Subthalamic nucleus deep brain stimulation with a multiple independent constant current-controlled device in Parkinson's disease (INTREPID): a multicentre, double-blind, randomised, sham-controlled study

Jerrold L. Vitek, Roshini Jain, Lilly Chen, Alexander I. Tröster, Lauren E. Schrock, Paul A. House, Monique L. Giroux, Adam O. Hebb, Sierra M. Farris, Donald M. Whiting, Timothy A. Leichliter, Jill L. Ostrem, Marta San Luciano, Nicholas Galifianakis, Leo Verhagen Metman, Sepehr Sani, Jessica A. Karl, Mustafa S. Siddiqui, Stephen B. Tatter, Ihtsham ul HaqAndre G. Machado, Michal Gostkowski, Michele Tagliati, Adam N. Mamelak, Michael S. Okun, Kelly D. Foote, Guillermo Moguel-Cobos, Francisco A. Ponce, Rajesh Pahwa, Jules M. Nazzaro, Cathrin M. Buetefisch, Robert E. Gross, Corneliu C. Luca, Jonathan R. Jagid, Gonzalo J. Revuelta, Istvan Takacs, Michael H. Pourfar, Alon Y. Mogilner, Andrew P. Duker, George T. Mandybur, Joshua M. Rosenow, Scott E. Cooper, Michael C. Park, Suketu M. Khandhar, Mark Sedrak, Fenna T. Phibbs, Julie G. Pilitsis, Ryan J. Uitti, Philip A. Starr

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Background: Deep brain stimulation (DBS) of the subthalamic nucleus is an established therapeutic option for managing motor symptoms of Parkinson's disease. We conducted a double-blind, sham-controlled, randomised controlled trial to assess subthalamic nucleus DBS, with a novel multiple independent contact current-controlled (MICC) device, in patients with Parkinson's disease. Methods: This trial took place at 23 implanting centres in the USA. Key inclusion criteria were age between 22 and 75 years, a diagnosis of idiopathic Parkinson's disease with over 5 years of motor symptoms, and stable use of anti-parkinsonian medications for 28 days before consent. Patients who passed screening criteria were implanted with the DBS device bilaterally in the subthalamic nucleus. Patients were randomly assigned in a 3:1 ratio to receive either active therapeutic stimulation settings (active group) or subtherapeutic stimulation settings (control group) for the 3-month blinded period. Randomisation took place with a computer-generated data capture system using a pre-generated randomisation table, stratified by site with random permuted blocks. During the 3-month blinded period, both patients and the assessors were masked to the treatment group while the unmasked programmer was responsible for programming and optimisation of device settings. The primary outcome was the difference in mean change from baseline visit to 3 months post-randomisation between the active and control groups in the mean number of waking hours per day with good symptom control and no troublesome dyskinesias, with no increase in anti-parkinsonian medications. Upon completion of the blinded phase, all patients received active treatment in the open-label period for up to 5 years. Primary and secondary outcomes were analysed by intention to treat. All patients who provided informed consent were included in the safety analysis. The open-label phase is ongoing with no new enrolment, and current findings are based on the prespecified interim analysis of the first 160 randomly assigned patients. The study is registered with ClinicalTrials.gov, NCT01839396. Findings: Between May 17, 2013, and Nov 30, 2017, 313 patients were enrolled across 23 sites. Of these 313 patients, 196 (63%) received the DBS implant and 191 (61%) were randomly assigned. Of the 160 patients included in the interim analysis, 121 (76%) were randomly assigned to the active group and 39 (24%) to the control group. The difference in mean change from the baseline visit (post-implant) to 3 months post-randomisation in increased ON time without troublesome dyskinesias between the active and control groups was 3·03 h (SD 4·52, 95% CI 1·3–4·7; p<0·0001). 26 serious adverse events in 20 (13%) patients occurred during the 3-month blinded period. Of these, 18 events were reported in the active group and 8 in the control group. One death was reported among the 196 patients before randomisation, which was unrelated to the procedure, device, or stimulation. Interpretation: This double-blind, sham-controlled, randomised controlled trial provides class I evidence of the safety and clinical efficacy of subthalamic nucleus DBS with a novel MICC device for the treatment of motor symptoms of Parkinson's disease. Future trials are needed to investigate potential benefits of producing a more defined current field using MICC technology, and its effect on clinical outcomes. Funding: Boston Scientific.

Original languageEnglish (US)
Pages (from-to)491-501
Number of pages11
JournalThe Lancet Neurology
Volume19
Issue number6
DOIs
StatePublished - Jun 2020

