BACKGROUND:Little is known about how people with Parkinson's conceptualize "quality of life." OBJECTIVE:To describe the meaning of "quality of life" from the perspective of people with Parkinson's. METHODS:Participants (N = 42) were asked "What does the term 'quality of life' mean to you?" Definitions were analyzed using inductive qualitative methods. RESULTS:Quality of life is captured in a framework illustrating how activities, experiences, and coping strategies generate positive feelings that collectively shape the mental state that defines quality of life. CONCLUSIONS:People with Parkinson's typically define what constitutes a good quality of life, with health status acting as an enabler (or barrier). Multiple factors, varying across individuals and potentially changing with circumstances, shape how people view their quality of life, and offer potential avenues for sustaining it. These personal, subjective and adaptive conceptualizations of quality of life should inform the design of interventions and measurement instruments.

BACKGROUND:Little is known about what matters most for quality of life in people with Parkinson's disease and how much it varies between individuals. OBJECTIVE:The goal was to define the relative impact of quality of life determinants in people with Parkinson's disease, including variation across individuals and by disease severity, gender, age, and ethnicity. METHODS:Sixty-one factors potentially associated with quality of life in people with Parkinson's disease were identified from the literature and nominated by participants with Parkinson's disease. Forty-four participants then rated their degree of impact on quality of life from "a lot" to "not at all," and identified their "top 3 most important" factors. RESULTS:At the individual level, determinants of utmost importance varied greatly, with 39 of 61 factors being reported at least once in the "top 3." There were 17 factors that at least 50% of the sample agreed affected quality of life "a lot," and only two were symptoms of the disease. Twelve (all positive experiences) retained at least 50% agreement across subgroups defined by disease severity, age, gender and ethnicity. Symptom-related factors of high importance varied markedly in mild disease subgroup in particular. CONCLUSIONS:Factors that are not direct consequences of the disease, but may be highly personal and interfere with what one finds meaningful, emerged as highly relevant. Symptoms also greatly impacted quality of life for most individuals, but specific symptoms varied across individuals. Quality of life determinants in people with Parkinson's disease appear highly individualized, and currently used measurement tools with fixed items may not be optimal. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background: For the past five years, our annual reports have been tracking the clinical development of new drug-based therapies for the neurodegenerative condition of Parkinson’s disease (PD). These reviews have followed the progress both of “symptomatic treatments” (ST – improves/reduces symptoms of the condition) and “disease-modifying treatments” (DMT – attempts to delay/slow progression by addressing the underlying biology of PD). Efforts have also been made to further categorize these experimental treatments based on their mechanisms of action and class of drug. Methods: A dataset of clinical trials for drug therapies in PD using trial data downloaded from the ClinicalTrials.gov online registry was generated. A breakdown analysis of all the studies that were active as of January 31st, 2024, was conducted. This analysis involved categorizing the trials based on both the mechanism of action (MOA) and the drug target. Results: There were 136 active Phase 1–3 trials evaluating drug therapies for PD registered on ClinicalTrials.gov, as of January 31, 2024. Of these trials, 76 (56%) were classified as ST trials and 60 (44%) were designated DMT. More than half (58%) of the trials were in Phase 2 testing stage, followed by Phase 1 (30%) and Phase 3 (12%). 35 of the trials were registered since our last report, with the remaining 101 trials appearing in at least one earlier report. Conclusions: The drug development pipeline for PD remains in a robust state with a wide variety of approaches being developed and evaluated in Phase 1 and 2. Yet again, however, only a limited number of DMTs are transitioning to Phase 3.

Background: Since 2020, annual reports on the clinical development of new drug-based therapies for the neurodegenerative condition of Parkinson’s disease (PD) have been generated. These reviews have followed the progress of both “symptomatic treatments” (ST – improves/reduces symptoms of the condition) and “disease modifying treatments” (DMT - attempts to delay/slow progression by addressing the underlying biology of PD). Additional efforts have been made to further categorize these experimental treatments based on their mechanisms of action and class of drug. Methods: A dataset of clinical trials for drug therapies in PD was obtained using trial data downloaded from the ClinicalTrials.gov online registry. A breakdown analysis of all the studies that were active as of January 31st, 2023, was conducted. Results: There was a total of 139 clinical trials registered on the ClinicalTrials.gov website as active (with 35 trials newly registered since our last report). Of these trials, 76 (55%) were considered ST and 63 (45%) were designated DMT. Similar to previous years, approximately a third of the studies were in Phase 1 ( n = 47; 34%), half ( n = 72, 52%) were in Phase 2 and there were 20 (14%) studies in Phase 3. Novel therapies again represented the most dominant group of experimental treatments in this year’s report with 58 (42%) trials testing new agents. Repurposed drugs are present in a third ( n = 49, 35%) of trials, with reformulations and new claims representing 19% and 4% of studies, respectively. Conclusions: Our fourth annual review of active clinical trials evaluating ST and DMT therapeutics for PD demonstrates that the drug development pipeline is dynamic and evolving. The slow progress and lack of agents transitioning from Phase 2 to Phase 3 is concerning, but collective efforts by various stakeholders are being made to accelerate the clinical trial process, with the aim of bringing new therapies to the PD community sooner.

