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 language | English (US) |
|---|---|
| Pages (from-to) | 795-803 |
| Number of pages | 9 |
| Journal | The Lancet Neurology |
| Volume | 14 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 1 2015 |
ASJC Scopus subject areas
- Clinical Neurology
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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 journal › Article › peer-review
}
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
N1 - Funding Information: 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 on the results of well conducted preclinical studies showing reproducible neuroprotective effects in tissue culture and animal models. 4,29,30 Unfortunately, this is another study in which animal models were not predictive of efficacy in human beings. A possible explanation for negative outcomes is that toxin animal models are not reflective of Parkinson's disease pathogenesis. Another possibility is that pioglitazone failed to reach the target nigral neurons and achieve sufficient drug exposure in this study, although good CNS penetration and target engagement were shown in primate studies. 13 Alternatively, it is possible that the beneficial effect of pioglitazone was missed owing to pitfalls of the study design, including the choice of the primary outcome measure. Although whether UPDRS is the best outcome measure for the assessment of disease-modifying benefit in early Parkinson's disease remains to be proven, it is the best validated measure and the one that has extensive data showing its sensitivity to change in early Parkinson's disease. 31 Consistent findings for all secondary outcomes, which included a spectrum of validated measures of quality of life, disability, and cognitive impairment, support an absence of biological effect rather than a failure to capture and measure an effect. The biomarkers also failed to show a separation of the active treatment groups from placebo and as such are concordant with the conclusions drawn from the clinical study (these results will be reported separately). If serum and urine biomarkers had shown a shift in the predicted direction, then an argument could have been made for a biological effect that was not captured by the clinical measures. The finding that both clinical and biological markers failed to move is disappointing, but solidifies the conclusion that pioglitazone is not promising for further testing in early Parkinson's disease. Another consideration is the short duration of this and other Parkinson's disease futility trials. 1 year or less amounts to a small proportion of the overall clinical course of Parkinson's disease. The major objective of futility studies is to screen out quickly compounds that do not work. Studies of such short duration might miss important disease-modifying effects that could be shown if patients were followed up for longer. Longer studies impose a greater burden on patients and higher cost. Ideally, future phase 2 studies of disease modification in Parkinson's disease will rely on biomarkers that will increase the sensitivity of the analysis over shorter follow-up. Another important consideration for future studies is how early Parkinson's disease is defined, as the onset of classic motor symptoms might be late biologically. Neuroprotection might not be feasible unless we intervene at the premotor stage of the disease. Of the other 12 agents recommended by CINAPS for clinical testing, most have entered phase 2 studies and four have completed phase 3 studies. Unfortunately, all studies have been negative so far. 15,32,33 A novel aspect of this study is that the participants were required to be treated with MAO-BI therapy at the time of enrolment. The rationale for this inclusion criterion was to reduce the number of patients who would need other dopaminergic treatment during the trial. Untreated Parkinson's disease patients are often enrolled to assess short-term (1 year or less) effects of a potential disease-modifying drug in exploratory trials. However, nearly half of the participants might need dopaminergic therapy before the end of follow-up. 34 This poses a major problem for the primary analysis because these patients' outcomes have to be carried forward from the last observed visit before initiation of dopaminergic therapy, or these data must be imputed. Treatment of de novo Parkinson's disease participants with low-dose MAO-BI therapy might delay the time to initiation of additional dopaminergic therapy by providing symptomatic benefit that might be mild enough to allow for detection of improvement due to a study intervention, should one exist. Indeed, only 30 (14%) participants needed additional dopaminergic therapy in this study, which is a two-to-three-fold reduction compared with the previously completed trials in similar populations. 