomized participants who received at least 1 dose of laquinimod.	9.2% 40/433 • Number of events 63 • Baseline up to Month 24 Safety analysis set included all randomized participants who received at least 1 dose of laquinimod.	6.6% 29/442 • Number of events 37 • Baseline up to Month 24 Safety analysis set included all randomized participants who received at least 1 dose of laquinimod.
Infections and infestations Upper respiratory tract infection	8.0% 36/449 • Number of events 43 • Baseline up to Month 24 Safety analysis set included all randomized participants who received at least 1 dose of laquinimod.	7.9% 34/433 • Number of events 41 • Baseline up to Month 24 Safety analysis set included all randomized participants who received at least 1 dose of laquinimod.	5.0% 22/442 • Number of events 27 • Baseline up to Month 24 Safety analysis set included all randomized participants who received at least 1 dose of laquinimod.
Musculoskeletal and connective tissue disorders Arthralgia	4.0% 18/449 • Number of events 26 • Baseline up to Month 24 Safety analysis set included all randomized participants who received at least 1 dose of laquinimod.	5.5% 24/433 • Number of events 27 • Baseline up to Month 24 Safety analysis set included all randomized participants who received at least 1 dose of laquinimod.	4.1% 18/442 • Number of events 21 • Baseline up to Month 24 Safety analysis set included all randomized participants who received at least 1 dose of laquinimod.
Musculoskeletal and connective tissue disorders Back pain	7.1% 32/449 • Number of events 50 • Baseline up to Month 24 Safety analysis set included all randomized participants who received at least 1 dose of laquinimod.	10.2% 44/433 • Number of events 61 • Baseline up to Month 24 Safety analysis set included all randomized participants who received at least 1 dose of laquinimod.	3.4% 15/442 • Number of events 30 • Baseline up to Month 24 Safety analysis set included all randomized participants who received at least 1 dose of laquinimod.
Nervous system disorders Headache	11.8% 53/449 • Number of events 105 • Baseline up to Month 24 Safety analysis set included all randomized participants who received at least 1 dose of laquinimod.	12.5% 54/433 • Number of events 100 • Baseline up to Month 24 Safety analysis set included all randomized participants who received at least 1 dose of laquinimod.	13.6% 60/442 • Number of events 99 • Baseline up to Month 24 Safety analysis set included all randomized participants who received at least 1 dose of laquinimod.

Additional Information

Director, Clinical Research

Teva Branded Pharmaceutical Products R&D, Inc.

Phone: 1-888-483-8279

Email: [email protected]

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