Background:
In the SPRINT-MS clinical trial, relative to placebo, ibudilast treatment was associated with significant reductions in rates of whole brain, brain substructure, and retinal atrophy in people with progressive multiple sclerosis (PMS). This effect was more pronounced in people with primary PMS (PPMS) than secondary PMS (SPMS). Whether ibudilast treatment modulates quality-of-life measures and the utility of baseline serum neurofilament light chain (sNfL) levels for predicting changes in these scores in PMS, and the differences therein between PPMS and SPMS remain unclear.
Objectives: To determine whether ibudilast treatment improves quality-of-life scores in people with PMS in the SPRINT-MS clinical trial and whether this effect differs between PPMS and SPMS. Moreover, we sought to assess the relationships between baseline sNfL levels and changes in physical and mental health quality-of-life scores in this PMS cohort.
Methods:
SPRINT‐MS was a randomized, placebo‐controlled 96‐week phase 2 trial that enrolled 134 people with PPMS and 121 with SPMS (129 randomized to ibudilast and 126 to placebo). The short form 36 health survey (SF-36) was used to derive the standardized physical composite summary (PCS) and mental composite summary (MCS) scores. Levels of sNfL were measured annually using single-molecule array immunoassay and were categorized as low (≤25.5 pg/mL) or high (>25.5 pg/mL). We examined the effect of ibudilast treatment and the relationship of baseline sNfL levels with PCS and MCS scores using linear mixed-effects regression models.
Results:
The rate of change in PCS was -5.5% per year in the ibudilast arm and -5.3% per year in the placebo arm (difference: -0.2%; 95% confidence interval (CI), -18.9% to 18.5%, p=0.6) and in MCS was 1.8% per year in the ibudilast cohort and -2.4% per year in the placebo arm (difference: 4.3%; 95% CI, -5.3% to 13.9%, p=0.4) over 96 weeks. Subgroup analyses did not show differential treatment effects of ibudilast relative to placebo on these quality-of-life scores in PPMS (for PCS, p=0.6; for MCS, p=0.2) or SPMS (for PCS, p=0.7; for MCS, p=0.6). Relative to those with lower baseline sNfL levels, people with higher baseline sNfL levels exhibited significantly greater decline in MCS scores (difference: -18.3%, 95% CI, -33% to -3.7% p=0.014) over the study period. This effect was primarily driven by the PPMS cohort (difference: -19.7%, 95% CI, -39.7% to 0.3%, p=0.054).
Conclusions:
Baseline sNfL levels may predict a decline in MCS scores in people with PMS, more prominently in the PPMS subtype. Although ibudilast treatment has been shown to reduce whole and substructural brain and retinal atrophy in people with PMS, it does not appear to improve SF-36 PCS or MCS quality-of-life scores. Ibudilast similarly did not reduce disability progression in this cohort. Thus, in PMS, measurable brain and retinal atrophy benefits may not necessarily translate into measurable clinical benefits.
Abstract
Background:
In the SPRINT-MS clinical trial, relative to placebo, ibudilast treatment was associated with significant reductions in rates of whole brain, brain substructure, and retinal atrophy in people with progressive multiple sclerosis (PMS). This effect was more pronounced in people with primary PMS (PPMS) than secondary PMS (SPMS). Whether ibudilast treatment modulates quality-of-life measures and the utility of baseline serum neurofilament light chain (sNfL) levels for predicting changes in these scores in PMS, and the differences therein between PPMS and SPMS remain unclear.
Objectives: To determine whether ibudilast treatment improves quality-of-life scores in people with PMS in the SPRINT-MS clinical trial and whether this effect differs between PPMS and SPMS. Moreover, we sought to assess the relationships between baseline sNfL levels and changes in physical and mental health quality-of-life scores in this PMS cohort.
Methods:
SPRINT‐MS was a randomized, placebo‐controlled 96‐week phase 2 trial that enrolled 134 people with PPMS and 121 with SPMS (129 randomized to ibudilast and 126 to placebo). The short form 36 health survey (SF-36) was used to derive the standardized physical composite summary (PCS) and mental composite summary (MCS) scores. Levels of sNfL were measured annually using single-molecule array immunoassay and were categorized as low (≤25.5 pg/mL) or high (>25.5 pg/mL). We examined the effect of ibudilast treatment and the relationship of baseline sNfL levels with PCS and MCS scores using linear mixed-effects regression models.
Results:
The rate of change in PCS was -5.5% per year in the ibudilast arm and -5.3% per year in the placebo arm (difference: -0.2%; 95% confidence interval (CI), -18.9% to 18.5%, p=0.6) and in MCS was 1.8% per year in the ibudilast cohort and -2.4% per year in the placebo arm (difference: 4.3%; 95% CI, -5.3% to 13.9%, p=0.4) over 96 weeks. Subgroup analyses did not show differential treatment effects of ibudilast relative to placebo on these quality-of-life scores in PPMS (for PCS, p=0.6; for MCS, p=0.2) or SPMS (for PCS, p=0.7; for MCS, p=0.6). Relative to those with lower baseline sNfL levels, people with higher baseline sNfL levels exhibited significantly greater decline in MCS scores (difference: -18.3%, 95% CI, -33% to -3.7% p=0.014) over the study period. This effect was primarily driven by the PPMS cohort (difference: -19.7%, 95% CI, -39.7% to 0.3%, p=0.054).
Conclusions:
Baseline sNfL levels may predict a decline in MCS scores in people with PMS, more prominently in the PPMS subtype. Although ibudilast treatment has been shown to reduce whole and substructural brain and retinal atrophy in people with PMS, it does not appear to improve SF-36 PCS or MCS quality-of-life scores. Ibudilast similarly did not reduce disability progression in this cohort. Thus, in PMS, measurable brain and retinal atrophy benefits may not necessarily translate into measurable clinical benefits.