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Copenhagen Head Injury Ciclosporin (CHIC) Study (CHIC)

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ClinicalTrials.gov Identifier: NCT01825044
Recruitment Status : Completed
First Posted : April 5, 2013
Last Update Posted : October 4, 2017
Sponsor:
Information provided by (Responsible Party):
Abliva AB ( NeuroVive Pharmaceutical AB )

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.

Condition or disease Intervention/treatment Phase
Traumatic Brain Injury Drug: NeuroSTAT 5 mg/kg/day Drug: NeuroSTAT 10 mg/kg/day Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 16 participants
Allocation: Non-Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : April 2013
Actual Primary Completion Date : September 21, 2017
Actual Study Completion Date : September 21, 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: NeuroSTAT 5 mg/kg/day
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
Intravenous bolus of NeuroSTAT (Ciclosporin) 2.5 mg/kg bodyweight followed by 5 days of 5 mg/kg bodyweight/day continuous infusion
Other Name: Ciclosporin 5 mg/kg/day

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




Primary Outcome Measures :
  1. Non-compartmental analysis of pharmacokinetics (PK) of Ciclosporin in whole blood [ Time Frame: Prespecified timepoints during 8 days (PK) ]
    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.

  2. Incidence of adverse events [ Time Frame: 38 days ]

    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.


Secondary Outcome Measures :
  1. Ciclosporin levels in cerebrospinal fluid (CSF) [ Time Frame: Prespecified timepoints during 8 days ]
    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

  2. Safety biomarkers for nephrotoxicity [ Time Frame: Measured at prespecified timepoints during 8 days ]
    Kidney Injury Molecule (KIM)-1, creatinine and Cystatin-C in urine samples


Other Outcome Measures:
  1. Electroencephalography (EEG). [ Time Frame: During 8 days ]
    The background pattern will be interpreted and analysed by an EEG program. The aim is to find evidence if EEG analyses could be used to predict clinical outcome.

  2. Biomarkers of brain injury in brain tissue [ Time Frame: Measured at prespecified timepoints during 8 days ]
    Microdialysis in the most and least traumatised side pre-treatment and every second hour until the end of day 8

  3. Brain tissue oxygen [ Time Frame: During 8 days ]
    Continuously (every 5th second) measured directly using an indwelling probe.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

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:

    1. Serum creatinine ≥ 1.5 x upper limit of normal (ULN).
    2. 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.
    3. Major rhabdomyolysis with serum creatine kinase > 5,000 IU/L.
    4. Renal injury resulting in loss of a kidney (either due to direct trauma or ischaemia).
    5. Vascular injury with renal ischaemia likely to cause an episode of acute renal failure.
    6. 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01825044


Locations
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Denmark
Dept. of Neurosurgery, Rigshospitalet, University of Copenhagen
Copenhagen, Denmark, 2100
Sponsors and Collaborators
NeuroVive Pharmaceutical AB
Investigators
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Principal Investigator: Jesper Kelsen, MD., PhD Dept. of Neurosurgery, Rigshospitalet, Copenhagen, Denmark
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Responsible Party: NeuroVive Pharmaceutical AB
ClinicalTrials.gov Identifier: NCT01825044    
Other Study ID Numbers: 2012.001
2012-000756-34 ( EudraCT Number )
First Posted: April 5, 2013    Key Record Dates
Last Update Posted: October 4, 2017
Last Verified: October 2017
Keywords provided by Abliva AB ( NeuroVive Pharmaceutical AB ):
Traumatic Brain Injury
TBI
ciclosporin
pharmacokinetic
safety
microdialysis
mitochondrial protection
Additional relevant MeSH terms:
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Brain Injuries
Brain Injuries, Traumatic
Wounds and Injuries
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Craniocerebral Trauma
Trauma, Nervous System
Cyclosporine
Cyclosporins
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents
Dermatologic Agents
Antirheumatic Agents
Calcineurin Inhibitors