Minority enrollment in Parkinson's disease clinical trials

Under-representation of minorities in clinical trials limits access to information relevant to all segments of the population. We assessed the enrollment of minority subjects with Parkinson's disease (PD) into clinical trials. We searched PubMed for published studies of PD trials conducted in the US over the past 20 years and found that only 41 reported racial/ethnic participation (17%). In those trials reporting race/ethnicity, 8% of subjects were non-white, compared to 20% of the non-white US population over age 60. Results of this study identified the need for better reporting of racial composition in clinical trials and for the enrollment of more minority participants in research studies.     

Neuroprotection in Parkinson's disease: clinical trials

Advances in our understanding of the cause and pathogenesis of Parkinson's disease (PD) have permitted the rational selection of putative neuroprotective agents for study in PD. However, the list of agents that might provide neuroprotective effects derived from laboratory studies is daunting, and we face the challenge of determining which agents to bring to the clinic and how to find the resources (patients and funds) to properly study so many promising therapeutic opportunities.1 Appropriate outcome variables that are not confounded by any symptomatic effect of the drug and are acceptable to clinicians and regulatory authorities also remain to be defined. The first clinical trials designed to test the capacity of putative neuroprotective agents to alter the natural history of PD have now been performed and illustrate some of these problems. The DATATOP (Deprenyl and Tocopherol Antioxidant Therapy of PD) study used the time to reach a disease milestone in untreated PD patients (ie, need for levodopa) as the primary end point. However, interpretation of results was confounded by the drug's symptomatic effect. The SINDEPAR (Sinemet-Deprenyl-Parlodel) study used the change in motor score between initial visit and final visit after washout of all study medications as the primary end point. However, here too there were concerns about confounding symptomatic effects, because antiparkinsonian medications have now been shown to have a long duration response that can persist for weeks and perhaps even months after withdrawal. More recent studies have used surrogate markers of the integrity of nigrostriatal function such as striatal uptake of fluorodopa on positron emission tomography (PET) or beta-CIT-on single-photon emission computerized tomography (SPECT) as primary outcome measures. However, it has not yet been confirmed that striatal uptake of these isotopes does in fact correlate with the remaining number of dopamine neurons or terminals, and the possibility of a confounding pharmacological effect has not yet been completely excluded. To date, no drug has been established to have a neuroprotective effect in PD, and none has been approved for a neuroprotective indication. Furthermore, regulatory agencies have not yet agreed that any of the outcome measures currently used will be acceptable for approval of a new drug. Resolution of these issues is of critical importance to convince pharmaceutical companies to expend the hundreds of millions of dollars necessary to bring a new drug to market. Drugs that already have been approved in PD for their symptomatic effects, such as dopamine agonists or propargylamines (eg, selegiline), offer the best opportunity for establishing that a drug is neuroprotective in PD in the immediate future, but herein also lies the difficulty of establishing that any benefits observed are not solely because of the drug's symptomatic properties. Currently, this will most likely entail demonstrating that the drug provides benefit for PD patients for both imaging and clinical markers of disease progression.     

Patterns of outcome measurement in Parkinson's disease clinical trials

The study examines the pattern of use and clinimetric properties of clinical endpoints used in randomized trials for Parkinson's disease (PD). Randomized drug trials for PD were identified through a Medline search conducted from January 1966 until August 1998. The endpoints used in these trials were abstracted. Reports examining the clinimetric properties of the disease-specific scales used in these trials were also abstracted. Data regarding the consistency, accuracy, discrimination and feasibility of scales used in at least 10% of trials were determined. One hundred and thirty-seven articles met the inclusion criteria; 70.8% of trials used some clinical scale for PD as an endpoint. The Unified Parkinson's Disease Rating Scale (UPDRS) was the most commonly used scale (32.8%). Factors independently associated with the use of the UPDRS included: the study location in the US, mean age of subjects over 62.7 years and publication after 1994. The UPDRS was more thoroughly studied and superior in most clinimetric domains compared to scales developed earlier. Few studies included generic health status (2.9%) or cognitive measures (16.8%) as secondary endpoints. There have been definite improvements in the area of disease-specific measurement in PD trials since the introduction of the UPDRS. The results of studies that used instruments with poor or unreported clinimetric properties should be critically interpreted.     

