Efficacy and safety of L-oxiracetam on cognitive function in patients with traumatic brain injury: a multicentre, randomised, double-blind, phase 3 clinical trial

To assess the efficacy and safety of L-oxiracetam, a novel nootropic agent, in improving cognition in patients with TBI, we performed a multicentre, double-blind, randomized controlled trial in China. Participants aged 18 to 75 years with TBI (Glasgow Coma Scale score of 10 to 15) were recruited from 51 hospitals from 2019 to 2024. Patients were randomly assigned to L-oxiracetam, 4 g/day, oxiracetam 6 g/day, or placebo in 2:2:1. The primary outcome was the change in the Loewenstein Occupational Therapy Cognitive Assessment (LOTCA) score from baseline to 90 days post treatment. Secondary outcomes included changes in additional cognitive evaluations, neurological function, activities of daily living (ADL), and adverse events (AEs). The trial was approved by the China National Medical Products Administration (2016L03521), and registered at Clinicaltrials.gov (NCT04205565) and Chinadrugtrials.org.cn (CTR20192539). Five hundred and ninety patients were included (mean age (SD), 50.9 (14.5); 421 males). The least squares (LS) mean of LOTCA change from baseline to 90 days post treatment was 20.45 (95% confidence interval [CI] 17.23, 23.66) in the L-oxiracetam group, 15.90 (95% CI 12.71, 19.10) in the oxiracetam group, and 11.47 (95% CI 7.75, 15.20) in the placebo group (P value < 0.05 for all groups). The LS mean difference of the L-oxiracetam was significantly higher than the placebo group (8.97, 95% CI 5.69,12.26; P < 0.001; Cohen's d = 0.48 [95% CI: 0.26,0.69]) and the oxiracetam group (4.54, 95% CI 1.85,7.23). Secondary efficacy outcomes did not differ between the L-oxiracetam and oxiracetam groups. The proportion of serious AEs did not differ among the three groups. L-oxiracetam could improve cognitive function in patients with mild-to-moderate TBI. L-oxiracetam might be more efficacious than oxiracetam. No significant safety concerns were reported. Despite limitations such as loss to follow-up, the findings of this study provide important evidence for the clinical management of cognitive dysfunction following TBI. Future studies in real-world clinical settings are warranted to further substantiate the efficacy of L-oxiracetam and oxiracetam.

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Journal
Signal Transduction and Targeted Therapy
Published
2025-12-12
DOI
https://doi.org/10.1038/s41392-025-02492-5
Primary Topic
Traumatic Brain Injury and Neurovascular Disturbances
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article
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article

Efficacy and safety of L-oxiracetam on cognitive function in patients with traumatic brain injury: a multicentre, randomised, double-blind, phase 3 clinical trial

Zengqiang Liu, Wei Feng, Tao Mei, Qiuhua Jiang et al.
Signal Transduction and Targeted Therapy
Traumatic Brain Injury and Neurovascular Disturbances
article

Efficacy and safety of L-oxiracetam on cognitive function in patients with traumatic brain injury: a multicentre, randomised, double-blind, phase 3 clinical trial

Zengqiang Liu, Wei Feng, Tao Mei, Qiuhua Jiang, Xingchang Li, Weiwei Jiang, Ying Xia, Zejun Chen, Ruijian Zhang, Lianshu Ding, Rutong Yu, Biao Zhao, Minzhi Zhang, Jian Chen, Rongcai Jiang, Wei Sheng, Huange Jiang, Ya Peng, Yezhong Wang, J. Li, Wen Cheng, Tong Tang, Linan Chen, Xiang Gao, Tao Liu, Hui Li, Gang Li, Li Li, Jianning Zhang, Meihua Li, Sheng Zhu, Chenglong Liu, Bin Li, Jian Ge, Zhihao Zhao, Tao Jiang, Weilong Li, Zhimin Wang, Jianrong Liang, Jian Wu, Ruisheng Lin, Xingen Zhu, Shaochun Yang, Gang Zhu, Yunhu Yu, Bo Fan, Jianbo Wei, Aiming Li, Lin Lou, Hengzhu Zhang, Liang Mi
article en

