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

2019 ◽  
Vol 57 (5) ◽  
pp. 331-338 ◽  
Author(s):  
Hampton Leonard ◽  
Cornelis Blauwendraat ◽  
Lynne Krohn ◽  
Faraz Faghri ◽  
Hirotaka Iwaki ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Clinical Trial ◽  
Parkinson's Disease ◽  
Clinical Trials ◽  
European Ancestry ◽  
Simulated Patients ◽  
Therapeutic Effects ◽  
Public Data ◽  
Significant Difference ◽  
Trial Outcomes

BackgroundClassical randomisation of clinical trial patients creates a source of genetic variance that may be contributing to the high failure rate seen in neurodegenerative disease trials. Our objective was to quantify genetic difference between randomised trial arms and determine how imbalance can affect trial outcomes.Methods5851 patients with Parkinson’s disease of European ancestry data and two simulated virtual cohorts based on public data were used. Data were resampled at different sizes for 1000 iterations and randomly assigned to the two arms of a simulated trial. False-negative and false-positive rates were estimated using simulated clinical trials, and per cent difference in genetic risk score (GRS) and allele frequency was calculated to quantify variance between arms.Results5851 patients with Parkinson’s disease (mean (SD) age, 61.02 (12.61) years; 2095 women (35.81%)) as well as simulated patients from virtually created cohorts were used in the study. Approximately 90% of the iterations had at least one statistically significant difference in individual risk SNPs between each trial arm. Approximately 5%–6% of iterations had a statistically significant difference between trial arms in mean GRS. For significant iterations, the average per cent difference for mean GRS between trial arms was 130.87%, 95% CI 120.89 to 140.85 (n=200). Glucocerebrocidase (GBA) gene-only simulations see an average 18.86%, 95% CI 18.01 to 19.71 difference in GRS scores between trial arms (n=50). When adding a drug effect of −0.5 points in MDS-UPDRS per year at n=50, 33.9% of trials resulted in false negatives.ConclusionsOur data support the hypothesis that within genetically unmatched clinical trials, genetic heterogeneity could confound true therapeutic effects as expected. Clinical trials should undergo pretrial genetic adjustment or, at the minimum, post-trial adjustment and analysis for failed trials.

Dance Rhythms Improve Motor Symptoms in Individuals with Parkinson’s Disease: A Randomized Clinical Trial

2021 ◽  
Author(s):  
Jéssica A. Moratelli ◽  
Kettlyn H. Alexandre ◽  
Leonessa Boing ◽  
Alessandra Swarowsky ◽  
Clynton L. Corrêa ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Clinical Trial ◽  
Parkinson's Disease ◽  
Randomized Clinical Trial ◽  
Rating Scale ◽  
Freezing Of Gait ◽  
Motor Symptoms ◽  
Score Change ◽  
Significant Difference ◽  
Binary Group

Background: Evidence-based practices involving dance modalities found in binary (two-beat rhythm) or quaternary (four-beat rhythm) show that dance positively influences the motor aspects of disease.Aim: This randomized clinical trial aimed to analyze the effect of two dance rhythm (binary and quaternary) on the balance, gait, and mobility in individuals with Parkinson’s disease (PD). Methods: Thirty-one individuals with PD were randomized into the binary group (n = 18) and the quaternary group (n = 13). Both groups participated in different dance rhythms lasting 12 weeks, twice a week, for 45 minutes. Results: The binary group showed a significant difference in balance (p = 0.003), freezing of gait (p = 0.007), as well as in the motor aspects of MDS-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), with emphasis on the total values with a score change of 3.23. In the quaternary group, significant differences were found in balance (p = 0.021) with a score change of -2.54 and in the motor aspects of the MDS-UPDRS Part III where the total values stood out with a change of 3.54. Discussion: When comparing the possible effects of binary and quaternary rhythms on the motor symptoms of individuals with PD, it was demonstrated that binary rhythm improved balance, freezing gait, and UPDRSIII. As for the quaternary rhythm, the benefits were in balance and the UPDRSIII. Conclusion: The binary and the quaternary rhythm dance protocols positively influenced the motor symptoms of individuals with PD after 12 weeks of intervention.

scholarly journals Self-Interested and Altruistic Motivations in Volunteering for Clinical Trials: A More Complex Relationship

2020 ◽  
Vol 15 (5) ◽  
pp. 443-451
Author(s):  
Lauren Olsen ◽  
Lindsay DePalma ◽  
John H. Evans
Keyword(s):  
Parkinson’S Disease ◽  
Clinical Trial ◽  
Parkinson's Disease ◽  
Clinical Trials ◽  
Grounded Theory ◽  
Empirical Studies ◽  
Complex Relationship ◽  
Theory Analysis ◽  
Research Participants ◽  
Self Interest

