
==== Front
Heliyon
Heliyon
Heliyon
2405-8440
Elsevier

S2405-8440(24)13327-0
10.1016/j.heliyon.2024.e37296
e37296
Research Article
Efficacy and safety of compound porcine cerebroside and ganglioside injection (CPCGI) versus piracetam on cognition and functional outcomes for adults with traumatic brain injury: A study protocol for randomized controlled trial
Liu Tao ab1
Yu Yunhu ac1
Mi Liang a1
Zhao Zhihao a
Liu Mingqi d
Wang Jiao e
Wang Xin f
Sha Zhuang a
Nie Meng a
Jiang Weiwei a
Wu Chenrui a
Yuan Jiangyuan a
Lv Chuanxiang g
Zhao Biao h
Lin Kun i
Li Zhanying j
Luo Zhenyu k
Liu Xuanhui a
Qian Yu a
Jiang Rongcai jiangrongcai@tmu.edu.cn
a⁎
a Department of Neurosurgery, Tianjin Neurological Institute, State Key Laboratory of Experimental Hematology, Key Laboratory of Post-Neuroinjury Neurorepair and Regeneration in Central Nervous System Tianjin & Ministry of Education, Tianjin Medical University General Hospital, Tianjin, China
b The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
c Department of Clinical Research Center for Neurological Disease, the People's Hospital of HongHuaGang District of ZunYi, Guizhou, China
d Department of Rehabilitation Medicine, Zhejiang Provincial People's Hospital, Hangzhou, China
e Department of Epidemiology, College of Preventive Medicine, Third Military Medical University, Chongqing, China
f Department of Neurology, The First Affiliated Hospital of China Medical University, Liaoning, China
g Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China
h Department of Neurosurgery, the Second Affiliated Hospital of Bengbu Medical University, Bengbu, China
i Department of Neurosurgery, Fujian Provincial Hospital, Fujian, China
j Department of Neurosurgery, Kailuan General Hospital, Hebei, China
k Department of Neurosurgery, Shandong Provincial Third Hospital, Jinan, China
⁎ Corresponding author. Department of Neurosurgery, Tianjin Medical University General Hospital; Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neurorepair and Regeneration in Central Nervous System, Tianjin & Ministry of Education, 154 Anshan Road, Heping District, Tianjin, 300052, China. jiangrongcai@tmu.edu.cn
1 These authors contributed equally to this work and share first authorship.

31 8 2024
15 9 2024
31 8 2024
10 17 e372969 6 2024
28 8 2024
30 8 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).
Background

Traumatic brain injury (TBI) is a common neurosurgical disease in emergency rooms with poor prognosis, imposing severe burdens on patients and their families. Evidence indicates that piracetam and compound porcine cerebroside and ganglioside injection (CPCGI) can improve cognitive levels in TBI patients to enhance functional prognosis, but there is still a research gap regarding the efficacy of CPCGI. This study aims to determine the effectiveness and safety of CPCGI in improving cognitive and functional outcomes in TBI patients.

Methods

This study is a multicenter, randomized, parallel-group, double-blind trial aiming to recruit 900 adult patients with mild to moderate TBI. After providing informed consent, 600 patients will be randomly assigned to the CPCGI group (20 ml/d, for 14 days), and 300 patients will be randomized to the piracetam group as a control (20 ml/d, for 14 days), followed up for 3 months after treatment. The primary outcome is the change in the Montreal Cognitive Assessment (MoCA) score from baseline after 3 months. The main secondary outcome measures include Mini-Mental State Examination (MMSE) scores, Glasgow Outcome Scale-Extended (GOS-E), and the Barthel Index at 1 and 3 months.

Discussion

This multi-center clinical trial aims to provide high-quality evidence on the efficacy and safety of CPCGI in improving cognitive and functional outcomes in mild to moderate TBI patients.

Trial registration

ChiCTR2000040466, date of registration: November 28, 2020.

Keywords

Traumatic brain injury
Cognitive
Compound porcine cerebroside and ganglioside injection
Piracetam
Outcome
Randomized controlled trial
==== Body
pmc1 Introduction

Traumatic brain injury (TBI) represents a predominant cause of mortality and morbidity globally across all demographics [1]. Despite over a century of extensive basic and clinical research, the medical community recognizes a dearth of efficacious treatments or pharmacological interventions for TBI [2]. Annually, an estimated sixty-nine million individuals worldwide incur a TBI, with survivors frequently enduring persistent symptoms that profoundly deteriorate their life quality especially its sequela from cognition impairments [3,4]. Cognitive impairments, manifesting as compromised attention, memory deficits, diminished executive functions, impulsivity, inadequate decision-making capabilities, and depression, serve as critical determinants of whether individuals with TBI can maintain autonomy or experience significant disability. Such disabilities impose a considerable toll on both the affected individuals and their families [[5], [6], [7], [8]]. Therefore, the identification and recommendation of effective therapeutic strategies to mitigate cognitive impairments in TBI patients are of paramount importance.

