Treatment Effect on T1 Hypointense Lesions: Evaluation of Two Different Methodologies in RRMS Subjects from the GALA Study

Background: When evaluating treatment effects on T1 hypointense lesions (T1H) in MS clinical trials, there is no guideline whether to assess all active T1H on pre-contrast MRI scans (T1H-total) or just those T1H on pre-contrast MRI scans that are simultaneously non-enhancing on post-contrast scans (T1H-non-enhancing).

Objectives: To examine new/enlarging T1H-total and T1H-non-enhancing between 0-6 and 6-12 months in the Glatiramer Acetate Low-frequency Administration (GALA) study.

Methods: GALA was a phase III trial that randomized 1404 relapsing-remitting MS subjects to receive GA 40 mg/1mL tiw or placebo for 12 months. MRI was obtained at baseline and months 6 and 12. Cumulative numbers of T1H-total and of T1H-non-enhancing were calculated and analyzed using an adjusted negative binomial regression model.

Results: Overall, 1325 patients were included in the analysis of T1H-total, and 1323 were included in the analysis of T1H-non-enhancing. Analyses of T1H-total revealed that 884 GA-treated patients developed a mean of 1.7 vs. 2.6 lesions in the 441 placebo arm patients (Risk Ratio [RR] = 0.67; 95% confidence interval 0.55-0.81, p<.0001). Analysis of T1H-non-enhancing revealed that  GA-treated patients developed a mean of 1.3 vs. 1.9 lesions in the placebo arm patients (RR = 0.71 [0.57-0.87], p=.0009).

Conclusions: Results using the two methodologies are comparable. However, T1H non-enhancing lesions may represent a distinct stage of lesion evolution, potentially showing a more advanced pathological substrate of tissue damage compared with T1H-total. On the other hand, T1H-total may capture additional aspects of lesion evolution, such as remyelination, thus obscuring mechanistic interpretation. This study is relevant to future clinical trials aiming to clarify mechanisms of treatment effect.