Empirical studies have found that altruism and self-interest are the two primary motivations for enrollment in clinical trials. Some studies have shown that in some cases these two motivations are contingent upon each other, which complicates our understanding of motivation. In this study, we interviewed 27 people with Parkinson’s disease about their willingness to enroll in a hypothetical clinical trial. Through inductive, grounded theory analysis of the interview transcripts, we find four different contingent relationships between altruism and self-interest. It is important for ethicists to be aware of these more complex motivations because some are ethically problematic and others not. Moreover, practitioners need to be aware of these contingent relationships so that they can understand the motivations of the research participants.

scholarly journals Bringing Advanced Therapy Medicinal Products (ATMPs) for Parkinson’s Disease to the Clinic: The Investigator’s Perspective

2021 ◽  
pp. 1-6
Author(s):  
Roger A. Barker ◽  
Emma V. Cutting ◽  
Danielle M. Daft
Keyword(s):  
Parkinson’S Disease ◽  
Clinical Trial ◽  
Parkinson's Disease ◽  
Clinical Trials ◽  
Medicinal Products ◽  
Advanced Therapy Medicinal Products ◽  
Advanced Therapy ◽  
Key Questions

There is much excitement around the use of advanced therapy medicinal products (ATMPs), including cell and gene treatments, in Parkinson’s disease (PD). However, taking an ATMP to clinical trials in patients with PD is complex. As such it is important from an investigator’s perspective that they ask themselves two key questions before embarking on such work: firstly, why are you doing it, and, secondly, do you understand what is needed to conduct a clinical trial with that product. In this article, we briefly discuss these two questions.

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

2018 ◽  
Author(s):  
Hampton Leonard ◽  
Cornelis Blauwendraat ◽  
Lynne Krohn ◽  
Faraz Faghri ◽  
Hirotaka Iwaki ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Clinical Trial ◽  
Parkinson's Disease ◽  
Clinical Trials ◽  
Sample Size ◽  
Risk Score ◽  
Genetic Risk ◽  
False Negative ◽  
Sample Sizes ◽  
Percent Difference

SummaryBackgroundImproper 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.FindingsSignificant 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. 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 36.71% for the main cohort and 2.00% for the GBA cohort at n = 200. When adding a drug effect to the simulations, 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 discovered 33.9% of trials resulted in false negatives.InterpretationsOur 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 or, at the minimum, post-trial adjustment and analysis for failed trials. Clinical trial arms should be balanced on genetic risk variants, as well as cumulative variant distributions represented by GRS, in order to ensure the maximum reduction in trial arm disparities. The reduction in variance after balancing allows smaller sample sizes to be utilized without risking the large disparities between trial arms witnessed in typical randomized trials. As the cost of genotyping will likely be far less than greatly increasing sample size, genetically balancing trial arms can lead to more cost-effective clinical trials as well as better outcomes.

scholarly journals Clinical Trial Highlights –Parkinson’s Disease Drug Therapies in the Clinical Trial Pipeline: 2021 Update

2021 ◽  
pp. 1-13
Author(s):  
Kevin McFarthing ◽  
Gary Rafaloff ◽  
Marco Baptista ◽  
Richard K. Wyse ◽  
Simon R. W. Stott
Keyword(s):  
Parkinson’S Disease ◽  
Clinical Trial ◽  
Parkinson's Disease ◽  
Clinical Trials ◽  
Active Drug ◽  
World Health Organisation ◽  
Considerable Change ◽  
World Health ◽  
Clinical Phase ◽  
Academic Researchers

