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Review
. 2024 Dec;30(5_suppl):41-47.
doi: 10.1177/13524585241274620. Epub 2024 Sep 8.

Selecting Informative Patients for Phase 2 Progressive Trials in MS: Design Considerations for Phase 2 Clinical Trials in Progressive MS

Marcus W Koch  1 , Carlos Camara-Lemarroy  1 , Eva Strijbis  2 , Jop Mostert  3 , Victoria M Leavitt  4 , Pavle Repovic  5 , James D Bowen  5 , Jacynthe Comtois  6 , Bernard Uitdehaag  2 , Gary Cutter  7
Affiliations
Review

Selecting Informative Patients for Phase 2 Progressive Trials in MS: Design Considerations for Phase 2 Clinical Trials in Progressive MS

Marcus W Koch et al. Mult Scler. 2024 Dec.

Abstract

While relapsing-remitting multiple sclerosis (MS) has many therapeutic options, progressive forms of MS remain largely untreatable. Phase 2 clinical trials are our main tool to advance new treatments for progressive MS. Given the complexities of progressive MS, it will likely require many phase 2 trials to improve its treatment. To conduct informative and efficient phase 2 trials, it is important that such trials are designed in a way that they can identify a successful treatment as quickly and with as few participants as possible. In this topical review, we discuss cohort selection, outcome selection, cohort enrichment, and dosing selection as strategies to optimize the efficiency of phase 2 clinical trials in progressive MS.

Keywords: Clinical trial; atrophy; disease modifying therapies; outcome measurement; progressive.

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Conflict of interest statement

Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Koch received consulting fees and travel support from Biogen, Novartis, Roche, Sanofi Genzyme, and EMD Serono. Dr. Camara-Lemarroy received consulting/speaker fees from EMD Serono, Novartis, Biogen, and Horizon Therapeutics. Dr. Leavitt received honoraria as consultant on advisory boards for Biogen, and as a reviewer for the National Institutes of Health and the United States Department of Defense. Dr. Repovic received consulting and/or speaking honoraria from Alexion, Biogen, Bristol Myers Squibb, EMD Serono, Genentech/Roche, Horizon/Amgen, Novartis, and TG therapeutics. Dr. Bowen received honoraria from serving on the scientific advisory board and speaker’s bureau of Biogen, Celgene, EMD Serono, Genentech and Novartis. He has received research support from AbbVie Inc, Alexion, Alkermes, Biogen, Celgene, Sanofi Genzyme, Genentech, Novartis, and TG Therapeutics. Dr. Comtois received consulting honoraria from Novartis and travel support from EDM Serono. Prof. Uitdehaag received consultancy fees and/or research support from Biogen, Sanofi Genzyme, EMD Serono, Novartis, Roche, Teva, and Immunic Therapeutics. Prof. Cutter served on Data and Safety Monitoring Boards: Astra-Zeneca, Avexis Pharmaceuticals, Biolinerx, Brainstorm Cell Therapeutics, Bristol Meyers Squibb/Celgene, CSL Behring, Galmed Pharmaceuticals, Horizon Pharmaceuticals, Hisun Pharmaceuticals, Mapi Pharmaceuticals LTD, Merck, Merck/Pfizer, Opko Biologics, OncoImmune, Neurim, Novartis, Ophazyme, Sanofi-Aventis, Reata Pharmaceuticals, Teva Pharmaceuticals, VielaBio Inc, Vivus, NHLBI (Protocol Review Committee), NICHD (OPRU oversight committee). Consulting or Advisory Boards: Biodelivery Sciences International, Biogen, Click Therapeutics, Genzyme, Genentech, GW Pharmaceuticals, Immunic, Klein-Buendel Incorporated, Medimmune, Medday, Neurogenesis LTD, Novartis, Osmotica Pharmaceuticals, Perception Neurosciences, Recursion/Cerexis Pharmaceuticals, Roche, TG Therapeutics. Dr. Cutter is employed by the University of Alabama at Birmingham and President of Pythagoras, Inc. a private consulting company located in Birmingham AL. Dr. Strijbis and Dr. Mostert report no disclosures.

Figures

Figure 1.
Figure 1.
A review of clinical trial phases. Phase 1 trials are concerned with the safety of treatments, and therefore do not investigate a treatment effect in the disease of interest. Phase 2 trials investigate whether a drug can affect the relevant pathophysiology, and phase 3 trials determine whether a drug works in typical people with the disease. Phase 2 trials often use surrogate outcomes or biomarkers of response as their primary outcome: contrast enhancing lesions in RRMS, and MRI brain atrophy in progressive MS.
Figure 2.
Figure 2.
Problems with surrogate outcomes in progressive MS phase 2 trials. Here, we use MRI brain atrophy as an example, but the overall concept is true for all surrogate outcomes. (a) Shows the ideal situation: MRI brain atrophy as the surrogate outcome precedes and predicts disability worsening. In this case, MRI brain atrophy can indeed “stand in” for physical disability. (b) Shows an intermediate scenario: here the disease process of progression drives both MRI brain atrophy and physical disability. In this case, it is possible to use MRI brain atrophy as the outcome, but it is not necessary, as it would be easier to measure physical disability directly. (c) shows the worst-case scenario: both MRI brain atrophy and physical disability are driven by the same pathophysiology, but there is no close relationship between the two, and one does not predict the other.
Figure 3.
Figure 3.
In SPMS, the percentage of people with significant (⩾ 20%) worsening in T25FW performance at 12 months increases as a function of baseline T25FW performance in this cohort of patients with baseline EDSS scores between 4.0 and 6.5. This cohort combines participants of two clinical trials and real-world data (n = 235; adapted from Koch et al.). This circumstance allows for the “enrichment” of trial populations: for example, by including people with a baseline T25FW performance of 7 seconds or more, we would expect 40% of this cohort to experience significant worsening at 12 months. If we include participants with a baseline T25FW performance of 12 seconds or more, the percentage is increased to almost 50% of the cohort.
See this image and copyright information in PMC

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