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September 28, 2011

ALS clinical trials
Do enrolled patients accurately represent the ALS population?

October 11, 2011 issue
77 (15) 1432-1437

Abstract

Objective:

To assess the effect of eligibility criteria in amyotrophic lateral sclerosis (ALS) clinical trials on the representativeness of the enrolled population.

Methods:

Patients enrolled in 8 placebo-controlled clinical trials in our ALS center from 2003 to 2008 were compared 1) to the patients included a prospective epidemiologic register (Piemonte and Valle d'Aosta register for ALS, PARALS) in the same period and 2) the subset of PARALS patients who met the usual criteria for inclusion in clinical trials (PARALS-ct) (definite, probable, probable laboratory-supported ALS; age between 18 and 75 years; disease duration <36 months; vital capacity at diagnosis ≥70%; score ≥3 at the items swallowing and respiratory insufficiency at the Amyotrophic Lateral Sclerosis Functional Rating Scale–revised scale; riluzole therapy).

Results:

A total of 164 patients were enrolled in 8 different clinical trials. The PARALS cohort included 813 patients, of whom 539 (66.3%) met the entry criteria for clinical trials. Patients enrolled in clinical trials were different from both epidemiologic cohorts, since they were younger, had a longer diagnostic delay, and were more likely to have a spinal onset, and to be men. Tracheostomy-free survival was significantly longer in the group of patients enrolled in clinical trials (median survival time, trial patients, 3.9 years [95% confidence interval (CI) 3.4–4.4]; PARALS, 2.6 [2.4–2.8]; PARALS-ct, 2.9 [2.7–3.1]).

Conclusions:

Patients enrolled in clinical trials do not satisfactorily represent the ALS population; consequently, the findings of ALS trials lack of external validity (generalizability). Efforts should be made to improve patients' recruitment in trials, particularly enrolling incident rather than prevalent cases.

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COINVESTIGATORS

The PARALS group: Project coordinator: A. Chiò, MD. Collaborating centers: Department of Neuroscience, University of Torino, and AOU S. Giovanni Battista, Torino (S. Cammarosano, MD, site investigator; A. Canosa, MD, site investigator; S. Gallo, MD, site investigator; D. Cocito, MD, advisory committee; R. Mutani, MD, advisory committee); Department of Neurology, University of Torino, and AOU S. Luigi Gonzaga, Orbassano (L. Durelli, MD, advisory committee; B. Ferrero, MD, site investigator; A. Bertolotto, MD, advisory committee); University of Torino, and Istituto Auxologico Italiano, IRCCS, Piancavallo (A. Mauro, MD, advisory committee); Department of Neurology, University of Piemonte Orientale Amedeo Avogadro, and AOU Maggiore, Novara (M. Leone, MD, advisory committee; F. Monaco, MD, advisory committee; N. Nasuelli, MD, site investigator); Department of Neurology, AOU S. Giovanni Battista, Torino (D. Giobbe, MD, site investigator); Department of Neurology, Ospedale Mauriziano, Torino (L. Sosso, MD, site investigator; M. Gionco, MD, site investigator); Department of Neurology, Ospedale Martini, Torino (D. Leotta, MD, site investigator); Department of Neurology, Ospedale Maria Vittoria, Torino (L. Appendino, MD, site investigator; D. Imperiale, MD, site investigator); Department of Neurology, Ospedale S. Giovanni Bosco, Torino (R. Cavallo, MD, site investigator); Department of Neurology, Ospedale Gradenigo, Torino (E. Oddenino, MD, site investigator); Department of Neurology, Ospedale di Ivrea (C. Geda, MD, advisory committee); Department of Neurology, Ospedale di Chivasso (C. Geda, MD, advisory committee); Department of Neurology, Ospedale di Pinerolo (F. Poglio, MD, site investigator; C. Doriguzzi Bozzo, MD, advisory committee); Department of Neurology, Ospedale di Vercelli (P. Santimaria, MD, site investigator); Department of Neurology, Ospedale di Biella (U. Massazza, MD, site investigator); Department of Neurology, Ospedale di Domodossola (A. Villani, MD, advisory committee; R. Conti, MD, site investigator); Fondazione S. Maugeri, Clinica del Lavoro e della Riabilitazione, IRCCS, Scientific Institute of Veruno (F. Pisano, MD, advisory committee); Department of Neurology, AOU Santi Antonio e Biagio, Alessandria (M. Palermo, MD, site investigator; E. Ursino, MD, advisory committee); Department of Neurology, Ospedale di Casale Monferrato (F. Vergnano, MD, site investigator; O. Sassone, MD, advisory committee); Department of Neurology, Ospedale di Novi Ligure (P. Provera, MD, site investigator); Department of Neurology, Ospedale di Tortona (M.T. Penza, MD, site investigator); Department of Neurology, Ospedale di Asti (M. Aguggia, MD, advisory committee; N. Di Vito, MD, site investigator); Department of Neurology, AOU S. Croce e Carle, Cuneo (P. Meineri, MD, site investigator); Department of Neurology, Ospedale di Savigliano (P. Ghiglione, MD, PhD, site investigator; D. Seliak, MD, site investigator); Department of Neurology, Ospedale di Alba (C. Cavestro, MD, site investigator; G. Astegiano, MD, advisory committee); Department of Neurology, Ospedale Regionale di Aosta (G. Corso, MD, site investigator; E. Bottacchi, MD, advisory committee).