Background: Despite the COVID-19 pandemic, there has been considerable activity in the clinical development of novel and improved drug-based therapies for the neurodegenerative condition of Parkinson’s disease (PD) during 2020. The agents that were investigated can be divided into “symptomatic” (alleviating the features of the condition) and “disease modifying” (attempting to address the underlying biology of PD) treatments, ST and DMT respectively, with further categorisation possible based on mechanism of action and class of therapy. Objective: Our goal in this report was to provide an overview of the pharmacological therapies –both ST and DMT - in clinical trials for PD during 2020–2021, with the aim of creating greater awareness and involvement in the clinical trial process. We also hope to stimulate collaboration amongst commercial and academic researchers as well as between the research and patient communities. Methods: We conducted a review of clinical trials of drug therapies for PD using trial data obtained from the ClinicalTrials.gov and World Health Organisation (WHO) registries, and performed a breakdown analysis of studies that were active as of February 18th 2021. We also assessed active drug development projects that had completed one clinical phase but were yet to start the next. Results: We identified 142 trials on ClinicalTrials.gov and 14 studies on the WHO registries that met our analysis criteria. Of these 156 trials, 91 were ST and 65 were DMT, Of the 145 trials registered on ClinicalTrials.gov in our 2020 analysis, 45 fell off the list and 42 were added. Despite this change, the balance of ST to DMT; the distribution across phases; the profile of therapeutic categories; and the proportion of repurposed therapies (33.5%); all remained very similar. There are only two DMTs in phase 3, and we identified 33 in-between-phase projects. Conclusions: Despite the effects of the coronavirus pandemic, investment and effort in clinical trials for PD appears to remain strong. There has been little change in the profile of the clinical trial landscape even though, over the past year, there has been considerable change to the content of the list.

scholarly journals Comparison of Different Platform Immunoassays for the Measurement of Plasma Alpha-Synuclein in Parkinson’s Disease Patients

2021 ◽  
pp. 1-12
Author(s):  
Priscilla Youssef ◽  
Woojin S. Kim ◽  
Glenda M. Halliday ◽  
Simon J.G. Lewis ◽  
Nicolas Dzamko
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Clinical Trials ◽  
Effect Size ◽  
Alpha Synuclein ◽  
Patient Stratification ◽  
Plasma Samples ◽  
Group Level ◽  
Total Plasma ◽  
Significant Difference

Background: The identification of reliable biomarkers in Parkinson’s disease (PD) would provide much needed diagnostic accuracy, a means of monitoring progression, objectively measuring treatment response, and potentially allowing patient stratification within clinical trials. Whilst the assessment of total alpha-synuclein in biofluids has been identified as a promising biomarker, conflicting trends in these levels across patient plasma samples relative to controls has limited its use. Different commercially available assay platforms that have been used to measure alpha-synuclein may contribute to different study outcomes. Objective: To compare different platform immunoassays for the measurement of total alpha-synuclein using the same plasma samples from 49 PD patients and 47 controls. Methods: Total plasma alpha-synuclein concentrations were assessed using the BioLegend, MesoScale Discovery, and Quanterix platform in plasma samples from PD patients and matched controls. Results: A significant increase in total plasma alpha-synuclein was observed in PD patients using the Biolegend (10%), Mesoscale Discovery (13%) and Quanterix (39%) assays. The Mesoscale Discovery and Quanterix assays showed the strongest correlations (r = 0.78, p < 0.0001) with each other, whilst the Quanterix platform demonstrated the lowest variation and highest effect size. Inclusion of age, sex and hemoglobin levels as covariates in the analysis of total alpha-synuclein improved the ability of all three immunoassays to detect a significant difference between patients and controls. Conclusion: All three immunoassays were sensitive enough to detect group level differences between PD patients and controls, with the largest effect size observed with the Quanterix assay. These results may help inform assay choices in ongoing clinical trials.

scholarly journals Donepezil for mild cognitive impairment in Parkinson’s disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kyoungwon Baik ◽  
Seon Myeong Kim ◽  
Jin Ho Jung ◽  
Yang Hyun Lee ◽  
Seok Jong Chung ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Treatment Group ◽  
Outcome Measures ◽  
Rating Scale ◽  
Secondary Outcome ◽  
Control Group ◽  
Significant Difference

AbstractWe investigated the efficacy of donepezil for mild cognitive impairment in Parkinson’s disease (PD-MCI). This was a prospective, non-randomized, open-label, two-arm study. Eighty PD-MCI patients were assigned to either a treatment or control group. The treatment group received donepezil for 48 weeks. The primary outcome measures were the Korean version of Mini-Mental State Exam and Montreal Cognitive Assessment scores. Secondary outcome measures were the Clinical Dementia Rating, Unified Parkinson’s Disease Rating Scale part III, Clinical Global Impression scores. Progression of dementia was assessed at 48-week. Comprehensive neuropsychological tests and electroencephalography (EEG) were performed at baseline and after 48 weeks. The spectral power ratio of the theta to beta2 band (TB2R) in the electroencephalogram was analyzed. There was no significant difference in the primary and secondary outcome measures between the two groups. However, the treatment group showed a significant decrease in TB2R at bilateral frontotemporoparietal channels compared to the control group. Although we could not demonstrate improvements in the cognitive functions, donepezil treatment had a modulatory effect on the EEG in PD-MCI patients. EEG might be a sensitive biomarker for detecting changes in PD-MCI after donepezil treatment.

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