Riluzole treatment, survival and diagnostic criteria in Parkinson plus disorders

The NNIPPS Study

G Bensimon, A Ludolph, Y Agid, M Vidailhet, C Payan, P N Leigh, C E Counsell, NNIPPS Study Group

Research output: Contribution to journalArticle

206 Citations (Scopus)

Abstract

Parkinson plus diseases, comprising mainly progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) are rare neurodegenerative conditions. We designed a double-blind randomized placebo-controlled trial of riluzole as a potential disease-modifying agent in Parkinson plus disorders (NNIPPS: Neuroprotection and Natural History in Parkinson Plus Syndromes). We analysed the accuracy of our clinical diagnostic criteria, and studied prognostic factors for survival. Patients with an akinetic-rigid syndrome diagnosed as having PSP or MSA according to modified consensus diagnostic criteria were considered for inclusion. The psychometric validity (convergent and predictive) of the NNIPPS diagnostic criteria were tested prospectively by clinical and pathological assessments. The study was powered to detect a 40 decrease in relative risk of death within PSP or MSA strata. Patients were randomized to riluzole or matched placebo daily and followed up to 36 months. The primary endpoint was survival. Secondary efficacy outcomes were rates of disease progression assessed by functional measures. A total of 767 patients were randomized and 760 qualified for the Intent to Treat (ITT) analysis, stratified at entry as PSP (362 patients) or MSA (398 patients). Median follow-up was 1095 days (range 2491095). During the study, 342 patients died and 112 brains were examined for pathology. NNIPPS diagnostic criteria showed for both PSP and MSA excellent convergent validity with the investigators assessment of diagnostic probability (point-biserial correlation: MSA r(pb) 0.93, P 0.0001; PSP, r(pb) 0.95, P 0.0001), and excellent predictive validity against histopathology [sensitivity and specificity (95 CI) for PSP 0.95 (0.880.98) and 0.84 (0.770.87); and for MSA 0.96 (0.880.99) and 0.91 (0.860.93)]. There was no evidence of a drug effect on survival in the PSP or MSA strata (3 year KaplanMeier estimates PSP-riluzole: 0.51, PSP-placebo: 0.50; MSA-riluzole: 0.53, MSA-placebo: 0.58; P 0.66 and P 0.48 by the log-rank test, respectively), or in the population as a whole (P 0.42, by the stratified-log-rank test). Likewise, rate of progression was similar in both treatment groups. There were no unexpected adverse effects of riluzole, and no significant safety concerns. Riluzole did not have a significant effect on survival or rate of functional deterioration in PSP or MSA, although the study reached over 80 power to detect the hypothesized drug effect within strata. The NNIPPS diagnostic criteria were consistent and valid. They can be used to distinguish between PSP and MSA with high accuracy, and should facilitate research into these conditions relatively early in their evolution.
Original languageEnglish
Pages (from-to)156-171
Number of pages56
JournalBrain
Volume132
Issue number1
Early online date23 Nov 2008
DOIs
Publication statusPublished - Jan 2009

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Riluzole
Progressive Supranuclear Palsy
Multiple System Atrophy
Survival
Therapeutics
Placebos
Natural History
Psychometrics
Pharmaceutical Preparations

Keywords

  • progressive supranuclear palsy
  • multiple system atrophy
  • Richardson-Olszewski-syndrome
  • amyotrophic-lateral-sclerosis
  • sporadic olivopontocerebellar atrophy
  • ninds neuropathological criteria
  • group emsa-sg
  • natural history
  • sriatonigral degeneration
  • huntingtons disease

Cite this

Bensimon, G., Ludolph, A., Agid, Y., Vidailhet, M., Payan, C., Leigh, P. N., ... NNIPPS Study Group (2009). Riluzole treatment, survival and diagnostic criteria in Parkinson plus disorders: The NNIPPS Study. Brain, 132(1), 156-171. https://doi.org/10.1093/brain/awn291

Riluzole treatment, survival and diagnostic criteria in Parkinson plus disorders : The NNIPPS Study. / Bensimon, G; Ludolph, A; Agid, Y; Vidailhet, M; Payan, C; Leigh, P N; Counsell, C E; NNIPPS Study Group.

In: Brain, Vol. 132, No. 1, 01.2009, p. 156-171.