Introduction Parkinson’s disease (PD) is a debilitating neurological disorder for which the identification of disease-modifying interventions represents a major unmet need. Diverse trial designs have attempted to mitigate challenges of population heterogeneity, efficacious symptomatic therapy and lack of outcome measures that are objective and sensitive to change in a disease modification setting. It is not clear whether consensus is emerging regarding trial design choices. Here, we report the protocol of a scoping review that will provide a contemporary update on trial design variability for disease-modifying interventions in PD.Methods and analysis The Population, Intervention, Comparator, Outcome and Study design (PICOS) framework will be used to structure the review, inform study selection and analysis. The databases MEDLINE, Web of Science, Cochrane and the trial registry ClinicalTrials.gov will be systematically searched to identify published studies and registry entries in English. Two independent reviewers will screen study titles, abstracts and full text for eligibility, with disagreements being resolved through discussion or by a third reviewer where necessary. Data on general study information, eligibility criteria, outcome measures, trial design, retention and statistically significant findings will be extracted into a standardised form. Extracted data will be presented in a descriptive analysis. We will report our findings using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Scoping Review extension.Ethics and dissemination This work will provide an overview of variation and emerging trends in trial design choices for disease-modifying trials of PD. Due to the nature of this study, there are no ethical or safety considerations. We plan to publish our findings in a peer-reviewed journal.

BACKGROUND:Design of disease modification (DM) trials for Parkinson's disease (PD) is challenging. Successful delivery requires a shared understanding of priorities and practicalities. OBJECTIVE:To seek stakeholder consensus on phase 3 trials' overall goals and structure, inclusion criteria, outcome measures, and trial delivery and understand where perspectives differ. METHODS:An international expert panel comprising people with Parkinson's (PwP), care partners (CP), clinical scientists, representatives from industry, funders and regulators participated in a survey-based Delphi study. Survey items were informed by a scoping review of DM trials and PwP input. Respondents scored item agreement over 3 rounds. Scores and reasoning were summarized by participant group each round until consensus, defined as≥70% of at least 3 participant groups falling within the same 3-point region of a 9-point Likert scale. RESULTS:92/121 individuals from 13 countries (46/69 PwP, 13/18 CP, 20/20 clinical scientists, representatives from 8/8 companies, 4/5 funders, and 1/1 regulator) completed the study. Consensus was reached on 14/31 survey items: 5/8 overall goals and structure, 1/8 Eligibility criteria, 7/13 outcome measures, and 1/2 trial delivery items. Extent of stakeholder endorsement for 428 reasons for scores was collated across items. CONCLUSIONS:This is the first systematic multi-stakeholder consultation generating a unique repository of perspectives on pivotal aspects of DM trial design including those of PwP and CP. The panel endorsed outcomes that holistically measure PD and the importance of inclusive trials with hybrid delivery models. Areas of disagreement will inform mitigating strategies of researchers to ensure successful delivery of future trials.

