Living systematic review and comprehensive network meta-analysis of ALS clinical trials: study protocol

Abstract

Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal neurogenerative disease with no effective treatment to date. Despite numerous clinical trials, the majority of studies have been futile in their effort to significantly alter the course of the disease. However, these studies may still provide valuable information for identifying patient subgroups and generating new hypotheses for future research. Additionally, synthesising evidence from these studies may help overcome the limitations of individual studies. Network meta-analysis may refine the assessment of efficacy in specific patient subgroups, evaluate intervention characteristics such as mode of administration or biological mechanisms of action, and rank order promising therapeutic areas of interest. Therefore, we aim to synthesise the available evidence from ALS clinical trials.

Methods and analysis: We will conduct a systematic review to identify all clinical trials that assessed disease-modifying pharmaceutical therapies, cell therapies, or supplements in patients with ALS. Outcomes of interest are clinical disease progression outcomes and survival. We will conduct this search in the period Q4 2024 in three databases: PubMed, Embase and ClinicalTrials.gov for studies from 1999 to 2023. Individual patient data and aggregate data will be collected and subsequentially synthesised in meta-analytical models. The final model will be presented as an open-source web application with biannual updates of the underlying data, thereby providing a 'living' overview of the ALS clinical trial landscape.

Ethics and dissemination: No ethics approvals are required. Findings will be presented at relevant conferences and submitted to peer-reviewed journals. Data will be stored anonymously in secure repositories.

Keywords: network meta-analysis; neuromuscular disease; systematic review.

Figure 1. Flow diagram of study selection. After study completion, the number (n) of studies selected at each step will be indicated in each box. The dotted line represents the reference screening in the included studies for those studies not found in the database search. ALSFRS-R, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale; VC, slow or forced vital capacity.

Figure 2. Hypothetical network diagram and harm/benefits table. The figure above represents a hypothetical network. The network consists of intervention and placebo nodes (grouped per administration mode) while the solid lines connecting them indicate direct comparisons. Non-invasive nodes consist of oral and transdermal, while invasive nodes consist of intravenous, intrathecal, intramuscular, and subcutaneous modes of administration. The dashed lines reflect ‘disconnected’ networks that are reconnected through matching and propensity score methods. The table ranks the interventions based on their expected benefit compared with placebo as well as the expected harm of administration modes estimated through matching.