The etiology and underlying mechanisms of TBI remain elusive. Prior research has established a correlation between severe outcomes in TBI and phenomena such as pronounced cerebral edema, neuronal apoptosis, inflammation, and diminished cerebral perfusion [[9], [10], [11]]. Our investigations have further substantiated that interventions targeting cerebral edema reduction and neuronal apoptosis prevention can enhance motor and cognitive outcomes post-TBI [12,13]. In the realm of clinical interventions for TBI, various pharmacological approaches have been evaluated for their prognostic benefits [14]. Amantadine, a dopamine agonist, has been recognized for its potential in mitigating cognitive deficits [15]. Methylphenidate, by inhibiting catecholamine reuptake, elevates levels of dopamine, noradrenaline, and serotonin, and has recently been applied in addressing cognitive impairments following TBI [[16], [17], [18], [19], [20]]. Furthermore, Piracetam, a cyclic GABA derivative, has been shown to bolster cerebral metabolism, alleviate intracranial pressure and edema, thereby improving cognitive and motor functions in TBI patients [[21], [22], [23]].

Approved by the China Food and Drug Administration in 2010, Compound Porcine Cerebroside and Ganglioside Injection (CPCGI) is a neurotrophic medication employed in the experimental management of conditions such as stroke, Alzheimer's disease, and central and peripheral nerve injuries [[24], [25], [26], [27]]. CPCGI comprises key components including polypeptides, gangliosides, and hypoxanthine [26]. Studies have illustrated that CPCGI administration markedly enhances cerebral blood flow and neurological function, reduces cellular apoptosis, and facilitates the restoration of synaptic and mitochondrial functionality in ischemic/reperfusion rats models [25,26]. Additionally, clinical research indicates CPCGI's efficacy in enhancing cerebral metabolism, contributing to neuronal growth, differentiation, and regeneration, and augmenting cerebral circulation in Alzheimer's disease [28]. Despite several clinical trials investigating CPCGI's application in TBI within China [[29], [30], [31]], high quality evidence remain scarce, thus weakening the evidential basis for CPCGI's broad clinical adoption in TBI treatment. We therefore initiated a multicenter, randomized, active control, double-blind trial to determine the efficacy and safety of CPCGI in patients with TBI.

2 Methods and analysis

2.1 Design

This protocol delineates a prospective, multicenter, phase III/Ⅳ randomized, active control, double-blind clinical trial aimed at assessing the efficacy and safety of CPCGI in patients with TBI, with piracetam serving as the comparator. This trial is planned to be conducted in 31 hospitals across China (Table 1). Participants shall not be enrolled in this study without obtaining informed consent from the subjects and/or their guardians/legal representatives. This study protocol is registered with the China Clinical Trial Registry (Registration number: ChiCTR2000040466; Registration date: November 28, 2020). Ethical approval has been granted by the ethics boards of Tianjin Medical University General Hospital and other involved institutions, adhering to the Declaration of Helsinki's ethical guidelines. During the implementation process, we strive to avoid some common mistakes [32]. The flowchart of this study is shown in Fig. 1, and the evaluation time points are presented in Table 2.Table 1 Medical centers in China participating in the study.

Table 1Number	Medical centers	
1	Tianjin Medical University General Hospital	
2	Tianjin First Central Hospital	
3	The First People's Hospital of Tancheng	
4	The Affiliated Hospital of Qingdao University	
5	The First Affiliated Hospital of Nanyang Medical College	
6	Taizhou Traditional Chinese Medicine Hospital	
7	Taizhou Second People's Hospital	
8	Taizhou Municipal Hospital	
9	Suzhou Municipal Hospital	
10	Xianyang Hospital of Yan'an University	
11	Huainan first people's Hospital	
12	Huai'an First People's Hospital	
13	Xinxiang Central Hospital	
14	The Second People's Hospital of Hefei	
15	The Second Hospital Universi ty of South China	
16	The First People's Hospital of Jinzhong	
17	The Fourth Affiliated Hospital of Anhui Medical University	
18	Qinghai Provincial People's Hospital	
19	Qinghai University Affiliated Hospital	
20	Yuncheng Central Hospital	
21	Affiliated Hospital of Nantong Hospital	
22	Nantong First People's Hospital	
23	Jiangsu Taizhou People's Hospital	
24	Yangzhou First People's Hospital	
25	Wuxi People's Hospital	
26	Wuxi Second People's Hospital	
27	Yixing People's Hospital	
28	The First People's Hospital of Changzhou	
29	The Affiliated Hospital of Xuzhou Medical Hospital	
30	Suqian First People's Hospital	
31	Shuyang People's Hospital	

Fig. 1 Flow chart to illustrate the design of the trial.

