Trial designs used to study neuroprotective therapy in Parkinson's disease (original) (raw)

Neuroprotection trials in Parkinson's disease: Systematic review

Movement Disorders, 2009

Treatments to slow the progression are a major unmet need in Parkinson's disease. Detailed assessment of randomized trials testing putative neuroprotective drugs was undertaken to inform the design, reporting, and interpretation of future studies. This study is a systematic review of trials testing neuroprotective drugs. Data were extracted independently by two coauthors. Fifteen completed, published trials involving 4,087 participants tested 13 different drugs in 18 double-blind comparisons with placebo. Seven comparisons involving 2,000 subjects assessed MAO-B inhibitors. The primary outcome was change in the Unified Parkinson's Disease Rating Scale score in eight trials and time to need for dopaminergic therapy in seven. Mean participant age was 62 years, 35% were women, the interval from diagnosis to entry averaged 11 months, and the number of participants averaged 272 (largest 5 806). Follow-up averaged <16 months in all but two trials. Detailed randomization methods and success of double-blinding were reported in 20% and 13%, respectively. Based on the investigators' conclusions, six trials were interpreted as consistent with a neuroprotective effect, three as negative, and five as either confounded or not meeting criteria for futility. Neuroprotection trials have involved relatively uniform groups of participants early in the clinical disease course, with outcomes weighted heavily toward motor deterioration. Future trials should include participants with wider ranges of disease stages and assess broader neurological outcomes.

A responsive outcome for Parkinson's disease neuroprotection futility studies

Annals of Neurology, 2005

for the NET-PD Investigators Futility studies are designed to test new treatments over a short period in a small number of subjects to determine if those treatments are worthy of larger and longer term studies, or if they should be abandoned. An appropriate outcome measure for a neuroprotection futility study in Parkinson's disease (sensitive to tracking disease progression in the short-term) has not been determined. Data sets from three clinical trials were used to compare Parkinson's disease outcome measures. Total Unified Parkinson's Disease Rating Scale (UPDRS; Mentation + Activities of Daily Living + Motor) change and Motor plus Activities of Daily Living UPDRS change, measured in untreated patients, required the smallest sample sizes of all the outcome measures explored. Other outcomes (UPDRS Motor, UPDRS Activities of Daily Living, and time to need levodopa) required somewhat larger sample sizes. Futility designs in Parkinson's disease are feasible in terms of short duration and small sample size requirements, and this design is being applied in two ongoing Parkinson's disease studies to select agents for future larger and longer term neuroprotection studies.

Prerequisites to launch neuroprotective trials in Parkinson's disease: An industry perspective

Movement disorders : official journal of the Movement Disorder Society, 2012

Realizing that 60% to 80% of dopaminergic nigrostriatal neurons are nonfunctional at the time of clinical diagnosis, there is an emerging consensus that disease-modifying treatments should be initiated in the earliest stages of Parkinson's disease (PD). To date, clinical trial designs and metrics in PD have been focused on motor symptoms as the core feature of the clinical disease. To identify earlier or "pre-motor" populations in PD, new markers have been proposed. We address the prerequisites needed to use these pre-motor markers in clinical trials for the selection of subjects, definition of populations, and monitoring of disease progression. This may require the development of new diagnostic criteria potentially based on non-motor clinical signs, imaging techniques, or biological features, all requiring discussion in a regulatory framework. Questions addressed include: Which steps must be taken to gain a broad consensus in the field from academic opinion leaders, ...

Neuroprotective agents for clinical trials in Parkinson's disease: A systematic assessment

Neurology, 2004

Background: Current therapies for PD ameliorate symptoms in the early phases of disease but become less effective over time, as the underlying disease progresses. Therapies that slow the progression of PD are needed. However, there have been relatively few clinical trials aimed at demonstrating neuroprotection. The authors sought to identify potential neuroprotective agents for testing in clinical trials. Methods: First a broad array of compounds were identified by working with clinicians and researchers in academics and industry. Specific criteria were drafted for drug evaluation, including scientific rationale, blood-brain barrier penetration, safety and tolerability, and evidence of efficacy in animal models or humans. Agents were prioritized based on these criteria. Results: The authors identified 59 potential neuroprotective compounds, proposed by 42 clinicians and scientists from 13 countries. After systematic reviews using the specified criteria they found 12 compounds to be attractive candidates for further clinical trials in PD. Conclusions: Several potential neuroprotective compounds, representing a wide range of mechanisms, are available and merit further investigation in PD.

Concerning neuroprotective therapy for Parkinson’s disease

Journal of Neural Transmission. Supplementa

Studying potential neuroprotective therapy for Parkinson's disease is conceptually problematic because of the heterogenous nature of the Parkinson's syndrome and complexities in operational definitions for neuroprotection. The current literature concerning neuroprotection provides no convincing evidence of any treatment as definitively neuroprotective in Parkinson's disease. Recent clinical trials and novel trial designs are reviewed that may identify meaningful therapy, resulting in maintenance of neurological function and quality of life for persons with Parkinson's disease.

Seven Solutions for Neuroprotection in Parkinson's Disease

Movement Disorders, 2020

Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra, and accumulation of iron and alpha-synuclein; it follows a characteristic pattern throughout the nervous system. Despite, decades of successful preclinical neuroprotective studies, no drug has then shown efficacy in clinical trials. Considering this dilemma, we have reviewed and organized solutions of varying importance that can be exclusive or additive and outline approaches to help generate successful development of neuroprotective drugs for PD: 1) select patients in which the targeted mechanism is involved in the pathological process associated with the monitoring of target engagement; 2) combine treatments that target multiple pathways; 3) establish earliest interventions and develop better prodromal biomarkers; 4) adopt rigorous methodology and specific disease-relevant designs for disease-modifying clinical trials; 5) customize drug with better brain biodistribution; 6) prioritize repurposed drugs as a first line approach; 7) adapt preclinical models to the targeted mechanisms with translational biomarkers to increase their predictive value.

Medical Management of Parkinsons Disease: Focus on Neuroprotection

Current Neuropharmacology, 2011

Neuroprotection refers to the protection of neurons from excitotoxicity, oxidative stress and apoptosis as principal mechanisms of cell loss in a variety of diseases of the central nervous system. Our interest in Parkinson's disease (PD) treatment is focused on drugs with neuroprotective properties in preclinical experiments and evidence-based efficacy in human subjects. To this date, neuroprotection has never been solidly proven in clinical trials but recent adequate markers and/or strategies to study and promote this important goal are described. A myriad of compounds with protective properties in cell cultures and animal models yield to few treatments in clinical practice. At present, markers of neuronal vitality, disease modifying effects and long term clinical stability are the elements searched for in clinical trials. This review highlights new strategies to monitor patients with PD. Currently, neuroprotection in subjects has not been solidly achieved for selegiline and pramipexole; however, a recent rasagiline trial design is showing new indications of disease course modifying effects. In neurological practice, it is of utmost importance to take into account the potential neuroprotection exerted by a treatment in conjunction with its symptomatic efficacy.