IRB indicates institutional review board; NINDS, National Institute of Neurologic Diseases and Stroke; PI, principal investigator.
ESC indicates extramural science committee; NEC, National Institute of Neurological Disorders and Stroke Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) executive committee; NINDS, National Institute of Neurologic Diseases and Stroke.
aFirst study funded prior to NeuroNEXT formation.
FPFV indicates first patient, first visit; NoGA, notice of grant award.
cIRB indicates central institutional review board; LPLV, last patient, last visit.
eTable. Proposals submitted to Network (Oct 2011 – June 2018)
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Cudkowicz M, Chase MK, Coffey CS, et al. Seven-Year Experience From the National Institute of Neurological Disorders and Stroke–Supported Network for Excellence in Neuroscience Clinical Trials. JAMA Neurol. Published online March 23, 2020. doi:10.1001/jamaneurol.2020.0367
One major advantage of developing large, federally funded networks for clinical research in neurology is the ability to have a trial-ready network that can efficiently conduct scientifically rigorous projects to improve the health of people with neurologic disorders.
National Institute of Neurological Disorders and Stroke Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) was established in 2011 and renewed in 2018 with the goal of being an efficient network to test between 5 and 7 promising new agents in phase II clinical trials. A clinical coordinating center, data coordinating center, and 25 sites were competitively chosen. Common infrastructure was developed to accelerate timelines for clinical trials, including central institutional review board (a first for the National Institute of Neurological Disorders and Stroke), master clinical trial agreements, the use of common data elements, and experienced research sites and coordination centers. During the first 7 years, the network exceeded the goal of conducting 5 to 7 studies, with 9 funded. High interest was evident by receipt of 148 initial applications for potential studies in various neurologic disorders. Across the first 8 studies (the ninth study was funded at end of initial funding period), the central institutional review board approved the initial protocol in a mean (SD) of 59 (21) days, and additional sites were added a mean (SD) of 22 (18) days after submission. The median time from central institutional review board approval to first site activation was 47.5 days (mean, 102.1; range, 1-282) and from first site activation to first participant consent was 27 days (mean, 37.5; range, 0-96). The median time for database readiness was 3.5 months (mean, 4.0; range, 0-8) from funding receipt. In the 4 completed studies, enrollment met or exceeded expectations with 96% overall data accuracy across all sites. Nine peer-reviewed manuscripts were published, and 22 oral presentations or posters and 9 invited presentations were given at regional, national, and international meetings.
Conclusions and Relevance
NeuroNEXT initiated 8 studies, successfully enrolled participants at or ahead of schedule, collected high-quality data, published primary results in high-impact journals, and provided mentorship, expert statistical, and trial management support to several new investigators. Partnerships were successfully created between government, academia, industry, foundations, and patient advocacy groups. Clinical trial consortia can efficiently and successfully address a range of important neurologic research and therapeutic questions.
Neurologic disorders impose a substantial burden on patients and society.1 Potential exists to change this if recent discoveries in basic neuroscience can be capitalized on. Challenges to efficient development of treatments include recruiting capable study sites, regulatory approval delays, recruitment barriers,2 and a paucity of suitable biomarkers for nervous system disorders and of individuals trained to design and lead multicenter trials.3 Interest in novel trial designs is increasing,4,5 and the National Institute of Neurological Disorders and Stroke (NINDS) Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) may provide clinical trialists with a unique opportunity to use such designs.
By facilitating collaboration, capacity, and training, trial networks can expedite therapy development.6 A successful federally supported network, Neurological Emergencies Treatment Trials, conducting phase III randomized clinical trials began in 2007.7 Master clinical trial agreements (MCTA) were used, but the environment was not ripe for central institutional review boards (cIRB).8 NeuroNEXT was uniquely positioned in 2011 to expand the capabilities and achievements of networks.9,10 StrokeNet, developed in 2013, focused on stroke prevention, intervention, and rehabilitation/recovery.11 In 2017, NINDS and the National Heart, Lung, and Blood Institute cofunded a new emergency network, Strategies to Innovate Emergency Care Clinical Trials Network, for emergencies in neurology, hematology, and cardiopulmonary medicine.
NeuroNEXT demonstrates that innovative technologies and experienced trial staff can speed start-up, accelerate enrollment, and ensure high-quality studies. The goal to conduct 5 to 7 studies during a 7-year funding period was exceeded, with 9 studies funded. NeuroNEXT infrastructure and metrics based on the first 7 years are described with suggestions for future networks and approaches for therapy development.
