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 Dahodwala & 28 others Richard 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

83 Citations (Scopus)

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

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pioglitazone
Parkinson Disease
Placebos
Medical Futility
Nitromifene
National Institute of Neurological Disorders and Stroke
Selegiline
Controlled Clinical Trials
Random Allocation

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Simuni, T., Kieburtz, K., Tilley, B., J Elm, J., Ravina, B., Babcock, D., ... 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

Pioglitazone in early Parkinson's disease : A phase 2, multicentre, double-blind, randomised trial. / Simuni, Tanya; Kieburtz, Karl; Tilley, Barbara; J Elm, Jordan; Ravina, Bernard; Babcock, Debra; Emborg, Marina; Hauser, Robert; Kamp, Cornelia; Morgan, John C.; Webster Ross, G.; K Simon, David; Bainbridge, Jacci; Baker, Liana; Bodis-Wollner, Ivan; Boyd, James; Cambi, Franca; Carter, Julie; Chou, Kelvin; Dahodwala, Nabila; Dewey, Richard B.; Dhall, Rohit; Fang, John; Farrow, Buff; Feigin, Andrew; Glazman, Sofya; Goudreau, John; LeBlanc, Pauline; Lee, Stephen; Leehey, Maureen; Lew, Mark F.; Lowenhaupt, Stephanie; Luo, Sheng; Pahwa, Rajesh; Perez, Adriana; Schneider, Jay; Scott, Burton; Shah, Binit; Shannon, Kathleen M.; Sharma, Saloni; Singer, Carlos; Truong, Daniel; Wagner, Renee; Williams, Karen; Marie Wills, Anne; Shieen Wong, Pei; Zadikoff, Cindy; Zweig, Richard.

In: The Lancet Neurology, Vol. 14, No. 8, 01.08.2015, p. 795-803.

Research output: Contribution to journalArticle

Simuni, T, Kieburtz, K, Tilley, B, J Elm, J, Ravina, B, Babcock, D, Emborg, M, Hauser, R, Kamp, C, Morgan, JC, Webster Ross, G, K Simon, D, Bainbridge, J, Baker, L, Bodis-Wollner, I, Boyd, J, Cambi, F, Carter, J, Chou, K, Dahodwala, N, Dewey, RB, Dhall, R, Fang, J, Farrow, B, Feigin, A, Glazman, S, Goudreau, J, LeBlanc, P, Lee, S, Leehey, M, Lew, MF, Lowenhaupt, S, Luo, S, Pahwa, R, Perez, A, Schneider, J, Scott, B, Shah, B, Shannon, KM, Sharma, S, Singer, C, Truong, D, Wagner, R, Williams, K, Marie Wills, A, Shieen Wong, P, Zadikoff, C & Zweig, R 2015, 'Pioglitazone in early Parkinson's disease: A phase 2, multicentre, double-blind, randomised trial', The Lancet Neurology, vol. 14, no. 8, pp. 795-803. https://doi.org/10.1016/S1474-4422(15)00144-1
Simuni, Tanya ; Kieburtz, Karl ; Tilley, Barbara ; J Elm, Jordan ; Ravina, Bernard ; Babcock, Debra ; Emborg, Marina ; Hauser, Robert ; Kamp, Cornelia ; Morgan, John C. ; Webster Ross, G. ; K Simon, David ; Bainbridge, Jacci ; Baker, Liana ; Bodis-Wollner, Ivan ; Boyd, James ; Cambi, Franca ; Carter, Julie ; Chou, Kelvin ; Dahodwala, Nabila ; Dewey, Richard B. ; Dhall, Rohit ; Fang, John ; Farrow, Buff ; Feigin, Andrew ; Glazman, Sofya ; Goudreau, John ; LeBlanc, Pauline ; Lee, Stephen ; Leehey, Maureen ; Lew, Mark F. ; Lowenhaupt, Stephanie ; Luo, Sheng ; Pahwa, Rajesh ; Perez, Adriana ; Schneider, Jay ; Scott, Burton ; Shah, Binit ; Shannon, Kathleen M. ; Sharma, Saloni ; Singer, Carlos ; Truong, Daniel ; Wagner, Renee ; Williams, Karen ; Marie Wills, Anne ; Shieen Wong, Pei ; Zadikoff, Cindy ; Zweig, Richard. / Pioglitazone in early Parkinson's disease : A phase 2, multicentre, double-blind, randomised trial. In: The Lancet Neurology. 2015 ; Vol. 14, No. 8. pp. 795-803.
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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.",
author = "Tanya Simuni and Karl Kieburtz and Barbara Tilley and {J Elm}, Jordan and Bernard Ravina and Debra Babcock and Marina Emborg and Robert Hauser and Cornelia Kamp and Morgan, {John C.} and {Webster Ross}, G. and {K Simon}, David and Jacci Bainbridge and Liana Baker and Ivan Bodis-Wollner and James Boyd and Franca Cambi and Julie Carter and Kelvin Chou and Nabila Dahodwala and Dewey, {Richard B.} and Rohit Dhall and John Fang and Buff Farrow and Andrew Feigin and Sofya Glazman and John Goudreau and Pauline LeBlanc and Stephen Lee and Maureen Leehey and Lew, {Mark F.} and Stephanie Lowenhaupt and Sheng Luo and Rajesh Pahwa and Adriana Perez and Jay Schneider and Burton Scott and Binit Shah and Shannon, {Kathleen M.} and Saloni Sharma and Carlos Singer and Daniel Truong and Renee Wagner and Karen Williams and {Marie Wills}, Anne and {Shieen Wong}, Pei and Cindy Zadikoff and Richard Zweig",
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TY - JOUR

T1 - Pioglitazone in early Parkinson's disease

T2 - A phase 2, multicentre, double-blind, randomised trial

AU - Simuni, Tanya

AU - Kieburtz, Karl

AU - Tilley, Barbara

AU - J Elm, Jordan

AU - Ravina, Bernard

AU - Babcock, Debra

AU - Emborg, Marina

AU - Hauser, Robert

AU - Kamp, Cornelia

AU - Morgan, John C.

AU - Webster Ross, G.

AU - K Simon, David

AU - Bainbridge, Jacci

AU - Baker, Liana

AU - Bodis-Wollner, Ivan

AU - Boyd, James

AU - Cambi, Franca

AU - Carter, Julie

AU - Chou, Kelvin

AU - Dahodwala, Nabila

AU - Dewey, Richard B.

AU - Dhall, Rohit

AU - Fang, John

AU - Farrow, Buff

AU - Feigin, Andrew

AU - Glazman, Sofya

AU - Goudreau, John

AU - LeBlanc, Pauline

AU - Lee, Stephen

AU - Leehey, Maureen

AU - Lew, Mark F.

AU - Lowenhaupt, Stephanie

AU - Luo, Sheng

AU - Pahwa, Rajesh

AU - Perez, Adriana

AU - Schneider, Jay

AU - Scott, Burton

AU - Shah, Binit

AU - Shannon, Kathleen M.

AU - Sharma, Saloni

AU - Singer, Carlos

AU - Truong, Daniel

AU - Wagner, Renee

AU - Williams, Karen

AU - Marie Wills, Anne

AU - Shieen Wong, Pei

AU - Zadikoff, Cindy

AU - Zweig, Richard

PY - 2015/8/1

Y1 - 2015/8/1

N2 - 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.

AB - 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.

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