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Original research
Long-term safety and efficacy of deutetrabenazine for the treatment of tardive dyskinesia
  1. Hubert H Fernandez1,
  2. David Stamler2,
  3. Mat D Davis3,
  4. Stewart A Factor4,
  5. Robert A Hauser5,
  6. Joohi Jimenez-Shahed6,
  7. William G Ondo7,8,
  8. L Fredrik Jarskog9,
  9. Scott W Woods10,
  10. Danny Bega11,
  11. Mark S LeDoux12,
  12. David R Shprecher13,14,
  13. Karen E Anderson15
  1. 1 Center for Neurological Restoration, Cleveland Clinic Foundation, Cleveland, Ohio, USA
  2. 2 Former employee of Teva Pharmaceuticals, La Jolla, California, USA
  3. 3 Teva Pharmaceuticals, Frazer, Pennsylvania, USA
  4. 4 Jean and Paul Amos Parkinson’s Disease and Movement Disorder Program, Emory University School of Medicine, Atlanta, Georgia, USA
  5. 5 University of South Florida Parkinson’s Disease and Movement Disorders Center, Tampa, Florida, USA
  6. 6 Baylor College of Medicine, Houston, Texas, USA
  7. 7 Methodist Neurological Institute, Houston, Texas, USA
  8. 8 Weill Cornell Medical College, New York, New York, USA
  9. 9 University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA
  10. 10 Yale University School of Medicine, New Haven, Connecticut, USA
  11. 11 Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
  12. 12 University of Tennessee Health Science Center, Memphis, Tennessee, USA
  13. 13 University of Utah, Salt Lake City, Utah, USA
  14. 14 Banner Sun Health Research Institute, Sun City, Arizona, USA
  15. 15 Georgetown University, Washington, District of Columbia, USA
  1. Correspondence to Professor Hubert H Fernandez, Center for Neurological Restoration, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; fernanh{at}ccf.org

Abstract

Objective To evaluate the long-term safety and efficacy of deutetrabenazine in patients with tardive dyskinesia (TD).

Method Patients with TD who completed the 12 week, phase 3, placebo-controlled trials were eligible to enter this open-label, single-arm study. The open-label study consisted of a 6 week dose-escalation phase and a long-term maintenance phase (clinic visits at Weeks 4, 6 and 15, and every 13 weeks until Week 106). Patients began deutetrabenazine at 12 mg/day, titrating up to a dose that was tolerable and provided adequate dyskinesia control, based on investigator judgement, with a maximum allowed dose of 48 mg/day (36 mg/day for patients taking strong cytochrome P450 2D6 (CYP2D6) inhibitors). Safety measures included incidence of adverse events (AEs) and scales used to monitor parkinsonism, akathisia/restlessness, anxiety, depression, suicidality and somnolence/sedation. Efficacy endpoints included the change in Abnormal Involuntary Movement Scale (AIMS) score (items 1 to 7) from baseline and the proportion of patients rated as ‘Much Improved’ or ‘Very Much Improved’ on the Clinical Global Impression of Change.

Results A total of 343 patients enrolled in the extension study, and there were 331 patient-years of exposure in this analysis. The exposure-adjusted incidence rates of AEs with long-term treatment were comparable to or lower than those observed in the phase 3 trials. The mean (SE) change in AIMS score was –4.9 (0.4) at Week 54 (n = 146), – 6.3 (0.7) at Week 80 (n = 66) and –5.1 (2.0) at Week 106 (n = 8).

Conclusions Overall, long-term treatment with deutetrabenazine was efficacious, safe, and well tolerated in patients with TD.

Trial registration number NCT02198794.