Research output: Contribution to journalArticle

Bensimon, G, Ludolph, A, Agid, Y, Vidailhet, M, Payan, C, Leigh, PN, Counsell, CE & NNIPPS Study Group 2009, 'Riluzole treatment, survival and diagnostic criteria in Parkinson plus disorders: The NNIPPS Study', Brain, vol. 132, no. 1, pp. 156-171. https://doi.org/10.1093/brain/awn291
Bensimon G, Ludolph A, Agid Y, Vidailhet M, Payan C, Leigh PN et al. Riluzole treatment, survival and diagnostic criteria in Parkinson plus disorders: The NNIPPS Study. Brain. 2009 Jan;132(1):156-171. https://doi.org/10.1093/brain/awn291
Bensimon, G ; Ludolph, A ; Agid, Y ; Vidailhet, M ; Payan, C ; Leigh, P N ; Counsell, C E ; NNIPPS Study Group. / Riluzole treatment, survival and diagnostic criteria in Parkinson plus disorders : The NNIPPS Study. In: Brain. 2009 ; Vol. 132, No. 1. pp. 156-171.
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N2 - Parkinson plus diseases, comprising mainly progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) are rare neurodegenerative conditions. We designed a double-blind randomized placebo-controlled trial of riluzole as a potential disease-modifying agent in Parkinson plus disorders (NNIPPS: Neuroprotection and Natural History in Parkinson Plus Syndromes). We analysed the accuracy of our clinical diagnostic criteria, and studied prognostic factors for survival. Patients with an akinetic-rigid syndrome diagnosed as having PSP or MSA according to modified consensus diagnostic criteria were considered for inclusion. The psychometric validity (convergent and predictive) of the NNIPPS diagnostic criteria were tested prospectively by clinical and pathological assessments. The study was powered to detect a 40 decrease in relative risk of death within PSP or MSA strata. Patients were randomized to riluzole or matched placebo daily and followed up to 36 months. The primary endpoint was survival. Secondary efficacy outcomes were rates of disease progression assessed by functional measures. A total of 767 patients were randomized and 760 qualified for the Intent to Treat (ITT) analysis, stratified at entry as PSP (362 patients) or MSA (398 patients). Median follow-up was 1095 days (range 2491095). During the study, 342 patients died and 112 brains were examined for pathology. NNIPPS diagnostic criteria showed for both PSP and MSA excellent convergent validity with the investigators assessment of diagnostic probability (point-biserial correlation: MSA r(pb) 0.93, P 0.0001; PSP, r(pb) 0.95, P 0.0001), and excellent predictive validity against histopathology [sensitivity and specificity (95 CI) for PSP 0.95 (0.880.98) and 0.84 (0.770.87); and for MSA 0.96 (0.880.99) and 0.91 (0.860.93)]. There was no evidence of a drug effect on survival in the PSP or MSA strata (3 year KaplanMeier estimates PSP-riluzole: 0.51, PSP-placebo: 0.50; MSA-riluzole: 0.53, MSA-placebo: 0.58; P 0.66 and P 0.48 by the log-rank test, respectively), or in the population as a whole (P 0.42, by the stratified-log-rank test). Likewise, rate of progression was similar in both treatment groups. There were no unexpected adverse effects of riluzole, and no significant safety concerns. Riluzole did not have a significant effect on survival or rate of functional deterioration in PSP or MSA, although the study reached over 80 power to detect the hypothesized drug effect within strata. The NNIPPS diagnostic criteria were consistent and valid. They can be used to distinguish between PSP and MSA with high accuracy, and should facilitate research into these conditions relatively early in their evolution.

AB - Parkinson plus diseases, comprising mainly progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) are rare neurodegenerative conditions. We designed a double-blind randomized placebo-controlled trial of riluzole as a potential disease-modifying agent in Parkinson plus disorders (NNIPPS: Neuroprotection and Natural History in Parkinson Plus Syndromes). We analysed the accuracy of our clinical diagnostic criteria, and studied prognostic factors for survival. Patients with an akinetic-rigid syndrome diagnosed as having PSP or MSA according to modified consensus diagnostic criteria were considered for inclusion. The psychometric validity (convergent and predictive) of the NNIPPS diagnostic criteria were tested prospectively by clinical and pathological assessments. The study was powered to detect a 40 decrease in relative risk of death within PSP or MSA strata. Patients were randomized to riluzole or matched placebo daily and followed up to 36 months. The primary endpoint was survival. Secondary efficacy outcomes were rates of disease progression assessed by functional measures. A total of 767 patients were randomized and 760 qualified for the Intent to Treat (ITT) analysis, stratified at entry as PSP (362 patients) or MSA (398 patients). Median follow-up was 1095 days (range 2491095). During the study, 342 patients died and 112 brains were examined for pathology. NNIPPS diagnostic criteria showed for both PSP and MSA excellent convergent validity with the investigators assessment of diagnostic probability (point-biserial correlation: MSA r(pb) 0.93, P 0.0001; PSP, r(pb) 0.95, P 0.0001), and excellent predictive validity against histopathology [sensitivity and specificity (95 CI) for PSP 0.95 (0.880.98) and 0.84 (0.770.87); and for MSA 0.96 (0.880.99) and 0.91 (0.860.93)]. There was no evidence of a drug effect on survival in the PSP or MSA strata (3 year KaplanMeier estimates PSP-riluzole: 0.51, PSP-placebo: 0.50; MSA-riluzole: 0.53, MSA-placebo: 0.58; P 0.66 and P 0.48 by the log-rank test, respectively), or in the population as a whole (P 0.42, by the stratified-log-rank test). Likewise, rate of progression was similar in both treatment groups. There were no unexpected adverse effects of riluzole, and no significant safety concerns. Riluzole did not have a significant effect on survival or rate of functional deterioration in PSP or MSA, although the study reached over 80 power to detect the hypothesized drug effect within strata. The NNIPPS diagnostic criteria were consistent and valid. They can be used to distinguish between PSP and MSA with high accuracy, and should facilitate research into these conditions relatively early in their evolution.

KW - progressive supranuclear palsy

KW - multiple system atrophy

KW - Richardson-Olszewski-syndrome

KW - amyotrophic-lateral-sclerosis

KW - sporadic olivopontocerebellar atrophy

KW - ninds neuropathological criteria

KW - group emsa-sg

KW - natural history

KW - sriatonigral degeneration

KW - huntingtons disease

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M3 - Article

VL - 132

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JO - Brain

JF - Brain

SN - 0006-8950

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