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®)

A Multinational, Multicenter, Randomized, Parallel-Group Study Performed in Subjects With Relapsing-Remitting Multiple Sclerosis (RRMS) to Assess the Efficacy, Safety and Tolerability of Laquinimod Over Placebo in a Double-blind Design and of a Reference Arm of Interferon β-1a (Avonex®) in a Rater-blinded Design

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00605215

Acronym

BRAVO

Enrollment

1331

Registered

2008-01-30

Start date

2008-04-24

Completion date

2011-06-10

Last updated

2022-04-21

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Multiple Sclerosis

Brief summary

The study aims to compare the effect of daily oral treatment of laquinimod capsules 0.6 milligrams (mg) with the effect of placebo capsules (capsules that contain no active medication) as well as with the effect of an existing Multiple Sclerosis (MS) injectable drug: Interferon β-1a (Avonex®).

Interventions

DRUGLaquinimod

Laquinimod will be administered per dose and schedule specified in the arm description.

DRUGPlacebo

Placebo matching to laquinimod will be administered per schedule specified in the arm description.

DRUGAvonex®

Avonex® will be administered per dose and schedule specified in the arm description.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 55 Years

Healthy volunteers

Inclusion criteria

1. Subjects must have a confirmed and documented MS diagnosis as defined by the Revised McDonald criteria \[Ann Neurol 2005: 58:840-846\], with a relapsing-remitting disease course. 2. Subjects must be ambulatory with converted Kurtzke EDSS score of 0-5.5. 3. Subjects must be in a stable neurological condition between screening (month -1) and baseline visits (month 0). 4. Subjects must have had experienced one of the following: 5. At least one documented relapse in the 12 months prior to screening 6. At least two documented relapses in the 24 months prior to screening 7. One documented relapse between 12 and 24 months prior to screening with at least one documented T1-Gd enhancing lesion in an MRI performed within 12 months prior to screening. 8. Subjects must be between 18 and 55 years of age, inclusive. 9. Subjects must have disease duration of at least 6 months (from first symptom) prior to screening. 10. Women of child-bearing potential must practice 2 acceptable methods of birth control \[acceptable methods of birth control in this study include: surgical sterilization, intrauterine devices, oral contraceptive, contraceptive patch, long-acting injectable contraceptive, partner's vasectomy or double-barrier method (condom or diaphragm with spermicide)\]. 11. Subjects must be willing and able to comply with the protocol requirements for the duration of the study.

Exclusion criteria

1. An onset of relapse or any treatment with corticosteroids (intravenous \[iv\], intramuscular \[im\] and/or per os \[po\]) or ACTH between month -1 (screening) and 0 (baseline). 2. Use of experimental or investigational drugs, and/or participation in drug clinical studies within the 6 months prior to screening. 3. Use of immunosuppressive (including Mitoxantrone (Novantrone®) or cytotoxic agents within 6 months prior to the screening visit. 4. Previous use of either of the following: natalizumab (Tysabri®), cladribine or laquinimod. 5. Previous treatment with glatiramer acetate (Copaxone®) or IVIG within 3 months prior to screening visit. 6. Previous treatment with Interferon beta-1a (Avonex® or Rebif®) or Interferon beta-1b (Betaseron®). 7. Systemic corticosteroid treatment of ≥30 consecutive days duration within 2 months prior to screening visit. 8. Previous total body irradiation or total lymphoid irradiation. 9. Previous stem-cell treatment, autologous bone marrow transplantation or allogenic bone marrow transplantation. 10. A known history of tuberculosis. 11. Acute infection 2 weeks prior to baseline visit. 12. Major trauma or surgery 2 weeks prior to baseline visit. 13. A history of vascular thrombosis (excluding catheter-site superficial venous thrombophlebitis). 14. A carrier state of factor V Leiden mutation (either homo- or heterozygous) by history or as disclosed at screening. 15. Positive screening test for Hepatitis B surface antigen, Hepatitis C antibody, or HIV antibody as disclosed at screening visit. 16. Use of potent inhibitors of CYP3A4 within 2 weeks prior to baseline visit (see detailed list of drugs in protocol) (1 month for fluoxetine). 17. Use of amiodarone within 2 years prior to screening visit. 18. Pregnancy or breastfeeding. 19. Subjects with a clinically significant or unstable medical or surgical condition that would preclude safe and complete study participation, as determined by medical history, physical examinations, ECG, laboratory tests or chest X-ray. Such conditions may include: * A cardiovascular or pulmonary disorder that cannot be well-controlled by standard treatment permitted by the study protocol. * A gastrointestinal disorder that may affect the absorption of study medication. * Renal, metabolic, endocrinological or hematological diseases. * Any form of chronic liver disease, including known non-alcoholic steatohepatitis. * A ≥2xULN serum elevation of either of the following at screening: ALT, AST or direct bilirubin. * A QTc interval (obtained from either two ECG recordings at screening or from the mean value calculated from three measurements at baseline visit) which is ≥450msec. * A family history of Long-QT syndrome. * A history of drug and/or alcohol abuse. * Major psychiatric disorder. * A history of a convulsive disorder. * Known hypersensitivity to either of the following: mannitol, meglumine or sodium stearyl fumarate. * Known hypersensitivity that would preclude administration of laquinimod. 20. The subject's inability to give informed consent, or to complete the study, or if the subject is considered by the investigator to be, for any reason, an unsuitable candidate for this study. 21. A known history of sensitivity to Gadolinium. 22. Inability to successfully undergo MRI scanning. 23. A known history of hypersensitivity to natural or recombinant interferon beta, human albumin, or any other component of the formulation of Avonex®. 24. Subjects who suffer from any form of progressive MS 25. Any condition which the investigator feels may interfere with participation in the study 26. Subjects with a clinically significant or unstable medical or surgical condition that would preclude safe and complete study participation 27. Subjects who received any investigational medication, immunosuppressives or cytotoxic agents within 6 months prior to screening 28. Previous treatment with immunomodulators within two months prior to screening 29. Pregnancy or breastfeeding

Design outcomes

Primary

Measure	Time frame	Description
Annualized Rate of Confirmed Relapses	Baseline up to Month 24	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.

