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A randomized placebo-controlled phase III trial of oral laquinimod for multiple sclerosis

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Abstract

The phase III placebo-controlled BRAVO study assessed laquinimod effects in patients with relapsing-remitting MS (RRMS), and descriptively compared laquinimod with interferon beta (IFNβ)-1a (Avonex® reference arm). RRMS patients age 18–55 years with Expanded Disability Status Scale (EDSS) scores of 0–5.5 and documented pre-study relapse (≥ 1 in previous year, 2 in previous 2 years, or 1 in previous 1–2 years and ≥ 1 GdE lesion in the previous year) were randomized (1:1:1) to laquinimod 0.6 mg once-daily, matching oral placebo, or IFNβ-1a IM 30 μg once-weekly (rater-blinded design), for 24 months. The primary endpoint was annualized relapse rate (ARR); secondary endpoints included percent brain volume change (PBVC) and 3-month confirmed disability worsening. In all, 1,331 patients were randomized: laquinimod (n = 434), placebo (n = 450), and IFNβ-1a (n = 447). ARR was not significantly reduced with laquinimod [−18 %, risk ratio (RR) = 0.82, 95 % CI 0.66–1.02; p = 0.075] vs. placebo. Laquinimod significantly reduced PBVC (28 %, p < 0.001). Confirmed disability worsening was infrequent (10 % laquinimod, 13 % placebo). The change in confirmed disability worsening with laquinimod measured using EDSS was −31 % [hazard ratio (HR) 0.69, p = 0.063], and using Multiple Sclerosis Functional Composite (MSFC) z-score was −77 % (p = 0.150), vs. placebo. IFNβ-1a reduced ARR 26 % (RR = 0.74, 95 % CI 0.60–0.92, p = 0.007), showed no effect on PBVC loss (+11 %, p = 0.14), and changes in disability worsening were −26 and −66 % as measured using the EDSS (HR 0.742, p = 0.13) and MSFC (p = 0.208), respectively. Adverse events occurred in 75, 82, and 70 % of laquinimod, IFNβ-1a, and placebo patients, respectively. Once-daily oral laquinimod 0.6 mg resulted in statistically nonsignificant reductions in ARR and disability progression, but significant reductions in brain atrophy vs. placebo. Laquinimod was well-tolerated.

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Acknowledgments

We thank the Independent Data Monitoring Committee, the staff of NeuroRx Research, the MRI Analysis Center, and the Principal Investigators for each country; Yulia Sidi, M.A. of the Teva Statistical Data Management Team (Netanya, Israel) managed the statistical analyses; Pippa Loupe, Ph.D. of Medical Affairs, Teva Pharmaceuticals (Kansas City, MO), and two independent medical writers, paid by the sponsor, James D. Bergstrom, Ph.D. of Mountain Stream Communications, LLC (Hillsborough, NJ), and Sheila Truten, B.S. of Medical Communication Company (Wynnewood, PA) collaborated with the authors on the first draft of the paper, copyedited the manuscript and prepared figures and tables.

Supported by Teva Pharmaceutical Industries, Ltd., Petach Tikva, Israel.

Conflicts of interest

TL Vollmer has received consulting fees, and his institution has received a grant and consulting fee for his participation in the BRAVO study; he is a board member of Rocky Mountain MS Center; his institution has received consultancy fees from Biogen Idec, Teva, Elan, Hoffman-LaRoche, Accelerated Cure Project, Genzyme, Bristol-Myers Squibb, Acorda, Novartis, Questor, Medscape, Xenoport, and Sanofi; his institution received fees for expert testimony from Ham VS Bennett and Wagner VS Strand; his institution received grants/grants pending from Teva, Biogen Idec, Genzyme, Ono, Eli Lilly, Novartis, BioMS, Orasi, Sanofi-Aventis, NIH, EMD Sorono, Acorda, Accelerated Cure Project, Hoffmann-LaRoche, Jensen Research, Daiichi Sankyo, Elan, Janssen Pharmaceutical, Avanir Pharmaceutical, MedImmune, Delta Quest, Biosite Inc., University of Alabama, and Genentech.

