Does treatment with oral inosine for up to 2 years slow progression of Parkinson disease?
In this randomized clinical trial that included 298 participants with early Parkinson disease, the rate of clinical disease progression as measured by the Movement Disorder Society Unified Parkinson Disease Rating Scale (parts I-III) total score prior to initiation of dopaminergic medication was 11.1 points per year in the inosine group and 9.9 points per year in the placebo group, a difference that was not statistically significant.
Urate-elevating inosine treatment was not clinically beneficial in early Parkinson disease.
Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data.
To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression.
Design, Participants, and Setting
Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019.
Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years.
Main Outcomes and Measures
The primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity.
Based on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine (MDS-UPDRS score, 11.1 [95% CI, 9.7-12.6] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, −0.59 to 3.11] points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years).
Conclusions and Relevance
Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD.
ClinicalTrials.gov Identifier: NCT02642393
Quiz Ref IDUrate is the enzymatic end product of purine metabolism in humans and other hominoids due to multiple mutations of the urate oxidase gene unique to primate evolution.1,2 The resulting urate elevation may have been advantageous as urate constitutes the main antioxidant circulating in human plasma.2,3 Oxidative damage is thought to play a role in the underlying dopaminergic neuron degeneration of Parkinson disease (PD), and urate protects dopaminergic neurons in cellular and animal models of PD.2,4,5 Clinically, concentrations of urate (or uric acid) that exceed the limits of its solubility cause crystallopathic disorders of gout and kidney stones, but elevated serum urate in healthy individuals is a reduced-risk factor for PD.6-8 In early PD, higher urate concentrations in serum and cerebrospinal fluid are associated with subsequently slower progression of motor and nonmotor disability and slower loss of striatal dopamine transporter.9-12
These findings prompted a phase 2 trial of oral inosine, a metabolic precursor of urate and dietary supplement, in early PD.13 Participants with a serum urate concentration below the population median of 6 mg/dL (360 μmol/L) were randomized to receive placebo or inosine titrated to elevate serum urate to either 6.1-7.0 mg/dL or 7.1-8.0 mg/dL for up to 2 years. Up to 3 g/d of oral inosine demonstrated adequate safety and tolerability, elevated serum and cerebrospinal fluid urate concentrations, and dose-dependently increased plasma antioxidant capacity and was associated with favorable clinical outcomes.13,14 A phase 3 trial of urate-elevating inosine in early PD was designed based on these collective findings, and its results are reported herein.
The trial design is detailed in the study protocol (Supplement 1), which was accepted under a noncommercial investigational new drug application (No. 100 896) to the US Food and Drug Administration and approved by institutional review boards of the administrative and coordination centers and all clinical sites. All participants provided written informed consent. A data and safety monitoring board provided independent oversight. Along with the study protocol in Supplement 1, the statistical analysis plan is available in Supplement 2. This study used the NINDS Common Data Elements (http://www.commondataelements.ninds.nih.gov/).15
Enrollment criteria for the Study of Urate Elevation in Parkinson Disease (SURE-PD3) were modeled on observational studies9,10 in which higher urate was predictive of slower disease progression among people with untreated PD. However, in SURE-PD3, only the subset of early PD participants whose serum urate concentration was below the expected median (<5.8 mg/dL) were included (see diagram on p 10 in the study protocol in Supplement 1), as this subpopulation is at risk of faster progression of disability and can more safely accommodate increases in serum urate. Individuals at greater risk due to elevated urate (ie, those with a history of gout or uric acid urolithiasis, urine pH ≤5.0 [a risk factor for uric acid urolithiasis], established cardiovascular disease, or estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2) were excluded. Eligibility criteria were assessed during 2 screening visits at 61 credentialed US clinical sites of the Parkinson Study Group (http://www.parkinson-study-group.org). Eligibility required a PD diagnosis by a movement disorders neurologist who judged the participant to be unlikely to require dopaminergic drug therapy other than an existing stable dose of a monoamine oxidase B inhibitor within 3 months of enrollment.13 Central adjudication of dopamine transporter ligand (DaTscan; GE Healthcare) uptake into the striatum excluded individuals lacking evidence of dopaminergic deficit. In keeping with federal funding requirements and to assess the effectiveness of efforts to improve participation of underrepresented groups in PD trials, race and ethnicity information was collected as self-determined by participants based on fixed categories. Sex information was also collected as self-identified by participants.
Eligible participants were randomized 1:1 to inosine or placebo by a computer-generated randomization schedule, stratified by site in permuted blocks of 4. Participants, all site staff, and all central staff other than the unblinded statistician and programmer and the central pharmacy were blinded to treatment assignment.
Intervention, Dose Titration, and Follow-up
Active drug (inosine) or matching placebo (lactose) were taken orally at dosages of up to two 500-mg capsules 3 times daily for 24 months after enrollment (period 1). Inosine dosing was titrated in a blinded manner (pp 37 and 51-52 in the study protocol in Supplement 1) to elevate and maintain serum urate and maintain concentrations between 7.1 and 8.0 mg/dL when measured prior to the first daily dose (when concentrations are approximately 0.7 mg/dL below near-peak concentrations13). Placebo dosing was based on an algorithm designed to match dose adjustments in the inosine group. During the 3-month washout following study drug discontinuation (period 2), participants were followed up monthly by telephone and completed a second dopamine transporter brain scan (see diagram on p 10 in the study protocol in Supplement 1). In January 2018, the maximum daily inosine dosage was reduced to 2 g/d to limit kidney stone risk.
Quiz Ref IDThe primary outcome was the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) parts I-III, a composite scale comprising patient- and clinician-reported outcomes, with higher scores reflecting greater disability (summed total range, 0-236 points). Secondary outcome variables addressed pharmacodynamics (via serum and urine urate concentrations), efficacy, and adverse events. Secondary efficacy outcomes were scores on the individual MDS-UPDRS parts (I, II, and III) and 2 functionally organized subsets of its component questions (ambulatory capacity and the patient-reported outcome of parts Ib and II combined), disability warranting initiation of dopaminergic therapy, 13 modules from the Quality of Life in Neurological Disorders assessment, the 39-item Parkinson Disease Questionnaire, the modified Schwab and England Activities of Daily Living Scale, the Montreal Cognitive Assessment, and 4 measures of orthostatic vital signs. Outcome scale descriptions (including reference ranges, directionality, and minimum clinically important differences when available) are detailed in eTable 1 in Supplement 3. Efficacy was also assessed by neuroimaging of loss of striatal dopamine transporter binding signal. Safety-related outcomes included adverse events, tolerability as assessed after 12 weeks, 12 months, and 24 months (defined as statistically significantly greater than 50% of participants continuing study drug treatment without more than 4 weeks of dose reduction), vital signs, and routine laboratory tests including electrocardiograms and measurement of blood lipids, glucose, electrolytes, cell counts, and spot and 24-hour urine. Secondary analyses were carried out stratified by sex or restricted to an as-treated sample. Exploratory outcomes included questionnaire responses on participants’ expectations (not reported herein) and probable rapid eye movement sleep behavior disorder. The schedule of activities (p 78 in the study protocol in Supplement 1) shows the timing of all assessments.