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Information & Authors

Information

Published In

Neurology®
Volume 77Number 15October 11, 2011
Pages: 1432-1437
PubMed: 21956723

Publication History

Received: March 20, 2011
Accepted: June 27, 2011
Published online: September 28, 2011
Published in print: October 11, 2011

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Disclosure

Dr. Chiò serves on the editorial advisory board of Amyotrophic Lateral Sclerosis and has received research support from Italian Ministry of Health (Ricerca Finalizzata and CCM grants), Regione Piemonte (Ricerca Finalizzata), Italian Ministry of University and Research, University of Torino, Fondazione Vialli e Mauro for ALS Research, ONLUS, Compagnia San Paolo, Federazione Italiana Giuoco Calcio, and European Commission (Health Seventh Framework Programme). Dr. Canosa, Dr. Gallo, Dr. Cammarosano, Dr. Moglia, and G. Fuda report no disclosures. Dr. Calvo has received research support from Regione Piemonte and Compagnia di San Paolo. Dr. Mora has served on the editorial advisory board of Amyotrophic Lateral Sclerosis and has received research support from the Italian Ministry of Health (Ricerca Finalizzata).

Authors

Affiliations & Disclosures

A. Chiò, MD
From the ALS Centre (A. Chiò, A. Canosa, S.G., S.C., C.M., G.F., A. Calvo), Department of Neuroscience, University of Turin, and San Giovanni Battista Hospital, Turin; the Neuroscience Institute of Torino (A. Chiò), Turin; and Fondazione Salvatore Maugeri (M.G.), Istituto Scientifico di Milano, Milan, Italy.
A. Canosa, MD
From the ALS Centre (A. Chiò, A. Canosa, S.G., S.C., C.M., G.F., A. Calvo), Department of Neuroscience, University of Turin, and San Giovanni Battista Hospital, Turin; the Neuroscience Institute of Torino (A. Chiò), Turin; and Fondazione Salvatore Maugeri (M.G.), Istituto Scientifico di Milano, Milan, Italy.
S. Gallo, MD
From the ALS Centre (A. Chiò, A. Canosa, S.G., S.C., C.M., G.F., A. Calvo), Department of Neuroscience, University of Turin, and San Giovanni Battista Hospital, Turin; the Neuroscience Institute of Torino (A. Chiò), Turin; and Fondazione Salvatore Maugeri (M.G.), Istituto Scientifico di Milano, Milan, Italy.
S. Cammarosano, MD
From the ALS Centre (A. Chiò, A. Canosa, S.G., S.C., C.M., G.F., A. Calvo), Department of Neuroscience, University of Turin, and San Giovanni Battista Hospital, Turin; the Neuroscience Institute of Torino (A. Chiò), Turin; and Fondazione Salvatore Maugeri (M.G.), Istituto Scientifico di Milano, Milan, Italy.
C. Moglia, MD
From the ALS Centre (A. Chiò, A. Canosa, S.G., S.C., C.M., G.F., A. Calvo), Department of Neuroscience, University of Turin, and San Giovanni Battista Hospital, Turin; the Neuroscience Institute of Torino (A. Chiò), Turin; and Fondazione Salvatore Maugeri (M.G.), Istituto Scientifico di Milano, Milan, Italy.
G. Fuda, BS
From the ALS Centre (A. Chiò, A. Canosa, S.G., S.C., C.M., G.F., A. Calvo), Department of Neuroscience, University of Turin, and San Giovanni Battista Hospital, Turin; the Neuroscience Institute of Torino (A. Chiò), Turin; and Fondazione Salvatore Maugeri (M.G.), Istituto Scientifico di Milano, Milan, Italy.
A. Calvo, MD, PhD
From the ALS Centre (A. Chiò, A. Canosa, S.G., S.C., C.M., G.F., A. Calvo), Department of Neuroscience, University of Turin, and San Giovanni Battista Hospital, Turin; the Neuroscience Institute of Torino (A. Chiò), Turin; and Fondazione Salvatore Maugeri (M.G.), Istituto Scientifico di Milano, Milan, Italy.
M. Gabriele
From the ALS Centre (A. Chiò, A. Canosa, S.G., S.C., C.M., G.F., A. Calvo), Department of Neuroscience, University of Turin, and San Giovanni Battista Hospital, Turin; the Neuroscience Institute of Torino (A. Chiò), Turin; and Fondazione Salvatore Maugeri (M.G.), Istituto Scientifico di Milano, Milan, Italy.
For the PARALS group
From the ALS Centre (A. Chiò, A. Canosa, S.G., S.C., C.M., G.F., A. Calvo), Department of Neuroscience, University of Turin, and San Giovanni Battista Hospital, Turin; the Neuroscience Institute of Torino (A. Chiò), Turin; and Fondazione Salvatore Maugeri (M.G.), Istituto Scientifico di Milano, Milan, Italy.

Notes

Study funding: Supported in part by Ministero della Salute, Centro Nazionale per la Prevenzione e il Controllo delle Malattie (CCM) (grant 31, 2009). The research leading to these results has received funding from the European Community's Health Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 259867.
Address correspondence and reprint requests to Prof. Adriano Chiò, ALS Centre, Department of Neuroscience, University of Torino, Via Cherasco 15, 10126 Torino, Italy [email protected]

Author Contributions

Dr. Chiò: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, acquisition of data, statistical analysis, study supervision, obtaining funding. Dr. Canosa: study concept or design, acquisition of data, study supervision. Dr. Gallo: analysis or interpretation of data, acquisition of data, statistical analysis. Dr. Cammarosano: drafting/revising the manuscript, acquisition of data. Dr. Moglia: study concept or design, acquisition of data, study supervision. G. Fuda: analysis or interpretation of data, acquisition of data, statistical analysis. Dr. Calvo: drafting/revising the manuscript, acquisition of data, study supervision. Dr. Mora: drafting/revising the manuscript, study concept or design, analysis or interpretation of data.

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