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

Study Overview
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Brief Summary
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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
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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: Formal written consent from patient relatives. 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. 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. The patients of the study will be randomly allocated into three groups.

Official Title
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The Impact and Outcomes of Combined Cerebrolysin and Amantadine Sulfate Administration on Management of Patients With Traumatic Brain Injury in the ICU

Conditions
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Traumatic Brain Injury

Intervention / Treatment
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* Drug: Cerebrolysin
* Drug: amantadine sulfate


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: standard of care<br>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 | |
| Experimental: standard of care + Cerebrolysin<br>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. | Drug: Cerebrolysin<br>* Cerebrolysin, a mixture of free amino acids and low molecular weight peptides, has a neurotrophic factor-like activity with immediate pleiotropic neuroprotective activity and long-term multimodal effects on endogenous post-lesional regulation. Cerebrolysin has been suggested to exert beneficial effects on neurobehavioural functions, cognitive performance , and neuro-motor recovery , as part of initial therapy in severe and moderate acute TBI.<br>|
| Experimental: standard of care + Cerebrolysin + Amantadine sulfate<br>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. | Drug: Cerebrolysin<br>* Cerebrolysin, a mixture of free amino acids and low molecular weight peptides, has a neurotrophic factor-like activity with immediate pleiotropic neuroprotective activity and long-term multimodal effects on endogenous post-lesional regulation. Cerebrolysin has been suggested to exert beneficial effects on neurobehavioural functions, cognitive performance , and neuro-motor recovery , as part of initial therapy in severe and moderate acute TBI.<br>Drug: amantadine sulfate<br>* The dopaminergic agonist amantadine enhances presynaptic dopamine release and inhibits dopamine reuptake, resulting in an increased amount of dopamine in the synaptic cleft. Amantadine may also increase the density of postsynaptic dopamine receptors and alter the conformation of these receptors. Amantadine acts as an NMDA receptor antagonist, blocking glutamate, an NMDA channel activator. This effect may be responsible for amantadine's possible beneficial effect soon after TBI<br>* Other names: PK-MERZ;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Glasgow Coma Scale (GCS) | The Glasgow Coma Scale (GCS) is used to assess the level of consciousness. It depends on the best motor, verbal and eye opening responses. GCS is used to classify insult severity as minor [GCS 13-15], moderate [GCS 9-12] and severe [GCS 3-8]. | 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. | 
| Disability rating-scale for severe head trauma (DRS) | Disability rating-scale for severe head trauma (DRS) includes measures of arousability, awareness and responsivity of eye opening, verbalization, and motor response; cognitive ability of for Self Care Activities: understanding of feeding, dressing, and grooming; degree of assistance and supervision required; and employability. Scores range from 0 to 29, with higher values indicating greater disability. | DRS score will be collected at baseline and weekly through week 6 (during 4 weeks of treatment and 2 weeks after discontinuation). | 
| Coma Recovery Scale-Revised (CRS-R) | Coma Recovery Scale-Revised (CRS-R) is a standardized neurobehavioral assessment tool comprising six organized subscales (i.e., auditory, visual, motor, oro-motor,verbal, communication, and arousal); scores range from 0 to 23, with higher scores indicating a higher level of neurobehavioral function. | CRS-R will be compared over the 4 weeks of treatment and during 2-weeks after discontinuation of treatment | 
| The Glasgow Outcome Scale (GOS) | The Glasgow Outcome Scale (GOS) is one of the most widely used outcome instruments to assess global disability and recovery after traumatic brain injury. Patients in all groups will be assessed with The Glasgow Outcome Scale (GOS) on the end of 6th week which classify patients into: dead, vegetative state, severe disability, moderate disability and good recovery. | atients in all groups will be assessed with The Glasgow Outcome Scale (GOS) on the end of 6th week. |