Early diaphragm pacing in patients with amyotrophic lateral sclerosis (RespiStimALS): a randomised controlled triple-blind trial(2016)

  • 2016.01.01 Friday
  • 09:00

Gonzalez-Bermejo J, Morélot-Panzini C, Tanguy ML, Meininger V, Pradat PF, Lenglet T, Bruneteau G, Forestier NL, Couratier P, Guy N, Desnuelle C, Prigent H, Perrin C, Attali V, Fargeot C, Nierat MC, Royer C, Ménégaux F, Salachas F, Similowski T. Early diaphragm pacing in patients with amyotrophic lateral sclerosis (RespiStimALS): a randomised controlled triple-blind trial. Lancet Neurol. 2016 Nov;15(12):1217-1227. doi: 10.1016/S1474-4422(16)30233-2. Epub 2016 Oct 11. Erratum in: Lancet Neurol. 2016 Dec;15(13):1301. PMID: 27751553.



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.

Findings: 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.

Interpretation: 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.

Funding: 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.




所見。2012年9月27日から2015年7月8日までの間に、74人の参加者が、積極的刺激(n=37)または偽刺激(n=37)のいずれかを受けるように無作為に割り付けられた。2015年7月16日、別の試験で低換気患者における横隔膜ペーシングによる過剰死亡率が示された後、計画外のマスキング解析が行われた(DiPALS、ISRCTN 53817913)。この所見を考慮して、我々の研究で死亡率を分析したところ、アクティブ刺激群では過剰な死亡率(あらゆる原因による死亡)が認められた。そのため、2015年7月16日に研究を終了した。非侵襲的換気なし生存期間中央値は、積極的刺激群では6〜0ヵ月(95%CI 3-6-8-7)であったのに対し、対照群(偽刺激群)では8〜8ヵ月(4-2-未到達)であった(ハザード比1-96[95%CI 1-08-3-56]、p=0〜02)。重篤な有害事象(主に僧帽弁胸または気胸、急性呼吸不全、静脈血栓塞栓症、胃瘻)が頻発した(活性刺激群24例[65%]対対照群22例[59%])。治療関連死は報告されなかった。


資金提供。フランス保健省臨床研究病院プログラム、フランスALS研究患者協会(Association pour la Recherche sur la Sclérose Latérale Amyotrophique)、およびThierry de Latran財団。


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