Bibliographical note

Funding Information:
JLV serves as a consultant for Medtronic, Boston Scientific, and Abbott, and serves on the scientific advisory board for Surgical Information Systems. RJ, LC, and SMF are salaried employees of Boston Scientific. At the start of this study, SMF and MLG were previously employed at the Movement and Neuroperformance Center of Colorado. AIT reports personal fees and consulting fees from Boston Scientific during the conduct of the study; personal fees from Medtronic, Axovant, Voyager Therapeutics, Takeda, and Aptinyx; grants from Barrow Neurological Foundation and Michael J Fox Foundation; and royalties from Oxford University Press, outside the submitted work. LES reports grants from Boston Scientific during the conduct of the study. JLO has received research grant support from the Michael J Fox Foundation, Boston Scientific, Cala Health, National Institutes of Health, Defense Advanced Research Projects Agency, Patient-Centered Outcomes Research Institute, and Biogen. She has also received training grant support from Boston Scientific and Medtronic, has served as a consultant for Acadia Pharmaceuticals and Medtronic, and has received grants from Allergan, Merz, and AbbVie for fellowship training, outside the submitted work. MSL reports personal fees from Boston Scientific, outside the submitted work. LVM reports personal fees from Boston Scientific, grants and personal fees from Abbott, and grants from Medtronic, outside the submitted work. MSS reports grants, personal fees, and non-financial support from Boston Scientific and AbbVie, and grants from Sunovion Pharma, Biogen, Theravance Biopharma, Neuropoint Alliance/Michael J Fox Foundation, Impax Lab, and Sun Pharma, outside the submitted work. SBT reports grants from Boston Scientific during the conduct of the study, and grants from Boston Scientific, outside the submitted work. IuH reports grants from Boston Scientific during the conduct of the study, and advisory board participation from Boston Scientific, outside the submitted work. He is also an investigator on ongoing grants supported directly or indirectly by Boston Scientific. AGM reports intellectual property and distribution rights from Enspire DBS and Cardionomics, grants and personal fees from Abbott, and grants from Medtronic, outside the submitted work. MT reports grants and personal fees from Medtronic and Abbott, and personal fees from Boston Scientific, outside the submitted work. MSO reports grants from National Institutes of Health (R01 NR014852 and R01NS096008), Tourette Association of America, Michael J Fox Foundation, and Parkinson's Foundation; book and continuing medical education programme royalties and education from Books4 Patients; speaker fees from Movement Disorders Society and American Academy of Neurology; and continuing medical education courses and steering committees from Medscape, WebMD, MedEdicus, Academy of Learning Healthcare, Boston University CME, and Vanderbilt University, outside the submitted work. KDF reports grants and personal fees from Medtronic and Boston Scientific, and grants from Abbott/St. Jude Medical and Functional Neuromodulation, outside the submitted work. FAP reports personal fees from Medtronic, Boston Scientific, and Abbott, outside the submitted work. RP reports clinical trial fees from Boston Scientific, during the conduct of the study; personal fees from Abbott, AbbVie, Acadia, Acorda, Adamas, Amneal, Cala, Global Kinetics, Impel Neuropharma, Kyowa, Lundbeck, Mitsubishi, Neurocrine, Orbis Bioscience, PhotoPharmics, Prilenia, Sunovion, Teva Neuroscience, and US World Meds; and grants from Abbott, AbbVie, Acorda, Biogen, Biohaven, Boston Scientific, Cala Health, Cavion, Cynapsus, Impax, Intec, Kyowa, Lilly, National Institutes of Health/National Institute of Neurological Disorders and Stroke, National Parkinson Foundation, Prelinia, Parkinson Study Group, Roche, Sunovion, Theranexus, Theravance, US WorldMeds, and Voyager, outside the submitted work. CMB reports grants from Boston Scientific, during the conduct of the study. REG reports grants from Boston Scientific, during the conduct of the study; personal fees from Boston Scientific and Abbott; and grants and personal fees from Medtronic, outside the submitted work. CCL reports personal fees from Boston Scientific, outside the submitted work. JRJ reports grants from Boston Scientific, and grants and personal fees from Medtronic, outside the submitted work. MHP reports personal fees from Boston Scientific, outside the submitted work. AYM reports grants and personal fees from Boston Scientific, during the conduct of the study. APD reports grants from Boston Scientific, during the conduct of the study. GTM reports grants and personal fees from Boston Scientific, Abbott, and Nevro, outside the submitted work. JMR reports research expenses from Boston Scientific, during the conduct of the study, and personal fees from Boston Scientific, outside the submitted work. SEC reports grant from Medtronic, outside the submitted work. MCP reports grants from Boston Scientific, during the conduct of the study; grants and personal fees from Boston Scientific and Medtronic; and personal fees from Zimmer Biomet, Smart Implant Systems/SynerFuse, Abbott, NeuroOne, and St. Jude Medical, outside the submitted work. He also reports a pending US patent (“Treating epilepsy and other neurological disorders by targeting therapy to the endopiriform nucleus using ultra-high field magnetic resonance imaging”). FTP reports consulting fees from Medtronic and Boston Scientific. JGP reports grants and consulting fees from Boston Scientific, during the conduct of the study. PAS reports non-financial support from Boston Scientific, during the conduct of the study, and non-financial support and funding for fellowship training from Medtronic, outside the submitted work. He also reports a patent (US patent number 9 295 838, “Methods and systems for treating neurological movement disorders”) relevant to deep brain stimulation. All other authors report no competing interests.

Funding Information:
The study was funded by Boston Scientific.

PubMed: MeSH publication types

  • Journal Article
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

Fingerprint Dive into the research topics of 'Subthalamic nucleus deep brain stimulation with a multiple independent constant current-controlled device in Parkinson's disease (INTREPID): a multicentre, double-blind, randomised, sham-controlled study'. Together they form a unique fingerprint.

Cite this