Sample Size Determination
With 270 randomized participants, the study was designed to have 80% power to detect a 20% reduction by inosine in the expected rate of progression; ie, a reduction in the 2-year increase in MDS-UPDRS parts I-III by 6.3 points, which corresponds with patient assessment of a minimum clinically important difference16 (Section 10.3.1 in the study protocol in Supplement 1).
The primary analysis included all randomized participants classified according to their randomization group assignment (as-randomized sample) to estimate the rate of change of MDS-UPDRS (parts I-III) total scores during period 1 in a random slopes model with shared baseline, censoring observations made after initiation of dopaminergic therapy (see details in the statistical analysis plan in Supplement 2). The model included fixed terms for time, treatment interaction with time, and 3 covariates (sex, baseline monoamine oxidase B inhibitor use, and baseline Schwab and England Activities of Daily Living Scale score) and their interactions with time. The model included random site- and participant-specific intercepts and slopes, each with unstructured covariance. The shared-baseline construction implicitly adjusted for baseline MDS-UPDRS score in addition to adjustment for the covariates. The random effects accommodated covariance among participants from the same site and among repeated observations from the same participant. The model accommodated data missing due to censoring after initiation of dopaminergic therapy and early termination or loss to follow-up, with unbiased estimates and appropriate adjustment in precision under a missing-at-random assumption conditional on the observed data and the model structure.
Additional analyses applied the primary model to secondary end points in the as-randomized sample, assessed an as-treated sample restricted to time receiving study drug, and determined incidence of time-to-event outcomes and rates of adverse events among a safety sample of participants who initiated study drug. Kaplan-Meier product-limit estimates were used to calculate the percentage of participants needing dopaminergic therapy by 12 months. Because of the potential for type I error due to multiple comparisons, findings for analyses of secondary end points should be interpreted as exploratory. Two prespecified, blinded interim analyses with early stopping rules for efficacy and nonbinding futility were completed after approximately one-third and three-quarters of total anticipated follow-up. Early stopping for efficacy used a Haybittle-Peto boundary at a 1-sided P < .001. Early stopping for futility used a β-spending rule linear in information time. The significance threshold for the primary analysis was a 2-tailed P < .046 to accommodate 2 interim analyses. All other safety and efficacy analyses were considered exploratory and were evaluated using 2-sided tests at a significance level of P < .05. All analyses were performed using SAS version 9.4 (SAS Institute Inc).
Quiz Ref IDIn September 2018, the data and safety monitoring board reviewed the second prespecified, nonbinding interim analysis for early stopping due to efficacy or futility of inosine treatment. Its results (87% of maximum information; z = 1.25; P = .21 in favor of placebo) met the prespecified criterion for futility (β-spending quadratic in information time) for the hypothesized beneficial effect on the primary outcome. The data and safety monitoring board considered this result along with cumulative safety data and on October 1, 2018, recommended an early, orderly completion of the study while preserving the opportunity to collect a final set of outcome data and biospecimens from patients still taking study drug. Sites and participants were apprised in October 2018 of the modified early completion plan, which included an option for participants to continue taking study drug until their next scheduled study visit, up to 3 months later. The last participant completed a final safety/washout visit in June 2019.
From July 12, 2016, to December 21, 2017, 587 participants consented from 61 sites, 289 had screening failure (64% had a serum urate concentration ≥5.8 mg/dL and 10% had a brain scan without evidence of dopaminergic deficit ) and 298 were randomized (149 to each group) (Figure 1). At baseline, randomized participants had demographic, clinical, and laboratory features (Table 1; eTable 2 in Supplement 3) typical of early, largely untreated PD, except for a higher proportion of women (equal to that of men) that resulted from exclusion of participants with serum urate levels equal to or greater than 5.8 mg/dL, only 16% of whom were women.
In the primary outcome analysis, the rate of clinical progression in early PD as measured by rate of change in MDS-UPDRS parts I-III prior to initiation of dopaminergic medication did not significantly differ between participants randomized to inosine vs placebo (11.1 vs 9.9 points per year, respectively; slope difference, 1.26 [95% CI, −0.59 to 3.11] points per year; P = .18) (Table 2). Early study completion, while shortening period 1 from the originally planned 24 months to 18.9 months, had little effect on the primary analysis because 85% of participants had already initiated dopaminergic therapy prior to their accelerated closeout and therefore were no longer contributing data to the primary analysis, and greater than 90% of the possible information for estimating rate of change in the primary outcome was already incorporated.
Among secondary analyses, urate elevation was a pharmacodynamic marker of target engagement by inosine. By design and through titration (see diagram on p 10 in the study protocol in Supplement 1), serum urate in the inosine group increased by 44% from a mean baseline of 4.6 mg/dL to targeted trough concentrations of 7.1 to 8.0 mg/dL within 3 months with a mean titrated inosine dosage of 1.8 g/d and remained at or near 7.0 mg/dL for up to 24 months (Figure 2A). Eighty-one percent of participants (121/149) receiving inosine achieved a measured trough serum urate of at least 7.1 mg/dL (vs 4.7% [7/149] in the placebo group). Despite a reduction of mean serum urate in the inosine group after early discontinuations of study drug (Figure 1), urate concentrations remained elevated in the as-randomized sample at more than 95%, on average, of that achieved among inosine group participants who continued study drug. Similarly, 24-hour urinary urate output increased only in the inosine treatment group and did so by 97% (Table 2).
