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

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.. 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.. 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. 22 ). 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.