Essai thérapeuthique 2009
Le centre de Référence Maladie Rare sur les Atrophies MultiSytématisées (AMS) des CHU de Toulouse et de Bordeaux coordonne un essai thérapeutique pour les patients atteints de cette maladie.
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Projet européen de recherche NNIPPS
Etude de l'efficacité et de la tolérance du Riluzole (200 mg/jour), chez des patients présentant une atrophie multisystémique (MSA) ou une paralysie progressive supranucléaire (PSP).
Etude multicentrique randomisée, stratifiée, en double-aveugle, contre placebo, en groupes parallèles.
Durée du contrat : 4 ans
Dates : du 1/10/2000 au 31/05/2005
Budget total : 2 055 100 euros
Subvention prévisionnelle de 613 022 euros de la Commission européenne
PARIS, 15 janvier 2007 (APM) - Le riluzole (Rilutek*, Sanofi-Aventis) n'a pas eu l'efficacité attendue ni n'a permis de prolonger la survie des patients atteints de paralysie supranucléaire progressive (PSP) ou d'atrophie multisystématisée (AMS), dans un essai européen auquel participait la France.
L'essai NNIPPS (Neuroprotection and Natural History in Parkinson's Plus Syndromes) est "la plus grande étude jamais entreprise" dans ces deux maladies rares, auprès de 766 patients, 363 atteints de PSP et 403 d'AMS, au Royaume-Uni, en France et en Allemagne, rappellent les auteurs de cette étude dans un communiqué de l'AP-HP diffusé la semaine dernière.
Après trois ans de traitement sous riluzole, qui est indiqué dans la sclérose latérale amyotrophique (SLA), ou placebo, "les résultats de l'analyse statistique ne permettent pas de conclure à l'efficacité du produit dans ces deux pathologies".
La paralysie supranucléaire progressive et l'atrophie multisystématisée sont associées à une espérance de vie de sept à dix ans après l'apparition des premiers symptômes.
L'analyse est en fait encore en cours mais l'absence d'effet a été établi et les investigateurs ont souhaité en informer rapidement les patients et les familles, indique à l'APM le Dr Gilbert Bensimon de l'hôpital de la Pitié-Salpêtrière à Paris (AP-HP), l'un des investigateurs français, ajoutant qu'un article sera soumis "très prochainement" à publication.
Malgré ce résultat "décevant", des données essentielles sur la nature et l'évolution naturelle de ces deux syndromes apparentés à la maladie de Parkinson ont été recueillies, notamment pour constituer une banque de matériel génétique et tissulaire qui commence à être exploitée, souligne le médecin.
La recherche s'oriente sur des pistes "non spécifiques", communes aux différentes maladies neurodégénératives: les facteurs de croissance neurotrophiques, les anti-apoptotiques ou les anti-radicaux libres, "qui n'ont pas jusqu'à présent trouvé d'indication", ou encore les inhibiteurs de la neuro-inflammation "dont on attend les résultats dans des essais en cours dans plusieurs pathologies neurodégénératives", poursuit-il.
L'étude NNIPPS était coordonnée par le Pr Nigel Leigh du King's College à Londres et financée par le cinquième programme cadre de recherche et de développement de l'Union européenne, avec le concours du ministère français de la santé dans le cadre d'un programme hospitalier de recherche clinique (PHRC).
LDKAF002 15/01/2007 18:00 SNC
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Article en anglais
NNIPPS: No Benefit of Riluzole on Survival in MSA and PSP
Susan Jeffrey Medscape Medical News 2007
June 7, 2007 (Istanbul) — A randomized trial of the neuroprotectant drug riluzole (Rilutek, Sanofi-Aventis) in patients with the "Parkinson plus syndromes" of multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) shows no effect on survival, either in the population as a whole or within the PSP or MSA strata, with treatment vs placebo.
However, the study supports the idea that large trials in neurodegenerative disorders can use survival as an end point and that it is feasible to include patients with these conditions quite early in their disease using the Parkinson-plus-syndrome concept.
The concept, for which this group has developed and validated diagnostic scales based on these data, "may be worthwhile when we have drugs that are promising," lead author P. Nigel Leigh, MD, PhD, from King's College, London, United Kingdom, who presented the results on behalf of the Neuroprotection and Natural History in Parkinson
Plus Syndromes (NNIPPS) Consortium, told attendees here."It has simple, pragmatic diagnostic criteria, which I suggest have some merit," he added, as well as high sensitivity and specificity for these difficult-to-diagnose conditions. The results were presented here at the 11th International Congress of Parkinson's Disease and Movement Disorders.
No Survival Benefit PSP and MSA often present as Parkinson plus syndromes — that is, having some of the classical features of Parkinson's disease but with some additional features. Early in the disease course, it can be very difficult to distinguish these conditions from each other, but for any intervention to be useful, it is important to enroll patients before diagnosis of PSP vs MSA is definitive.