Secondary analyses of clinical end points showed steady disease progression. The inosine and placebo groups were not significantly different in visit-specific increases in MDS-UPDRS (parts I-III) total score during treatment (mean change from baseline to 24 months, 15.9 points vs 14.1 points; difference, 1.85 [95% CI, −4.9 to 8.6] points; P = .59) (Figure 2B) or its patient-reported subscore (mean change from baseline to 24 months, 4.4 points vs 4.2 points; difference, 2.0 [95% CI, −3.2 to 3.6] points; P = .91) (eFigure 1 in Supplement 3) or after the 3-month study washout (mean change in MDS-UPDRS (parts I-III) total score from baseline to postwashout, 13.2 points vs 13.8 points; difference, −0.54 [95% CI, −4.8 to 3.7] points; P = .80; mean change in MDS-UPDRS patient-reported subscore from baseline to postwashout, 4.2 points vs 4.2 points; difference, −0.01 [95% CI, −2.2 to 2.2] points; P = .99).
The proportion of participants who developed disability warranting initiation of dopaminergic drug (symptomatic) therapy also increased at each time point and was not significantly different between groups (log-rank P = .50), with 59% (95% CI, 51%-67%) and 56% (95% CI, 49%-64%) needing dopaminergic drug therapy by 12 months in the inosine and placebo groups, respectively (Figure 2C). Worsening by these and other clinical measures of motor and nonmotor function and by composite quality-of-life scores did not significantly differ between those randomized to either treatment, except that rapid eye movement sleep behavior disorder appeared to worsen only with inosine in an exploratory analysis (mean slope during period 1, 0.15 points per year vs 0.02 points per year; difference, 0.13 [95% CI, 0.01-0.25] points per year; P = .03) (Table 2).
Follow-up dopamine transporter imaging was completed for 159 participants (53%) after discontinuation of study drug (a mean of 23 [SD, 4] months after baseline scan). The rate at which dopamine transporter binding in the striatum was lost did not significantly differ between inosine and placebo participants with serial imaging (Figure 2D and Table 2).
The as-treated analyses limited to data obtained while participants were taking study drug and thus maintaining higher urate levels in the inosine group (Figure 2A) did not show a significant between-group difference (eFigure 2 and eTable 3 in Supplement 3). Similarly, stratification by sex did not identify a sex-specific effect of inosine on any clinical outcome (eFigure 3 and eTable 4 in Supplement 3).
For most measures, overall adverse events during treatment with urate-elevating inosine appeared comparable with that of placebo (Table 3). However, fewer participants randomized to inosine than to placebo experienced serious adverse events (12% vs 17%), and these adverse events occurred at a lower rate in the inosine group (7.4 per 100 patient-years) than in the placebo group (13.1 per 100 patient-years), with a rate difference of −5.8 per 100 patient-years (95% CI, −11 to −0.4 per 100 patient-years). This reflects the numerically lower rates of cardiovascular and gastrointestinal serious adverse events in the inosine group being only partially offset by its higher rates of kidney/nephrolithiasis serious adverse events (Table 3). Participants taking inosine developed kidney stones at a rate of 7.0 per 100 patient-years vs 1.4 per 100 patient-years in the placebo group (in 17 vs 4 patients, respectively; rate difference, 5.6 per 100 patient-years [95% CI, 2.0-9.1 per 100 patient-years]; P = .003). Uric acid stone prophylaxis by urine alkalinization, typically with potassium citrate, was initiated based on blinded monitoring for acidic urine and uric acid crystalluria in 71 participants (24%), in similar proportions in the inosine group (25% [n = 37]) and the placebo group (23% [n = 34]).
Among the 21 participants who developed nephrolithiasis, 5 had their kidney stone composition determined. Four (all in the inosine group) had a uric acid component confirmed, and these participants had a significantly greater increase in serum urate prior to the kidney stone adverse event compared with others in the inosine group (by 3.4 vs 2.4 mg/dL; P = .02). There was increased likelihood in the inosine group of amorphous and uric acid crystals in the urine and a decreased risk of calcium oxalate crystalluria (Table 3). Relative to placebo, eGFR was significantly reduced (by 3.7 [95% CI, 2.2-5.2] mL/min/1.73 m2; P < .001) in participants in the inosine group (Table 2), who were also more likely to experience a clinically significant eGFR reduction (Table 3). The eGFR reduction was reversible, with a difference after washout of 1.3 mL/min/1.73 m2 (95% CI, −1.0 to 3.6 mL/min/1.73 m2; P = .26) between the inosine and placebo groups. In sensitivity analyses adjusting for presence of concurrent crystalluria, estimated treatment-dependent reduction in eGFR was unchanged (3.6-3.7 mL/min/1.73 m2). Body mass index, blood pressure, and glucose and lipid levels did not significantly change with inosine treatment (Table 2 and Table 3).
Inosine was tolerable over the first several months, but its tolerability declined over time. In the inosine group, 93% (95% CI, 88%-96%) were tolerant at 12 weeks and 76% (95% CI, 68%-82%) at 12 months. In the placebo group, 99% (95% CI, 95%-100%) and 91% (95% CI, 85%-95%) were tolerant at 12 weeks and 12 months, respectively (eTable 5 in Supplement 3).
Blinding to treatment assignment was effective at 6 weeks, when participants were nearly equally likely to correctly and incorrectly guess their assigned group (50.9% [147/289] and 49.1% [142/289], respectively), as were coordinators (47.9% [140/292] and 52.1% [152/292], respectively) and investigators (50.3% [146/290] and 49.7% [144/290], respectively). However, by the end of the study, more participants (57% [95% CI, 50%-63%]; P = .04 [151/265]) guessed their treatment assignment correctly than incorrectly, with that difference only partially attributable to kidney stones developing primarily in the inosine group (eTable 6 in Supplement 3). A single participant indicated unblinding herself and her investigator based on having obtained a serum urate measurement outside the study; that participant discontinued study participation at that time.
Quiz Ref IDThis trial showed that clinical progression of early PD, as assessed by the rate of change in the MDS-UPDRS (parts I-III) total score prior to dopaminergic medication initiation, was not slowed by long-term treatment with oral inosine dosed to elevate serum urate into a range associated with slower clinical decline in previous studies. Similarly, no significant benefit of inosine was seen on any secondary clinical measure of PD or on a dopamine transporter imaging biomarker of nigrostriatal dopaminergic neuron loss over 2 years.
