Elsevier

The Lancet Neurology

Volume 14, Issue 8, August 2015, Pages 795-803
The Lancet Neurology

Articles
Pioglitazone in early Parkinson's disease: a phase 2, multicentre, double-blind, randomised trial

https://doi.org/10.1016/S1474-4422(15)00144-1Get rights and content

Summary

Background

A systematic assessment of potential disease-modifying compounds for Parkinson's disease concluded that pioglitazone could hold promise for the treatment of patients with this disease. We assessed the effect of pioglitazone on the progression of Parkinson's disease in a multicentre, double-blind, placebo-controlled, futility clinical trial.

Methods

Participants with the diagnosis of early Parkinson's disease on a stable regimen of 1 mg/day rasagiline or 10 mg/day selegiline were randomly assigned (1:1:1) to 15 mg/day pioglitazone, 45 mg/day pioglitazone, or placebo. Investigators were masked to the treatment assignment. Only the statistical centre and the central pharmacy knew the treatment name associated with the randomisation number. The primary outcome was the change in the total Unified Parkinson's Disease Rating Scale (UPDRS) score between the baseline and 44 weeks, analysed by intention to treat. The primary null hypothesis for each dose group was that the mean change in UPDRS was 3 points less than the mean change in the placebo group. The alternative hypothesis (of futility) was that pioglitazone is not meaningfully different from placebo. We rejected the null if there was significant evidence of futility at the one-sided alpha level of 0·10. The study is registered at ClinicalTrials.gov, number NCT01280123.

Findings

210 patients from 35 sites in the USA were enrolled between May 10, 2011, and July 31, 2013. The primary analysis included 72 patients in the 15 mg group, 67 in the 45 mg group, and 71 in the placebo group. The mean total UPDRS change at 44 weeks was 4·42 (95% CI 2·55–6·28) for 15 mg pioglitazone, 5·13 (95% CI 3·17–7·08) for 45 mg pioglitazone, and 6·25 (95% CI 4·35–8·15) for placebo (higher change scores are worse). The mean difference between the 15 mg and placebo groups was −1·83 (80% CI −3·56 to −0·10) and the null hypothesis could not be rejected (p=0·19). The mean difference between the 45 mg and placebo groups was −1·12 (80% CI −2·93 to 0·69) and the null hypothesis was rejected in favour of futility (p=0·09). Planned sensitivity analyses of the primary outcome, using last value carried forward (LVCF) to handle missing data and using the completers' only sample, suggested that the 15 mg dose is also futile (p=0·09 for LVCF, p=0·09 for completers) but failed to reject the null hypothesis for the 45 mg dose (p=0·12 for LVCF, p=0·19 for completers). Six serious adverse events occurred in the 15 mg group, nine in the 45 mg group, and three in the placebo group; none were thought to be definitely or probably related to the study interventions.

Interpretation

These findings suggest that pioglitazone at the doses studied here is unlikely to modify progression in early Parkinson's disease. Further study of pioglitazone in a larger trial in patients with Parkinson's disease is not recommended.

Funding

National Institute of Neurological Disorders and Stroke.

Introduction

Parkinson's disease affects nearly 1% of the population aged over 60 years.1 Despite effective therapies to treat symptoms of Parkinson's disease and many clinical trials,2, 3 no interventions have been proven to slow progression of disability (ie, achieve disease modification). In 2001, the National Institute of Neurological Disorders and Stroke (NINDS) created the Neuroprotection Exploratory Trials of Parkinson's Disease (NET-PD) programme to assess therapies to slow progression of disability in Parkinson's disease (based on recommendations by the Committee to Identify Neuroprotective Agents in Parkinson's [CINAPS]).4 Pioglitazone was selected through a rigorous systematic review of agents to be tested by the NET-PD network as a potential disease-modifying agent in early Parkinson's disease.4 Pioglitazone is approved by the US Food and Drug Administration (FDA) for the treatment of type 2 diabetes and acts to reduce insulin resistance; it belongs to the class of thiazolidinediones, the peroxisome proliferator-activated receptor γ (PPAR-γ) agonists. Preclinical and early clinical evidence suggests that thiazolidinediones might have neuroprotective effects in Parkinson's disease and other neurodegenerative diseases.5, 6, 7, 8, 9 Although the precise mechanisms through which PPAR-γ agonists might provide neuroprotection are still unclear, they inhibit the activation of microglia and astrocytes and production of pro-inflammatory cytokines and nitric oxide.10 PPAR-γ coactivator 1-α (PGC-1α) is a transcriptional coactivator that controls mitochondrial biogenesis and oxidative stress.11 Preclinical data in rodent and primate Parkinson's disease models showed good CNS penetration of pioglitazone and neuroprotective effects at a dose in animals that is the equivalent of the FDA-approved dose for use in human beings.11, 12, 13, 14

