Clinical trial NCT06052787: Combined Cerebrolysin and Amantadine Sulfate Administration for Patients With Traumatic Brain Injury in the ICU
Official title: The Impact and Outcomes of Combined Cerebrolysin and Amantadine Sulfate Administration on Management of Patients With Traumatic Brain Injury in the ICU
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Traumatic Brain Injury
Lead sponsor: Ain Shams University
Sponsor class: OTHER
First posted: 2023-09-25
Enrollment: 150
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

Brief summary: 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.

Detailed 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.

Eligibility criteria: 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).

Primary outcomes:
measure: The Glasgow Coma Scale (GCS)
timeFrame: Glasgow coma scale (GCS) will be recorded on admission, and every week up to 6 weeks of trauma to detect the improvement in level of consciousness after management in all groups.
measure: Disability rating-scale for severe head trauma (DRS)
timeFrame: DRS score will be collected at baseline and weekly through week 6 (during 4 weeks of treatment and 2 weeks after discontinuation).
measure: Coma Recovery Scale-Revised (CRS-R)
timeFrame: CRS-R will be compared over the 4 weeks of treatment and during 2-weeks after discontinuation of treatment
measure: The Glasgow Outcome Scale (GOS)
timeFrame: atients in all groups will be assessed with The Glasgow Outcome Scale (GOS) on the end of 6th week.
Secondary outcomes:
Other outcomes:
Locations:
city: Cairo
country: Egypt
facility: Faculty of medicine - Ain shams university
Study officials:
affiliation: faculty of medicine - Ain shams university
name: Ragab D Elshabasy
role: PRINCIPAL_INVESTIGATOR
References:
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