Riluzole treatment, survival and diagnostic criteria in Parkinson plus disorders: the NNIPPS study.
Identifieur interne : 000A80 ( PubMed/Checkpoint ); précédent : 000A79; suivant : 000A81Riluzole treatment, survival and diagnostic criteria in Parkinson plus disorders: the NNIPPS study.
Auteurs : Gilbert Bensimon [France] ; Albert Ludolph ; Yves Agid [France] ; Marie Vidailhet ; Christine Payan ; P Nigel LeighSource :
- Brain : a journal of neurology [ 1460-2156 ] ; 2009.
English descriptors
- KwdEn :
- Aged, Disease Progression, Epidemiologic Methods, Female, Humans, Male, Middle Aged, Multiple System Atrophy (complications), Multiple System Atrophy (diagnosis), Multiple System Atrophy (drug therapy), Neuroprotective Agents (adverse effects), Neuroprotective Agents (therapeutic use), Parkinson Disease, Secondary (etiology), Prognosis, Psychometrics, Riluzole (adverse effects), Riluzole (therapeutic use), Severity of Illness Index, Supranuclear Palsy, Progressive (complications), Supranuclear Palsy, Progressive (diagnosis), Supranuclear Palsy, Progressive (drug therapy), Treatment Outcome.
- MESH :
- chemical , adverse effects : Neuroprotective Agents, Riluzole.
- complications : Multiple System Atrophy, Supranuclear Palsy, Progressive.
- diagnosis : Multiple System Atrophy, Supranuclear Palsy, Progressive.
- drug therapy : Multiple System Atrophy, Supranuclear Palsy, Progressive.
- etiology : Parkinson Disease, Secondary.
- chemical , therapeutic use : Neuroprotective Agents, Riluzole.
- Aged, Disease Progression, Epidemiologic Methods, Female, Humans, Male, Middle Aged, Prognosis, Psychometrics, Severity of Illness Index, Treatment Outcome.
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 249-1095). 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 (0.88-0.98) and 0.84 (0.77-0.87); and for MSA 0.96 (0.88-0.99) and 0.91 (0.86-0.93)]. There was no evidence of a drug effect on survival in the PSP or MSA strata (3 year Kaplan-Meier 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.
DOI: 10.1093/brain/awn291
PubMed: 19029129
Affiliations:
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pubmed:19029129Le document en format XML
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<front><div type="abstract" xml:lang="en">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 249-1095). 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 (0.88-0.98) and 0.84 (0.77-0.87); and for MSA 0.96 (0.88-0.99) and 0.91 (0.86-0.93)]. There was no evidence of a drug effect on survival in the PSP or MSA strata (3 year Kaplan-Meier 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.</div>
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<Abstract><AbstractText>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 249-1095). 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 (0.88-0.98) and 0.84 (0.77-0.87); and for MSA 0.96 (0.88-0.99) and 0.91 (0.86-0.93)]. There was no evidence of a drug effect on survival in the PSP or MSA strata (3 year Kaplan-Meier 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.</AbstractText>
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<Initials>C</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Pham</LastName>
<ForeName>H P</ForeName>
<Initials>HP</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Fermanian</LastName>
<ForeName>J</ForeName>
<Initials>J</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Brown</LastName>
<ForeName>R</ForeName>
<Initials>R</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>McCrone</LastName>
<ForeName>P</ForeName>
<Initials>P</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Dedise</LastName>
<ForeName>N</ForeName>
<Initials>N</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Hermine</LastName>
<ForeName>C</ForeName>
<Initials>C</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Sagnes</LastName>
<ForeName>S</ForeName>
<Initials>S</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Poître</LastName>
<ForeName>B</ForeName>
<Initials>B</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Foucart</LastName>
<ForeName>C</ForeName>
<Initials>C</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Dougherty</LastName>
<ForeName>A</ForeName>
<Initials>A</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Murphy</LastName>
<ForeName>C</ForeName>
<Initials>C</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Mason</LastName>
<ForeName>H</ForeName>
<Initials>H</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Hermann</LastName>
<ForeName>T</ForeName>
<Initials>T</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Klempp</LastName>
<ForeName>K</ForeName>
<Initials>K</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Niess</LastName>
<ForeName>A</ForeName>
<Initials>A</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Stange</LastName>
<ForeName>V</ForeName>
<Initials>V</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Ouslimani</LastName>
<ForeName>A</ForeName>
<Initials>A</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Lehmann</LastName>
<ForeName>B</ForeName>
<Initials>B</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Tibi</LastName>
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<Initials>A</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Agid</LastName>
<ForeName>Y</ForeName>
<Initials>Y</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Viallet</LastName>
<ForeName>F</ForeName>