NeuroNEXT comprises a clinical coordinating center (CCC), a data coordinating center (DCC), and 25 clinical sites (some of which comprise more than 1 institution) (Figure 1). A NINDS-supported data and safety monitoring board12 oversees funded studies, and an external scientific advisory board provides oversight. Sites were chosen based on experience in clinical trial recruitment and conduct, breadth of clinical expertise, and access to relevant populations; they are led by experienced clinical trialists and have a dedicated coordinator. The CCC provides clinical design advice, regulatory, project, and budget management and manages site contracts, cIRB, central laboratory, and central pharmacy, while the DCC provides statistical and trial design support, data management and analysis, and study monitoring.
Leadership and policy development are provided through the NeuroNEXT executive committee and other network committees listed in Figure 1. The NeuroNEXT executive committee provides guidance, reviews study proposals for feasibility, and selects sites for each study. The number of sites per study is recommended in each grant application and selection is based on detailed feasibility questionnaires completed by each network site after funding is awarded. The foundation of network operations was defined in the first 6 months of funding with the development of standard operating procedures, a network website, and execution of reliance agreements with each site by a newly established cIRB. The cIRB model developed was previously described.9 In collaboration with NINDS, the CCC developed an MCTA, tied to each site’s infrastructure grant with NINDS, which covers all studies conducted within the network.
Nine studies were funded through NeuroNEXT grant mechanisms (Table). All available grant mechanisms were used within the first set of funded proposals: 1 small business innovation research (U44), 1 industry (X01), and the remaining, academic (U01). Results from 3 studies have been published.13,17,19 A fourth study completed with the results presented and the primary manuscript drafted. The remaining studies are currently active.
Three of 9 funded protocol principal investigators are new clinical trial researchers, including 1 PhD investigator. In addition, the CCC and DCC assisted 25 investigators, including 12 who were writing a National Institutes of Health (NIH) grant for the first time to submit initial grant applications and 14 resubmissions. Nine peer-reviewed manuscripts were published,9,13-20 22 oral presentations or posters, and 9 invited presentations have been given at regional, national, or international meetings.
The preaward process and data from the 9 studies funded are detailed in Figure 2. The CCC and DCC staff work with investigators on study design, operational logistics, and preparation of a study budget. The DCC uses a team of faculty biostatisticians who partner with CCC clinical trialists (leads) to provide the appropriate design and outcome measures for a successful phase II trial. Per NIH policy, all studies anticipated to cost more than $500 000 in any grant year undergo review by the NINDS extramural science committee, which must grant approval for an applicant to proceed.
Grants are submitted by the protocol principal investigators with assistance from the CCC and DCC. In the first 7 years, the NeuroNEXT executive committee reviewed 148 proposals for a wide variety of neurologic diseases, 70 (47%) of which were deemed feasible based on data collected from sites to assess interest, availability of patient population, and resources to conduct the study. Of these, 17 were declined by the NINDS extramural science committee after NeuroNEXT executive committee approval (2 of those 17 were funded elsewhere), 3 were pending review by the extramural science committee, 25 were withdrawn (2 transferred to StrokeNet, 10 withdrew owing to inactivity, 13 withdrew owing to principal investigator choice), and 25 initial grant applications were submitted (the NN101 study was funded based on request for application issued prior to the network formation). One grant received a fundable score on initial review (NN107 study), 14 responded to critiques of initial review in a resubmission, and of those, 7 (50%) were funded. The timeline for preaward activities for each of the 8 funded grants are provided in Figure 3A. The median time from proposal submission to initial grant submission was 10 months, from initial proposal to grant resubmission was 19 months, and from initial proposal to funding was 27.5 months. The most frequent proposals received were in areas of neuromuscular diseases (34 [23%]), movement disorders (27 [18%]), demyelinating disease (14 [9.5%]), and epilepsy-related disorders (14 [9.5%]) (eTable in the Supplement).