TBI traumatic brain injury, CPCGI compound porcine cerebroside and ganglioside injection, MoCA Montreal Cognitive Assessment, MMSE Mini-Mental State Examination, GCS Glasgow Coma Scale, NIHSS National Institutes of Health Stroke Scale, GOS-E Glasgow Outcome Scale-Extended, AEs adverse events, ECG electrocardiogram.

Fig. 1

Table 2 Visit and assessment schedule of this trial.

Table 2Activities	Screening or baseline	Day 7–14 (treatment end)	Month 1 ± 3 D	Month 3 ± 3 D	
Informed consent	✓				
Inclusion/exclusion criteria	✓				
General information	✓				
Medical history	✓				
Personal history	✓				
Head CT/MRI	✓				
Pregnancy test	✓				
Concomitant medicationa	✓	✓	✓	✓	
Physical examination	✓	✓	✓	✓	
Neurological symptoms	✓	✓	✓	✓	
MoCAb	✓			✓	
MMSE	✓	✓		✓	
GCS/NIHSS	✓	✓			
GOS-E		✓		✓	
Barthel index			✓	✓	
Vital signs	✓	✓			
Laboratory testsc	✓	✓			
Electrocardiogram	✓	✓			
Adverse events		✓	✓	✓	
Drug dispensing	✓				
Drug recoveryd		✓			
D day, CT computerized tomography, MRI magnetic resonance imaging, MoCA Montreal Cognitive Assessment, MMSE Mini-Mental State Examination, GCS Glasgow Coma Scale, NIHSS National Institutes of Health Stroke Scale, GOS-E Glasgow Outcome Scale-Extended.

a Records of combination therapy are required until the end of the trial.

b An additional MoCA test will be completed at 7 ± 1 days after treatment as baseline.

c Laboratory tests include blood routine, urinalysis, liver and renal function electrolyte, lipids, coagulation.

d The remaining drugs need to be recovered.

2.2 Inclusion criteria

1) Ages 18–75 years old (inclusive of boundary values), irrespective of gender;

2) TBI patients meeting all of the following conditions:• Clear head trauma in the current diagnosis, including closed brain injuries or those accompanied by cerebrospinal fluid otorrhea and/or rhinorrhea and/or pneumocephalus;

• Confirmed by MRI or CT to have supratentorial intracranial hemorrhage (including cerebral contusion, subarachnoid hemorrhage, epidural hematoma, subdural hematoma, intracerebral hematoma, etc.), pneumocephalus, skull fractures, or transient loss of consciousness;

3) TBI classified as mild to moderate (Glasgow Coma Scale (GCS) score ≥9 and ≤ 15);

4) Conservative treatment, non-craniotomy surgery (invasive intracranial pressure monitoring may be included);

5) Life signs and condition stable within 72 h post-TBI, with a Mini-Mental State Examination (MMSE) score below normal; diagnostic thresholds vary by educational level: illiterate (uneducated) ≤19, primary education ≤22, junior high school and above ≤26;

6) Agreement to participate in this clinical trial and signing of the informed consent form.

2.3 Exclusion criteria

1) Known or suspected allergy to the trial medication or its components;

2) Guillain-Barre syndrome, extrapyramidal disorders, Huntington's disease;

3) History of severe TBI, structural brain lesions, cognitive impairments, or intellectual disabilities;

4) Conditions such as speech/hearing impairments that hinder completion of cognitive function assessments;

5) Secondary brain injury post-current TBI;

6) Need for craniotomy or external ventricular drainage;

7) Concurrent severe major organ injury or serious complications potentially life-threatening;

8) Active epilepsy with seizures within the past year;

9) Severe cardiac, pulmonary, hepatic, or renal disease (ALT or AST≥2.0 times the upper limit of normal, Scr > upper limit of normal), hematopoietic or blood disorders, gastrointestinal diseases, malignant tumors, or other severe or progressive systemic diseases, assessed as having severely abnormal coagulation functions;

10) Concurrent neurological or psychiatric diseases making cooperation difficult or unwillingness to cooperate;

11) Suspected or confirmed history of alcohol or drug abuse, or tendency towards drug dependence;

12) Pregnant or breastfeeding women or those with recent plans for pregnancy;

13) Participation in another clinical trial within the past three months;

14) Deemed by the researcher as unsuitable for participation in the clinical trial.

2.4 Randomization

This trial employs block randomization to divide successfully screened participants into two groups randomly. Random number tables are provided by Beijing Excellence Future International Pharmaceutical Technology Development Co., Ltd., using SAS9.4. Researchers at each participating trial center will obtain a random number for each eligible participant as they are screened, in chronological order of enrollment. This random number also serves as the drug number, which is used to distribute the corresponding trial medication according to the drug number.