PSP and MSA each have roughly the same frequency as amyotrophic lateral sclerosis (ALS), Dr. Leigh told Medscape, and "so are not insignificant adversaries." The idea of NNIPPS was to design a trial that would give a definitive answer, he said. "The whole field is deviled by small trials that never, ever, could have gotten a result. If we're going to choose a drug that's not ideal, like riluzole — no one was really expecting it to be a cure — let's at least be 80% or 90% sure that we're going to know in the end that it doesn't work or it does work."
They decided to use survival as an end point for.this trial. "Everybody said, you can't do it, it takes too long, but I think we've shown you can do it. It's tough, and it takes a long time, but maybe that will be worth it when we do have really good drugs," he noted.
Still, they had started out with the hope that riluzole might be effective. The natural history of MSA and PSP is poorly understood, they note in their abstract, but excitotoxicity may contribute to the neuronal damage. Riluzole, already approved for use in ALS, is a glutamate-release inhibitor and has been shown to prolong survival by about 2 months in clinical ALS trials and possibly between 6 and 19 months in retrospective data.
The NNIPPS trial, then, was a European multicenter, randomized, and stratified trial of riluzole in a dose of 50 to 200 mg per day vs placebo in patients with PSP and MSA. At the same time, investigators meant to investigate the natural history of these conditions presenting as Parkinson plus syndromes, acquiring prospective data on diagnostic criteria, MRI changes, and pathology.
The primary outcome was survival at 36 months; secondary outcome measures included functional status, cognition, quality of life, healthcare costs, and MRI abnormalities.
Power calculations were based on published estimates of survival in these conditions. In total, they enrolled 766 subjects from participating centers in the United Kingdom, France, and Germany. Six were later excluded because they either were found not to have proper informed consent or did not actually receive the drug, leaving 362 patients diagnosed clinically as PSP and 398 as MSA.
They used their own NNIPPS diagnostic criteria rather than the retrospectively validated existing criteria, he pointed out, because "we decided they were operationally extremely difficult in the setting of a clinical trial; they're too complicated, too complex," he said. In addition, "they're very good on specificity but they're weak on sensitivity, and we wanted sensitivity as well."
Median survival from onset was 7.8 years for PSP and 8.7 for MSA, with 171 deaths occurring in the PSP group and 171 in the MSA group.
Blinded Data In his presentation of the primary results here, Dr. Leigh noted that they have not yet unblinded the riluzole/placebo comparison because they hope still to do the other secondary analyses in a blinded fashion. Instead, he simply presented the survival results as "treatment A" vs "treatment B." Looking at the survival curves, however, he pointed out, "It doesn’t take much to show you that there was no significant difference, with the log rank clearly not significant. There was no difference, despite having adequate power."
Analysis of the intent-to-treat population showed no evidence of a significant treatment effect of riluzole either in the population as a whole or in the PSP or MSA strata.
"So the very least we can say is that riluzole does not work in this condition, but maybe this is a model for looking at other drugs, which we hope indeed it will be," he said.
Pathological diagnosis was confirmed in 112 cases where brain tissue has been donated and analyzed; another 20 brains have been donated but not yet analyzed, he noted. Overall, pathology-confirmed diagnosis showed that clinical diagnosis using the NNIPPS diagnostic criteria had an overall positive predictive value of 90% for PSP and 93% for MSA, "so we were encouraged by that," Dr. Leigh noted.
In an interview, Dr. Leigh pointed out that an earlier session here on the genetics of movement disorders underlines the "scary" genetic diversity of these diseases, making finding specific treatments for each subgroup with a different molecular mechanism a daunting task. "If you're going to find disease-modifying therapy in neurodegenerative diseases, the real challenge is to try to break across the boundaries of individual diseases and find common mechanisms."
They were disappointed with these results not only because they had hoped to help patients, but because if it had been positive that would have pointed to a common mechanism and provided some insight into how riluzole may be working in ALS as well, since this has not been well described.
"Still, I think, after recovering from the bad weekend when we got the news, that there's still a huge resource there," Dr. Leigh said.
Despite the fact that the trial was ultimately negative, NNIPPS provides a rich data set for understanding motor, cognitive, neuroimaging, and genetic factors in MSA and PSP.
For example, they devised and validated 2 diagnostic scales, the Parkinson Plus Scale and the Short Motor Scale, specifically designed for early use before a diagnosis of PSP or MSA is certain. They also have quality-of-life data and health costs that can be used in healthcare planning, he noted.
In addition, they have 633 baseline MRIs in these patients, with follow-up scans done at the end of the study in 187 patients; 521 DNA samples; and brains now from 131 patients, prospectively collected and being analyzed. Dr. Leigh invited any researchers interested in accessing these data to contact him about it.
The study was supported by the European Community. Study drug was provided by Sanofi-Aventis. Dr. Leigh disclosed has worked as a consultant for ONOPharma, Teva, Trophos, and GlaxoSmithKline.
11th International Congress of Parkinson's Disease and Movement Disorders: Oral Platform Presentations 4602: Abstract 10. June 3-7, 2007.