New considerations in the design of clinical trials for amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis is a devastating neurodegenerative disease caused by loss of motor neurons. Its pathophysiology remains unknown, but progress has been made in understanding its genetic and biochemical basis. Clinical trialists are working to translate basic science successes into human trials with more efficiency, in the hope of finding successful treatments. In the future, new preclinical models, including patient-derived stem cells may augment transgenic animal models as preclinical tools. Biomarker discovery projects aim to identify markers of disease onset and progression for use in clinical trials. New trial designs are reducing study time, improving efficiency and helping to keep pace with the increasing rate of basic and translational discoveries. Ongoing trials with novel designs are paving the way for amyotrophic lateral sclerosis clinical research.

Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

“…In these cases, trial [80] design must be modified to boost enrollment. Sometimes the elimination of placebo control is possible, but often this is not acceptable for scientific or regulatory reasons.…”

“…Intention-to-treat analysis preserves the benefits of randomization to balance known and unknown predictive factors. In order to promote patient enrollment in a phase III trial, randomization schemes weighted toward treatment versus placebo groups, as well as open-label extension, may be used [80]. Implementation trials involving cluster randomization or a stepped wedge design can assess realworld applicability.…”

“…In order to improve the traditionally slow process of study initiation, the Northeast ALS Consortium is implementing a central institutional review board and standard contracts for ALS clinical trials [80]. Consortia collaboration has also led to the establishment of biofluid and tissue repositories, as well as shared clinical datasets to promote the sharing of resources.…”

Moving forward in clinical trials for ALS: motor neurons lead the way please

“…Immense effort has been put into their methodological design and outcome measures, and they have been constantly improving with new considerations [18,19]. Although methodologies are of high quality, the limited number of patients and the unknown factors that cause pathology in patients add to the complexity.…”

Gene Therapy for Misfolding Protein Diseases of the Central Nervous System

“…Unfortunately, the variability between different studies and the unresolved challenges in delivery and off-target effects place the clinical development of these candidate therapies at a very early stage of development [136].…”