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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®) (BRAVO)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00605215
Recruitment Status : Completed
First Posted : January 30, 2008
Results First Posted : April 21, 2022
Last Update Posted : April 21, 2022
Sponsor:
Information provided by (Responsible Party):
Teva Branded Pharmaceutical Products R&D, Inc.

Study Description
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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®).

Condition or disease Intervention/treatment Phase
Multiple Sclerosis Drug: Laquinimod Drug: Placebo Drug: Avonex® Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1331 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : April 24, 2008
Actual Primary Completion Date : June 10, 2011
Actual Study Completion Date : June 10, 2011

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Placebo Comparator: Placebo
Participants will receive 1 capsule of placebo matching to laquinimod orally once daily for 24 months.
 Drug: Placebo
Placebo matching to laquinimod will be administered per schedule specified in the arm description.
Experimental: Laquinimod
Participants will receive 1 capsule of laquinimod 0.6 mg orally once daily for 24 months.
 Drug: Laquinimod
Laquinimod will be administered per dose and schedule specified in the arm description.
Active Comparator: Avonex®
Participants will receive an injection of Avonex® 30 micrograms (mcg) given intramuscularly (IM) once weekly for 24 months.
 Drug: Avonex®
Avonex® will be administered per dose and schedule specified in the arm description.
Other Name: Interferon β-1a


Outcome Measures
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Primary Outcome Measures :
  1. Annualized Rate of Confirmed Relapses [ Time Frame: 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 Outcome Measures :
  1. Change From Baseline in Disability as Assessed by the Multiple Sclerosis Functional Composite (MSFC) Score [ Time Frame: 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.

  2. Percent Change From Baseline in Brain Volume [ Time Frame: Baseline, Month 24 ]
    Change in brain volume was derived from MRI scans obtained at baseline and at Month 24.

  3. Accumulation of Physical Disability Measured by the Number of Participants With Confirmed Progression of EDSS [ Time Frame: 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.


Other Outcome Measures:
  1. 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 [ Time Frame: 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.

  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 [ Time Frame: 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.

  3. Cumulative Number of New or Enlarging Hypointense Lesions on Enhanced T1 Scans [ Time Frame: 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.

  4. Cumulative Number of Enhancing Lesions on T1-Weighted Images [ Time Frame: 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.


Eligibility Criteria
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Layout table for eligibility information
Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00605215


Locations
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Sponsors and Collaborators
Teva Branded Pharmaceutical Products R&D, Inc.
Investigators
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Study Director: Teva Medical Expert, M.D. Teva Branded Pharmaceutical Products R&D, Inc.
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Teva Branded Pharmaceutical Products R&D, Inc.
ClinicalTrials.gov Identifier: NCT00605215    
Other Study ID Numbers: MS-LAQ-302
2007-005450-23 ( EudraCT Number )
First Posted: January 30, 2008    Key Record Dates
Results First Posted: April 21, 2022
Last Update Posted: April 21, 2022
Last Verified: March 2022
Additional relevant MeSH terms:
Layout table for MeSH terms
Multiple Sclerosis
Multiple Sclerosis, Relapsing-Remitting
Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
 Interferons
Interferon beta-1a
Interferon-beta
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Adjuvants, Immunologic
Immunologic Factors
Physiological Effects of Drugs