2.5 Blinding

To ensure double-blinding during the clinical trial, each participating unit must appoint a dedicated unblinded research nurse. Throughout the trial, this unblinded nurse is prohibited from disclosing any medication dispensing information to anyone involved in the trial and does not participate in trial evaluations, being solely responsible for preparing the medications.

In the event of a serious adverse event, deterioration, or progression of a participant's condition, an emergency letter can initiate the unblinding process.

Step 1: After the researcher determines that a participant meets the protocol requirements, a random number is generated based on the enrollment sequence at the center. The drug administrator then issues the trial medication corresponding to the drug number to the unblinded research nurse, without selecting the medication. This drug number remains unchanged throughout the study.

Step 2: The unblinded research nurse prepares the medication according to its dosage and administration instructions.

Step 3: After preparation, a blinded nurse administers the medication to the participant.

After administration, the medication packaging is handed over by the unblinded research nurse to the drug administrator for storage.

During the trial, research physicians, participants, data management and statistical personnel, and monitors remain blinded, with only the drug administrator and the unblinded research nurse knowing which trial medication is used by each participant. All related personnel must strictly adhere to the blinding regulations to prevent information leakage.

2.6 Intervention

Trial Group: CPCGI 2 ml per vial. Approval number: H22026472. (Each 1 ml contains peptides 3.2 mg, monosialoganglioside (GM1) 0.24 mg, hypoxanthine 0.125 mg). Produced and supplied by Jilin Tiancheng Pharmaceutical Co., Ltd.

Control Group: Piracetam Injection, specification: 5 ml:1 g per vial. Approval number: H20054824, manufactured by Shanghai Modern Hasen (Shangqiu) Pharmaceutical Co., Ltd. Supplied by Jilin Tiancheng Pharmaceutical Co., Ltd.

All participants will undergo a 20 ml for 14-day treatment with CPCGI or Piracetam.

2.7 Standard care

Participants enrolled in the study will undergo standard therapeutic interventions for TBI, encompassing monitoring of vital signs, airway management, administration of analgesics and sedatives, and management of hemostasis and coagulopathies. Concurrent medication usage throughout the treatment duration, including the medication name, dosage, indication, and duration, will be meticulously documented.

The administration of Traditional Chinese Medicines (TCMs) purported to enhance cognitive function, including Congsheng Decoction and Herba Cistanche, is expressly prohibited during the study period [33,34]. Similarly, hormone replacement therapy is strictly disallowed.

2.8 Strategies to enhance adherence to intervention protocols

To optimize adherence to intervention protocols, strategies will encompass the provision of experimental drugs and laboratory assessments at no cost, and simplifying the regimen to a once-daily medication intake as opposed to multiple daily dosages. It is imperative that both patients and their familial guardians possess a comprehensive understanding of the trial's prerequisites and furnish informed consent accordingly. Additionally, during follow-up consultations, patients will be instructed to present all concurrently used medications for the purpose of evaluating their ancillary pharmaceutical consumption.

2.9 Efficacy outcomes

The primary outcome is the change in the MoCA score at 3 months post-medication relative to the baseline. Secondary outcomes include: 1) The change in the MMSE score at post-medication and 3 months relative to the baseline; 2) The percentage of participants in each Glasgow Outcome Scale-Extended (GOS-E) category at post-medication and 3 months post-medication; 3) The change in the GCS score at post-medication relative to the baseline; 4) The Barthel Index scores for activities of daily living at 1 month and 3 months post-medication; 5) The difference in the National Institutes of Health Stroke Scale (NIHSS) score at post-medication compared to the baseline.

Note: The MoCA score will be assessed by medical staffs who have the certificate. Other scales will be evaluated by neurologists with expertise in professional scale assessment. Unified training on the scales will be provided to personnel at all centers before the trial begins to ensure consistency in scale assessment.

2.10 Safety outcomes

1) Vital signs; 2) Laboratory tests: complete blood count, urinalysis, liver function tests, renal function tests; 3) 12-lead electrocardiogram (ECG); 4) Adverse events, serious adverse events, drug adverse reactions, suspected and unexpected serious adverse reactions.

2.11 Sample size

The sample size calculation of the study is based on the published data that mean ± SD of MoCA score change from baseline was 3.0 ± 4.5 after 3 months piracetam treatment for cute cerebral infarction [35]. We assume that mean ± SD of MoCA score change from baseline is 4.0 ± 4.5 after 3 months CPCGI treatment for TBI. Using the PASS11.0 application software, employing a one-tailed test with α = 0.025, β = 0.2 and a 2:1 sample ratio, we need to recruit 479 patients in experimental group and 240 in control group. Accounting for a 20 % dropout rate at each participating center, the sample size is expanded to 600:300 patients.

