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BRAVO Study: Laquinimod Double Blind Placebo Controlled Study in RRMS Patients 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. Identifier: NCT00605215
Recruitment Status : Completed
First Posted : January 30, 2008
Last Update Posted : August 26, 2013
Information provided by (Responsible Party):
Teva Pharmaceutical Industries

Tracking Information
First Submitted Date  ICMJE January 8, 2008
First Posted Date  ICMJE January 30, 2008
Last Update Posted Date August 26, 2013
Study Start Date  ICMJE April 2008
Actual Primary Completion Date November 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 10, 2011)
Assess efficacy, as measured by number of confirmed relapses [ Time Frame: 24 months ]
Original Primary Outcome Measures  ICMJE
 (submitted: January 17, 2008)
Relapse rate [ Time Frame: 24 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 10, 2011)
  • Accumulation of physical disability [ Time Frame: 24 months ]
    Measured by the time to confirmed progression of Expanded Disability Status Scale (EDSS). A confirmed progression of EDSS is 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.
  • The cumulative number of enhancing lesions on T1-weighted images [ Time Frame: 24 months ]
    Images taken at months 12 and 18
  • General health status [ Time Frame: 24 months ]
    Using Short Form (SF-36) survey subject-reported questionnaire obtained at month 0 and every 6 months thereafter.
  • The cumulative number of new hypointense lesions on enhanced T1 scans [ Time Frame: 24 months ]
    Taken at months 12 and 18
Original Secondary Outcome Measures  ICMJE
 (submitted: January 17, 2008)
Accumulation of disability Other MRI endpoints [ Time Frame: 24 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE BRAVO Study: Laquinimod Double Blind Placebo Controlled Study in RRMS Patients With a Rater Blinded Reference Arm of Interferon β-1a (Avonex®)
Official Title  ICMJE A Multinational, Multicenter, Randomized, Parallel-group Study Performed in Subjects With RRMS to Assess the Efficacy, Safety and Tolerability of Laquinimod Over Placebo in a Double-blind Design and a Reference Arm of Interferon β-1a (Avonex®) in a Rater-blinded Design.
Brief Summary The study aims to compare the effect of daily oral treatment of laquinimod capsules 0.6 mg with the effect of placebo capsules (capsules that contain no active medication) as well as with the effect of an existing MS injectable drug: Interferon β-1a (Avonex®).
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Multiple Sclerosis
Intervention  ICMJE
  • Drug: laquinimod
    0.6 mg oral once daily for 24 months
  • Drug: placebo
    oral placebo once daily for 24 months
  • Drug: Interferon β-1a (Avonex®)
    Interferon β-1a (Avonex®) 30 mcg IM once weekly for 24 months
Study Arms  ICMJE
  • Experimental: Laquinimod
    0.6 mg Laquinimod oral once daily
    Intervention: Drug: laquinimod
  • Placebo Comparator: Placebo
    oral placebo once daily
    Intervention: Drug: placebo
  • Active Comparator: Interferon
    Interferon β-1a (Avonex®) 30 mcg IM once weekly
    Intervention: Drug: Interferon β-1a (Avonex®)
Publications * Kolb-Sobieraj C, Gupta S, Weinstock-Guttman B. Laquinimod therapy in multiple sclerosis: a comprehensive review. Neurol Ther. 2014 May 6;3(1):29-39. doi: 10.1007/s40120-014-0017-6. eCollection 2014 Jun. Review.

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 9, 2011)
Original Estimated Enrollment  ICMJE
 (submitted: January 17, 2008)
Actual Study Completion Date  ICMJE December 2011
Actual Primary Completion Date November 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

    a. Exclusion Criteria:

  12. 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).
  13. Use of experimental or investigational drugs, and/or participation in drug clinical studies within the 6 months prior to screening.
  14. Use of immunosuppressive (including Mitoxantrone (Novantrone®) or cytotoxic agents within 6 months prior to the screening visit.
  15. Previous use of either of the following: natalizumab (Tysabri®), cladribine or laquinimod.
  16. Previous treatment with glatiramer acetate (Copaxone®) or IVIG within 3 months prior to screening visit.
  17. Previous treatment with Interferon beta-1a (Avonex® or Rebif®) or Interferon beta-1b (Betaseron®).
  18. Systemic corticosteroid treatment of ≥30 consecutive days duration within 2 months prior to screening visit.
  19. Previous total body irradiation or total lymphoid irradiation.
  20. Previous stem-cell treatment, autologous bone marrow transplantation or allogenic bone marrow transplantation.
  21. A known history of tuberculosis.
  22. Acute infection 2 weeks prior to baseline visit.
  23. Major trauma or surgery 2 weeks prior to baseline visit.
  24. A history of vascular thrombosis (excluding catheter-site superficial venous thrombophlebitis).
  25. A carrier state of factor V Leiden mutation (either homo- or heterozygous) by history or as disclosed at screening.
  26. Positive screening test for Hepatitis B surface antigen, Hepatitis C antibody, or HIV antibody as disclosed at screening visit.
  27. Use of potent inhibitors of CYP3A4 within 2 weeks prior to baseline visit (see detailed list of drugs in protocol) (1 month for fluoxetine).
  28. Use of amiodarone within 2 years prior to screening visit.
  29. Pregnancy or breastfeeding.
  30. 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.
  31. 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.
  32. A known history of sensitivity to Gadolinium.
  33. Inability to successfully undergo MRI scanning.
  34. A known history of hypersensitivity to natural or recombinant interferon beta, human albumin, or any other component of the formulation of Avonex®.

Exclusion Criteria:

  1. Subjects who suffer from any form of progressive MS
  2. Any condition which the investigator feels may interfere with participation in the study
  3. Subjects with a clinically significant or unstable medical or surgical condition that would preclude safe and complete study participation
  4. Subjects who received any investigational medication, immunosuppressives or cytotoxic agents within 6 months prior to screening
  5. Previous treatment with immunomodulators within two months prior to screening
  6. Pregnancy or breastfeeding
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 55 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Italy,   Bulgaria,   Croatia,   Czech Republic,   Estonia,   Georgia,   Germany,   Israel,   Lithuania,   Macedonia, The Former Yugoslav Republic of,   Poland,   Puerto Rico,   Romania,   Russian Federation,   Slovakia,   South Africa,   Spain,   Ukraine,   United States
Removed Location Countries Latvia,   Montenegro,   Turkey
Administrative Information
NCT Number  ICMJE NCT00605215
Other Study ID Numbers  ICMJE MS-LAQ-302
EUDRACT 2007-005450-23
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Teva Pharmaceutical Industries
Study Sponsor  ICMJE Teva Pharmaceutical Industries
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Timothy L. Vollmer St. Joseph's Hospital & Medical Center
PRS Account Teva Pharmaceutical Industries
Verification Date August 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP