Advances in clinical trials for movement disorders

Kieburtz, Karl; Olanow, C. Warren

doi:10.1002/mds.26371

Cited by 10 publications

(10 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…20,21 Most notably, rasagiline, which is approved for symptomatic treatment in Parkinson’s disease, showed inconclusive results in a delayed-start study 22 designed to assess effects on disease progression. In our trial, it might be tempting to view persistent benefits detectable after the washout period as evidence of disease modification.…”

Section: Discussionmentioning

confidence: 99%

Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial

et al. 2017

View full text Add to dashboard Cite

Summary Background Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has neuroprotective effects in preclinical models of Parkinson’s disease. We investigated whether these effects would be apparent in a clinical trial. Methods In this single-centre, randomised, double-blind, placebo-controlled trial, patients with moderate Parkinson’s disease were randomly assigned (1:1) to receive subcutaneous injections of exenatide 2 mg or placebo once weekly for 48 weeks in addition to their regular medication, followed by a 12-week washout period. Eligible patients were aged 25–75 years, had idiopathic Parkinson’s disease as measured by Queen Square Brain Bank criteria, were on dopaminergic treatment with wearing-off effects, and were at Hoehn and Yahr stage 2·5 or less when on treatment. Randomisation was by web-based randomisation with a two strata block design according to disease severity. Patients and investigators were masked to treatment allocation. The primary outcome was the adjusted difference in the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) motor subscale (part 3) in the practically defined off-medication state at 60 weeks. All efficacy analyses were based on a modified intention-to-treat principle, which included all patients who completed any post-randomisation follow-up assessments. The study is registered at ClinicalTrials.gov (NCT01971242) and is completed. Findings Between June 18, 2014, and March 13, 2015, 62 patients were enrolled and randomly assigned, 32 to exenatide and 30 to placebo. Our primary analysis included 31 patients in the exenatide group and 29 patients in the placebo group. At 60 weeks, off-medication scores on part 3 of the MDS-UPDRS had improved by 1·0 points (95% CI −2·6 to 0·7) in the exenatide group and worsened by 2·1 points (−0·6 to 4·8) in the placebo group, an adjusted mean difference of −3·5 points (−6·7 to −0·3; p=0·0318). Injection site reactions and gastrointestinal symptoms were common adverse events in both groups. Six serious adverse events occurred in the exenatide group and two in the placebo group, although none in either group were judged to be related to the study interventions. Interpretation Exenatide had positive effects on practically defined off-medication motor scores in Parkinson’s disease, which were sustained beyond the period of exposure. Whether exenatide affects the underlying disease pathophysiology or simply induces long-lasting symptomatic effects is uncertain. Exenatide represents a major new avenue for investigation in Parkinson’s disease, and effects on everyday symptoms should be examined in longer-term trials. Funding Michael J Fox Foundation for Parkinson’s Research.

show abstract

Section: Discussionmentioning

confidence: 99%

Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Current evaluation standards in Parkinson's disease (PD), such as the Unified Parkinson's Disease Rating Scale (UPDRS), are very useful, but have important limitations. As recently pointed out, these scales report a semiquantitative and subjective score, nonsensitive to subtle motor changes . In addition, these assessments typically require the patient to travel to the clinic, and they need to be performed by a trained specialist, representing an additional burden for the patient and hence being time and cost consuming.…”

mentioning

confidence: 99%

“…As recently pointed out, these scales report a semiquantitative and subjective score, nonsensitive to subtle motor changes. [2][3][4] In addition, these assessments typically require the patient to travel to the clinic, and they need to be performed by a trained specialist, representing an additional burden for the patient and hence being time and cost consuming.…”

mentioning

confidence: 99%

Remote Monitoring of Treatment Response in Parkinson's Disease: The Habit of Typing on a Computer

et al. 2019

View full text Add to dashboard Cite

Objective The recent advances in technology are opening a new opportunity to remotely evaluate motor features in people with Parkinson's disease (PD). We hypothesized that typing on an electronic device, a habitual behavior facilitated by the nigrostriatal dopaminergic pathway, could allow for objectively and nonobtrusively monitoring parkinsonian features and response to medication in an at‐home setting. Methods We enrolled 31 participants recently diagnosed with PD who were due to start dopaminergic treatment and 30 age‐matched controls. We remotely monitored their typing pattern during a 6‐month (24 weeks) follow‐up period before and while dopaminergic medications were being titrated. The typing data were used to develop a novel algorithm based on recursive neural networks and detect participants’ responses to medication. The latter were defined by the Unified Parkinson's Disease Rating Scale‐III (UPDRS‐III) minimal clinically important difference. Furthermore, we tested the accuracy of the algorithm to predict the final response to medication as early as 21 weeks prior to the final 6‐month clinical outcome. Results The score on the novel algorithm based on recursive neural networks had an overall moderate kappa agreement and fair area under the receiver operating characteristic (ROC) curve with the time‐coincident UPDRS‐III minimal clinically important difference. The participants classified as responders at the final visit (based on the UPDRS‐III minimal clinically important difference) had higher scores on the novel algorithm based on recursive neural networks when compared with the participants with stable UPDRS‐III, from the third week of the study onward. Conclusions This preliminary study suggests that remotely gathered unsupervised typing data allows for the accurate detection and prediction of drug response in PD. © 2019 International Parkinson and Movement Disorder Society

show abstract

“…Newly available, high quality evidence can be incorporated into the study design allowing for alteration of sample size based on observed variability, modifying ineffective doses, moving patients among various trial phases, or simply ending a trial early due to failure of efficacy (such as in the case of NET-PD and PRECEPT studies [47,48]). Although these designs can improve efficiency and reduce drug development time, they may introduce bias, require complex operational support from statisticians and safety monitoring boards in order to make real time decisions based on current data [2,49]. Additionally, in both futility and adaptive designs, characterising a response as "positive" or "negative" in a relatively short time period in a such a slowly progressive condition as PD can be challenging.…”

Section: Clinical Trial Designmentioning

confidence: 99%

“…However, "structural errors" pertaining to inadequate trial design, selection of inappropriate endpoints, poor patient selection, or mishandling of missing data, can be minimised and increase the chance of detecting true disease modifying effects [2,3]. This review will consider methodological issues relating to detecting efficacy in disease modification phase III trials and suggest future directions that are being explored that may improve the ability to detect any signal of effect.…”

mentioning

confidence: 99%

Challenges in detecting disease modification in Parkinson's disease clinical trials

Athauda

Foltynie

2016

Parkinsonism & Related Disorders

View full text Add to dashboard Cite

Despite the wealth of encouraging data from numerous compounds that demonstrate "neuroprotection" in pre-clinical studies of Parkinson's disease, and despite numerous clinical trials, to date, no intervention has been demonstrated to able to modify the course of disease progression.While this "failure to translate" is likely due to numerous factors including our incomplete understanding of the pathogenic mechanisms underlying PD together with excessive reliance on data from the toxin-based animal models of PD, here we will discuss the "structural issues" pertaining to inadequate clinical trial design, selection of inappropriate endpoints and poor patient selection which are often not addressed following failed disease modification trials. Future directions to overcome these challenges such as reducing the heterogeneity of patient cohorts,

show abstract

Advances in clinical trials for movement disorders

Cited by 10 publications

References 44 publications

Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial

Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial

Remote Monitoring of Treatment Response in Parkinson's Disease: The Habit of Typing on a Computer

Challenges in detecting disease modification in Parkinson's disease clinical trials

Contact Info

Product

Resources

About