2.12 Data analysis

Statistical analysis will be performed after data collection is completed. A 2-tailed test will be implemented and a p value < 0.05 is considered to indicate statistical significance. SAS 9.4 (SAS Institute Inc., Cary, NC, USA) will be used for statistical analysis. Analysis of covariance (ANCOVA) model will be used to compare the change of MoCA score from baseline after 3 months of medication. A model taking group as fixed effect and baseline MoCA score as covariate will be used. According to the model, the least squares mean of the change in MoCA score from baseline to 3 months after treatment will be calculated for both groups, as well as the difference of the corrected mean between experimental group and control group and its 95 % confidence interval. The parameters of continuous variable include cases, means, standard deviation, median, minimum value and maximum value. The MMSE score, GCS score, Barthel index score and NIHSS score will be analyzed via the same statistical analysis method as MoCA score. The percentage of subjects in each grade of GOS-E will be calculated after treatment and 3 months after the intervention, and a single ordered CMH chi-square test will be employed to compare the difference between two groups.

It should be noted that the study included patients aged 18–75. To minimize bias, we will divide the age groups into 18–60 and 60–75 for data analysis.

2.13 Interim analysis

No interim analysis will be conducted.

2.14 Auditing

A series of quality control audits for the database will be conducted before the end of the trial.

3 Methodology

The study is designed based on published trials in treating TBI patients with CPCGI in China, demonstrating that administration of CPCGI has therapeutic effects and high safety [[29], [30], [31]]. However, effects of CPCGI on clinical TBI treatment is not confirmed worldwide, thus we limit our recruitment to patients who are classified as mild or medium TBI (9 ≤ GCS≤15), and with no need for surgery. To prevent adverse risks, all patients will be closely monitored for acute neurological degradation. In case neurological symptoms or other vital signs change for the worse during the trial, patients will receive an emergency head CT scanning and surgery if necessary, and such patients will be excluded from the trial instantly.

CPCGI and piracetam are considered to be generally very safe, with this in mind, we decide not to waive SAE for this trial protocol. On the occasion a patient experiences any suspected related side effects, he or she will be removed from the trial immediately. If CPCGI or piracetam-related side effects are confirmed, treatment will be terminated and affected patients will be followed up for 3 months.

4 Discussion

We hold the belief that this trial is of great necessity because strategies for cognition improvement of TBI are very limited. Edaravone is a free radical scavenger that can mitigate damage induced by oxidative stress, and the potential mechanism may be resulted from activation of the Nrf 2/ARE pathway [36,37]. Unfortunately, clinical research on edaravone is still sparse, and its overall safety and efficacy in TBI patients remain uncertain [37]. Attention deficit hyperactivity disorder agonists such as MPh are increasingly applied to improve cognitive dysfunction after TBI by addressing underlying neurotransmitter imbalances [[38], [39], [40]]. However, the benefits of MPh on executive function and the associated mechanisms have not been firmly evaluated in patients with TBI [41]. Combining repetitive transcranial magnetic stimulation (rTMS) and cerebrolysin is another novel option to improve cognitive function in TBI patients, but the universality, optimal dosage and treatment protocol of this method have not been identified [42].

CPCGI has been widely assessed in China for central nervous system (CNS) disease via experimental animal model and no adverse reaction has been discovered during the administration [25], [26], [43]. In clinical studies, it is demonstrated that CPCGI can significantly shorten the time of fracture healing and improve the curative effect of fracture healing [44]. Besides, application of CPCGI has also been tested in clinical therapy for TBI, Alzheimer's disease, cerebral infarction, and found to have positive effects on promote cognitive function [[28], [29], [30],45]. This trial is based on the above experience, and we aim to explore and summarize the significance of CPCGI profound enough for its application in clinical strategy for TBI.

This CPCGI treatment trial for TBI, to our knowledge, is the first clinical trial that taking another administration widely used as control group, as compared to previous trials focusing on different efficacy between CPCGI and blank control. Besides, due to the extensive distribution of participating medical centers throughout China, the scientific randomization and sample size calculation, we believe our conclusion that whether put CPCGI into clinical therapy for TBI is feasible and beneficial will be more convincing, and more conductive to promotion in China and even around the world.

Trial status

This trial began in November 2020, and is still conducted.

Ethics approval and consent to participate

The trial was approved by the Ethics Committee of Tianjin Medical University General Hospital (IRB2020-124-01). All the participants will provide written informed consent.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Funding

This work was supported by grants from the 10.13039/501100001809 National Natural Science Foundation of China (via Grant No. 82071390 to R Jiang).

