Progression of <scp>MDS</scp>‐<scp>UPDRS</scp> Scores Over Five Years in De Novo Parkinson Disease from the Parkinson's Progression Markers Initiative Cohort

Holden, Samantha K.; Finseth, Taylor; Sillau, Stefan; Berman, Brian D.

doi:10.1002/mdc3.12553

Cited by 148 publications

(135 citation statements)

References 22 publications

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“…The selection of the structural model was based on logistic models that captured different stages of PD progression, with an increase of the progression rate when the scores were below the inflection point, and a decrease of the progression rate when the scores were above the inflection point (middle of the scale). The rate of progression reported in this work (~0.22 point per month) agrees with the work conducted by Holden et al 19 on progression of MDS-UPDRS scores over 5 years, in de novo Parkinson's Disease from the PPMI Cohort. They reported a natural disease progression of 4.7 points per year for MDS-UPDRS total scores (i.e., nonmotor and ARTICLE motor score) from which 0.99 points per year for MDS-UPDRS 2 and 2.4 points per year for MDS-UPDRS 3 .…”

Section: Structural Base Modelsupporting

confidence: 92%

Development of a Disease Progression Model for Leucine‐Rich Repeat Kinase 2 in Parkinson's Disease to Inform Clinical Trial Designs

Ahamadi

Conrado

Macha

et al. 2019

Clin Pharma and Therapeutics

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A quantitative assessment of Parkinson's disease (PD) progression is critical for optimizing clinical trials design. Disease progression model was developed using pooled data from the Progression Marker Initiative study and the Incidence of Cognitive Impairment in Cohorts with Longitudinal Evaluation in Parkinson's Disease study. Age, gender, concomitant medication, and study arms were predictors of baseline. A mutation in the leucine‐rich repeat kinase 2 (LRRK2) encoding gene was associated with the disease progression rate. The progression rate in subjects with PD who carried LRRK2 mutation was slightly slower (~0.170 points/month) than that in PD subjects without the mutation (~0.222 points/month). For a nonenriched placebo‐controlled clinical trial, approximately 70 subjects/arm would be required to detect a drug effect of 50% reduction in the progression rate with 80% probability, whereas 85, 93, and 100 subjects/arm would be required for an enriched clinical trial with 30%, 50%, and 70% subjects with LRRK2 mutations, respectively.

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Section: Structural Base Modelsupporting

confidence: 92%

Development of a Disease Progression Model for Leucine‐Rich Repeat Kinase 2 in Parkinson's Disease to Inform Clinical Trial Designs

Ahamadi

Conrado

Macha

et al. 2019

Clin Pharma and Therapeutics

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“…Changes in medication throughout the trial (expressed as levodopa equivalent dose) were similar across both groups, so this is an improbable explan ation for the observed between-group difference in MDS-UPDRS motor score tested in the off state. The attenuated worsening in motor performance after aerobic exercise is considered clinically relevant 18,28 and within the range of symptomatic pharma cological treatment effects. For example, the effect of levodopa initiated in early Parkinson's disease ranges between 3•8 and 6•6 points depending on the prescribed dose.…”

Section: Discussionmentioning

confidence: 99%

Effectiveness of home-based and remotely supervised aerobic exercise in Parkinson's disease: a double-blind, randomised controlled trial

Kolk

Vries

Kessels

et al. 2019

The Lancet Neurology

367

378

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Background High-intensity aerobic exercise might attenuate the symptoms of Parkinson's disease, but high-quality evidence is scarce. Moreover, long-term adherence remains challenging. We aimed to evaluate the effectiveness of aerobic exercise-gamified and delivered at home, to promote adherence-on relieving motor symptoms in patients with Parkinson's disease with mild disease severity who were on common treatment regimes. Methods In this single-centre, double-blind, randomised controlled trial (Park-in-Shape), we recruited sedentary patients with Parkinson's disease from the outpatient clinic at Radboudumc, Nijmegen, Netherlands. Patients were made aware of the study either by their treating neurologist or via information in the waiting room. Patients could also contact the study team via social media. We included patients aged 30-75 years with a Hoehn and Yahr stage of 2 or lower, who were on stable dopaminergic medication. Patients were randomly assigned (in a 1:1 ratio) to either aerobic exercise done on a stationary home-trainer (aerobic intervention group) or stretching (active control group) by means of a web-based system with minimisation for sex and medication status (treated or untreated) and permuted blocks of varying sizes of more than two (unknown to study personnel). Patients were only aware of the content of their assigned programme. Assessors were unaware of group assignments. Both interventions were home based, requiring 30-45 min training three times per week for 6 months. Both groups received a motivational app and remote supervision. Home trainers were enhanced with virtual reality software and real-life videos providing a so-called exergaming experience (ie, exercise enhanced by gamified elements). The primary outcome was the between-group difference in the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor section at 6 months, tested during the off state (≥12 h after last dopaminergic medication). The analysis was done on an intention-to-treat basis in patients who completed the follow-up assessment, regardless of whether they completed the assigned intervention. Patients reported adverse events directly to their coach and also after the 6-month visit retrospectively. A between-group difference of 3•5 points or more was deemed a-priori clinically relevant. The study is concluded and registered with the Dutch Trial Registry, NTR4743. Findings Between Feb 2, 2015, and Oct 27, 2017, 139 patients were assessed for eligibility in person, of whom 130 were randomly assigned to either the aerobic intervention group (n=65) or the active control group (n=65). Data from 125 (96%) patients were available for the primary analysis; five patients were lost to follow-up (four in the intervention group; one in the control group). 20 patients (ten in each group) did not complete their assigned programme. The off-state MDS-UPDRS motor score revealed a between-group difference of 4•2 points (95% CI 1•6-6•9, p=0•0020) in favour of aerobic exercise (mean 1•3 points [SE 1•8] in th...