BACKGROUND:Personal information, including health-related data, may be used in ways we did not intend when it was originally shared. However, the organizations that collect these data do not always have the necessary social license to use and share it. Although some technology companies have published principles on the ethical use of artificial intelligence, the foundational issue of what is and is not acceptable to do with data, not just the analytical tools to manage it, has not been fully considered. Furthermore, it is unclear whether input from the public or patients has been included. In 2017, the leadership at a web-based patient research network began to envision a new kind of community compact that laid out what the company believed, how the company should behave, and what it promised both to the individuals who engaged with them and to the community at large. While having already earned a social license from patient members as a trusted data steward with strong privacy, transparency, and openness policies, the company sought to protect and strengthen that social license by creating a socially and ethically responsible data contract. Going beyond regulatory and legislative requirements, this contract considered the ethical use of multiomics and phenotypic data in addition to patient-reported and generated data.OBJECTIVE:A multistakeholder working group sought to develop easy-to-understand commitments that established expectations for data stewardship, governance, and accountability from those who seek to collect, use, and share personal data. The working group cocreated a framework that was radically patient-first in its thinking and collaborative in the process of its codevelopment; it reflected the values, ideas, opinions, and perspectives of the cocreators, inclusive of patients and the public.METHODS:Leveraging the conceptual frameworks of cocreation and participatory action research, a mixed methods approach was used that included a landscape analysis, listening sessions, and a 12-question survey. The methodological approaches used by the working group were guided by the combined principles of biomedical ethics and social license and shaped through a collaborative and reflective process with similarities to reflective equilibrium, a method well known in ethics.RESULTS:Commitments for the Digital Age are the output of this work. The six commitments in order of priority are (1) continuous and shared learning; (2) respect and empower individual choice; (3) informed and understood consent; (4) people-first governance; (5) open communication and accountable conduct; and (6) inclusivity, diversity, and equity.CONCLUSIONS:These 6 commitments-and the development process itself-have broad applicability as models for (1) other organizations that rely on digitized data sources from individuals and (2) patients who seek to strengthen operational policies for the ethical and responsible collection, use, and reuse of that data.

Background: As the international community dealt with the ongoing COVID-19 pandemic, important progress continued to be made in the development of new drug-based therapies for the neurodegenerative condition of Parkinson’s disease (PD) in 2021. This progress included both “symptomatic treatments” (ST – improves/reduces symptoms of the condition) and “disease modifying treatments” (DMT - attempts to delay/slow progression by addressing the underlying biology of PD), which can be categorised further based on their mechanisms of action and class of drug. Objective: This report continues previous efforts to provide an overview of the pharmacological therapies - both ST and DMT - in clinical trials for PD during 2021– 2022, with the aim of creating greater awareness and involvement in the clinical trial process. We also hope to stimulate collaboration amongst all stakeholders, including industry, academia, advocacy organizations, and most importantly patient community. 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 January 31st 2022. We also assessed active drug development projects that had completed one clinical phase but were yet to start the next. Results: There was a total of 147 clinical trials registered on the ClinicalTrials.gov website as active during the period of analysis. Of these trials, 91 (62%)were investigating STs, while 56 (38%)focused on DMTs. Approximately 1/3 of the studies (34.7%; 51 trials) were in Phase 1, while over half of the trials were in Phase 2 (50.3%; 74 trials). Only 15% (22 trials) of the studies were in Phase 3, of which only 3 trials were evaluating DMTs. Novel therapeutics (42%)were the most common type of agents being tested across all phases of testing, followed by repurposed agents (34%)and reformulations (20%). Conclusion: Despite significant global health constraints, the development of new drug-based therapies for PD continued in 2021. Hopefully with a shift towards a post-pandemic world in which COVID-19 is better managed, we will see an increase in the number of clinical trials focused on drug development for PD. The need for more Phase 3 studies for DMTs remains acute.

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.

Key Points Question Do the safety, tolerability, exploratory clinical outcomes, brain penetration, and biomarker profile of nilotinib in aggregate support its development for treatment of Parkinson disease (PD)? Findings In this 6-month, multicenter, randomized placebo-controlled clinical trial of 76 participants with moderately advanced PD, nilotinib at 150-mg and 300-mg daily doses met prespecified safety and tolerability criteria. There was no evidence of symptomatic benefit of nilotinib on any measures of PD disability and there was trend toward worsening in the motor function in active treatment arms; in the cerebrospinal fluid, nilotinib level was less than 0.3% of that in the serum and failed to change dopamine metabolites levels. Meaning While nilotinib demonstrated acceptable safety and tolerability in this cohort, the low cerebrospinal fluid exposure, lack of biomarkers effects, and efficacy data trending in the negative direction indicate that further testing of nilotinib in treatment of Parkinson disease is not warranted.