PS Sorensen has received payment as co-principal investigator and for travel support for the BRAVO study from Teva; he has received consultancy fees from Merck Serono, Teva, Novartis, Sanofi-Aventis, and Biogen Idec; his institution has received research support grants/grants pending from Biogen Idec, Novartis, and Sanofi-Aventis; and he is on the speaker’s bureau of Merck Serono, Novartis, Bayer Schering, Teva, Sanofi-Aventis, Biogen Idec, and Genzyme.

K Selmaj has received compensation for consulting and speaking from Biogen Idec, Genzyme, Novartis, Merck Serono, Roche, and Teva.

F Zipp’s institution received a grant from Teva for participation in BRAVO and has received grants/grants pending from Novartis and Merck Serono; she has received fees for consultancy with Merck-Serono, Ono, Sanofi-Aventis, and Biogen; she is a board member of Octapharma; and serves on the speaker’s bureau of Novartis, Merck-Serono, Biogen, Genzyme, and Sanofi-Aventis.

E Havrdova’s institution received funding for clinical trial participation, she has received compensation for consultancy from Biogen Idec, Genzyme, Merck Serono, and Novartis; serves on the speaker’s bureaus of Biogen Idec, Merck Serono, Novartis, and Teva; her institution has received a grant/grant pending from Biogen Idec.

JA Cohen received, in the previous 2 years, compensation for consulting from Teva and Vaccinex; his institution received research support from Biogen Idec, Novartis, Receptos, Synthon, Teva, US Department of Defense, National Institutes of Health, and National MS Society.

N Sasson is employed by Teva; owns stock in and receives travel/meeting expenses from Teva.

Y Gilgun-Sherki is employed by Teva; owns stock in and receives travel/meeting expenses from Teva; and is a co-holder of patents with Teva.

D Arnold has received fees for consulting, travel support, and research related to the BRAVO study; has received consultancy fees from Biogen Idec, EMD Serono, Genentech, Glaxo Smith Kline, Merck Serono, Mitsubishi, Novartis, and Roche; his institution has received grants/grants pending from Bayer Healthcare, CIHR, and MSSC and owns US patent No. 6,347,239.

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Authors and Affiliations

  1. Department of Neurology, University of Colorado, Aurora, CO, USA

    T. L. Vollmer

  2. Danish Multiple Sclerosis Center, University of Copenhagen, Copenhagen, Denmark

    P. S. Sorensen

  3. Department of Neurology, Rigshospitalet, Copenhagen, Denmark

    P. S. Sorensen

  4. Department of Neurology, Medical University of Łódź, Lodz, Poland

    K. Selmaj

  5. Department of Neurology, Rhine Main Neuroscience Network, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany

    F. Zipp

  6. First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic

    E. Havrdova

  7. The Mellen Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA

    J. A. Cohen

  8. Teva Statistical Data Management Team, Teva Pharmaceuticals, Netanya, Israel

    N. Sasson

  9. Teva Innovative Research and Development, Teva Pharmaceuticals, Netanya, Israel

    Y. Gilgun-Sherki

  10. McGill University, Montreal, QC, Canada

    D. L. Arnold

  11. NeuroRx Research, Montreal, QC, Canada

    D. L. Arnold

  12. Rocky Mountain MS Center, Rocky Mountain MS Clinic, Anschutz Medical Center, University of Colorado, Denver, RM L15-5511, A01, Mail stop B185, 12631 E 17th Avenue, Aurora, CO, 80045, USA

    T. L. Vollmer

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On behalf of the BRAVO Study Group

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Correspondence to T. L. Vollmer.

Additional information

T. L. Vollmer and P. S. Sorensen were co-principal investigators for the BRAVO trial, contributed equally to the manuscript, and should be considered equal lead authors on this publication.

N. Sasson of Teva Pharmaceutical Industries provided statistical support for the manuscript.

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Vollmer, T.L., Sorensen, P.S., Selmaj, K. et al. A randomized placebo-controlled phase III trial of oral laquinimod for multiple sclerosis. J Neurol 261, 773–783 (2014). https://doi.org/10.1007/s00415-014-7264-4

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