Several features distinguish this clinical trial from prior, similarly negative disease modification trials.17 To our knowledge, this trial is the first placebo-controlled, randomized clinical trial to limit enrollment to patients with a striatal dopamine transporter deficit demonstrated by brain imaging, substantiating recent regulatory endorsement of this strategy to increase diagnostic confidence.18,19 Enriching for dopamine transporter deficiency can be particularly valuable for trials seeking to enroll untreated patients with PD within a year of diagnosis, when at least 10% of PD diagnoses are a misdiagnosis, even by movement disorders specialists.19 This study’s use of this diagnostic biomarker, which excluded 9% of otherwise eligible patients, allowed testing of the primary hypothesis with approximately 20% less participants (see pp 34-36 in the study protocol in Supplement 1).
The study population was enriched not only for neurodegenerative parkinsonism but also for a subpopulation that was more likely to benefit from the putatively protective intervention. By enrolling only participants with serum urate concentrations below the population median, the study targeted a subset of patients with PD for whom urate-elevating treatment was expected to offer greater benefit. Patients with early PD with lower urate levels decline more rapidly, both clinically and by dopamine transporter imaging.9-11
Another key feature of the trial was its demonstration that the intended molecular target of oral inosine, urate elevation, was engaged. Inosine increased serum urate levels to 7-8 mg/dL (with parallel cerebrospinal fluid urate elevation expected based on the phase 2 trial13), concentrations linked to slower disease progression.9-11 In contrast to prior negative PD trials of putative neuroprotectants, in which dosing was based on preclinical studies or maximum tolerated dose, in this study dosing of the active study drug (inosine) was based on and achieved sustained engagement of the intended target (urate), allowing for a clearer interpretation of the lack of hypothesized benefit.
The results of this trial do not support a protective effect of urate as the basis of the reproducible epidemiological link between higher urate and reduced risk and progression of PD,2,6-11 despite preclinical evidence in cellular and animal models of PD. Recent mendelian randomization studies also argue against a protective effect of higher urate on PD risk,20,21 although 1 such study supported a protective effect on progression in manifest PD.22
Quiz Ref IDWhile urate-elevating inosine treatment did not provide a demonstrable benefit, it did significantly increase the rate of kidney stone adverse events. Consistent with increased urinary urate excretion in the inosine group, most captured kidney stones contained uric acid crystals. Thirty-three percent of the kidney stone adverse events were classified as serious, and all occurred despite intensive protocol-driven efforts to prevent kidney stones, such as excluding participants with a history of kidney stones, increasing hydration, and alkalinizing acidic urine.
This study has several limitations. First, the lack of evidence for benefit of inosine treatment on PD progression for 1 to 2 years shortly after diagnosis, when most dopaminergic neurons may have already degenerated, does not exclude a beneficial effect of urate in PD with earlier (prediagnostic) or longer (years to decades) exposure.
Second, because the urate precursor inosine rather than urate was administered, it may have produced urate-independent deleterious effects offsetting benefits of urate elevation. For example, enhanced enzymatic synthesis of urate via xanthine oxidase generates reactive oxygen species as a byproduct. However, the conversion of oral inosine to urate takes place almost entirely peripherally such that the increased central nervous system urate concentrations generated by oral inosine13 are unlikely accompanied by increased purine metabolism locally. Oral inosine raises venous serum urate concentrations rapidly (within 60 minutes and with a maximum at approximately 3 hours) without a detectable increase in serum inosine.23
Third, the lack of demonstrated efficacy also does not exclude the possibility of benefit in a small subpopulation of patients with PD. The possibility of subpopulations possessing alternative genetic variants that have offsetting interactions with urate on PD progression has been suggested for INPPK5.24 Whole genome sequencing of the cohort in this trial is currently underway.25 Prior evidence of benefit of inosine among women but not men in the phase 2 trial26 was not replicated in this larger phase 3 trial.
Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD.
Corresponding Author: Michael A. Schwarzschild, MD, PhD, Department of Neurology, Massachusetts General Hospital, Mass General Institute for Neurodegenerative Disease, 114 16th St, Boston, MA 02129 (email@example.com).
Accepted for Publication: June 5, 2021.
Authors/Parkinson Study Group SURE-PD3 Investigators: Michael A. Schwarzschild, MD, PhD; Alberto Ascherio, MD, DrPH; Cindy Casaceli, MBA; Gary C. Curhan, MD, ScD; Rebecca Fitzgerald, JD; Cornelia Kamp, MBA; Codrin Lungu, MD; Eric A. Macklin, PhD; Kenneth Marek, MD; Dariush Mozaffarian, MD, DrPH; David Oakes, PhD; Alice Rudolph, PhD; Ira Shoulson, MD; Aleksandar Videnovic, MD; Burton Scott, MD, PhD; Lisa Gauger; Jason Aldred, MD; Melissa Bixby, MS; Jill Ciccarello, BA; Steven A. Gunzler, MD; Claire Henchcliffe, MD, DPhil; Matthew Brodsky, MD; Kellie Keith, BA; Robert A. Hauser, MD, MBA; Christopher Goetz, MD; Mark S. LeDoux, MD, PhD; Vanessa Hinson, MD, PhD; Rajeev Kumar, MD; Alberto J. Espay, MD; Joohi Jimenez-Shahed, MD; Christine Hunter, BSN; Chadwick Christine, MD; Aaron Daley, MA; Maureen Leehey, MD; J. Antonelle de Marcaida, MD; Joseph Harold Friedman, MD; Albert Hung, MD, PhD; Grace Bwala, MBBS, MPH; Irene Litvan, MD; David K. Simon, MD, PhD; Tanya Simuni, MD; Cynthia Poon, PhD; Mya C. Schiess, MD; Kelvin Chou, MD; Ariane Park, MD, MPH; Danish Bhatti, MBBS; Carolyn Peterson, BSN; Susan R. Criswell, MD, MSCl; Liana Rosenthal, MD, PhD; Jennifer Durphy, MD; Holly A. Shill, MD; Shyamal H. Mehta, MD, PhD; Anwar Ahmed, MD; Andres F. Deik, MD, MSEd; John Y. Fang, MD; Natividad Stover, MD; Lin Zhang, MD; Richard B. Dewey Jr, MD; Ashley Gerald, MA; James T. Boyd, MD; Emily Houston, BS; Valerie Suski, DO; Sherri Mosovsky, MPH; Leslie Cloud, MD, MSc; Binit B. Shah, MD; Marie Saint-Hilaire, MD; Raymond James, BS; Sarah Elizabeth Zauber, MD; Stephen Reich, MD; David Shprecher, DO, MSci; Rajesh Pahwa, MD; April Langhammer, BA; Kathrin LaFaver, MD; Peter A. LeWitt, MD; Patricia Kaminski, MSN; John Goudreau, DO, PhD; Doozie Russell, BS; David J. Houghton, MD; Ashley Laroche, BS; Karen Thomas, DO; Martha McGraw, MD; Zoltan Mari, MD, PhD; Carmen Serrano, MD; Karen Blindauer, MD; Marcie Rabin, MD; Roger Kurlan, MD; John C. Morgan, MD, PhD; Michael Soileau, MD; Melissa Ainslie; Ivan Bodis-Wollner, MD, DSc; Ruth B. Schneider, MD; Cheryl Waters, MD; Amber Servi Ratel, BA; Christopher A. Beck, PhD; Patrick Bolger, RPh, MBA; Katherine F. Callahan, BS; Grace F. Crotty, MD, BAO, MBBCH; David Klements, MS; Melissa Kostrzebski, MS; Gearoid Michael McMahon, MB, BCh; Lindsay Pothier, BA; Sushrut S. Waikar, MD, MPH; Anthony Lang, MD; Tiago Mestre, MD, MSc.
