Copenhagen Head Injury Ciclosporin (CHIC) Study

Study Overview
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Brief Summary
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This is an open label study on the pharmacokinetics and safety of ciclosporin in patients with severe traumatic brain injury, who require intensive care unit admission and monitoring of intracranial pressure via a ventricular catheter. 20 patients will be screened, and subsequently enrolled after clinical stabilisation. Thereafter, patients will receive 2.5 mg/kg bolus dose infusion of ciclosporin, followed by either 5 mg/kg/day or 10 mg/kg/day of ciclosporin as continuous infusion for 5 days+3 days monitoring at the intensive care unit. After an additional 30 days, a follow-up phone call will be made to the patient, or the patient's nursing staff, checking patient status and serious adverse events. The two dose levels will be investigated in 10 patients each, starting with the lower dose level for the first 10 patients. Patients will have samples of blood and cerebrospinal fluid drawn at pre-defined time points during the study for pharmacokinetic assessment and evaluation of biomarkers. Bedside monitoring with microdialysis and brain tissue oxygenation will be performed. The safety monitoring includes nephrotoxicity, hepatotoxicity, monitoring of intracranial pressure (ICP), infections monitoring and adverse events collection and reporting.

Official Title
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An Open-label, Uncontrolled Phase II-study to Investigate Pharmacokinetics, Safety and Biomarkers of Effectiveness of NeuroSTAT® (Ciclosporin) in Patients With Severe Traumatic Brain Injury (TBI)

Conditions
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Traumatic Brain Injury

Intervention / Treatment
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* Drug: NeuroSTAT 5 mg/kg/day
* Drug: NeuroSTAT 10 mg/kg/day


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients, age between 18 and 75 years, inclusive. Requirement for Intensive Care Unit (ICU) admission and clinical indication for External Ventricular Drainage (EVD) and Intracranial Pressure (ICP) monitoring. Evidence of non-penetrating severe TBI, confirmed by history and abnormalities consistent with a non-penetrating trauma on computerised tomography (CT) scan upon admission. Clinical examination with post-resuscitation Glasgow Coma Scale (GCS) of 4-8, inclusive. Hemodynamically stable after resuscitation (systolic blood pressure (SBP) >100 mm Hg). 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. Exclusion Criteria: Bilaterally fixed dilated pupils. Penetrating traumatic brain injury. Spinal cord injury. Pure epidural haematoma. Currently developed, known or a medical history of renal disorder, significant renal failure, or high risk renal failure, defined as: Serum creatinine ≥ 1.5 x upper limit of normal (ULN). Pre-existing chronic renal failure with estimated glomerular filtration rate (eGFR)< 60 ml/min/1.73m2 estimated by the simplified Modification of Diet in Renal Disease (MDRD) Study formula. Major rhabdomyolysis with serum creatine kinase > 5,000 IU/L. Renal injury resulting in loss of a kidney (either due to direct trauma or ischaemia). Vascular injury with renal ischaemia likely to cause an episode of acute renal failure. Any history of renal replacement therapy. Known or a medical history of hepatic disease. Prolonged and/or uncorrectable hypoxia, as judged by the investigator (PaO< 60 mmHg) or hypotension (SBP< 90 mmHg) upon admission. Suspected or confirmed pregnancy (positive urine sample,followed by confirmational serum human chorionic gonadotropin (HCG) pregnancy test). Immunosuppression due to drugs (for ex. ciclosporin) or disease (e.g. human immunodeficiency virus (HIV), malignancy). Known or a medical history of serious chronic viral or fungal infection. Known or a medical history of active mycobacterial infection or antituberculous treatment. Known or a medical history of any allergic reactions and/or anaphylactic reactions towards ciclosporin, egg, peanuts or soya-bean proteins. 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. Participation in other clinical trials. 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Treatment
Allocation: Non-Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: NeuroSTAT 5 mg/kg/day<br>Intravenous bolus of NeuroSTAT (Ciclosporin) 2.5 mg/kg bodyweight followed by 5 days of 5 mg/kg bodyweight/day continuous infusion | Drug: NeuroSTAT 5 mg/kg/day<br>* Intravenous bolus of NeuroSTAT (Ciclosporin) 2.5 mg/kg bodyweight followed by 5 days of 5 mg/kg bodyweight/day continuous infusion<br>* Other names: Ciclosporin 5 mg/kg/day;|
| Active Comparator: NeuroSTAT 10 mg/kg/day<br>Intravenous bolus of NeuroSTAT (Ciclosporin) 2.5 mg/kg bodyweight followed by 5 days of 10 mg/kg bodyweight/day continuous infusion | Drug: NeuroSTAT 10 mg/kg/day<br>* Intravenous bolus of NeuroSTAT (Ciclosporin) 2.5 mg/kg bodyweight followed by 5 days of 10 mg/kg bodyweight/day continuous infusion<br>* Other names: Ciclosporin 10 mg/kg/day;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Non-compartmental analysis of pharmacokinetics (PK) of Ciclosporin in whole blood | Peak Plasma Concentration (Cmax) of Ciclosporin and Area under the blood concentration versus time curve (AUC) of Ciclosporin. This will characterise the pharmacokinetic profile of the two chosen dosing regimens of ciclosporin in severe Traumatic Brain Injury (TBI) patients. | Prespecified timepoints during 8 days (PK) | 
| Incidence of adverse events | Including: Ciclosporin levels in whole blood. Markers of nephrotoxicity: plasma creatinine plasma Cystatin-C and blood urea nitrogen. Markers of hepatotoxicity: prothrombin time (PT), aspartate transaminase (AST), alanine transaminase (ALT) and bilirubin. Intracranial Pressure (ICP) Assessment of infections: according to standard procedures at intensive care unit. | 38 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ciclosporin levels in cerebrospinal fluid (CSF) | The CSF samples will be drawn from the EVD-catheter at the same time points as in blood to document central nervous system penetration of ciclosporin | Prespecified timepoints during 8 days | 
| Safety biomarkers for nephrotoxicity | Kidney Injury Molecule (KIM)-1, creatinine and Cystatin-C in urine samples | Measured at prespecified timepoints during 8 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Traumatic Brain Injury, TBI, ciclosporin, pharmacokinetic, safety, microdialysis, mitochondrial protection