34 MAO-BIs are unlikely to have masked a beneficial effect of pioglitazone because each treatment group in this study worsened similarly to those treated with 1 mg rasagiline in the TEMPO study, 26 which was used to estimate the placebo effect for the power calculations of this trial. On the basis of these data we propose to consider enrolment of patients on a stable regimen of a mild symptomatic therapy such as MAO-BIs in future phase 2 disease modification trials. Our data show that pioglitazone is unlikely to be efficacious as a disease-modifying intervention in early Parkinson's disease and therefore is not recommended for further testing for that indication. Although our negative results are disappointing, the design of this futility study is an example of a useful and efficient study design that can exclude a compound unlikely to be successful in larger and more costly phase 3 studies. Unfortunately, as was seen in the recent NET-PD study of creatine, 35 even compounds deemed non-futile in futility studies might also fail in longer studies. Accordingly, much attention has shifted to discovery and validation of biomarkers of disease progression, which we hope will accelerate the development of disease-modifying or curative agents. Correspondence to: Dr Tanya Simuni, Northwestern University Feinberg School of Medicine, Abbott Hall, 11th Floor, 710 North Lake Shore Drive, Chicago, IL 60611, USA tsimuni@nmff.org This online publication has been corrected. The corrected version first appeared at thelancet.com/neurology on September 14, 2015 Contributors TS (Principal Investigator) was responsible for study design, study oversight, data collection, data analysis, data interpretation, and writing of the final manuscript. KK (Principal Investigator, Coordination Center) was responsible for study design, study oversight, data interpretation, and critical review of the manuscript. BT (Principal Investigator, Statistical Center) was responsible for study design, data analysis, data interpretation, and manuscript review. DB was responsible for study design, data interpretation, and critical review of the manuscript. JJE was responsible for study design, data collection, data analysis, data interpretation, and writing the methods and results section. ME was responsible for literature search, study design, data interpretation, and critical review of the manuscript. RH, AF, and CS were responsible for data collection, data interpretation, and critical review of the manuscript. CK was responsible for study design, study drug supply chain management, original grant writing, procurement of funding, data collection, and critical review of the manuscript. JCM, GWR, and RBD were responsible for study design, data collection, data interpretation, and critical review of the manuscript. BR was responsible for study design, study oversight, data collection, data interpretation, and critical review of the manuscript. DKS was responsible for study design, data collection, data analysis, data interpretation, and critical review of the manuscript. JBa was responsible for data collection, data analysis, and critical review of the manuscript. LB, IB-W, JBo, FC, JC, KC, CWC, RD, JF, BF, SG, JG, PLB, SLe, ML, MFL, SLo, RP, JS, BSh, KMS, SS, DT, RW, AMW, PSW, RZ, and CZ were responsible for data collection and critical review of the manuscript. ND was responsible for data collection, review of results, and critical review of the manuscript. SLu was responsible for data analysis and critical review of the manuscript. AP was responsible for data interpretation, writing, and critical review of the manuscript. BSc was responsible for data collection, data interpretation, and critical review of the manuscript. KW was responsible for data collection and review of the manuscript. FS-ZONE Writing Committee Tanya Simuni MD (Principal Investigator; Northwestern University, Chicago, IL, USA); Karl Kieburtz MD (Principal Investigator, Coordination Center; University of Rochester, Rochester, NY, USA); Barbara Tilley PhD (Principal Investigator, Statistical Center; University of Texas Health Science Center at Houston, Houston, TX, USA); Jordan J Elm PhD (Medical University of South Carolina, Charleston, SC, USA); Bernard Ravina MD (Voyager Therapeutics, Cambridge, MA, USA); Debra Babcock MD (NINDS, National Institutes of Health, Bethesda, MD, USA); Marina Emborg MD (University of Wisconsin, Madison, WI, USA); Robert Hauser MD (University of South