CRediT authorship contribution statement

Tao Liu: Writing – review & editing, Visualization, Software, Project administration, Formal analysis, Data curation. Yunhu Yu: Writing – review & editing, Writing – original draft, Investigation, Formal analysis, Data curation. Liang Mi: Writing – original draft. Zhihao Zhao: Methodology. Mingqi Liu: Methodology. Jiao Wang: Formal analysis. Xin Wang: Investigation. Zhuang Sha: Data curation. Meng Nie: Investigation. Weiwei Jiang: Investigation. Chenrui Wu: Investigation. Jiangyuan Yuan: Investigation. Chuanxiang Lv: Methodology. Biao Zhao: Conceptualization. Kun Lin: Methodology. Zhanying Li: Methodology. Zhenyu Luo: Investigation. Xuanhui Liu: Investigation. Yu Qian: Investigation. Rongcai Jiang: Writing – review & editing, Validation, Supervision, Resources, Project administration, Funding acquisition, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

List of abbreviations

TBI traumatic brain injury

CPCGI Compound porcine cerebroside and ganglioside injection

MoCA Montreal Cognitive Assessment

MMSE Mini-Mental State Examination

GOS-E Glasgow Outcome Scale-Extended

GCS Glasgow Coma Scale

NIHSS National Institutes of Health Stroke Scale

MPh Methylphenidate

GMP good manufacturing practice

CFDA China Food and Drug Administration

ECG Electrocardiogram

ANCOVA Analysis of covariance

eCRF electronic Case Report Form

EDC Electronic Data Capture

SAEs Severe adverse drug reaction/events

rTMS repetitive transcranial magnetic stimulation

CNS central nervous system

Acknowledgements

We appreciate all the participating centers for their participation. In addition, we thank all the patients involved in the hospital for their valuable efforts in this trial.
==== Refs
References

