A Controlled Trial of Rasagiline in Early Parkinson Disease

Siderowf, Andrew; Stern, Matthew B.; Shoulson, Ira; Kieburtz, Karl; Oakes, David; Day, Denni; Shinaman, Aileen; Plumb, Sandra; Fahn, Stanley; Blindauer, Karen; Lew, Mark F.; Hurtig, Howard I.; Lloyd, Mary; Hauser, Robert A.; Gauger, Lisa; Golbe, Lawrence I.; Wojcieszek, Joanne; Belden, Joann; Feigin, Andrew; Klimek, Mary Lou; Shannon, Barbara; Ondo, William G.; Hunter, Christine; Calabrese, Vincent P.; Atchison, Paul; Allen, Cathy W.; Marshall, Frederick J.; Berry, Debra; Gardiner, Irenita; Miyasaki, Janis; Rizzo, Luisa Del; Mendis, Tilak; Mendis, N. M. P.; Gray, Peggy; Hubble, Jean; Betcher, Karen; Pahwa, Rajesh; Molho, Eric; Brown, Diane; Shulman, Lisa M.; Rajput, Ali H.; Ewanishin, Marianne; Stacy, Mark; Williamson, Kelli; Bertoni, John M.; Peterson, Carolyn; Tuite, Paul J.; Ebbitt, Brenda; Shannon, Kathleen M.; Jaglin, Jean A.; Tanner, Caroline M.; Marek, Kenneth; Stavris, Karen; Aminoff, Michael J.; DiMinno, Mariann; Dowling, Glenna A.; Kang, Un Jung; Richman, Judy; Sethi, Kapil D.; Martin, W. R. Wayne; King, Pamela S.; McInnes, Germaine; Adler, Charles H.; LeWitt, Peter A.; DeAngelis, Maryan; Schear, Myrna; Gordon, Mark Forrest; Winnick, Roberta; Feldman, Robert G.; Thomas, Cathi A.; Conn, Kelly M.; Brocht, Alicia; Chadwick, Chris; Connolly, Jeannette; Daigneault, Susan; Eberly, Shirley; Bausch, Janice; Josephson, Lee; Oliva, Rosemary; Schwid, Steven R.; Lang, Anthony E.; Cox, Christopher; Irvine, Carrie; Nutt, John G.; White, William Β.; Oren, Sheila; Levy, R.; Eyal, Eli; Ladkani, David; Houck, Wayne

doi:10.1001/archneur.59.12.1937

Cited by 498 publications

(104 citation statements)

References 23 publications

(22 reference statements)

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“…26 The approximate mean UPDRS change from 8 weeks to 52 weeks (ie, 44 weeks) was 4.5 (SD 8.0), which provided an estimate of μ p and was the rationale for the 44 week duration of our study. Under the null hypothesis we assumed μ to be μ p – 3, which is 1.5.…”

Section: Methodsmentioning

confidence: 89%

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

2015

The Lancet Neurology

222

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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.

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Section: Methodsmentioning

confidence: 89%

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

2015

The Lancet Neurology

222

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“…The UPDRS is a valid and reliable measure of PD disability that has been effectively used in a number of PD trials 21, 27, 28…”

Section: Methodsmentioning

confidence: 99%

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

Biglan

Oakes

Lang

et al. 2017

Ann Clin Transl Neurol

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ObjectiveTo describe the rationale for a novel study design and baseline characteristics of a disease‐modifying trial of isradipine 10 mg daily in early Parkinson disease (PD).Methods STEADY‐PDIII is a 36‐month, Phase 3, parallel group, placebo‐controlled study of the efficacy of isradipine 10 mg daily in 336 participants with early PD as measured by the change in the Unified Parkinson Disease Rating Scale (UPDRS) Part I‐III score in the practically defined ON state. Secondary outcome measures include clinically meaningful measures of disability progression in early PD: (1) Time to initiation and utilization of dopaminergic therapy; (2) Time to onset of motor complications; (3) Change in nonmotor disability. Exploratory measures include global measures of functional disability, quality of life, change in the ambulatory capacity, cognitive function, and pharmacokinetic analysis. Rationale for the current design and alternative design approaches are discussed.ResultsThe entire cohort of 336 participants was enrolled at 55 Parkinson Study Group sites in North America. The percentage of male participants were 68.5% with a mean age of 61.9 years (sd 9.0), mean Hoehn and Yahr stage of 1.7 (sd 0.5), mean UPDRS total of 23.1 (sd 8.6), and MoCA of 28.1 (sd 1.4).Interpretation STEADY‐PD III has a novel and innovative design allowing for the determination of longer duration benefits on clinically relevant outcomes in a relatively small cohort on top of the benefit derived from symptomatic therapy. Baseline characteristics are similar to those in previously enrolled de novo PD trials. This study represents a unique opportunity to evaluate the potential impact of a novel therapy to slow progression of PD disability and provide clinically meaningful benefits.

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“…The monotherapy indication was based in part on the TEMPO study [9], which was a randomized, double-blind, placebo-controlled, 26-week trial comparing 1 mg/day rasagiline (n = 134), 2 mg/day rasagiline (n = 132) and placebo (n = 138) in early PD patients who had not been previously exposed to antiparkinsonian medications other than anticholinergics. At 26 weeks, significantly less worsening of UPDRS total scores was observed with both rasagiline doses compared to placebo; those treated with 1 mg/day rasagiline experienced a 4.2-point improvement relative to placebo and those treated with 2 mg/day rasagiline had a 3.6-point benefit relative to placebo (p < 0.001 for both comparisons; primary outcome).…”

Section: Treatment Of Motor Symptomsmentioning

confidence: 99%

“…Large multicenter, randomized, double-blind, placebo-controlled trials examining the effects of L -dopa [7], selegiline [8], rasagiline [9], pramipexole [10, 11], ropinirole [12, 14] and rotigotine [15, 16, 18] in the treatment of early PD have been conducted. Although it is tempting to compare the results of these trials, it is important to appreciate that direct comparisons in most cases cannot be made; however, considering the data in terms of both the similarities and differences between these independent clinical trials and their resulting data sets can help guide clinical judgments.…”

Section: Treatment Of Motor Symptomsmentioning

confidence: 99%

Treatment of Early Parkinson’s Disease

et al. 2009

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The management of early Parkinson’s disease (PD) involves the treatment of motor symptoms and, increasingly, non-motor symptoms. Given the fast pace of clinical research in PD, clinicians are faced with the challenge of integrating the latest findings into the ongoing care of individual PD patients. Part 1 of this 2-part article reviews motor symptom efficacy data for the newest PD treatment options, as well as for established therapies. Safety and tolerability data are also reviewed. Part 2 of the article reviews key findings relevant to the assessment of potential neuroprotective therapies and the treatment of non-motor symptoms.

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A Controlled Trial of Rasagiline in Early Parkinson Disease

Abstract: Rasagiline is effective as monotherapy for patients with early PD. The 2 dosages in this trial were both effective relative to placebo. Further study is warranted to evaluate the longer-term effects of rasagiline in PD.

Cited by 498 publications

References 23 publications

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

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

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

Treatment of Early Parkinson’s Disease

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