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“…All virtual patients were randomly assigned a baseline UPDRS score on a range from 15 to 25, such that scores within that range followed a uniform distribution. For each of the two simulated years, all virtual patients were assigned a random progression in MDS-UPDRS score of either 1 or 2 points per year, a more conservative progression rate based upon the average increase in MDS-UPDRS scores found in the Holden et al study 23 , for simulation purposes. Carriers of both the rs9298897 and rs17710829 variant received an additional increase in UPDRS score in accordance with the model effect size reported in Latourelle et al (β = 2.374, SE = 0.436).…”

Section: Virtual Cohort Simulation: Rs9298897 and Rs17710829mentioning

confidence: 99%

Genetic variability and potential effects on clinical trial outcomes: perspectives in Parkinson’s disease

Leonard¹,

Blauwendraat²,

Krohn

et al. 2018

Preprint

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BackgroundImproper randomization in clinical trials can result in the failure of the trial to meet its primary end-point. The last ~10 years have revealed that common and rare genetic variants are an important disease factor and sometimes account for a substantial portion of disease risk variance. However, the burden of common genetic risk variants is not often considered in the randomization of clinical trials and can therefore lead to additional unwanted variance between trial arms. We simulated clinical trials to estimate false negative and false positive rates and investigated differences in single variants and mean genetic risk scores (GRS) between trial arms to investigate the potential effect of genetic variance on clinical trial outcomes at different sample sizes. MethodsSingle variant and genetic risk score analyses were conducted in a clinical trial simulation environment using data from 5851 Parkinson's Disease patients as well as two simulated virtual cohorts based on public data. The virtual cohorts included a GBA variant cohort and a two variant interaction cohort. Data was resampled at different sizes (n = 200-5000 for the Parkinson's Disease cohort) and (n = 50-800 and n = 50-2000 for virtual cohorts) for 1000 iterations and randomly assigned to the two arms of a trial. False negative and false positive rates were estimated using simulated clinical trials, and percent difference in genetic risk score and allele frequency was calculated to quantify disparity between arms. ResultsSignificant genetic differences between the two arms of a trial are found at all sample sizes. Approximately 90% of the iterations had at least one statistically significant difference in individual risk SNPs between each trial arm. Approximately 10% of iterations had a statistically significant difference between trial arms in polygenic risk score mean or variance. For significant iterations at sample size 200, the average percent difference for mean GRS between trial arms was 130.87%, decreasing to 29.87% as sample size reached 5000. By using simulated drug effects, we found that unbalanced genetics with an effect on the chosen measurable clinical outcome can result in high false negative rates among trials, especially at small sample sizes. At a sample size of n = 50 and a targeted drug effect of -0.5 points in UPDRS per year, we found 35.0% of trials resulted in false negatives. In the GBA only simulations we see an average 18.86% difference in GRS scores between trial arms at n = 50, decreasing to 3.09% as sample size reaches 2000. Balancing patients by genotype reduced mean percent difference in GRS between arms to 8.16% for the main cohort and 2.00% for the GBA cohort at n = 200. ConclusionsOur data support the hypothesis that within genetically unmatched clinical trials, particularly those below 1000 participants, heterogeneity could confound true therapeutic effects as expected. This is particularly important in the changing environment of drug approvals. Clinical trials should undergo pre-trial genetic adjustment ...

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Progression of MDS‐UPDRS Scores Over Five Years in De Novo Parkinson Disease from the Parkinson's Progression Markers Initiative Cohort

Cited by 148 publications

References 22 publications

Development of a Disease Progression Model for Leucine‐Rich Repeat Kinase 2 in Parkinson's Disease to Inform Clinical Trial Designs

Development of a Disease Progression Model for Leucine‐Rich Repeat Kinase 2 in Parkinson's Disease to Inform Clinical Trial Designs

Effectiveness of home-based and remotely supervised aerobic exercise in Parkinson's disease: a double-blind, randomised controlled trial

Genetic variability and potential effects on clinical trial outcomes: perspectives in Parkinson’s disease

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