Comparing methods to combine functional loss and mortality in clinical trials for amyotrophic lateral sclerosis

Objective: Amyotrophic lateral sclerosis (ALS) clinical trials based on single end points only partially capture the full treatment effect when both function and mortality are affected, and may falsely dismiss efficacious drugs as futile. We aimed to investigate the statistical properties of several strategies for the simultaneous analysis of function and mortality in ALS clinical trials. Methods: Based on the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database, we simulated longitudinal patterns of functional decline, defined by the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) and conditional survival time. Different treatment scenarios with varying effect sizes were simulated with follow-up ranging from 12 to 18 months. We considered the following analytical strategies: 1) Cox model; 2) linear mixed effects (LME) model; 3) omnibus test based on Cox and LME models; 4) composite time-to-6-point decrease or death; 5) combined assessment of function and survival (CAFS); and 6) test based on joint modeling framework. For each analytical strategy, we calculated the empirical power and sample size. Results: Both Cox and LME models have increased false-negative rates when treatment exclusively affects either function or survival. The joint model has superior power compared to other strategies. The composite end point increases false-negative rates among all treatment scenarios. To detect a 15% reduction in ALSFRS-R decline and 34% decline in hazard with 80% power after 18 months, the Cox model requires 524 patients, the LME model 794 patients, the omnibus test 526 patients, the composite end poi

An old friend who has overstayed their welcome : the ALSFRS-R total score as primary endpoint for ALS clinical trials

Objective: The ALSFRS-R is limited by multidimensionality, which originates from the summation of various subscales. This prevents a direct comparison between patients with identical total scores. We aim to evaluate how multidimensionality affects the performance of the ALSFRS-R in clinical trials. Methods: We simulated clinical trial data with different treatment effects for the ALSFRS-R total score and its subscales (i.e. bulbar, fine motor, gross motor and respiratory). We considered scenarios where treatment reduced the rate of ALSFRS-R subscale decline either uniformly (i.e. all subscales respond identically to treatment) or non-uniformly (i.e. subscales respond differently to treatment). Two main analytical strategies were compared: (1) analyzing only the total score or (2) utilizing a subscale-based test (i.e. alternative strategy). For each analytical strategy, we calculated the empirical power and required sample size. Results: Both strategies are valid when there is no treatment benefit and provide adequate control of type 1 error. If all subscales respond identically to treatment, using the total score is the most powerful approach. As the differences in treatment responses between subscales increase, the more the total score becomes affected. For example, to detect a 40% reduction in the bulbar rate of decline with 80% power, the total score requires 1380 patients, whereas this is 336 when using the alternative strategy. Conclusions: Ignoring the multidimensional structure of the ALSFRS-R total score could have negative consequences for ALS clinical trials. We propose determining treatment benefit on a subscale level, prior to stating whether a treatment is generally effective

TRICALS: creating a highway toward a cure

A change in our current approach toward drug development is required to improve the likelihood of finding effective treatment for patients with amyotrophic lateral sclerosis (ALS). The aim of the Treatment Research Initiative to Cure ALS (TRICALS) is to extend the collective effort with industry and consolidate drug development paths. TRICALS has begun a series of meetings on how to best move the field forward collaboratively, thereby addressing five major topics in ALS clinical trials: (1) preclinical research, (2) biomarker development, (3) eligibility criteria, (4) efficacy endpoints and (5) innovative trial design. There is an appetite for ongoing discussions of these major topics in clinical trials between representatives from academia, patient advocacy groups, industry partners and funding bodies. Industry is open to fundamentally change drug development for ALS and shorten the time to effective therapy for patients by implementing promising innovations in biomarker development, trial design, and patient selection. There is however, a pressing need from all stakeholders for regulatory discussions and amendments of current guidelines to successfully adopt innovation in future clinical development lines

Innovating clinical trials for amyotrophic lateral sclerosis : challenging the established order

