Oxiracetam and physical activity in preventing cognitive decline after stroke: A multicenter, randomized controlled trial

Abstract

Introduction: This multicenter, double-blind, placebo-controlled trial, commissioned by South Korea's Ministry of Food and Drug Safety, evaluated the effect of oxiracetam for preventing post-stroke cognitive impairment (PSCI) and explored potential interaction with physical activity using neuroimaging.

Patients and methods: Patients at high risk of PSCI, reporting subjective cognitive decline ⩾3 months after stroke, were randomized 1:1 to receive oxiracetam or placebo for 36 weeks. Physical activity was tracked via wrist-worn actigraphy. Coprimary endpoints were changes in Mini-Mental State Examination (MMSE) and Clinical Dementia Rating-Sum of Boxes (CDR-SB). Secondary outcomes included neuropsychological assessments and resting-state functional magnetic resonance imaging network metrics.

Results: Of 500 enrolled participants (mean age 68.9 years; median 32 months post-stroke), 457 completed the study. There were no statistically significant differences between groups in changes in MMSE (oxiracetam: +0.13 ± 2.27 vs placebo: +0.27 ± 2.09; p = 0.49) or CDR-SB scores (-0.14 ± 0.70 vs -0.08 ± 0.80; p = 0.38). No evidence of interaction was observed between oxiracetam and physical activity. Exploratory analyses suggested favorable trends in functional segregation and CDR-SB scores among highly active oxiracetam participants.

Discussion and conclusion: Oxiracetam did not demonstrate benefit in preventing PSCI in high-risk patients. These findings support the recent regulatory decision to suspend its use in South Korea.

Keywords: Vascular dementia; clinical trials; exercise; oxiracetam; physical activity.

Graphical abstract

Figure 1.

Overview of scheduled visits, assessments, and follow-up timeline.

Figure 2.

CONSORT diagram showing participant enrollment, randomization, and analysis populations. The follow-up population includes participants who received at least one dose of study drug and completed both baseline and 36-week cognitive assessments.

Figure 3.

Changes in MMSE and CDR-SB scores from baseline (Visit 1) to week 36 (Visit 5) by treatment allocation and baseline physical activity status (N = 457) Error bars represent standard errors (SE) of the mean changes. (a and b) Mean changes in MMSE and CDR-SB scores for the oxiracetam and placebo groups, respectively. (c and d) Mean changes in MMSE and CDR-SB scores among participants allocated to oxiracetam, stratified by baseline physical activity (Physically Active vs Physically Inactive). (e and f) Corresponding mean changes in the placebo group. For clarity, the direction of the CDR-SB was inverted so that upward trends represent cognitive improvement, as with the MMSE. As physical activity at baseline was balanced across randomized groups, the mean changes in MMSE and CDR-SB scores (follow-up [V5] − baseline scores [V1]) between treatment groups were compared using Student’s t test. In addition, the significance of the interaction effect between treatment group and baseline physical activity was tested using a 5% significance level through multiple linear regression analysis with sequential conditional mean model (SCMM). Physically Active was defined as engaging in ⩾20 min/day of MVPA at baseline; Physically Inactive was defined as <20 min/day of MVPA. Abbreviations: MMSE, mini-mental state examination; CDR-SB, clinical dementia rating-sum of boxes; MVPA, moderate-to-vigorous physical activity.