Executing an MCTA that covers all studies across the network eliminated the need for contract negotiation, bringing time for contract execution to 0 for all studies. Establishing a cIRB decreased the time required to add sites to a trial once the first site is approved. The time required for initial review still depends on factors including Food and Drug Administration clearance and drug supply. In the first 7 years, the cIRB reviewed and approved 8 protocols, 133 site submissions, 18 continuing reviews, and 579 other amendments (eg, protocols, safety reports, deviations, staff changes). Across the first 8 studies, protocols were approved in a mean (SD) of 59 (21) days and sites in a mean (SD) of 22 (18) days after submission to the cIRB. The median time from cIRB approval to first site activation was 47.5 days (mean, 102.1; range, 1-282) and from first site activation to first participant consent was 27 days (mean, 37.5; range, 0-96). The timeline for postaward study start-up activities for each of the 8 studies are provided in Figure 3B.
The efficiencies of a cIRB go beyond the study initiation phase. The median time from annual renewal review to approval was 16 days (range, 0-33 days). Moreover, having protocol amendments and annual renewals occur for all sites simultaneously creates efficiency by allowing seamless implementation of study protocol changes at a single time point. Thus, when a protocol amendment affects data collection, cIRB approval for all sites can be coordinated to occur simultaneously and be synchronized with required changes to the electronic data capture system. Additionally, having 1 IRB review adverse events at all study sites facilitates a higher level of safety oversight for each trial. It should be noted that the NeuroNEXT cIRB has invited ad hoc members to ensure the appropriate level of expertise in their review of specific protocols and related safety reviews.
The DCC leverages the use of NINDS common data elements, 8 network core case report forms, and 5 core database modules (adverse event reporting system, drug dispensing module, manage case report form module, query system, and monitoring module) to more efficiently bring the electronic data capture system into production and ready for first enrollment. To facilitate this, the DCC hosts a case report form development meeting to ensure efficient, complete, and accurate data collection for the trials. With these tools and methods, the DCC achieved database readiness within 3.5 months (mean, 4.0; range, 0-8) of funding receipt for the first 8 studies (NN101 through NN108), compared with 8.6 months for recent nonnetwork trials (data not published). In collaboration with the University of Rochester Clinical Materials Services Unit, the DCC developed a blinded, site-based kit drug distribution system and an in-house interactive web response system. This resulted in a reduction in total drug supply waste from an industry standard of 30% (Patrick Bolger, RPh, MBA; University of Rochester Clinical Materials Services Unit, written communication, December 6, 2019) to 5% in the NN102 SPRINT-MS study, and 21% in the NN105 STAIR study.
High-performing sites share best practices to enhance recruitment. The recruitment, retention, and diversity committee is brought in early to evaluate and advise on recruitment techniques within the disease population and to assist with participant retention. Screening information is actively reviewed for reasons that participants might choose not to enroll in a study.
Recruitment was completed for the first 6 studies, is underway in the NN107 and NN108 studies and scheduled to start soon for NN109 study. We report here data on the first 4 trials that have completed data analysis of the primary outcome. Enrollment met or exceeded expectations and norms within disease-specific clinical trials (Figure 4). The NN101 study met the timeline for recruitment, despite the requirement for enrolling infants with spinal muscular atrophy as well as healthy controls. Recruitment strategies used in this study were reported by Bartlett et al14 in 2018. In the NN102 study, the average enrollment rate was 0.51 per site per month, about twice as fast as enrollment in other NIH21,22 and industry-sponsored trials in multiple sclerosis (estimated from ClinicalTrial.gov EXPAND (NCT01665144), ORATORIO (NCT01194570), and ASCEND (NCT01416181) trials [Robert Fox, MD, Cleveland Clinic, oral and written communication, December 2016). The enrollment rate (0.1/site/mo) for the NN103 study was twice as fast as that reported for another myasthenia gravis trial.23 The NN104 trial completed enrollment on schedule, which is superior to the general experience in acute stroke clinical trials.24 An extensive search of all trials in these disorders was not conducted and could be the focus for separate manuscript. Two additional studies completed enrollment. One was delayed by approximately 8 months owing to a drug manufacturing delay that required a 3-month pause in enrollment, and the other completed enrollment within 3 months of target.
NeuroNEXT sites consistently provided timely and accurate data. The DCC develops the electronic data capture with the user in mind but also with attention to collecting clean, accurate, and analyzable data. Site performance report cards are issued to sites biannually to provide an overall view of performance across network studies. Each site receives data on their performance in enrollment, retention, data accuracy, and data quality, compared with all other performance sites in a blinded fashion. These reports provide an opportunity for sites to track performance and identify potential areas for improvement. Report card data demonstrates that the overall retention rate across all studies is high, with an average of 89% of participants retained; the average data accuracy (percentage of case report forms requiring no data changes) across all sites was 96%. Moreover, across all studies, the sites entered on average 81% of the required forms within 7 days of the visit, 94% within 30 days, and 82% of participants had no major protocol deviations.