<Initials>F</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Couratier</LastName>
<ForeName>C</ForeName>
<Initials>C</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Arguillère</LastName>
<ForeName>S</ForeName>
<Initials>S</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Payan-Cassin</LastName>
<ForeName>H</ForeName>
<Initials>H</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Vassault</LastName>
<ForeName>G M</ForeName>
<Initials>GM</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Henon</LastName>
<ForeName>P</ForeName>
<Initials>P</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Gimeno</LastName>
<ForeName>S</ForeName>
<Initials>S</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Dubas</LastName>
<ForeName>F</ForeName>
<Initials>F</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Fressinaud</LastName>
<ForeName>C</ForeName>
<Initials>C</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Tanguy</LastName>
<ForeName>J Y</ForeName>
<Initials>JY</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Legall</LastName>
<ForeName>D</ForeName>
<Initials>D</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Rumbach</LastName>
<ForeName>L</ForeName>
<Initials>L</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Vidry</LastName>
<ForeName>E</ForeName>
<Initials>E</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Kraehenbuhl</LastName>
<ForeName>J</ForeName>
<Initials>J</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Bonneville</LastName>
<ForeName>J F</ForeName>
<Initials>JF</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Chopard</LastName>
<ForeName>G</ForeName>
<Initials>G</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>LeDoze</LastName>
<ForeName>F</ForeName>
<Initials>F</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Defer</LastName>
<ForeName>G</ForeName>
<Initials>G</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Viader</LastName>
<ForeName>F</ForeName>
<Initials>F</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Marié</LastName>
<ForeName>R-M</ForeName>
<Initials>RM</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Huet</LastName>
<ForeName>H</ForeName>
<Initials>H</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Daniel</LastName>
<ForeName>F</ForeName>
<Initials>F</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Lalevée</LastName>
<ForeName>C</ForeName>
<Initials>C</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Durif</LastName>
<ForeName>F</ForeName>
<Initials>F</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Debilly</LastName>
<ForeName>B</ForeName>
<Initials>B</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Derost</LastName>
<ForeName>Ph</ForeName>
<Initials>P</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Tilignac</LastName>
<ForeName>C</ForeName>
<Initials>C</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Gabrillargues</LastName>
<ForeName>J</ForeName>
<Initials>J</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Lauvergne Crégu</LastName>
<ForeName>D</ForeName>
<Initials>D</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Rosière</LastName>
<ForeName>C</ForeName>
<Initials>C</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Besson</LastName>
<ForeName>G</ForeName>
<Initials>G</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Mallaret</LastName>
<ForeName>C</ForeName>
<Initials>C</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Grand</LastName>
<ForeName>S</ForeName>
<Initials>S</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Klinger</LastName>
<ForeName>H</ForeName>
<Initials>H</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Funkiewiez</LastName>
<ForeName>A</ForeName>
<Initials>A</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Destée</LastName>
<ForeName>A</ForeName>
<Initials>A</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Defebvre</LastName>
<ForeName>L</ForeName>
<Initials>L</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Delmaire</LastName>
<ForeName>C</ForeName>
<Initials>C</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Dujardin</LastName>
<ForeName>K</ForeName>
<Initials>K</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Couratier</LastName>
<ForeName>P</ForeName>
<Initials>P</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Boncoeur-Martel</LastName>
<ForeName>M P</ForeName>
<Initials>MP</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Chazot-Balcon</LastName>
<ForeName>M</ForeName>
<Initials>M</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Broussole</LastName>
<ForeName>E</ForeName>
<Initials>E</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Mollion</LastName>
<ForeName>H</ForeName>
<Initials>H</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Hermier</LastName>
<ForeName>M</ForeName>
<Initials>M</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Bouvard</LastName>
<ForeName>M</ForeName>
<Initials>M</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Azulay</LastName>
<ForeName>J P</ForeName>
<Initials>JP</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Witjas</LastName>
<ForeName>T</ForeName>
<Initials>T</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Delfini</LastName>
<ForeName>M</ForeName>
<Initials>M</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Camu</LastName>
<ForeName>W</ForeName>
<Initials>W</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Portet</LastName>
<ForeName>F</ForeName>
<Initials>F</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Khoris</LastName>