Affiliations of Authors/Parkinson Study Group SURE-PD3 Investigators: Mass General Institute for Neurodegenerative Disease, Boston, Massachusetts (Schwarzschild); Massachusetts General Hospital, Boston (Schwarzschild, Macklin, Videnovic, Hung, Bwala, Callahan, Crotty, Klements, Pothier); Harvard School of Public Health, Boston, Massachusetts (Ascherio); University of Rochester, Rochester, New York (Casaceli, Kamp, Oakes, Rudolph, Schneider, Bolger, Kostrzebski); Brigham and Women’s Hospital, Boston, Massachusetts (Curhan, McMahon); Parkinson’s Foundation Research Advocates, Parkinson’s Foundation, New York, New York (Fitzgerald); Division of Clinical Research, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland (Lungu); Harvard Medical School, Boston, Massachusetts (Macklin); Institute for Neurodegenerative Disorders, New Haven, Connecticut (Marek); Tufts School of Medicine and Division of Cardiology, Tufts Medical Center, Boston, Massachusetts (Mozaffarian); Friedman School of Nutrition Science and Policy, Boston, Massachusetts (Mozaffarian); Department of Neurology, University of Rochester Medical Center, Rochester, New York (Shoulson); Duke University, Durham, North Carolina (Scott); Duke Medical Center, Durham, North Carolina (Gauger); Inland Northwest Research, Spokane, Washington (Aldred, Bixby, Ciccarello); Selkirk Neurology, Spokane, Washington (Aldred); University Hospitals Cleveland Medical Center, Cleveland, Ohio (Gunzler); University of California, Irvine (Henchcliffe); Weill Cornell Medical College, New York, New York (Henchcliffe); Oregon Health & Science University, Portland (Brodsky, Keith); University of South Florida, Tampa (Hauser); Rush University Medical Center, Chicago, Illinois (Goetz); Veracity Neuroscience LLC, Memphis, Tennessee (LeDoux); Medical University of South Carolina, Charleston (Hinson); Rocky Mountain Movement Disorders Center, Englewood, Colorado (Kumar); University of Cincinnati, Cincinnati, Ohio (Espay); Icahn School of Medicine at Mount Sinai, New York, New York (Jimenez-Shahed); Baylor College of Medicine, Houston, Texas (Hunter); University of California, San Francisco (Christine, Daley); University of Colorado, Denver (Leehey); Ayer Neuroscience Institute, Hartford HealthCare, Hartford, Connecticut (de Marcaida); Butler Hospital, Providence, Rhode Island (Friedman); University of California, San Diego (Litvan); Beth Israel Deaconess Medical Center, Boston, Massachusetts (Simon); Northwestern University Feinberg School of Medicine, Chicago, Illinois (Simuni, Poon, LaFaver); The University of Texas Health Science Center, Houston McGovern Medical School, Houston (Schiess); University of Michigan, Ann Arbor (Chou); The Ohio State University Wexner Medical Center, Columbus (Park); University of Nebraska Medical Center, Omaha (Bhatti, Peterson); Washington University School of Medicine in St Louis, St Louis, Missouri (Criswell); Johns Hopkins School of Medicine, Baltimore, Maryland (Rosenthal); Albany Medical College, Albany, New York (Durphy); Banner Sun Health Research Institute, Sun City, Arizona (Shill, Shprecher); University of Arizona School of Medicine–Phoenix (Shill, Shprecher); Mayo Clinic Arizona, Scottsdale (Mehta); Cleveland Clinic, Cleveland, Ohio (Ahmed); University of Pennsylvania, Philadelphia (Deik); Vanderbilt University Medical Center, Nashville, Tennessee (Fang); The University of Alabama at Birmingham (Stover); UC Davis, Davis, California (Zhang); University of Texas Southwestern Medical Center, Dallas (Dewey Jr, Gerald); University of Vermont, Burlington (Boyd); University of Vermont Medical Center, Burlington (Houston); University of Pittsburgh, Pittsburgh, Pennsylvania (Suski, Mosovsky); VCU Parkinson’s & Movement Disorders Center, Richmond, Virginia (Cloud); University of Virginia, Charlottesville (Shah); Boston University School of Medicine, Boston, Massachusetts (Saint-Hilaire, Waikar); Boston Medical Center, Boston, Massachusetts (James, Waikar); Indiana University, Bloomington (Zauber); University of Maryland School of Medicine, Baltimore (Reich); University of Kansas Medical Center, Kansas City (Pahwa, Langhammer); Henry Ford Hospital–West Bloomfield, West Bloomfield Township, Michigan (LeWitt, Kaminski); Michigan State University, East Lansing (Goudreau, Russell); Ochsner Medical Center, Jefferson, Louisiana (Houghton); Ochsner Health System, Jefferson, Louisiana (Laroche); Sentara Neurology Specialists, Norfolk, Virginia (Thomas); Center for Movement Disorders and Neurodegenerative Disease, Northwestern Medicine/Central DuPage Hospital, Winfield, Illinois (McGraw); Cleveland Clinic–Las Vegas, Las Vegas, Nevada (Mari); University of Puerto Rico, San Juan (Serrano); Medical College of Wisconsin, Milwaukee (Blindauer); Atlantic Neuroscience Institute, Summit, New Jersey (Rabin, Kurlan); Augusta University, Augusta, Georgia (Morgan); Texas Movement Disorder Specialists, Georgetown (Soileau); Scott & White Healthcare/Texas A&M University, Temple (Soileau); Baylor Scott & White Health, Temple, Texas (Ainslie); State University of New York Downstate Medical Center, Brooklyn (Bodis-Wollner); Columbia University, New York, New York (Waters, Ratel); University of Rochester Medical Center, Rochester, New York (Beck); University of Toronto, Toronto, Ontario, Canada (Lang); Edmond J. Safra Program in Parkinson’s Disease, Toronto Western Hospital, Toronto, Ontario, Canada (Lang); University of Ottawa, Ottawa, Ontario, Canada (Mestre).