Florida, Tampa, FL, USA); Cornelia Kamp MBA (University of Rochester, Rochester, NY, USA); John C Morgan MD (Georgia Regents University, Augusta, GA, USA); G Webster Ross MD (Veterans Affairs Pacific Health Care System, Honolulu, HI, USA); David K Simon MD (Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA); Jacci Bainbridge PharmD (University of Colorado Denver, Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Clinical Pharmacy and Neurology, Aurora, CO, USA); Liana Baker MPH (University of Rochester, Rochester, NY, USA); Ivan Bodis-Wollner MD (SUNY Downstate Medical Center, Brooklyn, NY, USA); James Boyd MD (University of Vermont, Burlington, VT, USA); Franca Cambi MD (University of Kentucky, Lexington, KY, USA); Julie Carter ANP (Oregon Health & Science University, Portland, OR, USA); Kelvin Chou MD (Departments of Neurology and Neurosurgery, University of Michigan, Ann Arbor, MI, USA); Chadwick W Christine MD (Department of Neurology, University of California, San Francisco, San Francisco, CA, USA); Nabila Dahodwala MD (University of Pennsylvania, Philadelphia, PA, USA); Richard B Dewey Jr MD (University of Texas Southwestern Medical Center, Dallas, TX, USA); Rohit Dhall MD (Barrow Neurological Institute, Phoenix, AZ, USA); John Fang MD (Vanderbilt University, Nashville, TN, USA); Buff Farrow BS (Georgia Regents University, Augusta, GA, USA); Andrew Feigin MD (The Feinstein Institute for Medical Research, North Shore – LIJ Health System, Manhasset, NY, USA); Sofya Glazman MD (SUNY Downstate Medical Center, Brooklyn, NY, USA); John Goudreau DO (Department of Neurology, Michigan State University, East Lansing, MI, USA); Pauline LeBlanc BS (Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA); Stephen Lee MD (Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA); Maureen Leehey MD (University of Colorado Denver, Aurora, CO, USA); Mark F Lew MD (University of Southern California, Los Angeles, CA, USA); Stephanie Lowenhaupt RN (University of Virginia, Charlottesville, VA, USA); Sheng Luo PhD (The University of Texas Health Science Center at Houston, Houston, TX, USA); Rajesh Pahwa MD (University of Kansas Medical Center, Kansas City, KS, USA); Adriana Perez PhD (University of Texas Health Science Center at Houston, Austin, TX, USA); Jay Schneider PhD (Thomas Jefferson University, Department of Pathology, Anatomy and Cell Biology, Philadelphia, PA, USA); Burton Scott MD (Duke University, Durham, NC, USA); Binit Shah MD (University of Virginia, Charlottesville, VA, USA); Kathleen M Shannon MD (Rush University Medical Center, Chicago, IL, USA); Saloni Sharma MBBS (University of Rochester, Rochester, NY, USA); Carlos Singer MD (University of Miami, Miami, FL, USA); Daniel Truong MD (Parkinson's & Movement Disorder Institute, Fountain Valley, CA, USA); Renee Wagner RN (University of Kentucky, Lexington, KY, USA); Karen Williams (Northwestern University, Chicago, IL, USA); Anne Marie Wills MD (Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA); Pei Shieen Wong PharmD (University of Colorado Denver, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA; Singapore General Hospital, Singapore); Cindy Zadikoff MD (Northwestern University, Chicago, IL, USA); Richard Zweig MD (LSU Health Shreveport, Shreveport, LA, USA). Declaration of interests TS reports personal fees from Acadia, Abbvie, Allergan, Eli Lilly, Harbor, Ibsen, Merz, UCB Pharma, and US World Meds; grants, personal fees, honorarium, consulting fees, educational grant support from, and is a speaker for, GE Medical and TEVA; consulting fees from, and is an advisory board member and speaker for, IMPAX; personal fees and consulting fees from, and is a speaker for, Lundbeck; research funding from Auspex, Biotie, Civitas, NIH, and Michael J. Fox Foundation, during the conduct of the study. KK reports grants from National Institutes of Health, during the conduct of the study; grants from National Institutes of Health (NEI, NIH, NINDS); personal fees from Acorda, Astellas Pharma, AstraZeneca, Auspex, Biotie, Britannia, Cangene, CHDI, Civitas, Clearpoint Strategy Group, Clintrex, Cynapsus, INC Research, Intec, Isis, Lilly, Lundbeck, Medavante, Medivation, Melior Discovery, Neuroderm, Neurmedix, Omeros, Otsuka, Pfizer, Pharma2B, Prothena/Neotope/Elan Pharmaceutical, Raptor Pharmaceuticals, Roche/Genentech, Sage Bionetworks, Serina, Stealth Peptides, Synagile, Teikoku Pharma, Titan, Turing Pharmaceuticals, Upsher-Smith, US WorldMeds, Vaccinex, Voyager, and Weston Brain Institute; grants from Michael J Fox Foundation and Teva, outside the submitted work. BT reports personal fees from Roche, grants from MDS, and non-financial support from Michael J. Fox