  • tardive dyskinesia
  • deutetrabenazine
  • movement disorders
  • vmat2 inhibitor

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Footnotes

  • Contributors HHF, significant content-related direction, data acquisition and analysis, contribution to the writing of the draft and feedback on all relevant materials throughout the development of the manuscript. DS, significant content-related direction, data acquisition and analysis, contribution to the writing of the draft and feedback on all relevant materials throughout the development of the manuscript. MDD, significant content-related direction, data acquisition and analysis, contribution to the writing of the draft and feedback on all relevant materials throughout the development of the manuscript. SAF, significant content-related direction, data acquisition and analysis, contribution to the writing of the draft and feedback on all relevant materials throughout the development of the manuscript. RAH, significant content-related direction, data acquisition and analysis, contribution to the writing of the draft and feedback on all relevant materials throughout the development of the manuscript. JJ-S, significant content-related direction, data acquisition and analysis, contribution to the writing of the draft and feedback on all relevant materials throughout the development of the manuscript. WGO, significant content-related direction, data acquisition and analysis, contribution to the writing of the draft and feedback on all relevant materials throughout the development of the manuscript. LFJ, significant content-related direction, data acquisition and analysis, contribution to the writing of the draft and feedback on all relevant materials throughout the development of the manuscript. SWW, significant content-related direction, data acquisition and analysis, contribution to the writing of the draft and feedback on all relevant materials throughout the development of the manuscript. DB, significant content-related direction, data acquisition and analysis, contribution to the writing of the draft and feedback on all relevant materials throughout the development of the manuscript. MSL, significant content-related direction, data acquisition and analysis, contribution to the writing of the draft and feedback on all relevant materials throughout the development of the manuscript. DRS, significant content-related direction, data acquisition and analysis, contribution to the writing of the draft and feedback on all relevant materials throughout the development of the manuscript. KEA, significant content-related direction, data acquisition and analysis, contribution to the writing of the draft and feedback on all relevant materials throughout the development of the manuscript.

  • Funding This study was funded by Teva Pharmaceuticals, Petach Tikva, Israel.

