Copenhagen Head Injury Ciclosporin (CHIC) Study

NCT01825044 | Completed Phase 2 DMC

• 2 other identifiers: 2012.0012012-000756-34
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Traumatic Brain Injury

Keywords

Traumatic Brain Injury; TBI; ciclosporin; pharmacokinetic; safety; microdialysis; mitochondrial protection

Outcome Measures

Primary Outcomes (2)

• 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: 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.

  38 days

Secondary Outcomes (2)

• Ciclosporin levels in cerebrospinal fluid (CSF)

  Prespecified timepoints during 8 days

• Safety biomarkers for nephrotoxicity

  Measured at prespecified timepoints during 8 days

Other Outcomes (3)

• Electroencephalography (EEG).

  During 8 days

• Biomarkers of brain injury in brain tissue

  Measured at prespecified timepoints during 8 days

• Brain tissue oxygen

  During 8 days

Study Arms (2)

NeuroSTAT 5 mg/kg/day

ACTIVE COMPARATOR

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

NeuroSTAT 10 mg/kg/day

ACTIVE COMPARATOR

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

Interventions

NeuroSTAT 5 mg/kg/day DRUG

Intravenous bolus of NeuroSTAT (Ciclosporin) 2.5 mg/kg bodyweight followed by 5 days of 5 mg/kg bodyweight/day continuous infusion

Also known as: Ciclosporin 5 mg/kg/day

NeuroSTAT 5 mg/kg/day

NeuroSTAT 10 mg/kg/day DRUG

Intravenous bolus of NeuroSTAT (Ciclosporin) 2.5 mg/kg bodyweight followed by 5 days of 10 mg/kg bodyweight/day continuous infusion

Also known as: Ciclosporin 10 mg/kg/day

NeuroSTAT 10 mg/kg/day

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• NeuroVive Pharmaceutical AB: lead

Study Sites (1)

Dept. of Neurosurgery, Rigshospitalet, University of Copenhagen

Copenhagen, 2100, Denmark

Location

Related Publications (1)

• Hansson MJ, Elmer E. Cyclosporine as Therapy for Traumatic Brain Injury. Neurotherapeutics. 2023 Oct;20(6):1482-1495. doi: 10.1007/s13311-023-01414-z. Epub 2023 Aug 10.

  PMID: 37561274 DERIVED

MeSH Terms

Conditions

Brain Injuries, Traumatic

Interventions

Cyclosporine

Condition Hierarchy (Ancestors)

Brain Injuries; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Wounds and Injuries

Intervention Hierarchy (Ancestors)

Cyclosporins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins

Study Officials

• Jesper Kelsen, MD., PhD

  Dept. of Neurosurgery, Rigshospitalet, Copenhagen, Denmark

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 20, 2013
• First Posted: April 5, 2013
• Study Start: April 1, 2013
• Primary Completion: September 21, 2017
• Study Completion: September 21, 2017
• Last Updated: October 4, 2017

Record last verified: 2017-10

Locations

DK (1)