NeuroNEXT, established in 2011 and renewed in 2018, developed processes to increase efficiency and quality of randomized clinical trials, promote participant recruitment and retention, and increase the number of clinical investigators and research staff trained to lead and conduct multicenter trials. Challenges faced during the initiation of the network included establishing a cIRB and terms for the MCTA that were acceptable to all institutions and facilitating communication and collaboration between senior investigators from diverse areas of neurology. The network alleviates bottlenecks in the development of new treatments including allowing any investigator with a phase II question to apply and providing expert advice on trial design/conduct. Rigor of the basic science and design is mandatory for all proposals so that adequate justification, blinding, and replication are ensured; thus, the time to prepare, submit, and receive NIH funding for a clinical trial is still long. However, once funded, the cIRB and MCTA speed study start-up and streamline regulatory oversight, and the network provides expertise in recruitment and retention, thereby ensuring high quality data in a timely manner.25 Rigorous studies answering phase II trial questions promote efficient and cost-effective conduct of pivotal randomized clinical trials and reduce the likelihood of costly failures.
The coordination of efforts between NINDS personnel and NeuroNEXT facilitates research results of high quality. Project vetting within NINDS and the network are closely aligned. This process was formalized and standardized but flexible enough to engage academic partners as well as industry partners.
Several features ensure protection of study participants. Having a cIRB that sees cumulative safety data allows for comprehensive oversight rather than a distributed model where site IRBs only see events that occur at their sites. The data and safety monitoring board ensured a consistent approach for data presentation and review across studies. Similarly, having a common system for safety reporting and monitoring of studies streamlined processes and ensured good oversight of study safety.
Efficiency and performance of a network is based on several factors. The initiative with the largest positive effect on study start-up was the MCTA requirement. In contrast, others have reported that execution of contracts, typically done individually for each study at a site without an MCTA framework in place, is the most significant contributor to delay in study initiation.26
Efficiency was achieved in drug distribution by developing novel randomization and drug distribution systems for trials with limited drug supply. This system led to a low level of drug supply waste in the NN102 SPRINT-MS (NCT01982942) (5%) and NN105 STAIR (NCT02507284) (21%) studies.
Recruitment of participants, including underrepresented populations, and retention of participants are considered challenges in most fields6 but can be particularly complex in neurologic disorders. Slow enrollment can increase study costs or lead to inconclusive results if there is incomplete accrual. Loss of follow-up can result in challenges to interpretation of study results.27,28 NeuroNEXT studies have enrolled on or ahead of schedule. Retention was high in all studies. The combination of experienced sites, with infrastructure support and an engaged recruitment, retention and diversity committee helped ensure trial success. NeuroNEXT was also designed to lower the barriers for investigators with good ideas for a phase II trial or biomarker study to lead their study. Three of the 9 study principal investigators had not led a multicenter study previously. Several first-time investigators submitted grant applications to use the network, benefitting from mentorship and training in randomized clinical trials design from network principal investigators as well as CCC and DCC lead investigators.
There are several other ways that success or return on investment can be assessed for NeuroNEXT. One is the training of young investigators to lead multicenter trials. Several of the NeuroNEXT trials were led by first-time clinical trial investigators. While the number of papers from the network is currently small, this is largely because it is typical for most publications from clinical trials to be published after the study has ended. Our productivity from a manuscript perspective reflects that we did not close out several trials until late in the initial 7-year cycle of the network. Several of the studies published design and baseline data articles, and we expect this approach to continue. In addition, the data sets from closed studies are now publicly available through the NINDS,29 and several secondary papers are in preparation. Another metric of return on investment is clear decisions on whether to proceed or not to additional studies. This has been clear in all completed studies to date. Moreover, one of the overarching goals for the network was to provide an opportunity for productive collaboration between different disciplines within neurology, and while unmeasurable, NINDS has seen this come to fruition.
Two key lessons that were learned in the first 7 years of NeuroNEXT are that engagement and collaboration across all disciplines is essential to develop and continuation of the network and that ongoing training must be established to foster the next generation of clinical neuroscience researchers. After the initial 7-year funding period, modifications were made to further enhance ongoing training, including the addition of clinical research fellows at each funded site, additional initiatives by the education committee to provide ongoing training, and additional partnership with the NINDS clinical trials methodology course, which is part of a larger training program across all of the NINDS-funded networks and the field of neurology as a whole.
