A Pilot Randomized Clinical Trial of Early Ventilation in Amyotrophic Lateral Sclerosis (EVENT ALS)

Description

Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with high morbidity and universal mortality predominantly due to respiratory failure. Non-invasive ventilation (NIV) improves quality of life (QoL) and extends survival in ALS beyond any medication.1-3 However, the best timing for NIV initiation is based only on expert opinion.4,5 For example, clinicians in the United States initiate NIV much later than European or Canadian guidelines,4,6,7 as payors do not cover NIV until significant respiratory impairment occurs. While potentially beneficial, early NIV initiation could increase burden for patients due to mask intolerance, claustrophobia, and disturbed sleep, possibly negating any clinical benefit. Similarly, there are no surrogate endpoints to guide NIV settings and mask selection. Thus, clinicians employ generic approaches despite significant disease heterogeneity. Given the variable onset and progression of ALS, strategies for anticipating respiratory risk and personalizing NIV management are critical to maximize NIV benefit while reducing its burden.

Our ultimate goal is to conduct Phase III multicenter clinical trials which investigate early NIV strategies to improve quality of life and survival in individuals with ALS. Before embarking on a large RCT of early NIV in ALS, we first must collect pilot data on feasibility, effect sizes, and personal factors associated with NIV usage. Our prior work has developed a novel clinical prediction tool which can stratify ALS patients at presentation into high versus low risk of respiratory insufficiency within 6 months, capable of identifying an enriched subgroup suitable for an interventional study. We have performed semi-structured interviews which suggest that ALS patients value being proactive about their respiratory care. We have shown that improving transcutaneous carbon dioxide (CO2) levels is associated with improved survival in ALS, suggesting that transcutaneous CO2 could be a surrogate endpoint for guiding NIV management. We also have found that factors at time of NIV initiation, such as ALSFRS-R speech and dyspnea scores, are significantly associated with NIV adherence.

Clinical Intervention: In this RCT of patients who have yet to meet insurance criteria for NIV coverage, we will randomize individuals to early NIV versus usual care, stratified by 6-month risk of respiratory insufficiency as determined by our novel clinical prediction tool.

Objective(s): Our objectives in this pilot study are to collect: 1) feasibility data on randomization to early NIV; 2) estimates of effect sizes of early NIV versus usual care on endpoints such as QoL, transcutaneous CO2, symptoms, and survival; and 3) identify factors present at time of NIV initiation which predispose to low hourly usage of NIV. We will analyze our results across randomization groups, as well as assess the interaction between randomization and predicted risk of respiratory insufficiency.

Study Design: We will conduct a 3-center phase II pilot randomized clinical trial of incident ALS patients diagnosed in the last 6 months.

Clinical Impact: The proposed study will help us understand the feasibility and safety of starting early NIV in ALS. We will assess effect sizes on clinical endpoints, which will be critical for planning a future large RCT. Lastly, we will learn about patient characteristics that may predispose to lower NIV adherence. We will examine our results across randomization and the interaction with predicted risk of respiratory insufficiency. Leveraging our clinical prediction tool may help identify an enriched patient population suitable for future interventional studies.