Foundation, outside the submitted work. DB is an employee of NINDS. JJE reports grants from NINDS, during the conduct of the study. RH reports grants from NIH, during the conduct of the study; personal fees from Teva Pharmaceuticals, USB Biosciences, AbbVie, Eli Lilly, Novartis, Biotie, Lundbeck, Pfizer, Allergan Neuroscience, Neurocrine, Chelsea, Auspex, Acadia, Michael J Fox Foundation, GLG, AstraZeneca, Acordia, and Impax Pharmaceuticals, outside the submitted work. JCM reports grants from NIH, during the conduct of the study; personal fees from Veloxis, Teva, Lundbeck, Impax Labs, and Movement Disorders Society, and grants and personal fees from National Parkinson Foundation, outside the submitted work. BR reports equity in, and is an employee of, Voyager Therapeutics. GWR reports grants from NINDS-NIH, during the conduct of the study. DKS reports grants from Lysosomal Therapeutics, outside the submitted work. JBa reports grants from National Institutes of Health (NIH), during the conduct of the study. JBo reports grants from University of Vermont, during the conduct of the study; grants and personal fees from AbbVie and Auspex, personal fees from Lundbeck, grants from Biotie, Cure HD Initiative Foundation, and MJ Fox Foundation, outside the submitted work. KC reports grants from NIH, during the conduct of the study; personal fees from Medtronic, Inc., outside the submitted work. CWC reports grants from NIH, during the conduct of this study; grants from Kinemed, Inc. and Michael J Fox Foundation, outside the submitted work. ND reports grants from NIH, National Parkinson Foundation, and PD Council, outside the submitted work. RBD reports grants from NINDS, during the conduct of the study; personal fees from Teva Neuroscience, Merz, Xenoport, UCB, Acadia, US World Meds, Impax, and Lundbeck, outside the submitted work. JF reports grants from NIH/NINDS, outside the submitted work. BF reports grants from NIH/NINDS, during the conduct of the study. AF reports personal fees from Lundbeck, US World Meds, Auspex, and Prana, grants from Voyager Therapeutics, outside the submitted work. JG reports grants from National Institutes of Health, during the conduct of the study; personal fees from Teva Neuroscience, grants from Michael J. Fox Foundation and National Institutes of Health, outside the submitted work. ML reports grants from NIH, during the conduct of the study; personal fees from Neurologic Movement Disorders Market Research Team, Giudepoint Global, Scientiae, LLC, Health Practices Research Institute, Gerson Lehman; grants from Allergan, Medtronic, Teva, US World Meds, LLC, Adamas Pharmaceuticals, Pharma2B, outside the submitted work; and grants from NINDS, NIH, and Colorado Department of Health and Environment. MFL reports grants and personal fees from Teva Pharmaceuticals, personal fees from Lundbeck, Impax, UCB, Auspex, Baxter, Acadia, and Abbvie, outside the submitted work. SLu receives research funding from NIH, Movement Disorder Society, and CHDI Foundation. RP reports grants from NIH, during the conduct of the study; grants and personal fees from Teva Neuroscience, Acadia Pharma, Adamas, UCB Pharma, Medtronic, US World Meds, Impax Pharma, Lundbeck, AbbiVie, NPF, Parkinson Study Group; personal fees from St Jude Medical; grants from Avid, Biotie, Boston Scientific, Chelesea, Civitas, Kyowa, outside the submitted work; royalties from Oxford Press and Informa Health; is a member of the data and safety monitoring committee for an ISIS study; and is co-editor-in-chief of the International Journal of Neuroscience. DT reports receiving grants for this work. RW reports grants from NINDS, during the conduct of the study; grants and personal fees from Abbvie, and grants from Teva, outside the submitted work. PSW reports grants from NIH, during the conduct of the study. CZ reports consulting fees and honoraria from Teva and Abbie, and honoraria from UCB, outside the submitted work. RZ reports grants from NINDS (NIH), during the conduct of the study. ME, CK, LB, IBW, FC, JC, RD, SG, PL, SLe, SLo, AP, JS, BSc, BSh, KMS, SS, CS, KW, and AMW declare no competing interests. Acknowledgments We would like to thank the FS-ZONE participants for their commitment to this study and to Parkinson's disease research.
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.
UR - http://www.scopus.com/inward/record.url?scp=84937520622&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84937520622&partnerID=8YFLogxK
U2 - 10.1016/S1474-4422(15)00144-1
DO - 10.1016/S1474-4422(15)00144-1
M3 - Article
C2 - 26116315
AN - SCOPUS:84937520622
VL - 14
SP - 795
EP - 803
JO - The Lancet Neurology
JF - The Lancet Neurology
SN - 1474-4422
IS - 8
ER -