TIBOHCA: Safety, Tolerability and Pharmacokinetics of 2-Iminobiotin (2-IB) After OHCA

NCT02836340 | Terminated Phase 1 DMC

• 1 other identifier: AMC-TIBOHCA
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

Brief Summary

Following successful cardiopulmonary resuscitation (CPR) after out of hospital cardiac arrest (OHCA), 50% of patients admitted to the Intensive Care Unit (ICU) die. As most patients die due to brain damage sustained during cardiac arrest and the subsequent reperfusion phase, effective neuroprotective strategies could potentially improve 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. Since 2-IB has not shown any safety issues in preclinical and clinical studies. Before embarking on large studies with efficacy as primary endpoint, safety, tolerability and pharmacokinetics need to be established. Objective: Evaluate short term safety and tolerability, and the pharmacokinetic properties of 2-IB in adult patients after OHCA. Study design: Phase 2, single-centre, open-label, dose-escalation intervention study. Study population: Three cohorts of eight evaluable patients admitted to the ICU after OHCA due to a cardiac cause. Intervention: The first eight patients will receive 0,055 mg/kg 2-IB every 4 hours intravenously, 6 times in total (part A). The second eight patients (cohort B) will receive 0,165 mg/kg every 4h iv, 6 times in total. The third eight patients (cohort C) will receive 0,5 mg/kg every 4h iv, 6 times in total. Medication has to be given as soon as possible and within 6h after OHCA. Escalation to the next dose level will only be done after pharmacokinetic analyses have performed, no relevant safety issues have been encountered, and the DSMB approves to move to the next dose level. Main study parameters/endpoints: Study parameters to evaluate short term safety and tolerability will be vital signs (heart frequency, blood pressure, cardiac ischemia) before and until 15 minutes after administration. (Serious) Adverse Events will be recorded on the ICU (up to 7 days) or until discharge from the ICU. For evaluation of the pharmacokinetics profile of 2-IB, 9 plasma samples will be analysed. Secondary parameters: Biochemical markers Neuron specific Enolase and s100b at 24h and 48h after start of study drug, occurrence of SAEs until 30 days after OHCA including death, long term term efficacy as determined by the Cerebral Performance Category (CPC), the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) or the Telephone Interview Cognitive Status (TICS) scale at 30 days after OHCA.

Conditions

Cardiac Arrest; Hypoxic Ischemic Brain Injury

Keywords

neuroprotection

Outcome Measures

Primary Outcomes (1)

• Number of patients with treatment related adverse events

  Safety assessed as changes in heart frequency, blood pressure, cardiac ischemia (ST changes) during administration of study drug and 15 minutes thereafter and any interventions needed to maintain stability. Feasibility will be assessed by investigating whether treatment can be initiated succesfully within 6 hours after CPR.

  7 days

Secondary Outcomes (3)

• Cerebral Performance Category

  30 days

• Plasma levels of 2-IB

  24hours

• IQ-Code

  30 days

Study Arms (1)

2-Iminobiotin

EXPERIMENTAL

Increasing dosage of study drug

Drug: 2-Iminobiotin

Interventions

2-Iminobiotin DRUG

The Investigational Medicinal Product (IMP) under study is 2-IB, which is a biotin (Vitamin H or B7) analogue and a selective inhibitor of neuronal and inducible nitric oxide synthase (NOS).

2-Iminobiotin

Eligibility Criteria

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

You may qualify if:

• Admission to the ICU after OHCA and successful CPR due to a cardiac cause
• Post anoxic coma on admission
• Ability to start study medication as soon as possible, but ultimately within 6h after OHCA via a central venous line
• Age 18 years or older
• Eligible for treatment with a target temperature management of 36⁰ C

You may not qualify if:

• 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
• Inability to insert a central venous line

Sponsors & Collaborators

• Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA): lead

Study Sites (1)

Academic Medical Center, Intensive Care

Amsterdam, Netherlands

Location

MeSH Terms

Conditions

Heart Arrest; Hypoxia-Ischemia, Brain

Interventions

2-iminobiotin

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Brain Ischemia; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hypoxia, Brain; Vascular Diseases; Hypoxia; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Janneke Horn, MD, PhD

  Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: June 1, 2016
• First Posted: July 19, 2016
• Study Start: May 1, 2016
• Primary Completion: December 1, 2019
• Study Completion: April 1, 2020
• Last Updated: February 18, 2021

Record last verified: 2021-02

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)