The primary objective of this study is to evaluate the short term safety and tolerability, and pharmacokinetic properties of 2-IB when administered to adult patients after OHCA. Secondary objectives include safety and efficacy parameters at 30 days…
ID
Source
Brief title
Condition
- Cardiac arrhythmias
- Encephalopathies
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main study parameters used for evaluating the short term safety and
tolerability will be vital signs ((heart frequency and blood pressure) before
and until 15 minutes after administration of the study drug and the need for
intervention), biochemistry and haematology taken as part of the clinical
protocol, and the occurrence of (Serious) Adverse Events ((S)AEs) until a
maximum of 7 days on the ICU or until discharge from the ICU, whichever occurs
earlier.
For evaluation of the pharmacokinetics profile of 2-IB six plasma samples will
be taken and analysed. Pharmacokinetic parameters to be determined will include
Cmax, AUC, Tmax, t1/2, clearance (Cl), and volume of distribution (Vd).
Secondary outcome
Secondary parameters that will be evaluated:
1. Short term efficacy as determined by biochemical markers NSE and s100b at
24h and 48h after OHCA.
2. Longer term safety as determined by the occurrence of SAEs until 30 days
after OHCA including death.
3. Longer term efficacy as determined by the Cerebral Performance Category
(CPC) and IQCODE at 30 days after OHCA or alternatively the Adult Lifestyles
and Function Interview (ALFI) scale (by telephone).
Background summary
Following successful cardiopulmonary resuscitation (CPR) after out of hospital
cardiac arrest (OHCA), 50% of the patients admitted to the Intensive Care Unit
(ICU) die. Since most patients die due to brain damage sustained during cardiac
arrest and the subsequent reperfusion phase, effective neuroprotective
strategies could potentially improve neurological outcome. In animal
experiments, 2-iminobiotin (2-IB), a selective neuronal and inducible nitric
oxide synthase (NOS) inhibitor, given upon reperfusion has been shown to
improve memory function in a four vessel occlusion model in rats. Since 2-IB
has not shown any safety issues in preclinical and clinical studies, this drug
may be an effective strategy for reducing neurological damage after cardiac
arrest. Before embarking on large studies with efficacy as a primary endpoint
in this population, safety, tolerability and pharmacokinetics of this
treatment need to be established in an exploratory Phase II study.
Study objective
The primary objective of this study is to evaluate the short term safety and
tolerability, and pharmacokinetic properties of 2-IB when administered to adult
patients after OHCA.
Secondary objectives include safety and efficacy parameters at 30 days after
OHCA.
Study design
A Phase 2 open-label, dose-escalation intervention study.
Intervention
The first cohort of eight patients will receive 2-IB in a dose of 0,055
mg/kg/dose every 4 h iv, 6 times (part A). In part B the second cohort of eight
patients will receive a dose based on the kidney function assessed with the
estimated glomerular filtration rate (eGFR). In both treatment groups no safety
issues occured. In part C of the study the third group of eight patients will
be treated with a three times increased dosage (compared to group B) based on
the kidney function. With this step the safety and pharmacokinetics can be
investigate optimally.
The DSMB has approved to move to the next dose level.
Study burden and risks
We consider the risk for the patients in this study as moderate (matig risico).
No toxicity has been demonstrated in preclinical studies and no adverse
reactions that could be attributed to 2-IB have been shown in a Phase I study
in adult humans and a Phase II pilot safety study in newborns with perinatal
asphyxia.
Based on this, using the NFU classification, the risk could be classified as
negligible. Since the patient population is very vulnerable, however, we
increased the risk classification to "moderate" (matig risico).
The extra burden of participation is limited, since most assessments done are
part of standard clinical care. All patients will receive 2-IB using an
existing intravenous catheter (central of peripheral) and will receive 6 doses.
Additional blood samples for Pk will be taken using existing lines. Cognitive
functioning will be assessed 30 days after hospitalisation.
The three dose levels to be given in this study are derived from effective dose
levels in animal models that were neuroprotective after hypoxia-ischemia, both
in newborn and in adult animals. In order to investigate whether 2-IB will also
have a neuroprotective effect in adult patients after OHCA, clinical studies
need to be performed. At present it is unknown whether these doses will also
have a positive effect in human adults after OHCA.
Meibergdreef 9
Amsterdam 1105 AZ
NL
Meibergdreef 9
Amsterdam 1105 AZ
NL
Listed location countries
Age
Inclusion criteria
* Admission to the ICU after OHCA and successful CPR due to a cardiac cause
* Duration of resuscitation no longer than 30 minutes
* Shockable rhythm as presenting rhythm
* Post anoxic coma on admission
* Ability to start study medication within 6 hours after cardiac arrest
* Age 18 years or older
* Eligible for treatment with a target temperature management of 36° C
Exclusion criteria
* No informed consent
* Known co-morbidity with a life expectancy of <6 months prior to cardiac arrest
* Women aged 49 or less
* Severe cognitive impairment (documented dementia) known prior to OHCA
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-003902-17-NL |
| ClinicalTrials.gov | NCT02836340 |
| CCMO | NL54915.018.15 |