Many networks are formed around a disease theme, such as stroke11 or Alzheimer disease.30 NeuroNEXT is unique in that it covers a wide variety of neurologic disorders. Therefore, it did bring together various experts, which promotes sharing of knowledge across disciplines. It posed a challenge initially because the investigators did not know each other well. It also meant that the investigators needed to know the members of their faculty well to know who to tap into for site investigators or to complete feasibility requests across a large range of pediatric and adult disorders.
Developing a rigorously designed trial with a clear phase II question, in an appropriate patient population, using relevant outcome measures, is an iterative process requiring input from both clinicians and statisticians. The median time for the initial development process leading to submission of a grant application in NeuroNEXT is 10 months. The network was not designed to change the peer review process and rigor at NIH. As such, many grants require changes after initial review and resubmission for rereview, which results in a longer timeline from initial proposal to receipt of funding (median of 27.5 months).
In the initial funding period, the network established policies on publication and data sharing. As the complexity and importance of data sharing continues to evolve, the network is well positioned to lead in the area and as such has developed a separate data sharing committee to oversee these activities.
What is needed for the future in the NeuroNEXT network? Education and training of future trialists has already been initiated with a training course as well as principal investigator and site investigator webinars. Increasing the number of trainees and impact of this education and training will be important for the next generation of clinical neuroscience researchers.
In the future, NeuroNEXT studies in amyotrophic lateral sclerosis, Parkinson disease, epilepsy, neuroimmunology, additional pediatric diseases, and other neurologic disorders may be considered. Increased engagement with disease foundations will continue to bring in the most exciting targets and treatments for testing in NeuroNEXT. There is a strong relationship between the NINDS clinical trials methodology course with lectures and small group instructors from the NeuroNEXT coordinating centers and clinical sites, as well as from 2 other NINDS-supported networks: StrokeNet and Neurological Emergencies Treatment Trials/Strategies to Innovate Emergency Care Clinical Trials Network. NeuroNEXT was recently renewed for an additional 5 years. In the renewal period, additional fellowship and other training opportunities will be implemented, and opportunities for collaboration with broader networks, including the Clinical and Translational Science Awards Program, will be explored. The networks must provide a conduit to the future with new investigators in all the clinical neurosciences and related fields to add to the current cohort of seasoned and successful investigators.
The network metrics of success have shown rapid study start-up of 8 studies, efficient enrollment, high-quality data, and optimized central monitoring, as well as efficient use of a central pharmacy and laboratory and sharing of standard operating procedures. Overall, this is a cohesive, well-functioning network. Feasibility assessments ensure that a trial can be completed in a timely fashion within the network. The key to success appears to be engagement of the entire network, neurologists, statisticians, neurosurgeons, PhD scientists, coordinators and others.
Corresponding Author: Merit Cudkowicz, MD, MSc, Massachusetts General Hospital, 165 Cambridge St, Ste 600, Boston, MA 02114 (email@example.com).
Accepted for Publication: December 12, 2019.