Patient diaries as a clinical endpoint in Parkinson's disease clinical trials

Parkinson's disease (PD) is the second most common neurodegenerative disorder with an estimated 4 million patients worldwide. L-dopa is standard, and often initial, therapy for patients with this condition; however, with continued dopaminergic treatment and as the disease progresses, the majority of patients experience complications such as "wearing-off" symptoms, dyskinesias, and other motor complications. These complications may become disabling and profoundly affect quality of life. Treatment modification and combination therapies with L-dopa, dopamine agonists, monoamine oxidase type B inhibitors, and catechol-O-methyltransferase inhibitors are commonly used to manage complications. In recent years regulatory agencies, clinical researchers, and sponsors have widely accepted and utilized changes in "ON" and "OFF" time measured by Patient Hauser Diaries as endpoints for measuring efficacy of therapeutics seeking approval for symptomatic treatment of PD. Successful antiparkinsonian medications have been associated with treatment effects of more than 1 h in either reduction of "OFF" time of increase in "ON" time. Accurate "ON" and "OFF" time registration during clinical studies requires rigorous patient training. Reduced compliance, recall bias and diary fatigue are common problems seen with patient diary reported measures. Electronic diaries may help reducing some of these problems but may be associated with other challenges in large, multicenter studies.     

Disease modification in Parkinson's disease

Several separate gene mutations have now been identified in familial Parkinson's disease and important environmental influences modulating risk for the idiopathic form of the disease have also been recognised. These insights have provided important clues in the development of disease modifying therapies. Some compounds have already been shown to potentially delay disease progression in early clinical trials. The most important challenge, particularly for those drugs that might have a symptomatic effect, is defining appropriate markers that will confirm a neuroprotective effect.     

Impact of placebo assignment in clinical trials of Parkinson's disease.

Informed consent procedures in placebo-controlled trials are developed to ensure that subjects entering studies clearly understand the possibility of placebo assignment. The extent of patient understanding and the impact of learning that they were assigned placebo treatment have not been extensively studied. By using a standardized questionnaire, we interviewed 50 consecutive placebo-treated patients from 14 placebo-controlled clinical trials of Parkinson's disease (PD) after completion of their involvement. All patients interviewed understood that their study contained a placebo arm. All had hoped to receive the study drug rather than placebo, and more than half the subjects believed they had improved clinically during their placebo exposure. Positive impressions of enrollment in placebo-controlled trials were more frequent than negative, included helping to advance science (86%); liking the experience, education, and attention associated with the clinical trial (90%); and participating in research for the benefit of other patients as well as for themselves (80%). If another placebo-controlled trial was offered, 88% expressed that they would possibly, likely, or definitely be interested in enrollment. PD patients clearly understand the concept of placebo-controlled trials they complete them, but they are inaccurate in assessing whether they received placebo treatment. Although most wish they received the active compound being tested, the overall view of participation in placebo-controlled trials is viewed very positively by PD patients.     

Designing neuroprotection trials in Parkinson's disease

A major goal of the neuroscience community is to develop neuroprotective treatment strategies that will slow or forestall the progression of Parkinson's disease, one of the most common adult-onset neurodegenerative disorders, affecting approximately 1 million people in North America. Although prior research to identify neuroprotective interventions has not been conclusive, recent advances in the understanding of the pathogenesis of Parkinson's disease, including the development of relevant animal models, provide the opportunity for rational clinical trials to assess neuroprotective treatments.     