  • Competing interests HHF has received honoraria from Prime Education, Inc, International Parkinson and Movement Disorders Society, Carling Communications, Medscape (speaker in CME events), AbbVie, Biogen, GE Health Care, Inventiv, Kyowa Hakko Kirin, Lundbeck, Merz Pharmaceuticals, Voyager, Sunovion, Pfizer Pharmaceuticals (as a consultant). He has received grant and research support from: AbbVie, Acadia, Teva, Biotie/Acorda Therapeutics, Civitas, Kyowa/Prostrakan, Michael J. Fox Foundation, Movement Disorders Society, NIH/NINDS, Parkinson Study Group, Rhythm, Synosia; he has no owner interest in any pharmaceutical company. He has received royalties from: Demos Publishing (serving as a book author/editor). The Cleveland Clinic has a contract with Teva for his role as a Co-Principal Investigator in SD-809 tardive dyskinesia global studies. He also serves as a member of the publication committee for Acorda Pharmaceuticals but does not receive any personal compensation for this. He receives a stipend from the International Parkinson and Movement Disorders Society for serving as Medical Editor of the MDS Web Site. DS is a former employee of Teva Pharmaceuticals; he has received salary and benefits from Auspex Pharmaceuticals, and has patents pending: US20160346270, US20160287574. MDD is an employee of Teva Pharmaceuticals. SAF has received honoraria from Neurocrine, Lundbeck, Teva, Avanir, UCB, US WorldMeds, Sunovion, Adamas; he has received research support from Ipsen, Medtronic, Auspex, US WorldMeds, Pharm-Olam, Cynapsus Therapeutics/Sunovion, Vaccinex, Solstice, CHDI Foundation, Michael J. Fox Foundation, NIH; he has received royalties from Demos, Blackwell Futura for textbooks, and UpToDate. RAH has served as a consultant for Teva Pharmaceuticals, AbbVie, Inc, Acorda Therapeutics, Adamas Pharmaceuticals, AstraZeneca, Biotie Therapies, Cynapsus Therapeutics, Impax Laboratories, Inc, Lundbeck LLC, Michael J Fox Foundation, Neurocrine Biosciences, Neuropore Therapies, Pfizer Inc, Prexton Therapeutics, US WorldMeds, Guidepoint Global, Gerson Lehrman Group (GLG), LCN Consulting, Putnam Associates, National Parkinson Foundation, eResearch Technology, Inc, Sarepta Therapeutics, Back Bay Life Science, National Institutes of Health, Projects in Knowledge, Vista Research, LifeMax, Peerview Press, ClinicalMind Medical and Therapeutic Communications, Sunovion Pharmaceuticals, Academy for Continued Healthcare Learning, Outcomes Insights, Expert Connect, HealthLogix, Cowen and Company, Pharma Two B, Ltd, RMEI Medical Education for Better Outcomes, ClearView Healthcare Partners, Health Advances, Kyowa Kirin Pharmaceutical Development, Ltd, Quintiles, and Eli Lilly and Company. JJ-S has received research support from Acadia Pharmaceuticals, St. Jude Medical, Biotie, Michael J. Fox Foundation; she has served as a consultant for Teva, St. Jude Medical, Medtronic; she has also received honoraria from Vindico Medical Education. WGO has received research support from Lundbeck, Tremor Research Group, Dystonia Coalition, Restless Leg Syndrome Foundation, Acorda. Speakers’ Bureau: Teva, Lundbeck, UCB, US WorldMeds; he has served as a consultant for Teva, Lundbeck, Acadia. LFJ has received grant support Auspex/Teva, Boehringer Ingelheim, Otsuka, NIH; he has served as a consultant for Roche. SWW has received research support from Teva, Pfizer; he has served as a consultant for Boehringer Ingelheim, Nutria Health. DB has received research support from National Parkinson Foundation; he has served on the speaker’s bureau for Teva Pharmaceuticals and Acadia Pharmaceuticals, Inc; he has served as a consultant for Teva, Cynapsus, Acadia. MSL has served on the speakers’ bureau for Lundbeck, Acadia, and Teva; he has served as a consultant for Teva Neuroscience, US WorldMeds, the Mayo Clinic, Starnes-Davis-Florie, Elite Medical Experts, Spears, Moore, Rebman receives research support from the National Institutes of Health (R01 NS082296, R21 GM118962, U54 TR001456, 5U01 NS090259), Department of Defense (W81XWH-17-1-0062), Michael J. Fox Foundation, Dorothy/Daniel Gerwin Parkinson’s Research Fund, Auspex, Teva, Acorda, US WorldMeds, Axovant and CHDI; and receives royalty payments from Elsevier for editing ‘Animal Models of Movement Disorders’ and ‘Movement Disorders: Genetics and Models.’ DRS has served as a consultant for Eli Lilly, Teva, Lundbeck, and Weston Brain Institute; he has received speaker’s fees from Acadia, Baylor College of Medicine, the Arizona Psychiatric Society, Lundbeck, Teva US World Meds and the Tourette Association of America; he has received research support from Arizona Alzheimer’s Consortium, Axovant, Biotie, Intec, Kyowa, Teva, US WorldMeds, Neurocrine, Michael J. Fox Foundation, and the NIH. KEA has served as a scientific adviser and was the North American study Co-Principal Investigator for LEGATO-HD, Global Principal Investigator for AIM-TD, and Global Co-Principal Investigator for ARM-TD; she was the site Principal Investigator for Pride-HD, First-HD, ARC-HD for Teva; she was the scientific advisor and site Principal Investigator for ENROLL-HD for CHDI Foundation; she was a scientific advisor for Prana and site Principal Investigator for Vaccinex; she served as a consultant for the NeuroNext 105 study for Azevan; she has received salary support from the Griffin Foundation. She has also received honoraria from Vindico Medical Education.

  • Patient consent for publication Obtained.

  • Ethics approval Before this study was initiated, the protocol was submitted to the Independent Ethics Committee (IEC)/Institutional Review Board (IRB) according to national or local regulations. Any protocol amendments were also submitted. Written informed consent was obtained from each patient before any study procedures or assessments were done.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

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