Designing Multi-arm Multistage Adaptive Trials for Neuroprotection in Progressive Multiple Sclerosis

Abstract

Progressive multiple sclerosis (PMS) is a significant health problem with few treatments shown to slow disability progression. One challenge has been efficiently testing the pipeline of candidate therapies from preclinical studies in clinical trials. Multi-arm multi-stage (MAMS) platform trials may accelerate evaluation of new therapies compared to traditional sequential clinical trials. We describe a MAMS design in PMS, focusing on selection of interim and final outcome measures, sample size and statistical considerations.The UK MS Society Expert Consortium for Progression in MS Clinical Trials reviewed recent phase II and III PMS trials to inform interim and final outcome selection and design parameters. Simulations were performed to evaluate trial operating characteristics under different treatment effect, recruitment rate and sample size assumptions. People with MS formed a Patient and Public Involvement group and contributed to the trial design ensuring it would meet the needs of the MS community.The proposed design evaluates three experimental arms compared to a common standard of care arm in two stages. Stage 1 (interim) outcome will be whole brain atrophy on MRI at 18 months, assessed for 123 participants per arm. Treatments with sufficient evidence for slowing brain atrophy will continue to the second stage. The stage 2 (final) outcome will be time to six-month confirmed disability progression, based on a composite clinical score comprising the Expanded Disability Status Score, Timed 25-Foot Walk and 9-Hole Peg Test. To detect a hazard ratio of 0.75 for this primary final outcome with 90% power, 600 participants per arm are required. Assuming one treatment progresses to stage 2, the trial will recruit around 1,900 participants and last around 6 years. This is approximately two-thirds the size and half the time of separate two-arm phase II and III trials.The proposed MAMS trial design will substantially reduce duration and sample size compared to traditional clinical trials, accelerating discovery of effective treatment for PMS. The design was also well-received by people with MS. The practical and statistical principles of MAMS trial design may be applicable to other neurodegenerative conditions to facilitate efficient testing of new therapies.

Longitudinal network-based brain grey matter MRI measures are clinically relevant and sensitive to treatment effects in multiple sclerosis

“…Further, the Lasso model (trained on a separate cohort) could be applied to another to look for treatment effects, and again results were materially the same as those derived from an ICA in the application cohort. While ideally an ICA would be undertaken when the whole cohort completes a study, the results suggest that the Lasso model measures are a reasonable substitute, and they have the advantage that they can be used in interim analyses or decision-making (for example in multi-arm clinical trials 40 ).…”

Enhancing involvement of people with multiple sclerosis in clinical trial design

“…Optimal Clinical Trials Platform for Progressive Multiple Sclerosis (OCTOPUS, ISRCTN140448364) is a multi-arm multi-stage (MAMS) adaptive platform trial that aims to accelerate the development of re-purposed or novel treatments to slow or stop the accumulation of disability progression, relative to other clinical trial designs. 26 , 27 In MAMS trials flexibility is planned, such that interventions being tested can change over time, all of which are compared to a common control arm (multi-arm); interventions that appear effective in an early stage can continue on into a later stage (multi-stage). OCTOPUS will incorporate phase 3 evaluations of selected treatments in double-blind, randomized, comparison to standard of care.…”

Clinical trials in multiple sclerosis: past, present, and future

“…Trials involving non-active progressive MS in particular might benefit from further validation of such methods. Non-traditional trial designs, such as multi-arm multistage adaptive trials or recruiting from biomarker-driven MS endophenotypes, to maximise the potential for response to new treatments, may further facilitate the validation of effective therapies in progressive MS [75,76].…”