Neuroprotection trials in Parkinson's disease: Systematic review

Abstract

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 = 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.

Nanomicellar formulation of coenzyme Q10 (Ubisol-Q10) effectively blocks ongoing neurodegeneration in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model: potential use as an adjuvant treatment in Parkinson's disease

“…The trial concludes that patients receiving the highest dose of CoQ 10 (1.2 g/day) develop less disability in comparison to patients receiving placebo. It remains unclear from these reports whether CoQ 10 had a symptomatic benefit or it was actually neuroprotective because the true assessment of neuroprotection would require quantification of the dopamine neuron survival, which is not presently possible in vivo (Hart et al, 2009). The investigators of this trial, encouraged by the results, conducted a much larger clinical trial to test the effectiveness of CoQ 10 at 2.4 g per day.…”

“…Accordingly, it is envisioned that compounds capable of reducing the levels of free radicals in the central nervous system (CNS) might be able to interfere with the progression of neurodegeneration and serve as a therapeutic strategy for PD (Koppula et al, 2012a). However, numerous antioxidant compounds, some directly targeting mitochondria, have been investigated, but none of them have been used yet as the effective disease therapy (Hart et al, 2009;Lew, 2011).…”

A novel design of a Phase III trial of isradipine in early Parkinson disease (STEADY‐PD III)

“…Most of the previously conducted disease‐modifying studies enrolled participants with newly diagnosed PD not yet requiring ST and followed them for a relatively short period of time (12–24 months) assuming that if benefit is shown it will persist long term 42. In case the participant required initiation of ST, the last observation prior to symptomatic treatment was carried forward.…”

Progression of Parkinson’s Disease and Unmet Needs in Mid- to Late-stage Patients

“…Unfortunately, however, no treatments investigated in the last 10 years have demonstrated any neuroprotective or neurorescuing efficacy in PD. 4 While clinical trial methodology may have been part of the problem to date, our increasing understanding of the aetiology and pathogenesis of PD points to the possibility that a single drug with a specific mechanism of action may fail because several different pathogenic mechanisms are implicated, including oxidative stress, mitochondrial dysfunction, excitotoxicity and inflammation. 5 At present, from mid-stage disease the focus of treatment generally shifts gradually towards achieving an optimal balance between managing the motor symptoms and minimising the motor response complications of fluctuations and dyskinesia that commonly occur as a result of chronic dopaminergic therapy (see Figure 2).…”