Published Online: March 23, 2020. doi:10.1001/jamaneurol.2020.0367
The NeuroNEXT Clinical Study Sites Authors: Shlomo Shinnar, MD, PhD; Donna Patch, RN; Basil T. Darras, MD; Audrey Ellis, BA; Roger J. Packer, MD; Karen S. Marder, MD, MPH; Claudia A. Chiriboga, MD, MPH; Claire Henchcliffe, MD, DPhil; Joyce Ann Moran, BS; Blagovest Nikolov, MD; Stewart A. Factor, DO; Carole Seeley, RN; Steven M. Greenberg, MD, PhD; Anthony A. Amato, MD; Sara DeGregorio, MHA; Tanya Simuni, MD; Tina Ward, MS; John T. Kissel, MD; Stephen J. Kolb, MD, PhD; Amy Bartlett, BA; Joseph F. Quinn, MD; Kellie Keith, BA; Steven R. Levine, MD; Nadege Gilles, MPH; Patricia K. Coyle, MD; Jessica Lamb, BS; Gil I. Wolfe, MD; Annemarie Crumlish, BA; Luis Mejico, MD; Muhammad Maaz Iqbal, MBBS; James D. Bowen, MD; Caryl Tongco, AA; Louis B. Nabors, MD; Khurram Bashir, MD, MPH; Melanie Benge, RN; Craig M. McDonald, MD; Erik K. Henricson, MPH, PhD; Björn Oskarsson, MD; Bruce H. Dobkin, MD; Catherine Canamar, PhD; Tracy A. Glauser, MD; Daniel Woo, MD; Angela Molloy, RN; Peggy Clark, DNP, APRN, PPCNP-BC; Timothy L. Vollmer, MD; Alexander J. Stein, MS, MBA; Richard J. Barohn, MD; Mazen M. Dimachkie, MD; Jean-Baptiste Le Pichon, MD, PhD; Michael G. Benatar, MD, MBChB, DPhil; Julie Steele, RN; Lawrence Wechsler, MD; Paula R. Clemens, MD; Christine Amity, MSN, RN; Robert G. Holloway, MD, MPH; Christine Annis, BS; Mark P. Goldberg, MD; Mariam Andersen, MA; Susan T. Iannaccone, MD; A. Gordon Smith, MD; J. Robinson Singleton, MD; Mariana Doudova, ADN; E. Clarke Haley, MD; Mark S. Quigg, MD, MSc; Stephanie Lowenhaupt, RN, BSN, MBA; Beth A. Malow, MS, MD; Karen Adkins, MS, RN; David B. Clifford, MD; Mengesha A. Teshome, MD; Noreen Connolly, MS.
Affiliations of The NeuroNEXT Clinical Study Sites Authors: Massachusetts General Hospital, Boston (Greenberg, Amato, DeGregorio); Montefiore Medical Center: Einstein Campus, Bronx, New York (Shinnar, Patch); Boston Children’s Hospital, Boston, Massachusetts (Darras, Ellis); Children’s National Hospital, Washington, DC (Packer); Columbia University Irving Medical Center, New York, New York (Marder, Chiriboga, Henchcliffe, Moran, Nikolov); Weill Cornell Medical, New York, New York (Marder, Chiriboga, Henchcliffe, Moran, Nikolov); Emory University School of Medicine, Atlanta, Georgia (Factor, Seeley); Brigham and Women’s Hospital, Boston, Massachusetts (Greenberg, Amato, DeGregorio); Northwestern University Feinberg School of Medicine, Chicago, Illinois (Simuni, Ward); Ohio State University Wexner Medical Center, Columbus (Kissel, Kolb, Bartlett); Oregon Health & Science University, Portland (Quinn, Keith); SUNY Downstate Medical Center, Brooklyn, New York (Levine, Gilles); Stony Brook University, State University of New York, Stony Brook (Coyle, Lamb); University at Buffalo, State University of New York, Buffalo (Wolfe, Crumlish); SUNY Upstate Medical University, Syracuse, New York (Mejico, Iqbal); Swedish Medical Center, Seattle, Washington (Bowen, Tongco); University of Alabama at Birmingham, Birmingham (Nabors, Bashir, Benge); Univeristy of California, Davis, Davis (McDonald, Henricson, Oskarsson); University of California, Los Angeles, Los Angeles (Dobkin, Canamar); Cincinnati Children’s Hospital, University of Cincinnati, Cincinnati, Ohio (Glauser, Woo, Molloy, Clark); University of Colorado, Aurora (Vollmer, Stein); Children’s Mercy Hospital, University of Kansas, Kansas City, Missouri (Barohn, Dimachkie, Le Pichon); University of Miami Miller School of Medicine, Coral Gables, Florida (Benatar, Steele); University of Pittsburgh, Pittsburgh, Pennsylvania (Wechsler, Clemens, Amity); University of Rochester, Rochester, New York (Holloway, Annis, Connolly); UT Southwestern Medical Center, Dallas, Texas (Goldberg, Andersen, Iannaccone); University of Utah, Salt Lake City (Smith, Singleton, Doudova); University of Virginia, Charlottesville (Haley, Quigg, Lowenhaupt); Vanderbilt University, Nashville, Tennessee (Malow, Adkins); Washington University, St Louis, Missouri (Clifford, Teshome).