A review of disease progression models of Parkinson's disease and applications in clinical trials

Quantitative disease progression models for neurodegenerative disorders are gaining recognition as important tools for drug development and evaluation. In Parkinson's disease (PD), several models have described longitudinal changes in the Unified Parkinson's Disease Rating Scale (UPDRS), one of the most utilized outcome measures for PD trials assessing disease progression. We conducted a literature review to examine the methods and applications of quantitative disease progression modeling for PD using a combination of key words including “Parkinson disease,” “progression,” and “model.” For this review, we focused on models of PD progression quantifying changes in the total UPDRS scores against time. Four different models reporting equations and parameters have been published using linear and nonlinear functions. The reasons for constructing disease progression models of PD thus far have been to quantify disease trajectories of PD patients in active and inactive treatment arms of clinical trials, to quantify and discern symptomatic and disease‐modifying treatment effects, and to demonstrate how model‐based methods may be used to design clinical trials. The historical lack of efficiency of PD clinical trials begs for model‐based simulations in planning for studies that result in more informative conclusions, particularly around disease modification. © 2016 International Parkinson and Movement Disorder Society     

A recommended scale for cognitive screening in clinical trials of Parkinson's disease

Cognitive impairment is common in Parkinson's disease (PD). There is a critical need for a brief, standard cognitive screening measure for use in PD trials whose primary focus is not on cognition. The Parkinson Study Group (PSG) Cognitive/Psychiatric Working Group formed a Task Force to make recommendations for a cognitive scale that could screen for dementia and mild cognitive impairment in clinical trials of PD where cognition is not the primary outcome. This Task Force conducted a systematic literature search for cognitive assessments previously used in a PD population. Scales were then evaluated for their appropriateness to screen for cognitive deficits in clinical trials, including brief administration time (<15 minutes), assessment of the major cognitive domains, and potential to detect subtle cognitive impairment in PD. Five scales of global cognition met the predetermined screening criteria and were considered for review. Based on the Task Force's evaluation criteria the Montreal Cognitive Assessment (MoCA), appeared to be the most suitable measure. This Task Force recommends consideration of the MoCA as a minimum cognitive screening measure in clinical trials of PD where cognitive performance is not the primary outcome measure. The MoCA still requires further study of its diagnostic utility in PD populations but appears to be the most appropriate measure among the currently available brief cognitive assessments. Widespread adoption of a single instrument such as the MoCA in clinical trials can improve comparability between research studies on PD. © 2010 Movement Disorder Society     

The evidence for disease modification in Parkinson's disease

Disease modification or slowing the progression of any neurodegenerative disorder represents a dire unmet need. There have been trials for several decades specifically designed to help evaluate whether a specific therapy might be able to slow the progression of Parkinson's disease (PD) or be disease modifying. Trials evaluating the use of coenzyme Q10, pramipexole, and levodopa suggest that these medications offer symptomatic benefit uniquely, while other studies reveal that rasagiline and selegiline may be disease modifying. This review will discuss in detail the design and results of clinical trials for varied medical therapies that were specifically undertaken to discern whether a particular treatment might be disease modifying in the treatment of PD.     

Using global statistical tests in long‐term Parkinson's disease clinical trials

Parkinson's disease (PD) impairments are multidimensional, making it difficult to choose a single primary outcome when evaluating treatments to stop or lessen the long‐term decline in PD. We review commonly used multivariate statistical methods for assessing a treatment's global impact, and we highlight the novel Global Statistical Test (GST) methodology. We compare the GST to other multivariate approaches using data from two PD trials. In one trial where the treatment showed consistent improvement on all primary and secondary outcomes, the GST was more powerful than other methods in demonstrating significant improvement. In the trial where treatment induced both improvement and deterioration in key outcomes, the GST failed to demonstrate statistical evidence even though other techniques showed significant improvement. Based on the statistical properties of the GST and its relevance to overall treatment benefit, the GST appears particularly well suited for a disease like PD where disability and impairment reflect dysfunction of diverse brain systems and where both disease and treatment side effects impact quality of life. In future long term trials, use of GST for primary statistical analysis would allow the assessment of clinically relevant outcomes rather than the artificial selection of a single primary outcome. © 2009 Movement Disorder Society