Objective: Disease modification in Parkinson disease (PD) has remained an elusive goal, in spite of large investments over several decades. Following a large meeting of experts, this review article discusses the state of the science, possible reasons for past PD trials' failures to demonstrate disease-modifying benefit, and potential solutions. Methods: The National Institute of Neurological Disorders and Stroke (NINDS) convened a meeting including leaders in the field and representatives of key stakeholder groups to discuss drug therapy with the goal of disease modification in PD. Results: Important lessons can be learned from previous attempts, as well as from other fields. The selection process for therapeutic targets and agents differs among various organizations committed to therapeutic development. The areas identified as critical to target in future research include the development of relevant biomarkers, refinements of the targeted patient populations, considerations of novel trial designs, and improving collaborations between all stakeholders. Conclusions: We identify potential barriers to progress in disease modification for Parkinson's and propose a set of research priorities that may improve the likelihood of success.

Background: Nilotinib, a tyrosine kinase Abelson inhibitor, exhibits neuroprotective effects in preclinical Parkinson disease (PD) models. Methods: This Phase 2A double-blind placebo-controlled study in moderate/advanced PD randomized participants 1:1:1 to placebo:150:300 mg nilotinib once daily for 6 months. The primary outcomes were safety and tolerability, the latter defined as ability to complete the study on assigned dose. Secondary outcomes included change in PD disability (Movement Disorder Society Unified Parkinsons Disease Rating Scale (MDS-UPDRS), Part 3 OFF/ON). Exploratory outcomes included serum and cerebrospinal fluid (CSF) pharmacokinetic (PK) profile, and CSF dopamine metabolites. Findings: The study screened 125 and enrolled 76 participants (39% screen failure) between November 2017 and December 2018 at 25 US sites. At baseline, mean (standard deviation) age was 64.6 years (7.5), disease duration 9.9 years (4.7), MDS-UPDRS Part 1-3 OFF score 66.4(19.3) and ON score 48.4(16.2), Montreal Cognitive Assessment (MoCA) score 27.1(2.2). Tolerability was 21(84%):19 (76%):20 (77%) in placebo:150:300 mg arm, respectively. Both active doses were safe. The most common reasons for drug suspension were dose dependent elevations of amylase and/or lipase. There was no difference in the change of MDS-UPDRS-3 OFF from baseline to 6 months between the groups (p=0.17). CSF/serum PK ratio was 0.2-0.3%. There was no evidence of treatment-related elevation of dopamine metabolites. Interpretation: Both doses of nilotinib were safe and tolerable. There was no evidence of any symptomatic benefit of nilotinib. The drug had low CSF exposure and failed to change dopamine metabolites. These findings do not warrant further testing of nilotinib in PD. Funding: The study was funded by Funded by Michael J Fox Foundation for Parkinsons Research / The Cure Parkinson Trust / Van Andel Institute. Clinicaltrials.gov NCT03205488

Tuesday, April 28April 14, 2020Free AccessPharmacokinetics and Biomarker Changes in NILO-PD, A Phase 2A Study of Nilotinib in Patients with Moderate to Advance Parkinson’s Disease (4418)Kalpana Merchant, Tanya Simuni, Brian Fiske, Christopher Coffey, Helen Matthews, Richard Wyse, Patrik Brundin, … Show All … , David Simon, Michael Schwarzschild, David Weiner, Jamie Adams, Charles Venuto, Laura Trusso, Liana Baker, Melissa Kostrzebski, Tina Ward, and Gary Rafaloff Show FewerAuthors Info & AffiliationsApril 14, 2020 issue94 (15_supplement)https://doi.org/10.1212/WNL.94.15_supplement.4418 Letters to the Editor

Background: The majority of current pharmacological treatments for Parkinson's disease (PD) were approved for clinical use in the second half of the last century and they only provide symptomatic relief. Derivatives of these therapies continue to be explored in clinical trials, together with potentially disease modifying therapies that can slow, stop or reverse the condition. Objective: To provide an overview of the pharmacological therapies-both symptomatic and disease modifying-currently being clinically evaluated for PD, with the goal of creating greater awareness and opportunities for 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 database and performed a breakdown analysis of studies that were active as of January 21, 2020. Results: We identified 145 registered and ongoing clinical trials for therapeutics targeting PD, of which 51 were Phase 1 (35% of the total number of trials), 66 were Phase 2 (46%), and 28 were Phase 3 (19%). There were 57 trials (39%) focused on long-term disease modifying therapies, with the remaining 88 trials (61%) focused on therapies for symptomatic relief. A total of 50 (34%) trials were testing repurposed therapies. Conclusion: There is a broad pipeline of both symptomatic and disease modifying therapies currently being tested in clinical trials for PD.