Severe Traumatic Brain Injury
Conditions
Interventions
Product Name: NeuroSTAT
Pharmaceutical Form: Emulsion for infusion
INN or Proposed INN: ciclosporin
CAS Number: 59865-13-3
Other descriptive name: cyclosporine, cyclosporin A
Concentration unit: mg/ml
Sponsors
NeuroVive Pharmaceutical AB
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male or female patients, age between 18 and 75 years, inclusive. 2. Requirement for Intensive Care Unit (ICU) admission and clinical indication for External Ventricular Drainage (EVD) and Intracranial Pressure (ICP) monitoring. 3. Evidence of non-penetrating severe TBI, confirmed by history and abnormalities consistent with a non-penetrating trauma on computerised tomography (CT) scan upon admission. 4. Clinical examination with post-resuscitation Glasgow Coma Scale (GCS) of 4-8, inclusive. 5. Hemodynamically stable after resuscitation (systolic blood pressure (SBP) >100 mm Hg). 6. Informed consent for participation waived: obtained by two independent physicians and subsequently, the patient’s Legally Acceptable Representative (LAR) and General Practitioner (GP). If GP is unavailable, the Danish Health and Medicines Authority can give consent together with the LAR. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 14 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 6
Exclusion criteria
Exclusion criteria: 1. Bilaterally fixed dilated pupils. 2. Penetrating traumatic brain injury. 3. Spinal cord injury. 4. Pure epidural haematoma. 5. Currently developed, known or a medical history of renal disorder, significant renal failure, or high risk renal failure, defined as: a. Serum creatinine = 1.5 x upper limit of normal (ULN). b. Pre-existing chronic renal failure with estimated glomerular filtration rate (eGFR) 5,000 IU/L. d. Renal injury resulting in loss of a kidney (either due to direct trauma or ischaemia). e. Vascular injury with renal ischaemia likely to cause an episode of acute renal failure. f. Any history of renal replacement therapy. 6. Known or a medical history of hepatic disease. 7. Prolonged and/or uncorrectable hypoxia, as judged by the investigator (PaO< 60 mmHg) or hypotension (SBP< 90 mmHg) upon admission. 8. Suspected or confirmed pregnancy (positive urine sample, followed by confirmational serum human chorionic gonadotropin (HCG) pregnancy test). 9. Immunosuppression due to drugs (for ex. ciclosporin) or disease (e.g. human immunodeficiency virus (HIV), malignancy). 10. Known or a medical history of serious chronic viral or fungal infection. 11. Known or a medical history of active mycobacterial infection or antituberculous treatment. 12. Known or a medical history of any allergic reactions and/or anaphylactic reactions towards ciclosporin, egg, peanuts or soya-bean proteins. 13. Ongoing preinjury therapy with any of these drugs: rosuvastatin, tacrolimus, Hypericum perforatum (St.John´s Wort; a herbal dietary supplement), stiripentol, aliskiren, bosentan, diltiazem, verapamil and antiepileptics. 14. Participation in other clinical trials. 15. Any significant disease or disorder including abnormal laboratory tests which, in the opinion of the investigator, may either put the patient at risk because of participation in the study, or may influence the results of the study.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To establish safety and to characterise the pharmacokinetic profile of two dosing regimens of ciclosporin in severe Traumatic Brain Injury (TBI) patients. ;Secondary Objective: •To gain preliminary insight into the risk of over - or underdosing of specified dosing schedules in patients with severe traumatic brain injury. In patients where it is possible: •To study the effect of ciclosporin on the secondary cascade of biochemical events after a brain injury, defined as changes in microdialysis biochemistry and mitochondrial dysfunction and further clinical deterioration of the injury. ;Primary end point(s): • Non-compartmental analysis (NCA) of pharmacokinetics of ciclosporin in whole blood. • Safety parameters and adverse events, including: 1. Ciclosporin levels in whole blood. 2. Markers of nephrotoxicity: plasma creatinine, plasma Cystatin-C and blood urea nitrogen. 3. Markers of hepatotoxicity: prothrombin time (PT), aspartate transaminase (AST), alanine transaminase (ALT) and bilirubin. 4. Intracranial Pressure (ICP) 5. Assessment of infections: according to standard procedures at intensive care unit. ;Timepoint(s) of evaluation of this end point: At database lock N#1, when data has been obtained from 10 evaluable patients on first dosing step, then consecutively at the final database lock, when data has been obtained for additonal 10 evaluable patients on the second dosing step. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Ciclosporin levels in cerebrospinal fluid (CSF). • Safety biomarkers for nephrotoxicity: Kidney Injury Molecule (KIM)-1, creatinine and Cystatin-C in urine samples. The following only if available: • Biomarkers of brain injury in brain tissue, measured using microdialysis in the most and least traumatised side. • Brain tissue oxygen (BrTiO2) measured directly using probe. • Biomarkers of brain injury in CsA and/or blood, if possible The below explorative endpoint will be reported separately: • Electroencephalography (EEG). ;Timepoint(s) of evaluation of this end point: -The secondary endpoint: Biomarkers of brain injury in brain tissue, measured using microdialysis, will be included, and the data accessible at database lock N=#1 (after 10 patients in the first dosing Group). These data will not be part of the IDSMB interimanalysis assessment. Also, these data (from the 10 patients) will not be evaluated until after the final database lock: (after 20 patients; after both dosing groups). -All secondary endpoints will be evaluated at the final database lock , when results have been obtained from 20 evaulable patients. -For the secondary exploratory endpoint this will be reported separately, after the final database lock. | — |
Countries
Denmark
Contacts
Public ContactDep. Clinical Trials & Reg. Affairs
NeuroVive Pharmaceutical AB
Outcome results
None listed