Conflict of Interest Disclosures: Dr Chase reported grants from National Institutes of Health (NIH) during the conduct of the study. Dr Coffey reported grants from NIH/National Institute of Neurological Disorders and Stroke (NINDS) during the conduct of the study. Dr Ecklund reported grants from NIH during the conduct of the study. Dr Lungu reported honoraria from Elsevier for editorial work. Dr Shefner reported grants from NINDS during the conduct of the study and outside the submitted work. Dr Foster reported grants from NIH/NINDS during the conduct of the study and personal fees from Ferring Pharmaceuticals outside the submitted work. Dr Long reported personal fees from Vaccinex, TripleT, Wave Life Sciences, Roche, Azevan Pharmaceuticals, uniQure, and Genentech outside the submitted work. Dr Torner reported grants from NIH during the conduct of the study. Dr Shinnar reported grants from NINDS during the conduct of the study. Dr Darras reported grants from NINDS during the conduct of the study; personal fees from Genentech, Biogen, Cytokinetics, Vertex, Roche, and Sarepta Therapeutics; grants from SMA Foundation, Cure SMA, Biogen, AveXis, FibroGen, PTC, Roche, Santhera, Sarepta, and Summit; and other support from Elsevier UpToDate outside the submitted work. Dr Marder reported grants from Columbia during the conduct of the study; grants from NIH, Huntington's Disease Society of America, CHDI, Parkinson Foundation, The Michael J. Fox Foundation for Parkinson's Research, Teva, Auspex, Genentech, and Azevan; and personal fees from Voyager, Novartis, CHDI Foundation, and Parkinson Foundation outside the submitted work. Dr Chiriboga reported grants and personal fees from AveXis, Biogen, and Roche and personal fees from Genentech and Cytokinetics outside the submitted work. Dr Henchcliffe reported grants from NINDS during the conduct of the study and grants from NIH/ National Center for Advancing Translational Sciences outside the submitted work. Dr Moran reported grants from NINDS during the conduct of the study. Dr Factor reported grants from NIH (U10 NS077366) during the conduct of the study; personal fees from Lundbeck, Teva, Sunovion, Biogen, Acadia, Neuroderm, Acorda, CereSpir, Bracket Global, and CNS Ratings; grants from Ipsen, Medtronic, Boston Scientific, Teva, US WorldMeds, Sunovion, Vaccinex, Voyager, Jazz Pharmaceuticals, Eli Lilly and Company, CHDI Foundation, and The Michael J. Fox Foundation for Parkinson's Research outside the submitted work; and royalties for textbooks from: Blackwell Futura, Demos Medical Publishing, and Springer. Dr Greenberg reported grants from the NIH during the conduct of the study. Dr Amato reported grants from NIH during the conduct of the study and outside the submitted work. Dr Simuni reported personal fees from Acadia, AbbVie, Adamas Pharmaceuticals, Anavex Life Sciences, Allergan, Acorda Therapeutics, BlueRock Therapeutics, Denali Therapeutics, NeuroDerm, Neurocrine Biosciences, Revance, Sanofi, Sunovion, Teva, Takeda, Voyager, and US WorldMeds; grants from Biogen, Roche, NeuroDerm, Sanofi, Sun Pharma, NINDS, Michael J. Fox Foundation for Parkinson's Research, Parkinson's Foundation; and personal fees from Michael J. Fox Foundation for Parkinson's Research and Parkinson's Foundation during the conduct of the study. Dr Kissel reported grants from NIH during the conduct of the study. Dr Quinn reported grants from NIH during the conduct of the study. Dr Keith reported grants from NINDS during the conduct of the study. Dr Coyle reported grants from SUNY Stony Brook during the conduct of the study; other support from Accordant, Alexion, Bayer, Biogen, Celgene, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, Mylan, Novartis, Serono, TG Therapeutics, Teva, and Oxford PharmaGenesis; and grants from Genentech/Roche, Novartis, Actelion, Alkermes, Corrona, MedDay, NINDS, and Patient-Centered Outcomes Research Institute outside the submitted work. Dr Iqbal reported grants from NINDS NeuroNEXT Infrastructure Grant during the conduct of the study. Dr Bowen reported grants from NINDS during the conduct of the study. Dr Nabors reported personal fees from Karyopharm Therapeutics, BTG Pharma, Blue Earth Diagnostics, and KIYATEC outside the submitted work. Dr Bashir reported grants from National Institutes of Health during the conduct of the study and other support from National Multiple Sclerosis Society outside the submitted work. Dr McDonald reported grants from the NIH during the conduct of the study; grants and other support from Sarepta