Author Contributions: Drs Schwarzschild and Macklin had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Schwarzschild, Ascherio, Casaceli, Curhan, Fitzgerald, Kamp, Macklin, Marek, Oakes, Rudolph, Shoulson, Kostrzebski, Pothier, Bhatti, Kurlan, Simuni, Stover.
Acquisition, analysis, or interpretation of data: Schwarzschild, Ascherio, Casaceli, Curhan, Fitzgerald, Kamp, Lungu, Macklin, Marek, Mozaffarian, Rudolph, Videnovic, Beck, Bolger, Callahan, Crotty, Klements, Kostrzebski, McMahon, Waikar, Lang, Mestre, Ahmed, Aldred, Blindauer, Boyd, Brodsky, Chou, Christine, Cloud, Criswell, de Marcaida, Deik, Dewey, Durphy, Espay, Fang, Friedman, Goetz, Goudreau, Gunzler, Hauser, Henchcliffe, Hinson, Houghton, Hung, Jimenez-Shahed, Kumar, Kurlan, LaFaver, LeDoux, Leehey, LeWitt, Litvan, Mari, McGraw, Mehta, Morgan, Pahwa, Park, Rabin, Reich, Rosenthal, Saint-Hilaire, Schiess, Schneider, Scott, Serrano, Shah, Shill, Shprecher, Simon, Soileau, Stover, Suski, Thomas, Waters, Zauber, Zhang, Ainslie, Bixby Sanchez, Bwala, Ciccarello, Daley, Gauger, Gerald, Houston, Hunter, James, Kaminski, Keith, Langhammer, Laroche, Mosovsky, Peterson, Ratel, Russell, Bodis-Wollner, Poon.
Drafting of the manuscript: Schwarzschild, Casaceli, Fitzgerald, Macklin, Marek, Callahan, Crotty, Goudreau, Simuni, Thomas, Ciccarello.
Critical revision of the manuscript for important intellectual content: Schwarzschild, Ascherio, Curhan, Fitzgerald, Kamp, Lungu, Mozaffarian, Oakes, Rudolph, Shoulson, Videnovic, Beck, Bolger, Callahan, Crotty, Klements, Kostrzebski, McMahon, Pothier, Waikar, Lang, Mestre, Ahmed, Aldred, Bhatti, Blindauer, Boyd, Brodsky, Chou, Christine, Cloud, Criswell, de Marcaida, Deik, Dewey, Durphy, Espay, Fang, Friedman, Goetz, Goudreau, Gunzler, Hauser, Henchcliffe, Hinson, Houghton, Hung, Jimenez-Shahed, Kumar, Kurlan, LaFaver, LeDoux, Leehey, LeWitt, Litvan, Mari, McGraw, Mehta, Morgan, Pahwa, Park, Rabin, Reich, Rosenthal, Saint-Hilaire, Schiess, Schneider, Scott, Serrano, Shah, Shill, Shprecher, Simon, Simuni, Soileau, Stover, Suski, Waters, Zauber, Zhang, Ainslie, Bixby Sanchez, Bwala, Daley, Gauger, Gerald, Houston, Hunter, James, Kaminski, Keith, Langhammer, Laroche, Mosovsky, Peterson, Ratel, Russell, Bodis-Wollner, Poon.
Statistical analysis: Casaceli, Macklin, Marek, Oakes, Beck, Simuni.
Obtained funding: Schwarzschild, Casaceli, Curhan, Oakes, Shoulson.
Administrative, technical, or material support: Schwarzschild, Casaceli, Fitzgerald, Kamp, Lungu, Mozaffarian, Oakes, Rudolph, Videnovic, Bolger, Callahan, Crotty, Klements, Kostrzebski, Pothier, Waikar, Ahmed, Aldred, Cloud, Criswell, Dewey, Goetz, Goudreau, Kurlan, LeDoux, LeWitt, McGraw, Park, Rabin, Shah, Ainslie, Bixby Sanchez, Bwala, Gerald, Houston, James, Keith, Langhammer, Mosovsky, Peterson, Ratel, Russell.
Supervision: Schwarzschild, Ascherio, Curhan, Lungu, Macklin, Shoulson, Videnovic, Klements, Durphy, LeDoux, Leehey, Litvan, Mehta, Serrano, Stover, Kaminski.