Development of effective treatments for amyotrophic lateral sclerosis (ALS) has been hampered by disease heterogeneity, a limited understanding of underlying pathophysiology, and methodologic design challenges. We have evaluated 2 major themes in the design of pivotal, phase 3 clinical trials for ALS—(1) patient selection and (2) analytical strategy—and discussed potential solutions with the European Medicines Agency. Several design considerations were assessed using data from 5 placebo-controlled clinical trials (n = 988), 4 population-based cohorts (n = 5,100), and 2,436 placebo-allocated patients from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. The validity of each proposed design modification was confirmed by means of simulation and illustrated for a hypothetical setting. Compared to classical trial design, the proposed design modifications reduce the sample size by 30.5% and placebo exposure time by 35.4%. By making use of prognostic survival models, one creates a potential to include a larger proportion of the population and maximize generalizability. We propose a flexible design framework that naturally adapts the trial duration when inaccurate assumptions are made at the design stage, such as enrollment or survival rate. In case of futility, the follow-up time is shortened and patient exposure to ineffective treatments or placebo is minimized. For diseases such as ALS, optimizing the use of resources, widening eligibility criteria, and minimizing exposure to futile treatments and placebo is critical to the development of effective treatments. Our proposed design modifications could circumvent important pitfalls and may serve as a blueprint for future clinical trials in this population

A road map for remote digital health technology for motor neuron disease

Despite recent and potent technological advances, the real-world implementation of remote digital health technology in the care and monitoring of patients with motor neuron disease has not yet been realized. Digital health technology may increase the accessibility to and personalization of care, whereas remote biosensors could optimize the collection of vital clinical parameters, irrespective of patients’ ability to visit the clinic. To facilitate the wide-scale adoption of digital health care technology and to align current initiatives, we outline a road map that will identify clinically relevant digital parameters; mediate the development of benefit-to-burden criteria for innovative technology; and direct the validation, harmonization, and adoption of digital health care technology in real-world settings. We define two key end products of the road map: (1) a set of reliable digital parameters to capture data collected under free-living conditions that reflect patient-centric measures and facilitate clinical decision making and (2) an integrated, open-source system that provides personalized feedback to patients, health care providers, clinical researchers, and caregivers and is linked to a flexible and adaptable platform that integrates patient data in real time. Given the ever-changing care needs of patients and the relentless progression rate of motor neuron disease, the adoption of digital health care technology will significantly benefit the delivery of care and accelerate the development of effective treatments

Pharmacogenetic interactions in amyotrophic lateral sclerosis: a step closer to a cure?

Genetic mutations related to amyotrophic lateral sclerosis (ALS) act through distinct pathophysiological pathways, which may lead to varying treatment responses. Here we assess the genetic interaction between C9orf72, UNC13A, and MOBP with creatine and valproic acid treatment in two clinical trials. Genotypic data was available for 309 of the 338 participants (91.4%). The UNC13A genotype affected mortality (p = 0.012), whereas C9orf72 repeat-expansion carriers exhibited a faster rate of decline in overall (p = 0.051) and bulbar functioning (p = 0.005). A dose-response pharmacogenetic interaction was identified between creatine and the A allele of the MOBP genotype (p = 0.027), suggesting a qualitative interaction in a recessive model (HR 3.96, p = 0.015). Not taking genetic information into account may mask evidence of response to treatment or be an unrecognized source of bias. Incorporating genetic data could help investigators to identify critical treatment clues in patients with ALS.Perioperative Medicine: Efficacy, Safety and Outcome (Anesthesiology/Intensive Care

Mastication in Patients with Spinal Muscular Atrophy Types 2 and 3 is Characterized by Abnormal Efficiency, Reduced Endurance, and Fatigue

