SHINKEI-TBI

SHINKEI-TBI

A Phase 2, multicenter, double-blind, randomized, placebo controlled, study to assess the safety of amantadine hydrochloride intravenous (IV) solution (MR-301), 50 mg/mL, in patients with severe traumatic brain injury (TBI).

Name of sponsor: SHINKEI Therapeutics

Study centers: Approximately 15 clinical sites in the US

Study population: Approximately 45 patients will be randomized 2:1 to study drug (MR-301 or placebo infusion) to achieve a sample size of 30 patients in the treatment group and 15 in the placebo group

Objectives: To assess the safety and tolerability of MR-301 in improving rate of recovery in patients with severe non-penetrating TBI

Inclusion Criteria 

1. Age 18 to 75 years  
2. Initial neuroimaging consistent with the diagnosis of acute, non-penetrating, traumatic brain injury (Normal CT, consistent with Marshall 1, is not exclusionary).
3. Closed head trauma between 72 hours to 1 week prior to randomization
4. No significant polytrauma that would interfere with ongoing outcome assessments or follow-up. This would include injuries that, at the discretion of the investigator may necessitate ongoing surgical management, prolonged sedation, or mechanical ventilation
5. Admitted to an acute care setting no less than 2 days prior to randomization.
6. Glasgow Coma Score of 3 to 8
7. Unable to consistently follow commands or engage in functional communication
8. At least one reactive pupil
9. LAR able to provide consent
10. Stable for a minimum of 24 hours prior to randomization on vitals (SBP>90 mmHg and PaO2>60 mmHg. 

Exclusion Criteria 

1. Life expectancy of less than 24 hours
2. Spinal cord injury
3. Penetrating head injury
4. Bilaterally fixed dilated pupils
5. History of any medical or psychiatric disorder, or any severe concomitant disease that would, in the opinion of the Investigator, interfere with clinical assessment
6. History of poorly controlled seizure more than one per month prior to enrollment
7. Prior history of status epilepticus
8. Patient has a sensitivity or has had prior treatment with at least 5 doses of amantadine HCl or amantadine prior to randomization or patient is receiving IP within 24 hours of having received amantadine.
9. Screening lab measurements outside the normal range. This will include, but is not limited to: 
   • Absolute neutrophil count (ANC): ≤ 1.5 x 10⁹/L 
   • Hemoglobin ≤ 7 g/dL or active bleeding requiring ongoing transfusion 
   • Platelets ≤ 80 x 10⁹/L or active bleeding requiring ongoing transfusion 
   • ALT, AST, ALP or total bilirubin ≥ 2x the upper limit of normal
   • eGFR < 60. 
10. Treatment with an investigational drug, CNS stimulant or dopamine antagonist/agonist within 4 weeks prior to screening
11. History of NYHA Class 3 or Class 4 Congestive Heart Failure within the last 5 years 
12. Females who are nursing, pregnant, or planning to become pregnant while in the study and for 4 weeks after the last dose of study medication
13. Any other clinically significant medical condition as determined by the Investigator, that may unfavorably alter the risk-benefit of study participation, adversely affect study compliance, or confound interpretation of study results
14. QT syndrome in familial history or history of prolonged QT interval (Bazette QTc>420 ms) or discernible U waves or congenital
15. Chronic treatment with a systemic anticholinergic medication within 1 week prior to screening 

Primary endpoint: Safety and tolerability will be compared between active treatment and placebo groups as measured by frequency, severity, and type of drug-related adverse events and serious adverse events between treatment and placebo groups

Secondary endpoints:

• Change from baseline in Glasgow Outcome Scale-Extended (GOS-E) (Evaluated at D21 and D35)
• Change from baseline in DRS scale (Evaluated at D5, D10, D15 and D21)
• Change from baseline in Coma Recovery Scale – Revised (CRS-R) (Evaluated at D5, D10, D15 and D21)
• Change from baseline in Full Outline of UnResponsiveness (FOUR) score (Evaluated every day up to D21)
• Time to intensive care unit (ICU) discharge to hospital floor
• Time to hospital discharge
• Mortality assessment at end of treatment period (D21)
• Mortality assessment at end of study period (D35)

Investigational product, dosage and mode of administration:

MR-301 will be administered at 100 mg IV infusion as the starting dose and escalated to 200 mg IV infusion as maintenance dose.

• On first day, patient will receive MR-301 at 100 mg/3-hr intravenous infusion BID
• On second day, the dose is elevated to 150 mg/3-hr intravenous infusion BID
• On third day, the dose is further elevated to 200 mg/3-hr intravenous infusion BID and maintained up to Week 3

Upon completion of therapy, patients will be down-titrated to 100 mg BID on first day, 100 mg AM on second day and discontinue from third day onwards.