Conflict of Interest Disclosures: In keeping with the conflict of interest policy of the Parkinson Study Group, the authors have attested that they have no conflicts of interest with any company determined to be involved in the study (Tuoxin Group, Euticals, and University of Iowa Pharmaceuticals). Dr Curhan reported receipt of grants from the National Institutes of Health (NIH); receipt of personal fees from Allena, Dicerna, and AstraZeneca; being a part-time employee for OM1; and receipt of royalties from UpToDate. Dr Lungu reported receipt of compensation from Elsevier for editorial work. Dr Macklin reported receipt of personal fees from Novartis, Shire Human Genetic Therapies, Biogen, Enterin, Stoparkinson Healthcare Systems, Cerevance Cortexyme, Intrance, Inventram, and Partner Therapeutics and grants to his institution from Acorda Therapeutics, Amylyx Pharmaceuticals, GlaxoSmithKline, and Mitsubishi Tanabe Pharmaceuticals of America. Dr Marek reported receipt of personal fees from GE Healthcare, Takeda, Invicro, the Michael J Fox Foundation, Roche, UCB, Neuron23, Hemacure, Inhibikase, Alkahest, BioHaven, and Sanofi. Dr Mozaffarian reported receipt of grants from the NIH, the Gates Foundation, and the Rockefeller Foundation; receipt of personal fees from GOED, Danone, Motif FoodWorks, Barilla, Amarin, Acasti Pharma, the Cleveland Clinic Foundation, and America’s Test Kitchen; scientific advisory board membership for Beren Therapeutics, Brightseed, Calibrate, DayTwo, Elysium Health, Filtricine, Foodome, HumanCo, January Inc, and Tiny Organics; and royalties from UpToDate. Dr Videnovic reported receipt of personal fees from Alexion Pharmaceuticals, Axovant Pharmaceuticals, Jazz Pharmaceuticals, and Biogen. Dr Beck reported receipt of grants from Boston Scientific, the American Orthopaedic Foot & Ankle Society, the US Food and Drug Administration, Auspex Pharmaceuticals, Abeona Therapeutics, and PCORI and personal fees from the American Academy of Neurology, Neurocrine Biosciences, and Azevan Pharmaceuticals. Dr Lang reported personal fees from AbbVie, AFFiRis Biogen, Denali, Janssen, Lundbeck, Maplight, Roche, Sun Pharma, and Sunovion. Dr Mestre reported personal fees from AbbVie, CHDI Foundation/Management, Sunovion, Valeo Pharma, nQ Medical, Merz, Medtronic, Biogen, and Roche and grants from uOBMRI, Parkinson Canada, the Michael J. Fox Foundation for Parkinson’s Research, the Canadian Institutes of Health Research, the Ontario Research Fund, Brain Canada, the LesLois Foundation, and the PSI Foundation. Dr Aldred reported receipt of honoraria for consulting or speaker’s bureau participation from Abbott, AbbVie, Acorda, Adamas, Allergan, Biogen, Boston Scientific, Medtronic, Neurocrine, Sunovion, Teva, and US WorldMeds; Dr Aldred is also retained as an expert. Dr Bhatti reported receipt of personal fees for speaking or advisory group membership from Adamas, Accadia, Barret Hodgson, PharmEvo, Amneal, and Accorda. Dr Boyd reported receipt of personal fees from Neuroderm and Neurocrine. Dr Criswell reported being site principal investigator for clinical trials with AbbVie, Impax, and the NIH. Dr de Marcaida reported receipt of speakers bureau personal fees from Acorda Therapeutics, AbbVie, and US WorldMeds. Dr Dewey reported receipt of personal fees from Amneal, Acorda, Supernus, Eva, Adamas, and US WorldMeds. Dr Espay reported receipt of personal fees as a scientific advisory consultant and/or honoraria for speaking services from AbbVie, Neuroderm, Neurocrine, Amneal, Acadia, Acorda, Kyowa Kirin, Sunovion, Lundbeck, and US WorldMeds. Dr Goetz reported receipt of grants/research funding by his institution from the NIH, the Department of Defense, and the Michael J. Fox Foundation for Parkinson’s Research; receipt of a faculty stipend from the International Parkinson and Movement Disorder Society; guest professorship honorarium from the University of Chicago and Illinois State Neurological Society; editor stipend from Elsevier; royalties from Elsevier and Wolters Kluwer; and salary from Rush University Medical Center. Dr Goudreau reported industry-sponsored research for Intec Pharma, Biotie Therapies, Global Kinetics, Pharma 2B, Voyager Therapeutics, Impax Pharmaceutical, Sunovion Pharmaceutical, and Acadia Pharmaceutical and speaker bureau participation for Adamas Pharmaceutical and Teva. Dr Gunzler reported receipt of grants from the NIH, Amneal, and Biogen. Dr Hauser reported receipt of personal fees from Acadia, Acorda, Adamas, Affiris, Amneal, Apopharma, Axovant, Cadent, Cerevel, Curium, Denali, Enterin, Hoffman-LaRoche, Impax, Impel, Inhibikase, Jazz, Kashiv, Kyowa Kirin, Lundbeck, Neurocrine, Neuroderm, Orion, Pharmather, Regenera, Revance, Seelos, Sunovion, Supernus, Teva, Tolmar, US WorldMeds, Cerespir, Axial Therapeutics, and Cerevance. Dr Henchcliffe reported personal fees from US WorldMeds, Adamas, Mitsubishi Tanabe Pharma, Prevail Therapeutics, InSightec, and Zywie. Dr Jimenez-Shahed reported receipt of personal fees from St Jude Medical, Amneal, and Impel and grants from Impax. Dr LaFaver reported receipt of advisory board fees from Acorda. Dr Litvan reported personal fees from Lundbeck and grants from Roche, AbbVie, Biogen, EIP-Pharma, and Biohaven. Dr McGraw reported receipt of personal fees from Adamas, Acorda, Acadia, Anneal, Lundbeck, and Teva. Dr Morgan reported receipt of personal fees from Sunovion, Kyowa Kirin, Acadia, Biogen, and Amneal and grants from Cerevel, Takeda, Pharma2B, Neuraly, Aptinyx, Prilenia, and the Parkinson Foundation. Dr Rabin reported speakers bureau participation for Allergan, Merz, and Teva. Dr Reich reported receipt of grants from the National Institute of Neurological Disorders and Stroke (NINDS); personal fees from Best Doctors, Enterin, and UpToDate; and royalties from Oxford University Press and Springer. Dr Saint-Hilaire reported receipt of grants from the NIH and PSG. Dr Schiess reported consultancy for Medtronic. Dr Schneider reported receipt of grants from Acadia Pharmaceuticals, Biohaven, the Michael J. Fox Foundation for Parkinson’s Research, the Parkinson Study Group, the Canadian Institute of Health Research, Teva, Pfizer, the CHDI Foundation, and NINDS. Dr Serrano reported receipt of grants from Eli Lilly. Dr Shill reported receipt of grants from Impax Laboratories, Biogen, US WorldMeds, Sunovion, and Intec Pharma and personal fees from Acorda Therapeutics, Kyowa Kirin, Acadia Pharmaceuticals, and Mitsubishi Tanabe. Dr Shprecher reported being employed by Banner Health; receipt of research support from the Arizona Alzheimer’s Consortium, AbbVie, Acadia, Aptinyx, Axovant, Biogen, Eisai, Eli Lilly, Enterin, Neurocrine, the Michael J Fox Foundation, the NIH, Nuvelution, Theravance, and Teva; consultant fees from Amneal, Emalex, Forensis, and Neurocrine; and speaker honoraria from Acorda, Amneal, Neurocrine, Sunovion, Teva, and US WorldMeds/Supernus. Dr Simon reported receipt of personal fees from Biogen and Bial Biotech and grants from Voyager Therapeutics and Neuraly. Dr Simuni reported receipt of grants from Biogen, Roche, Neuroderm, Sanofi, Sun Pharma, Amneal, Prevail, and UCB and personal fees from Acadia, Denali, GE, Neuroderm, Sanofi, Sinopia, Sunovion, Roche, Takeda, and Voyager. Dr Soileau reported receipt of personal fees from AbbVie, Medtronic, Abbott, Teva, Sunovion, Amneal, Neurocrine, Acorda, and Merz. Dr Waters reported receipt of grants from Sanofi and Biogen and personal fees from Kyowa, Amneal, Neurocrine, Adamas, and Sunovion. Dr Zauber reported receipt of personal fees from AbbVie and grants from the Parkinson’s Foundation. Mrs Peterson reported receipt of grants from the University of Nebraska Medical Center. No other disclosures were reported.