Mastication problems can have a negative impact on the intake of food and quality of life. This cross-sectional study characterizes mastication problems using clinical and instrumental assessments in patients with spinal muscular atrophy (SMA) types 2 and 3 with self-reported bulbar problems. We included 27 patients (aged 13-67 years), 18 with SMA type 2 and 9 patients with SMA type 3 (of whom three were still ambulant) and applied a questionnaire, clinical mastication tests (TOMASS and 6-min mastication test), and muscle ultrasound of the mastication muscles. Non-ambulant patients demonstrated inefficient mastication as reflected by median z scores for masticatory cycles (z = 1.8), number of swallows (z = 4.3) and time needed to finish the cracker (z = 3.4), and limited endurance of continuous mastication as demonstrated by the median z scores of the 6-min mastication test (z = - 1.5). Patients reported increased fatigue directly after the 6-min mastication test as well as 5 min after completing the test (p < 0.001; p = 0.003). Reduced maximal mouth opening was associated with mastication problems (p < 0.001). Muscle ultrasound of the mastication muscles showed an abnormal muscle structure in 90% of both ambulant and non-ambulant patients. This study aims to understand the nature and underlying mechanisms of mastication problems in patients with SMA types 2 and 3 with reported bulbar problems

Swallowing Problems in Spinal Muscular Atrophy Types 2 and 3: A Clinical, Videofluoroscopic and Ultrasound Study.

BACKGROUND: Spinal muscular atrophy (SMA) is a hereditary motor neuron disorder, characterized by the degeneration of motor neurons and progressive muscle weakness. There is a large variability of disease severity, reflected by the classification of SMA types 1-4. OBJECTIVE: The aim of this cross-sectional study was to determine the nature of swallowing problems and underlying mechanisms in patients with SMA types 2 and 3, and the relationship between swallowing and mastication problems. METHODS: We enrolled patients (aged 13-67 years) with self-reported swallowing and/or mastication problems. We used a questionnaire, the functional oral intake scale, clinical tests (dysphagia limit, and timed test swallowing, the test of mastication and swallowing solids), a videofluoroscopic swallowing study (VFSS), and muscle ultrasound of the bulbar muscles (i.e. digastric, geniohyoid and tongue muscles). RESULTS: Non-ambulant patients (n = 24) had a reduced dysphagia limit (median 13 ml (3-45), and a swallowing rate at the limit of normal (median 10 ml/sec (range 4-25 ml). VFSS revealed piecemeal deglutition and pharyngeal residue. We found pharyngo-oral regurgitation in fourteen patients (58%), i.e. they transported the residue from the hypopharynx back into the oral cavity and re-swallowed it. Six patients (25%) demonstrated impaired swallowing safety (i.e. penetration aspiration scale > 3). Muscle ultrasound revealed an abnormal muscle structure of the submental and tongue muscles. Ambulant patients (n = 3), had a normal dysphagia limit and swallowing rate, but VFSS showed pharyngeal residue, and muscle ultrasound demonstrated an abnormal echogenicity of the tongue. Swallowing problems were associated with mastication problems (p = 0.001)

Patient perspectives on digital healthcare technology in care and clinical trials for motor neuron disease : an international survey

Introduction To capture the patient’s attitude toward remote monitoring of motor neuron disease (MND) in care and clinical trials, and their concerns and preferences regarding the use of digital technology. Methods We performed an international multi-centre survey study in three MND clinics in The Netherlands, the United Kingdom, and Australia. The survey was co-developed by investigators and patients with MND, and sent to patients by e-mail or postal-mail. The main topics included: patients’ attitude towards remote care, participating in decentralized clinical trials, and preferences for and concerns with digital technology use. Results In total, 332 patients with MND participated. A majority of patients indicated they would be happy to self-monitor their health from home (69%), be remotely monitored by a multidisciplinary care team (75%), and would be willing to participate in clinical trials from home (65%). Patients considered respiratory function and muscle strength most valuable for home-monitoring. The majority of patients considered the use of at least three devices/apps (75%) once a week (61%) to be acceptable for home-monitoring. Fifteen percent of patients indicated they would not wish to perform home-measurements; reporting concerns about the burden and distress of home-monitoring, privacy and data security. Conclusion Most patients with MND exhibited a positive attitude toward the use of digital technology in both care and clinical trial settings. A subgroup of patients reported concerns with home-monitoring, which should be addressed in order to improve widespread adoption of remote digital technology in clinical MND care