Therapeutics, PTC Therapeutics, Santhera Pharmaceuticals, Capricor Therapeutics, Italfarmaco, Astellas Pharma, Cardero Therapeutics, and grants and other from Catabasis; and grants from Roche and Pfizer outside the submitted work. Dr Oskarsson reported grants from NINDS during the conduct of the study. Dr Canamar reported grants from University of California, Los Angeles during the conduct of the study. Dr Glauser reported grants NINDS during the conduct of the study. Dr Woo reported grants from NIH during the conduct of the study. Dr Clark reported grants from NIH during the conduct of the study. Dr Vollmer reported grants from National Institute of Neurological and Communicative Disorders and Stroke during the conduct of the study; grants and personal fees from Biogen, Genentech/Roche, Rocky Mountain MS Center, and F. Hoffmann-La Roche; personal fees from Siranax, Celgene, EMD Serono, and Novartis; and grants from Actelion and TG Therapeutics outside the submitted work. Dr Dimachkie reported serving as a consultant or on the speaker’s bureau for Alnylam, Audentes Therapeutics, CSL Behring, Sanofi Genzyme, Momenta, Nufactor, RMS Medical, Shire/Takeda, and Terumo. Dr Dimachkie received grants from Alexion, Alnylam Pharmaceuticals, Amicus, BioMarin, Bristol-Myers Squibb, Catalyst, CSL Behring, Food and Drug Administration/Orphan Products Development, GlaxoSmithKline, Genentech, Grifols, Muscular Dystrophy Association, NIH, Novartis, Genzyme, Octapharma Plasma, Orphazyme, UCB Biopharma, ViroMed Laboratories, and TMA. Dr Benatar reported grants from NIH during the conduct of the study and personal fees from Viela Bio outside the submitted work. Dr Steele reported grants from NINDS during the conduct of the study. Dr Wechsler reported other support from Biogen, Athersys, AAN Telestroke Webinar, Silk Road, and Forest Devices during the conduct of the study. Dr Clemens reported grants from NIH during the conduct of the study. Dr Amity reported grants from NINDS during the conduct of the study. Dr Holloway reported grants from University of Rochester during the conduct of the study. Dr Annis reported grants from University of Rochester during the conduct of the study. Dr Goldberg reported grants from NIH during the conduct of the study. Dr Iannaccone reported grants from NIH during the conduct of the study; grants from NIH, grants from Muscular Dystrophy Association, and grants from Cure SMA; and other support from AveXis, Biogen, Catabasis, Eli Lilly and Company, FibroGen, Regeneron Pharmaceuticals, Sarepta Therapeutics, Scholar Rock, Mallinckrodt, and PTC Therapeutics outside the submitted work. Dr Singleton reported grants from NINDS during the conduct of the study. Dr Haley reported grants from University of Virginia during the conduct of the study and other support from NINDS outside the submitted work. Dr Malow reported personal fees from Neurim Pharmaceuticals, Vanda Pharmaceuticals, and Janssen Pharmaceuticals and grants from Neurim Pharmaceuticals and Autism Speaks outside the submitted work. Dr Clifford reported personal fees from Biogen, Takeda, Sanofi, Pfizer, Amgen, Genentech, GlaxoSmithKline, Merck/Serono, Inhibikase Therapeutics, Dr. Reddy’s Laboratories, Shire, F. Hoffmann-La Roche, Atara Biotherapeutics, Wave Life Sciences, and MitsubishiTanabe Pharma outside the submitted work. Dr Teshome reported grants from NIH/NINDS during the conduct of the study. No other disclosures were reported.
Funding/Support: The NeuroNEXT Network is supported by the National Institute of Neurological Disorders and Stroke (clinical coordinating center: grant UO1NS077179; data coordinating center: grant UO1NS077352) and individual grants to each of the NeuroNEXT clinical study sites.
Role of the Funder/Sponsor: The National Institute of Neurological Disorders and Stroke supported teams at the Coordination Centers and sites to work in the design and conduct of the study, collection, management, analysis and interpretation of the data. The National Institute of Neurological Disorders and Stroke program staff were part of the teams interpreting the data, preparing and reviewing the manuscript.
Additional Contributions: We acknowledge the work of the partners human research committee for coordination and implementation of the single institutional review board model; and the administrative assistance of Ian Whalen, BS, and Lynne Sheridan, MEd, both at Massachusetts General Hospital in Boston. No compensation was received outside of their standard salary.
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