1 Khellaf A. Khan D.Z. Helmy A. Recent advances in traumatic brain injury J. Neurol. 266 11 2019 2878 2889 10.1007/s00415-019-09541-4 31563989
2 Menon D.K. Maas A.I. Traumatic brain injury in 2014. Progress, failures and new approaches for TBI research Nat. Rev. Neurol. 11 2 2015 71 72 10.1038/nrneurol.2014.261 25582447
3 Dewan M.C. Rattani A. Gupta S. Baticulon R.E. Hung Y.C. Punchak M. Estimating the global incidence of traumatic brain injury J. Neurosurg. 130 4 2018 1080 1097 10.3171/2017.10.Jns17352 29701556
4 Norup A. Kruse M. Soendergaard P.L. Rasmussen K.W. Biering-Sørensen F. Socioeconomic consequences of traumatic brain injury: a Danish nationwide register-based study J. Neurotrauma 37 24 2020 2694 2702 10.1089/neu.2020.7064 32808586
5 Stuss D.T. Traumatic brain injury: relation to executive dysfunction and the frontal lobes Curr. Opin. Neurol. 24 6 2011 584 589 10.1097/WCO.0b013e32834c7eb9 21968550
6 Swick D. Honzel N. Larsen J. Ashley V. Justus T. Impaired response inhibition in veterans with post-traumatic stress disorder and mild traumatic brain injury J. Int. Neuropsychol. Soc. : JINS 18 5 2012 917 926 10.1017/s1355617712000458 22595028
7 Wammes J.D. Good T.J. Fernandes M.A. Autobiographical and episodic memory deficits in mild traumatic brain injury Brain Cognit. 111 2017 112 126 10.1016/j.bandc.2016.11.004 27886529
8 Wilson L. Horton L. Kunzmann K. Sahakian B.J. Newcombe V.F. Stamatakis E.A. Understanding the relationship between cognitive performance and function in daily life after traumatic brain injury J. Neurol. Neurosurg. Psychiatr. 2020 10.1136/jnnp-2020-324492
9 Liu M. Huang J. Liu T. Yuan J. Lv C. Sha Z. Exogenous interleukin 33 enhances the brain's lymphatic drainage and toxic protein clearance in acute traumatic brain injury mice Acta neuropathologica communications 11 1 2023 61 10.1186/s40478-023-01555-4 37024941
10 Shi M. Mi L. Li F. Li Y. Zhou Y. Chen F. Fluvoxamine confers neuroprotection via inhibiting infiltration of peripheral leukocytes and M1 polarization of microglia/macrophages in a mouse model of traumatic brain injury J. Neurotrauma 39 17–18 2022 1240 1261 10.1089/neu.2021.0355 35502478
11 Xiao Y. Zhang Y. Yuan W. Wang C. Ge Y. Huang T. Piezo 2 contributes to traumatic brain injury by activating the RhoA/ROCK1 pathways Mol. Neurobiol. 2024 10.1007/s12035-024-04058-y
12 Lv C. Han S. Sha Z. Liu M. Dong S. Zhang C. Cerebral glucagon-like peptide-1 receptor activation alleviates traumatic brain injury by glymphatic system regulation in mice CNS Neurosci. Ther. 29 12 2023 3876 3888 10.1111/cns.14308 37353947
13 Mi L. Min X. Shi M. Liu L. Zhang Y. Zhu Y. Neutrophil extracellular traps aggravate neuronal endoplasmic reticulum stress and apoptosis via TLR9 after traumatic brain injury Cell Death Dis. 14 6 2023 374 10.1038/s41419-023-05898-7 37365190
14 Liu T. Yu S. Liu M. Zhao Z. Yuan J. Sha Z. Cognitive impairment in Chinese traumatic brain injury patients: from challenge to future perspectives Front. Neurosci. 18 2024 10.3389/fnins.2024.1361832
15 Mohamed M.S. El Sayed I. Zaki A. Abdelmonem S. Assessment of the effect of amantadine in patients with traumatic brain injury: a meta-analysis J. Trauma Acute Care Surg. 92 3 2022 605 614 10.1097/ta.0000000000003363 34284464
16 Volkow N.D. Wang G.J. Fowler J.S. Logan J. Franceschi D. Maynard L. Relationship between blockade of dopamine transporters by oral methylphenidate and the increases in extracellular dopamine: therapeutic implications Synapse (New York, NY) 43 3 2002 181 187 10.1002/syn.10038
17 Wagner A.K. Drewencki L.L. Chen X. Santos F.R. Khan A.S. Harun R. Chronic methylphenidate treatment enhances striatal dopamine neurotransmission after experimental traumatic brain injury J. Neurochem. 108 4 2009 986 997 10.1111/j.1471-4159.2008.05840.x 19077052
18 Dorer C.L. Manktelow A.E. Allanson J. Sahakian B.J. Pickard J.D. Bateman A. Methylphenidate-mediated motor control network enhancement in patients with traumatic brain injury Brain Inj. 32 8 2018 1040 1049 10.1080/02699052.2018.1469166 29738277
19 Manktelow A.E. Menon D.K. Sahakian B.J. Stamatakis E.A. Working memory after traumatic brain injury: the neural basis of improved performance with methylphenidate Front. Behav. Neurosci. 11 2017 58 10.3389/fnbeh.2017.00058 28424597
20 Moreno-López L. Manktelow A.E. Sahakian B.J. Menon D.K. Stamatakis E.A. Anything goes? Regulation of the neural processes underlying response inhibition in TBI patients Eur. Neuropsychopharmacol : the journal of the European College of Neuropsychopharmacology 27 2 2017 159 169 10.1016/j.euroneuro.2016.12.002
21 Li J.S.Z. Shao G. Hui W. Clinical effect analysis of piracetam injection combined with mannitol in the treatment of cerebral edema after traumatic brain injury Modern Medicine and Health Research 7 1 2023 74 77 (in Chinese)
22 Xiu J.L.X. Chen G. Huang R. Tan Y. Clinical study of 20% piracetam injection to reduce intracranial pressure in patients with craniocerebral injury Chin J Clin Neurosurg 16 9 2011 553 554 (in Chinese)
23 Xie X.Y.Z. Zhai S. Qian W. Clinical Observation on breviscapine combined with piracetam on moderate head injury Journal of Hubei University of Chinese Medicine 24 2 2022 53 55 (in Chinese)
