- Adaptive platform trials (APTs), pioneered in oncology, run indefinitely and investigate multiple therapies concurrently via collaboration between academia, industry, government agencies, foundations and patients
- Because of shared trial infrastructure and a shared pool of placebo recipients, investigation of regimens in APTs is more efficient, faster and less costly than standalone trials
- The Healey Platform ALS Trial, headquartered at Massachusetts General Hospital, is comparing the efficacy of novel/emerging therapies against a shared placebo group for participants with sporadic or familial amyotrophic lateral sclerosis
- Enrollment began in July 2020 and the first five therapies under investigation are zilucoplan, verdiperstat, CNM-Au8, pridopidine and trehalose
- The first primary completion date is predicted to be April 2023
Improved understanding of amyotrophic lateral sclerosis (ALS) disease mechanisms, pathophysiology and biomarkers, and several promising new therapeutic targets, have led the ALS community to launch two adaptive platform trials (APTs) in which the focus is on the disease rather than a drug. One of them, the Healey ALS Platform Trial, is headquartered at Massachusetts General Hospital.
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Sabrina Paganoni, MD, PhD, of the Sean M. Healey & AMG Center for ALS and Spaulding Rehabilitation Hospital, James D. Berry, MD, MPH, director of the Neurological Clinical Research Institute, and Merit E. Cudkowicz, MD, MSc, chief of the Department Neurology and director of the Sean M. Healey & AMG Center for ALS at Mass General, and colleagues in the Healey ALS Platform Trial Study Group describe the trial in detail in Annals of Neurology.
Background on Adaptive Platform Trials
APTs, which were pioneered in oncology, run indefinitely and investigate multiple therapies concurrently. They are typically run by a centralized coordination center with collaboration between academia, industry, government agencies, foundations and patients.
A parent protocol is established at the outset of the trial, and therapies continually enter or leave the platform on the basis of a predefined decision algorithm. Regimen-specific appendices to the protocol provide flexibility with regard to inclusion criteria, endpoints, sample size and more.
Investigational therapies in an APT are usually compared with placebo. The placebo arms for each regimen serve as a natural history registry and biorepository, and forming a placebo pool reduces the total number of participants who must be randomized to placebo.
The Healey ALS Platform Trial
Inception—The primary aim of the Healey ALS Platform Trial is to compare the efficacy of novel/emerging therapies against a shared placebo group for participants with sporadic or familial ALS. Dr. Cudkowicz submitted the initial investigational new drug application to the FDA, so she serves as the study sponsor.
Investigators communicated early with the FDA about the parent protocol, primary analysis and key sensitivity analyses to ensure any positive trial results will support regulatory review of novel agents.
Governance—The Healey Center, the central coordination center, is supported by expert consultants and collaborators. An Executive Committee oversees all trial activities, receiving reports from committees, task forces and the data safety monitoring board. Each regimen-specific appendix has its own steering committee, which also reports to the Executive Committee.
Candidate drug selection—The Therapy Evaluation Committee of leading ALS researchers reviewed initial submissions and selected among agents with preclinical data and previous dosing, target engagement and safety data in humans. The first three therapies chosen were zilucoplan, verdiperstat and CNM-Au8. Pridopidine was incorporated shortly afterward and a study of trehalose (SLS-005) was launched at the end of 2021.
Statistical design—The primary outcome measure is change in disease severity over 24 weeks as measured by the ALS Functional Rating Scale–Revised. The primary analysis is a Bayesian shared parameter model of ALSFRS-R and survival. This approach will synthesize all available data across the treatment group and shared control group while modeling heterogeneity in the rates of progression of shared controls.
Financing—Healey Center philanthropic funding and foundation grants enabled the trial's launch. In the future, industry partners will assume the full costs of their respective regimens. Because of the shared placebo arm, shared infrastructure and substantial time savings, investigation of each regimen is projected to cost substantially less than a standalone trial.
State of the trial—Enrollment began in July 2020 and has been exceeding expectations ever since. The first primary completion date is expected to be April 2023.
The executive committee of the Healey Platform ALS Trial has the goal of engaging regulatory authorities outside the United States to discuss the implications of the APT approach for drug approvals in other countries.
The other APT to watch in ALS is the Motor Neuron Disease–Systematic Multi-arm Adaptive Randomisation Trial (MND SMART), headquartered at the University of Edinburgh.
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