Combined Cerebrolysin and Amantadine Sulfate Administration for Patients With Traumatic Brain Injury in the ICU

Ain Shams University

Status and phase: Enrolling; Phase 3

Conditions: Traumatic Brain Injury

Treatments: Drug: Cerebrolysin; Drug: amantadine sulfate

Study type: Interventional

Funder types: Other

Identifiers

NCT06052787

pharmacotherapy in TBI in ICU

Details and patient eligibility

About

The goal of this interventional study is to Measure the potential benefits of combined administration of cerebrolysin and amantadine sulfate as an add-on therapy to the standard management of patients admitted to the ICU with traumatic brain injury.

Full description

Sixty-nine million individuals worldwide are estimated to sustain a TBI each year. The proportion of TBIs resulting from road traffic collisions was greatest in Africa and Southeast Asia (both 56%) and lowest in North America (25%).

Head injury remains the leading cause of death and severe disability in young adults, and it is also the most important single injury contributing to traumatic mortality and morbidity.

Traumatic brain injury (TBI) is a non-degenerative, non-congenital insult to the brain from an external mechanical force, possibly leading to permanent or temporary impairment of cognitive, physical, and psychosocial functions, with an associated diminished or altered state of consciousness.

There is growing evidence that medications may speed recovery by enhancing some neurological functions without impacting others. Pharmacotherapy is increasingly being used in both the sub-acute (less than 1 month post-TBI) and chronic (more than 1 month post-TBI) phases.

Amantadine is known to enhance neurotransmission, through the activation of dopamine-dependent brain circuits, and increases dopamine activity in pre-synapses and post- synapses, acting as an antagonist of the N-methyl D-aspartate receptor.

A study done on 184 patients of severe traumatic brain injury found better οutϲοme in the treatment group with amantadine sulfate as compared with the plaϲeƅο group over the 4-week treatment interval, and they demonstrated that amantadine improved recovery in patients with moderate and severe TBI.

Giaϲinο et al. used amantadine in 184 patients for 4 to 16 weeks after TBI, They found that Amantadine accelerated the pace of functional recovery during active treatment in patients with post-traumatic disorders of consciousness.

Cerebrolysin is a peptide preparation produced by a biotechnological process, a standardized enzymatic breakdown of purified, lipid-free brain proteins, a pharmacological agent with neuro-restorative and neuro-protective effects. It stimulates neuronal survival and differentiation, axonal growth and sprouting, the formation of new synapses, and neurogenesis in the dentate gyrus.

El Sayed et al. published a meta-analysis of the effect of different neuroprotective drugs in management of patients with traumatic brain injury resulting in substantial superiority of the cerebrolysin that was reflected in three-fold cognitive improvement and favorable Glasgow outcome score.

In a prospective, randomized, double-blind, placebo-controlled, parallel-group, multi-center phase IIIb/IV trial, the CAPTAIN I trial registered beneficial effects of Cerebrolysin after moderate to severe TBI.

The CAPTAIN II trial, enrolled 142 patients with moderate to severe TBI in a single-center, prospective, randomized, double-blind, placebo-controlled clinical trial confirms the benefits of Cerebrolysin in moderate to severe TBI.

In their retrospective case -control study, Lee et al., identified that an amantadine-plus-cerebrolysin regimen was shown to additively affect the conscious state of patients with prolonged disturbed consciousness secondary to acute brain injury, especially in patients who remained in a prolonged vegetative state.

• Type of the Study: a single-center, prospective, randomized, double-blinded (Patients, healthcare providers, data collectors, and outcome assessors are blinded to treatment allocation), and phase III clinical trial.
• Study setting: The study will be conducted at Ain Shams university hospitals.
• Study period: The study will be conducted over 18-24 months.
• Study population: patients admitted to the ICU with traumatic brain injury who are eligible according to the inclusion and exclusion criteria.

sample size : 150 patients in three groups , 50 patients in each group.

Study procedures:

All selected patients fulfilling the inclusion criteria will be subjected to the following on admission:

1. Formal written consent from patient relatives.
2. Clinical data of all patients will be recorded in the admission sheets of ICU, these data includes: Demographic characteristics, etiology of trauma ,GCS ,vital signs (mean arterial blood pressure (MAP), heart rate, oxygen saturation) ,electrocardiogram (ECG), Pupil (size, reactivity and if symmetrical or not) and any other body trauma as bone fractures, chest trauma ,etc.
3. The imaging findings: CT will be done to all patients on admission to ICU to detect the basal pathological lesions as brain edema, hemorrhagic contusions, extradural hemorrhage, and subdural hemorrhage.
4. The patients of the study will be randomly allocated into three groups.

Enrollment: 150 estimated patients

Sex: All

Ages: 18 to 70 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Age between 18 and 70 years.
• Clinical diagnosis of head injury with moderate to severe TBI and a Glasgow coma scale (GCS) score of 7-12 at the time of hospital admission.
• Pre-hospital intubation/sedation/paralysis was accepted if the GCS score had been assessed before intubation/sedation/paralysis by trained staff.

Exclusion criteria

• History of intracranial interventions as well as ischemic or hemorrhagic stroke.
• Any neurological or non-neurological condition independent from TBI that might influence the functional outcome or other efficacy outcome measures.
• Clear clinical signs of intoxication influencing the evaluation, in the investigator's judgment.
• Patients with penetrating brain injury.
• Pregnancy or lactation.
• Patient with sever renal impairment (creatinine clearance > 30 ml/ minute).

Trial design

Primary purpose: Supportive Care

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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150 participants in 3 patient groups

standard of care

No Intervention group

Description:

patients receiving the standard protocol of management of head injury in the ICU including * Ventilatory support, sedation and analgesia. * Hemodynamic support. * Hyperosmolar therapy. * Early post traumatic seizure prophylaxis. * Nutritional support: will try to start enteral feeds as soon as possible or total parenteral * nutrition will be used in the case of enteral feeding intolerance. * Temperature management: to maintain normothermia * Glycemic control: to maintain a glucose level of \[140 -180 mg/dl\] * Peptic ulcer prophylaxis: * Deep venous thrombosis (DVT) prophylaxis

standard of care + Cerebrolysin

Experimental group

Description:

patients receiving the standard protocol of management of head injury in the ICU plus 2 cycles of Cerebrolysin , each cycle 10 days, for total 20 days. From day 1 to day 10: cerebrolysin 50 ml once daily diluted in 250 ml normal saline intravenous infusion over 15 minutes. From day 21-30 : cerebrolysin 20 ml once daily diluted in 250 ml normal saline intravenous infusion over 15 minutes.

Treatment:

Drug: Cerebrolysin

standard of care + Cerebrolysin + Amantadine sulfate

Experimental group

Description:

patients receiving the standard protocol of management of head injury in the ICU plus amantadine sulfate at a dose of 100 mg twice daily on the day after randomization, with this dose will be continued for 14 days. The dose will be increased to 150 mg twice daily at week 3 and to 200 mg twice daily at week 4 (total 4 weeks), combined with 2 cycles of Cerebrolysin , each cycle 10 days, for total 20 days. From day 1 to day 10: cerebrolysin 50 ml once daily diluted in 250 ml normal saline intravenous infusion over 15 minutes. From day 21-30 : cerebrolysin 20 ml once daily diluted in 250 ml normal saline intravenous infusion over 15 minutes.

Treatment:

Drug: amantadine sulfate

Drug: Cerebrolysin