Funding/Support: This study was funded by the NIH/NINDS via grants U01NS090259 to Massachusetts General Hospital as the study’s clinical coordinating center (principal investigator, Dr Schwarzschild) and U01NS089666 to the University of Rochester as the study’s data coordinating center (principal investigator, Dr Oakes), with additional support from the Michael J. Fox Foundation for Parkinson’s Research via grants 11942 and 14489 (including funding for blood and imaging biomarker substudies) and GE Healthcare (all DaTscan doses).
Role of the Funder/Sponsor: Neither the funding organizations (NINDS and the Michael J. Fox Foundation for Parkinson’s Research) nor GE Healthcare had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication, with the exception that a NINDS scientific program director served on the study steering committee.
Group Information: The nonauthor collaborators of the Parkinson Study Group SURE-PD3 Investigators are listed in Supplement 4. The Parkinson Study Group SURE-PD3 Investigators authoring the article are as follows: Steering committee: Michael A. Schwarzschild, MD, PhD (chair); Alberto Ascherio, MD, DrPH (cochair); Cindy Casaceli, MBA; Gary C. Curhan, MD, ScD; Rebecca Fitzgerald, JD; Cornelia Kamp, MBA; Codrin Lungu, MD; Eric A. Macklin, PhD; Kenneth Marek, MD; Dariush Mozaffarian, MD, DrPH; David Oakes, PhD; Alice Rudolph, PhD; Ira Shoulson, MD; Aleksandar Videnovic, MD. Clinical site investigators and coordinators (in descending order of their site’s number of enrolled participants): Burton Scott, MD, PhD; Lisa Gauger; Jason Aldred, MD; Melissa Bixby, MS; Jill Ciccarello; Steven A. Gunzler, MD; Claire Henchcliffe, MD, DPhil; Matthew Brodsky, MD; Kellie Keith; Robert A. Hauser, MD, MBA; Christopher Goetz, MD; Mark S. LeDoux, MD, PhD; Vanessa Hinson, MD, PhD; Rajeev Kumar, MD; Alberto J. Espay, MD; Joohi Jimenez-Shahed, MD; Christine Hunter; Chadwick Christine, MD; Aaron Daley, MA; Maureen Leehey, MD; J. Antonelle de Marcaida, MD; Joseph Harold Friedman, MD; Albert Hung, MD, PhD; Grace Bwala, MBBS, MPH; Irene Litvan, MD; David K. Simon, MD, PhD; Tanya Simuni, MD; Cynthia Poon, PhD; Mya C. Schiess, MD; Kelvin Chou, MD; Ariane Park, MD, MPH; Danish Bhatti, MBBS; Carolyn Peterson; Susan R. Criswell, MD, MSCl; Liana Rosenthal, MD, PhD; Jennifer Durphy, MD; Holly A. Shill, MD; Shyamal H. Mehta, MD, PhD; Anwar Ahmed, MD; Andres F. Deik, MD, MSEd; John Y. Fang, MD; Natividad Stover, MD; Lin Zhang, MD; Richard B. Dewey Jr, MD; Ashley Gerald, MA; James T. Boyd, MD; Emily Houston; Valerie Suski, DO; Sherri Mosovsky, MPH; Leslie Cloud, MD, MSc; Binit B. Shah, MD; Marie Saint-Hilaire, MD; Raymond James; Sarah Elizabeth Zauber, MD; Stephen Reich, MD; David Shprecher, DO, MSci; Rajesh Pahwa, MD; April Langhammer; Kathrin LaFaver, MD; Peter A. LeWitt, MD; Patricia Kaminski, MSN; John Goudreau, DO, PhD; Doozie Russell; David J. Houghton, MD; Ashley Laroche; Karen Thomas, DO; Martha McGraw, MD; Zoltan Mari, MD, PhD; Carmen Serrano, MD; Karen Blindauer, MD; Marcie Rabin, MD; Roger Kurlan, MD; John C. Morgan, MD, PhD; Michael Soileau, MD; Melissa Ainslie; Ivan Bodis-Wollner, MD, DSc; Ruth B. Schneider, MD; Cheryl Waters, MD; Amber Servi Ratel. Coordination centers and other non–clinical site investigators: Christopher A. Beck, PhD; Patrick Bolger, RPh, MBA; Katherine F. Callahan; Grace F. Crotty, MD, BAO, MBBCH; David Klements, MS; Melissa Kostrzebski; Gearoid Michael McMahon, MB, BCh; Lindsay Pothier; Sushrut S. Waikar, MD, MPH; Anthony Lang, MD; Tiago Mestre, MD, MSc.
Data Sharing Statement: See Supplement 5.
Additional Contributions: The University of Rochester’s Clinical Materials Service Unit coordinated the supply chain for the investigational product, including the labeling and distribution to clinical sites. The contributions made by the study participants and their families are deeply appreciated, as are the expertise and guidance of the data and safety monitoring board (which was convened and compensated by the NIH directly): Caroline M. Tanner, MD, PhD (chair; University of San Francisco), Inmaculada Aban, PhD (University of Alabama at Birmingham), Karen Anderson, MD (Georgetown University), David Goldfarb, MD (New York University), Joel Grace, PhD (Parkinson’s Disease Foundation), Leslie McClure, PhD (Drexel University), and G. Webster Ross, MD (University of Hawaii). Contributions made by all site staff, including clinical coordinators Lisa Richardson of Sentara Clinical Research and Marie Mejaki, BA, of the Medical College of Wisconsin (who were not compensated outside of their usual salary), are greatly appreciated.
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