Secondary

Measure	Time frame	Description
Accumulation of Physical Disability Measured by the Number of Participants With Confirmed Progression of EDSS	Baseline up to Month 24	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.
Change From Baseline in Disability as Assessed by the Multiple Sclerosis Functional Composite (MSFC) Score	Baseline, Month 24	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.
Percent Change From Baseline in Brain Volume	Baseline, Month 24	Change in brain volume was derived from MRI scans obtained at baseline and at Month 24.

Other

Measure	Time frame	Description
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	Baseline, Month 6, Month 12, Month 18, Month 24	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.
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	Baseline, Month 6, Month 12, Month 18, Month 24	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.
Cumulative Number of New or Enlarging Hypointense Lesions on Enhanced T1 Scans	Months 12 and 24	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.
Cumulative Number of Enhancing Lesions on T1-Weighted Images	Months 12 and 24	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.

Countries

Bulgaria, Croatia, Czechia, Estonia, Georgia, Germany, Israel, Italy, Lithuania, North Macedonia, Poland, Puerto Rico, Romania, Russia, Slovakia, South Africa, Spain, Ukraine, United States

Participant flow

Participants by arm

Arm	Count
Placebo Participants received 1 capsule of placebo matched to laquinimod orally once daily for 24 months.	450
Laquinimod Participants received 1 capsule of laquinimod 0.6 mg orally once daily for 24 months.	434
Avonex® Participants received an injection of Avonex® 30 mcg given IM once weekly for 24 months.	447
Total	1,331

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Adverse Event	19	21	26
Overall Study	Death	0	0	1
Overall Study	Lost to Follow-up	8	5	2
Overall Study	Other than specified	0	2	1
Overall Study	Pregnancy	8	5	4
Overall Study	Protocol Violation	3	4	1
Overall Study	Refusal to sign the re-consent form	8	3	3
Overall Study	Request of Primary Care Physician or Investigator	6	4	4
Overall Study	Withdrawal by Subject	39	37	27

Baseline characteristics

Characteristic	Placebo	Laquinimod	Avonex®	Total
Age, Continuous	37.5 years STANDARD_DEVIATION 9.5	37.0 years STANDARD_DEVIATION 9.3	38.2 years STANDARD_DEVIATION 9.5	37.6 years STANDARD_DEVIATION 9.5
Race/Ethnicity, Customized Asian	0 Participants	1 Participants	1 Participants	2 Participants
Race/Ethnicity, Customized Black/African American	2 Participants	1 Participants	4 Participants	7 Participants
Race/Ethnicity, Customized Black of African Heritage	1 Participants	1 Participants	0 Participants	2 Participants
Race/Ethnicity, Customized Hispanic	3 Participants	3 Participants	1 Participants	7 Participants
Race/Ethnicity, Customized Other	1 Participants	2 Participants	1 Participants	4 Participants
Race/Ethnicity, Customized White	443 Participants	426 Participants	440 Participants	1309 Participants
Sex: Female, Male Female	321 Participants	282 Participants	307 Participants	910 Participants
Sex: Female, Male Male	129 Participants	152 Participants	140 Participants	421 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 449	1 / 433	1 / 442
other Total, other adverse events	146 / 449	158 / 433	286 / 442
serious Total, serious adverse events	36 / 449	31 / 433	25 / 442

Outcome results

Primary

Annualized Rate of Confirmed Relapses

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.

Time frame: Baseline up to Month 24

Population: ITT analysis set included all randomized participants.

Arm	Measure	Value (MEAN)
Placebo	Annualized Rate of Confirmed Relapses	0.344 relapse per year
Laquinimod	Annualized Rate of Confirmed Relapses	0.283 relapse per year
Avonex®	Annualized Rate of Confirmed Relapses	0.255 relapse per year

Comparison: Analysis was performed using baseline-adjusted negative binomial regression, where a participant's number of relapses during the double-blind, placebo-controlled phase served as the response variable and an offset based on the log of participant's exposure in years was employed to adjust for variability of treatment exposure. The model included baseline EDSS score, log of (prior 2-year number of relapses+1) and CGR as covariates.p-value: 0.074695% CI: [0.664, 1.02]Negative Binomial Regression

Comparison: Analysis was performed using baseline-adjusted negative binomial regression, where a participant's number of relapses during the double-blind, placebo-controlled phase served as the response variable and an offset based on the log of participant's exposure in years was employed to adjust for variability of treatment exposure. The model included baseline EDSS score, log of (prior 2-year number of relapses+1) and CGR as covariates.p-value: 0.006795% CI: [0.596, 0.92]Negative Binomial Regression

Secondary

Accumulation of Physical Disability Measured by the Number of Participants With Confirmed Progression of EDSS

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.

Time frame: Baseline up to Month 24

Population: ITT analysis set included all randomized participants.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Placebo	Accumulation of Physical Disability Measured by the Number of Participants With Confirmed Progression of EDSS	60 Participants
Laquinimod	Accumulation of Physical Disability Measured by the Number of Participants With Confirmed Progression of EDSS	42 Participants
Avonex®	Accumulation of Physical Disability Measured by the Number of Participants With Confirmed Progression of EDSS	47 Participants

Secondary

Change From Baseline in Disability as Assessed by the Multiple Sclerosis Functional Composite (MSFC) Score

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.

Time frame: Baseline, Month 24