title: Early diaphragm pacing in patients with amyotrophic lateral sclerosis (RespiStimALS): a randomised controlled triple-blind trial.
abstract: BACKGROUND
  Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder associated with respiratory muscle weakness and respiratory failure. Non-invasive ventilation alleviates respiratory symptoms and prolongs life, but is a palliative intervention. Slowing the deterioration of diaphragm function before respiratory failure would be desirable. We aimed to assess whether early diaphragm pacing could slow down diaphragm deterioration and would therefore delay the need for non-invasive ventilation.
  
  
  METHODS
  We did a multicentre, randomised, controlled, triple-blind trial in patients with probable or definite ALS in 12 ALS centres in France. The main inclusion criterion was moderate respiratory involvement (forced vital capacity 60-80% predicted). Other key eligibility criteria were age older than 18 years and bilateral responses of the diaphragm to diagnostic phrenic stimulation. All patients were operated laparoscopically and received phrenic stimulators. Clinicians randomly assigned patients (1:1) to receive either active or sham stimulation with a central web-based randomisation system (computer-generated list). Investigators, patients, and an external outcome allocation committee were masked to treatment. The primary outcome was non-invasive ventilation-free survival, analysed in the intention-to-treat population. Safety outcomes were also assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01583088.
  
  
  RESULTS
  Between Sept 27, 2012, and July 8, 2015, 74 participants were randomly assigned to receive either active (n=37) or sham (n=37) stimulation. On July 16, 2015, an unplanned masked analysis was done after another trial showed excess mortality with diaphragm pacing in patients with hypoventilation (DiPALS, ISRCTN 53817913). In view of this finding, we analysed mortality in our study and found excess mortality (death from any cause) in our active stimulation group. We therefore terminated the study on July, 16, 2015. Median non-invasive ventilation-free survival was 6·0 months (95% CI 3·6-8·7) in the active stimulation group versus 8·8 months (4·2-not reached) in the control (sham stimulation) group (hazard ratio 1·96 [95% CI 1·08-3·56], p=0·02). Serious adverse events (mainly capnothorax or pneumothorax, acute respiratory failure, venous thromboembolism, and gastrostomy) were frequent (24 [65%] patients in the active stimulation group vs 22 [59%] patients in the control group). No treatment-related death was reported.
  
  
  CONCLUSIONS
  Early diaphragm pacing in patients with ALS and incipient respiratory involvement did not delay non-invasive ventilation and was associated with decreased survival. Diaphragm pacing is not indicated at the early stage of the ALS-related respiratory involvement.
  
  
  BACKGROUND
  Hospital Program for Clinical Research, French Ministry of Health; French Patients' Association for ALS Research (Association pour la Recherche sur la Sclérose Latérale Amyotrophique); and Thierry de Latran Foundation.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique, Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Service de Pneumologie et Réanimation Médicale (Département "R3S"), Paris, France. Electronic address: jesus.gonzalez@psl.aphp.fr.
authors.forename: Jésus
authors.initials: J
authors.lastname: Gonzalez-Bermejo
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique, Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Service de Pneumologie et Réanimation Médicale (Département "R3S"), Paris, France.
authors.forename: Capucine
authors.initials: C
authors.lastname: Morélot-Panzini
authors.affiliation: AP-HP, Groupe Hospitalier Pitié Salpêtrière Charles Foix, Unité de Recherche Clinique, Paris, France.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Tanguy
authors.affiliation: AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Centre de Référence Maladies Rares SLA, Département des Maladies du Système Nerveux, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Meininger
authors.affiliation: AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Centre de Référence Maladies Rares SLA, Département des Maladies du Système Nerveux, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, CNRS, INSERM, Laboratoire d'Imagerie Biomédicale, Paris, France.
authors.forename: Pierre-François
authors.initials: PF
authors.lastname: Pradat
authors.affiliation: AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Centre de Référence Maladies Rares SLA, Département des Maladies du Système Nerveux, Paris, France.
authors.forename: Timothée
authors.initials: T
authors.lastname: Lenglet
authors.affiliation: AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Centre de Référence Maladies Rares SLA, Département des Maladies du Système Nerveux, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Institut du Cerveau et de la Moëlle Epinière, ICM, Paris, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Bruneteau
authors.affiliation: AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Centre de Référence Maladies Rares SLA, Département des Maladies du Système Nerveux, Paris, France.
authors.forename: Nadine Le
authors.initials: NL
authors.lastname: Forestier
authors.affiliation: CHU Limoges, Centre de Compétence SLA, Limoges, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Couratier
authors.affiliation: CHU Gabriel Montpied, Service de Neurologie, Clermont-Ferrand, France; Faculté de Chirurgie Dentaire, Neuro-Dol, INSERM U1107, Douleur Trigéminale et Migraine, Clermont-Ferrand, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Guy
authors.affiliation: Hôpital Pasteur 2, Centre de Référence SLA, Nice, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Desnuelle
authors.affiliation: AP-HP, GHU Paris Ouest-site Raymond Poincaré-Service de Physiologie et d'Explorations Fonctionnelles, Garches, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Prigent
authors.affiliation: CH de Cannes, Service de Pneumologie, Cannes, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Perrin
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique, Paris, France; AP-HP, Groupe Hospitalier Pitié Salpêtrière Charles Foix, Service des Pathologies du Sommeil (Département "R3S"), Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Attali
authors.affiliation: AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Service Pharmacie UFDMS, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Fargeot
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique, Paris, France.
authors.forename: Marie-Cécile
authors.initials: MC
authors.lastname: Nierat
authors.affiliation: AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Département d'Anesthésie et Réanimation, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Royer
authors.affiliation: AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Service de Chirurgie Viscérale, Paris, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Ménégaux
authors.affiliation: AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Centre de Référence Maladies Rares SLA, Département des Maladies du Système Nerveux, Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Salachas
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique, Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Service de Pneumologie et Réanimation Médicale (Département "R3S"), Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Similowski
mesh_terms: D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000150:complications / Q000628:therapy*; D003964:Diaphragm / Q000294:innervation / Q000503:physiopathology*; D004311:Double-Blind Method; D057239:Early Termination of Clinical Trials; D004599:Electric Stimulation Therapy / Q000009:adverse effects / Q000379:methods*; D005260:Female; D006801:Humans; D010535:Laparoscopy; D008297:Male; D008875:Middle Aged; D010791:Phrenic Nerve; D012120:Respiration Disorders; D012121:Respiration, Artificial; D012131:Respiratory Insufficiency / Q000517:prevention & control*