<ForeName>J</ForeName>
<Initials>J</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Pageot</LastName>
<ForeName>N</ForeName>
<Initials>N</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Garrigues</LastName>
<ForeName>G</ForeName>
<Initials>G</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Viaud</LastName>
<ForeName>B</ForeName>
<Initials>B</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Martin</LastName>
<ForeName>K</ForeName>
<Initials>K</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Bernard</LastName>
<ForeName>J</ForeName>
<Initials>J</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Borg</LastName>
<ForeName>M</ForeName>
<Initials>M</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Chanalet</LastName>
<ForeName>S</ForeName>
<Initials>S</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Vidailhet</LastName>
<ForeName>M</ForeName>
<Initials>M</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Sangla</LastName>
<ForeName>S</ForeName>
<Initials>S</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Ranoux</LastName>
<ForeName>D</ForeName>
<Initials>D</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Brandel</LastName>
<ForeName>J P</ForeName>
<Initials>JP</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>De Broucker</LastName>
<ForeName>T</ForeName>
<Initials>T</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Agid</LastName>
<ForeName>Y</ForeName>
<Initials>Y</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Dubois</LastName>
<ForeName>B</ForeName>
<Initials>B</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Cesaro</LastName>
<ForeName>P</ForeName>
<Initials>P</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Fenelon</LastName>
<ForeName>G</ForeName>
<Initials>G</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Agid</LastName>
<ForeName>Y</ForeName>
<Initials>Y</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Bloch</LastName>
<ForeName>F</ForeName>
<Initials>F</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Bonnet</LastName>
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<Initials>AM</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Lacomblez</LastName>
<ForeName>L</ForeName>
<Initials>L</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Maltête</LastName>
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<Initials>D</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Memin</LastName>
<ForeName>A</ForeName>
<Initials>A</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Torni</LastName>
</Investigator>
<Investigator ValidYN="Y"><LastName>Welter</LastName>
<ForeName>M L</ForeName>
<Initials>ML</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Worbe</LastName>
<ForeName>J</ForeName>
<Initials>J</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Lalam</LastName>
<ForeName>T</ForeName>
<Initials>T</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Tourbah</LastName>
<ForeName>A</ForeName>
<Initials>A</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Marsault</LastName>
<ForeName>C</ForeName>
<Initials>C</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Dormont</LastName>
<ForeName>D</ForeName>
<Initials>D</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Pillon</LastName>
<ForeName>B</ForeName>
<Initials>B</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Czernecki</LastName>
<ForeName>V</ForeName>
<Initials>V</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Picard</LastName>
<ForeName>A</ForeName>
<Initials>A</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Passaquet</LastName>
<ForeName>B</ForeName>
<Initials>B</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Caparros-Lefebvre</LastName>
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<Initials>D</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Lannuzel</LastName>
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<Initials>A</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Verlut</LastName>
<ForeName>F</ForeName>
<Initials>F</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Gil</LastName>
<ForeName>R</ForeName>
<Initials>R</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Bailbe</LastName>
<ForeName>M</ForeName>
<Initials>M</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Venisse</LastName>
<ForeName>S</ForeName>
<Initials>S</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Moumy</LastName>
<ForeName>H</ForeName>
<Initials>H</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Mesnage</LastName>
<ForeName>V</ForeName>
<Initials>V</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Houeto</LastName>
<ForeName>J L</ForeName>
<Initials>JL</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Petit</LastName>
<ForeName>F</ForeName>
<Initials>F</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Vandermarcq</LastName>
<ForeName>P</ForeName>
<Initials>P</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Bonnaud</LastName>
<ForeName>V</ForeName>
<Initials>V</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Ornon</LastName>
<ForeName>C</ForeName>
<Initials>C</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Verin</LastName>
<ForeName>M</ForeName>
<Initials>M</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Rolland</LastName>
<ForeName>Y</ForeName>
<Initials>Y</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Trébon</LastName>
<ForeName>P</ForeName>
