A Double-Blind, Placebo-Controlled, Randomized, Multi-Centre, Phase Iii Study Of Mlc901 (Neuroaid Iitm) For The Treatment Of Cognitive Impairment After Mild Traumatic Brain Injury

IntroductionAbout half of the world population will suffer from a traumatic brain injury (TBI) during their lifetime, of which about 90% of cases are mild TBI. About 15-40% of adults with TBI experience persistent cognitive deficits, and there is a lack of proven-effective treatment to facilitate cognitive recovery after mild TBI. Methods and analysisThis randomized placebo-controlled multi-centre clinical trial aimed to examine the safety and efficacy of herbal supplement MLC901 (NeuroAiD II) on cognitive functioning following mild TBI. Adults aged 18-65 years, who were 1-12-months post-mild TBI and experienced cognitive impairment, were assigned to receive either MLC901 (0.8g capsules/day) or placebo for 6 months in 7 research centres in Russia using centralized stratified permuted block randomization. The primary outcome was cognitive functioning as assessed by an online neuropsychological test (CNS Vital signs). Secondary outcomes included Rivermead Post-Concussion Symptoms Questionnaire (RPQ; neurobehavioral sequelae), Health Related Quality of Life (QOLIBRI), the Hospital Anxiety and Depression Scale (HADS), and adverse events. Assessments were completed at baseline and 3-, 6-, and 9-month follow-ups. Mixed effects models of repeated measures with intention to treat analysis were employed, with the primary outcome time-point of 6-months. A Least Square Mean Difference (LSMD) from baseline to 3-, 6-, and 9-month follow-up was calculated with 95% confidence intervals (CI). ResultsOne hundred and eighty-two participants (mean age 40.6{+/-}14.2 in the MLC901 group and 40.1{+/-}12.0 in the Placebo group, 50% and 47.8% females, respectively) were included in the analysis. Baseline variables were comparable between groups. Multivariate mixed effects model analysis did not reveal significant improvements in complex attention (LSMD=-1.18 [95% CI -5.40; 3.03; p=0.58] and other cognitive domains at 6-months in the MLC901 group compared to the Placebo group. There were significant improvements in RPQ, QOLIBRI, anxiety and depression in the MLC901 group compared to the Placebo group at 6 and 9-months (LSMD -4.36 [-6.46; -2.26] and -4.07 [-6.22; -1.92], 4.84 [1.58; 8.10] and 3.74 [0.44; 7.03], -1.50 [-2.29; -0.71 and -0.96 [-1.84; -0.08], -1.14 [-1.92; -0.35] and -1.14 [-1.94; -0.34], respectively. No serious adverse events were reported. ConclusionsThe 6-month treatment with MLC901 did not result in a statistically significant difference with placebo for CNS-VS measurement of complex attention and other cognitive outcomes in individuals with mild TBI. The study showed a clinically and statistically significant improvement in all clinical scales assessed by the investigators (post-concussion symptoms, quality of life, and mood). This study showed that post-mild TBI treatment with MLC901 0.8g/day is safe. Trial registrationClinicalTrials.gov identifier NCT04861688.