Research in context

Evidence before this study

We searched PubMed for articles published in English before Jan 15, 2015, using the terms “Parkinson's disease”, “disease modification”, “clinical trials”, and “pioglitazone”. As of that date, no agents had proven to be disease-modifying agents (ie, to slow progression) in patients with Parkinson's disease and no studies had assessed the potential disease-modifying effects of pioglitazone.

Added value of this study

This is the first randomised controlled trial of pioglitazone, a peroxisome proliferator-activated receptor γ agonist, as a potential disease-modifying agent in patients with Parkinson's disease. The rationale for the choice of study agent was based on the robust preclinical data showing a neuroprotective effect in animal models at the doses approved for use in human beings. Although the findings of this trial do not warrant further testing of pioglitazone in patients with Parkinson's disease, the design of our study could guide that of other studies, as we have shown that this design is useful and efficient to exclude a compound unlikely to be successful in larger and more costly phase 3 trials.

Implications of all available evidence

These findings suggest that pioglitazone at the doses studied here is unlikely to modify progression in early Parkinson's disease. Further study of pioglitazone in a larger trial in Parkinson's disease is not recommended, although other peroxisome proliferator-activated receptor γ agonists might deserve further exploration as disease-modifying agents in Parkinson's disease.

Our primary objective was to assess the effect of pioglitazone on the progression of Parkinson's disease to establish whether further study of this agent is futile. The study known as FS-ZONE was based on the futility design (non-superiority) that has been used in two phase 2 studies done by NET-PD.15, 16 Futility studies are phase 2 clinical trials designed to identify and eliminate compounds that have low likelihood of being efficacious in definitive efficacy studies by comparing the primary outcome measure in the treatment group versus placebo to a prespecified threshold value.17, 18 Progression of Parkinson's disease was measured by change in total Unified Parkinson Disease Rating Scale score (UPDRS parts I–III)19 between the baseline and the 44 week visit. If both doses of pioglitazone were non-futile, the plan was to select the dose that was associated with the smallest (better) change of the UPDRS score. A final decision about whether to continue studying that dose had also to take into account tolerability, toxicity, and other safety issues.

Section snippets

Study design and participants

The trial was a multicentre, three-group, double-blind, placebo-controlled parallel group study. The trial was organised by the Clinical Trials Coordination Center (CTCC) at the University of Rochester, NY, USA, the Statistical Center at the Division of Biostatistics, University of Texas School of Public Health, TX, USA, and the NINDS.

Participants were men and women aged 30 years or older with idiopathic Parkinson's disease based on UK Brain Bank diagnostic criteria20 diagnosed within 5 years

Results

Between May 10, 2011, and July 31, 2013, 604 potential participants were identified from pre-screening chart review. Of these, 208 were ineligible, 186 declined study participation, and the remaining 210 eligible patients were randomly assigned to the three treatment groups at 35 sites (figure 1). Baseline demographics and clinical characteristics were similar across the three treatment groups except for a difference in GDS-15 (table 1).

The primary analysis suggested that the 45 mg treatment

Discussion

Our results suggest that both doses of pioglitazone are unlikely to be effective as interventions to slow progression of disability in early Parkinson's disease and we do not recommend that they are considered for further study. Although 15 mg pioglitazone was not futile in the primary analysis, absence of efficacy on all preplanned sensitivity analyses and the secondary outcome measures suggest this dose is futile as well.

Pioglitazone was chosen by the CINAPS panel of experts for testing based

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  • Cited by (0)

    Writing committee members are listed at the end of the paper and the study group members are listed in the appendix

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