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

Tanya Simuni, Karl Kieburtz, Barbara Tilley, Jordan J Elm, Bernard Ravina, Debra Babcock, Marina Emborg, Robert Hauser, Cornelia Kamp, John C. Morgan, G. Webster Ross, David K Simon, Jacci Bainbridge, Liana Baker, Ivan Bodis-Wollner, James Boyd, Franca Cambi, Julie Carter, Kelvin Chou, Nabila DahodwalaRichard B. Dewey, Rohit Dhall, John Fang, Buff Farrow, Andrew Feigin, Sofya Glazman, John Goudreau, Pauline LeBlanc, Stephen Lee, Maureen Leehey, Mark F. Lew, Stephanie Lowenhaupt, Sheng Luo, Rajesh Pahwa, Adriana Perez, Jay Schneider, Burton Scott, Binit Shah, Kathleen M. Shannon, Saloni Sharma, Carlos Singer, Daniel Truong, Renee Wagner, Karen Williams, Anne Marie Wills, Pei Shieen Wong, Cindy Zadikoff, Richard Zweig

Research output: Contribution to journalArticle

109 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)795-803
Number of pages9
JournalThe Lancet Neurology
Volume14
Issue number8
DOIs
StatePublished - Aug 1 2015

ASJC Scopus subject areas

  • Clinical Neurology

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    Simuni, T., Kieburtz, K., Tilley, B., J Elm, J., Ravina, B., Babcock, D., Emborg, M., Hauser, R., Kamp, C., Morgan, J. C., Webster Ross, G., K Simon, D., Bainbridge, J., Baker, L., Bodis-Wollner, I., Boyd, J., Cambi, F., Carter, J., Chou, K., ... Zweig, R. (2015). Pioglitazone in early Parkinson's disease: A phase 2, multicentre, double-blind, randomised trial. The Lancet Neurology, 14(8), 795-803. https://doi.org/10.1016/S1474-4422(15)00144-1