24 Chen X. Hua X. Sun D. Fan W. [Compound porcine cerebroside and ganglioside relieves brain injury and promotes expression of cerebellin 4 in neonatal mice with intrauterine hypoxia] Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 35 8 2019 721 726 31638570
25 Miao Y. Wang R. Wu H. Yang S. Qiu Y. CPCGI confers neuroprotection by enhancing blood circulation and neurological function in cerebral ischemia/reperfusion rats Mol. Med. Rep. 20 3 2019 2365 2372 10.3892/mmr.2019.10472 31322214
26 Wang M. Zhang Y. Feng L. Zheng J. Fan S. Liu J. Compound porcine cerebroside and ganglioside injection attenuates cerebral ischemia-reperfusion injury in rats by targeting multiple cellular processes Neuropsychiatric Dis. Treat. 13 2017 927 935 10.2147/NDT.S129522
27 Wang X. Zhao J. Neuroprotective effect of CPCGI on Alzheimer's disease and its mechanism Mol. Med. Rep. 21 1 2020 115 122 10.3892/mmr.2019.10835 31939621
28 Wang H.J.H. Li J. Clinical study of compound porcine cerebroside and ganglioside injection on alzheimer disease Chinese Community doctors. 12 2010 127 128 (in Chinese)
29 Feng J.L.P. Guo M. Zhong B. Study on the therapeutic effect of compound procine cerebroside and ganglioside injection on traumatic brain injury Shenzhen Journal of Integrated Traditional Chinese and Western Medicine 29 12 2019 108 109 (in Chinese)
30 Tan A.W.J. Wen J. Hu L. Bi X. Reevaluation of the safety of compound porcine cerebroside and ganglioside in the treatment of 3,884 patients with craniocerebral injury J Mol Diagn Ther 15 10 2023 1680 1684 (in Chinese)
31 Zhang X.D.H. Hua W. Xian S. Yang S. Yu A. Clinical trial of compound cerebropeptide and ganglioside in the treatment of acute brain injury and on the effect of serum neuron regeneration factor Chin J Clin Pharmacol. 36 5 2020 493 495+502 (in Chinese)
32 Liu T. Liu M. Sha Z. Wu C. Zhao Z. Yuan J. Chinese neurosurgical randomized controlled trials: dynamics in trial implementation and completion Neurosurgery 94 3 2024 497 507 10.1227/neu.0000000000002702 37796000
33 Zhu L.G.Y. Lin S. Pan L. A clinical trial on the effects of ruanmai Congsheng decoction on senile patients with vascular cognitive impairment no dementia belong to renal deficiency and deficiency syndrome Geriatrics & Health Care 26 2 2020 220 223 (in Chinese)
34 Ran Z. Ju B. Cao L. Hou Q. Wen L. Geng R. Microbiome-metabolomics analysis reveals the potential effect of verbascoside in alleviating cognitive impairment in db/db mice Food Funct. 14 8 2023 3488 3508 10.1039/d2fo03110h 37000613
35 Li X.L.X. Yuan L. Wang J. Lin L. Cao S. Effects of piracetam combined with citicoline on cognitive and neurological functions in patients with acute cerebral infarction Prog. Mod. Biomed. 20 6 2020 1142 1145 (in Chinese)
36 Wang H. Liu L. Zhou X. Guan Y. Li Y. Chen P. Efficacy and safety of short-term edaravone or nerve growth factor add-on therapy for alcohol-related brain damage: a multi-centre randomised control trial Addiction 119 4 2024 717 729 10.1111/add.16398 38049955
37 Ismail H. Shakkour Z. Tabet M. Abdelhady S. Kobaisi A. Abedi R. Traumatic brain injury: oxidative stress and novel anti-oxidants such as mitoquinone and edaravone Antioxidants 9 10 2020 10.3390/antiox9100943
38 Levin H. Troyanskaya M. Petrie J. Wilde E.A. Hunter J.V. Abildskov T.J. Methylphenidate treatment of cognitive dysfunction in adults after mild to moderate traumatic brain injury: rationale, efficacy, and neural mechanisms Front. Neurol. 10 2019 925 10.3389/fneur.2019.00925 31572283
39 Monti J.M. Voss M.W. Pence A. McAuley E. Kramer A.F. Cohen N.J. History of mild traumatic brain injury is associated with deficits in relational memory, reduced hippocampal volume, and less neural activity later in life Front. Aging Neurosci. 5 2013 41 10.3389/fnagi.2013.00041 23986698
40 Whyte J. Hart T. Vaccaro M. Grieb-Neff P. Risser A. Polansky M. Effects of methylphenidate on attention deficits after traumatic brain injury: a multidimensional, randomized, controlled trial Am. J. Phys. Med. Rehabil. 83 6 2004 401 420 10.1097/01.phm.0000128789.75375.d3 15166683
41 Peattie A.R.D. Manktelow A.E. Sahakian B.J. Menon D.K. Stamatakis E.A. Methylphenidate ameliorates behavioural and neurobiological deficits in executive function for patients with chronic traumatic brain injury J. Clin. Med. 13 3 2024 10.3390/jcm13030771
42 Verisezan Rosu O. Jemna N. Hapca E. Benedek I. Vadan I. Muresanu I. Cerebrolysin and repetitive transcranial magnetic stimulation (rTMS) in patients with traumatic brain injury: a three-arm randomized trial Front. Neurosci. 17 2023 1186751 10.3389/fnins.2023.1186751
43 Norup A. Kruse M. Soendergaard P.L. Rasmussen K.W. Biering-Sorensen F. Socioeconomic consequences of traumatic brain injury: a Danish nationwide register-based study J. Neurotrauma 37 24 2020 2694 2702 10.1089/neu.2020.7064 32808586
44 Zamfir A.D. Neurological analyses: focus on gangliosides and mass spectrometry Adv. Exp. Med. Biol. 806 2014 153 204 10.1007/978-3-319-06068-2_8 24952183
45 Gao Z.S.X. Wang L. Yue L. Observation on the clinical effect of compound porcine cerebroside and ganglioside injection in the treatment of cognitive impairment after cerebral infarction China Prac Med 13 10 2018 105 106 (in Chinese)