<Initials>P</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Salicé</LastName>
<ForeName>G</ForeName>
<Initials>G</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Tranchant</LastName>
<ForeName>C</ForeName>
<Initials>C</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Steinmetz</LastName>
<ForeName>G</ForeName>
<Initials>G</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Dietemann</LastName>
<ForeName>J L</ForeName>
<Initials>JL</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Rascol</LastName>
<ForeName>O</ForeName>
<Initials>O</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Galitzky</LastName>
<ForeName>M</ForeName>
<Initials>M</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Thalamas</LastName>
<ForeName>C</ForeName>
<Initials>C</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Manelfe</LastName>
<ForeName>P</ForeName>
<Initials>P</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Lemoal</LastName>
<ForeName>S</ForeName>
<Initials>S</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Deneuville</LastName>
<ForeName>M C</ForeName>
<Initials>MC</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Delabaere</LastName>
<ForeName>H</ForeName>
<Initials>H</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Prunier</LastName>
<ForeName>C</ForeName>
<Initials>C</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Autret</LastName>
<ForeName>A</ForeName>
<Initials>A</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Corsia</LastName>
<ForeName>P</ForeName>
<Initials>P</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Cottier</LastName>
<ForeName>P</ForeName>
<Initials>P</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Gallas</LastName>
<ForeName>S</ForeName>
<Initials>S</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Beauchamp</LastName>
<ForeName>D</ForeName>
<Initials>D</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Noth</LastName>
<ForeName>J</ForeName>
<Initials>J</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Kosinski</LastName>
<ForeName>C</ForeName>
<Initials>C</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Geyer</LastName>
<ForeName>C</ForeName>
<Initials>C</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Kronenbürger</LastName>
<ForeName>M</ForeName>
<Initials>M</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Schlangen</LastName>
<ForeName>C</ForeName>
<Initials>C</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Doenges</LastName>
<ForeName>M</ForeName>
<Initials>M</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Kémeny</LastName>
<ForeName>S</ForeName>
<Initials>S</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Kronenbürger</LastName>
<ForeName>M</ForeName>
<Initials>M</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Einhaeupl</LastName>
<ForeName>K</ForeName>
<Initials>K</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Arnold</LastName>
<ForeName>G</ForeName>
<Initials>G</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Hauptmann</LastName>
<ForeName>B</ForeName>
<Initials>B</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Lipp</LastName>
<ForeName>A</ForeName>
<Initials>A</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Villringer</LastName>
<ForeName>A</ForeName>
<Initials>A</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Lipp</LastName>
<ForeName>A</ForeName>
<Initials>A</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Fassdorf</LastName>
<ForeName>K</ForeName>
<Initials>K</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Przuntek</LastName>
<ForeName>H</ForeName>
<Initials>H</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Müller</LastName>
<ForeName>T</ForeName>
<Initials>T</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Gagel-Schweibold</LastName>
<ForeName>G</ForeName>
<Initials>G</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Siepmann</LastName>
<ForeName>M</ForeName>
<Initials>M</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Benz</LastName>
<ForeName>S</ForeName>
<Initials>S</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Schmid</LastName>
<ForeName>G</ForeName>
<Initials>G</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Finger</LastName>
<ForeName>M</ForeName>
<Initials>M</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Klotz</LastName>
<ForeName>P</ForeName>
<Initials>P</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Reichmann</LastName>
<ForeName>H</ForeName>
<Initials>H</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Herting</LastName>
<ForeName>B</ForeName>
<Initials>B</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>von Kummer</LastName>
<ForeName>R</ForeName>
<Initials>R</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Mucha</LastName>
<ForeName>D</ForeName>
<Initials>D</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Reissner</LastName>
<ForeName>E</ForeName>
<Initials>E</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Lücking</LastName>
<ForeName>C H</ForeName>
<Initials>CH</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Bötefür</LastName>
<ForeName>I</ForeName>
<Initials>I</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Braune</LastName>
<ForeName>S</ForeName>
<Initials>S</Initials>
</Investigator>
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<name sortKey="Payan, Christine" sort="Payan, Christine" uniqKey="Payan C" first="Christine" last="Payan">Christine Payan</name>
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