Abstract

To assess the efficacy and safety of L-oxiracetam, a novel nootropic agent, in improving cognition in patients with TBI, we performed a multicentre, double-blind, randomized controlled trial in China. Participants aged 18 to 75 years with TBI (Glasgow Coma Scale score of 10 to 15) were recruited from 51 hospitals from 2019 to 2024. Patients were randomly assigned to L-oxiracetam, 4 g/day, oxiracetam 6 g/day, or placebo in 2:2:1. The primary outcome was the change in the Loewenstein Occupational Therapy Cognitive Assessment (LOTCA) score from baseline to 90 days post treatment. Secondary outcomes included changes in additional cognitive evaluations, neurological function, activities of daily living (ADL), and adverse events (AEs). The trial was approved by the China National Medical Products Administration (2016L03521), and registered at Clinicaltrials.gov (NCT04205565) and Chinadrugtrials.org.cn (CTR20192539). Five hundred and ninety patients were included (mean age (SD), 50.9 (14.5); 421 males). The least squares (LS) mean of LOTCA change from baseline to 90 days post treatment was 20.45 (95% confidence interval [CI] 17.23, 23.66) in the L-oxiracetam group, 15.90 (95% CI 12.71, 19.10) in the oxiracetam group, and 11.47 (95% CI 7.75, 15.20) in the placebo group (P value < 0.05 for all groups). The LS mean difference of the L-oxiracetam was significantly higher than the placebo group (8.97, 95% CI 5.69,12.26; P < 0.001; Cohen's d = 0.48 [95% CI: 0.26,0.69]) and the oxiracetam group (4.54, 95% CI 1.85,7.23). Secondary efficacy outcomes did not differ between the L-oxiracetam and oxiracetam groups. The proportion of serious AEs did not differ among the three groups. L-oxiracetam could improve cognitive function in patients with mild-to-moderate TBI. L-oxiracetam might be more efficacious than oxiracetam. No significant safety concerns were reported. Despite limitations such as loss to follow-up, the findings of this study provide important evidence for the clinical management of cognitive dysfunction following TBI. Future studies in real-world clinical settings are warranted to further substantiate the efficacy of L-oxiracetam and oxiracetam.

Signal Transduction and Targeted TherapyVol. 10(1)
Ningbo University (CN), Jiangsu University (CN), Nanchang University (CN), Henan University of Science and Technology (CN), Xuzhou Medical College (CN), Capital Medical University (CN), Anhui Medical University (CN), Nantong University (CN), Yichun University (CN), Sichuan University (CN), Kunming Medical University (CN), East Yangon General Hospital (MM), Tianjin Medical University General Hospital (CN), Karolinska Institutet (SE), UNSW Sydney (AU), Haikou City People's Hospital (CN), Affiliated Hospital of Nantong University (CN), West China Hospital of Sichuan University (CN), Liuzhou Maternal and Child Health Hospital (CN), Second People 's Hospital of Jinzhong (CN), Second Affiliated Hospital of Guangzhou Medical University (CN), Zhumadian Central Hospital (CN), Xuan Wu Hospital of the Capital Medical University (CN), Suzhou Kowloon Hospital (CN), Ganzhou People's Hospital (CN), Huaian First People’s Hospital (CN), Tianjin Huanhu Hospital (CN), Zhangzhou Municipal Hospital of Fujian Province (CN), The First People's Hospital of Changzhou (CN), Second Affiliated Hospital of Nanchang University (CN), People's Hospital of Kaizhou District (CN), The George Institute for Global Health (AU), Affiliated Hospital of Jiangsu University (CN), Shenyang First People's Hospital (CN), First People’s Hospital of Zunyi (CN), Zhujiang Hospital (CN), The First People's Hospital of Changde (CN), Inner Mongolia People's Hospital (CN), Second People’s Hospital of Huai’an (CN), The First People’s Hospital of Lianyungang (CN), Zhejiang Provincial People's Hospital (CN), Second Hospital of Tianjin Medical University (CN), First Affiliated Hospital of Gannan Medical University (CN), Sanya Central Hospital (CN), Fourth Affiliated Hospital of Guangxi Medical University (CN), First Affiliated Hospital of Henan University of Science and Technology (CN), First Affiliated Hospital of Anhui Medical University (CN), Huizhou Central People's Hospital (CN), Panzhihua Central Hospital (CN), Puer University (CN), The Second Affiliated Hospital of Bengbu Medical College (CN), Taizhou First People's Hospital (CN), Yan'an Hospital Affiliated To Kunming Medical University (CN), Shanxi Provincial Children's Hospital (CN), First People's Hospital of Nanning (CN), Guangdong Provincial People's Hospital (CN), First Affiliated Hospital of Nanchang University (CN), Yueqing People's Hospital (CN), Beijing Chaoyang Emergency Medical Center (CN), Dawu County People's Hospital (CN), Tianjin Medical University (CN), Southern Medical University (CN), Nanjing Medical University (CN), Guangzhou Medical University (CN)
Huazhong University of Science and Technology, Nanjing Medical University
Openalex Percentile: Top 46%
Traumatic Brain Injury and Neurovascular Disturbances
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