Safety of Clonidine in Infants With Hypoxic Ischemic Encephalopathy During Therapeutic Hypothermia (HIE)

December 4, 2017 updated by: Johns Hopkins University

Phase I-II Clinical Trial to Determine the Safety of Clonidine in Infants With Hypoxic Ischemic Encephalopathy During Therapeutic Hypothermia

This research is being done to find out the safety of the investigational study drug, Clonidine Hydrochloride ( CLON). , in infants who are undergoing whole body cooling for the treatment of hypoxic ischemic encephalopathy (HIE). The only known and effective treatment for HIE is therapeutic hypothermia or whole body cooling for72 hours. During the cooling process, babies get agitated, shiver and are uncomfortable. To treat these side effects morphine is frequently used. CLON is very effective in decreasing shivering in adults and children. Furthermore, in some preclinical studies, clonidine has been shown to be neuroprotective (safe for the brain in models of brain injury)..This is a Phase I-II to determine if low dose CLON will reduce the incidence of shivering and whether it has short term cardiovascular safety. In this Phase I-II study, the investigators will determine the (i) the maximum tolerated dose of CLON during cooling for HIE, (ii) the effects of CLON on heart rate, blood pressure, core body temperature and cerebral autoregulation (ability to maintain constant blood flow to the brain) and (iii) association between blood levels and changes in the above parameters. In this study the investigators hope to find ways to improve sedation, shivering and agitation in newborn infants with HIE on the cooling protocol. Our ultimate goal is determine the potential neuro-protective properties of clonidine in newborn babies with HIE.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

The most desirable sedative-analgesic agent used in infants with HIE would 1) have an excellent safety profile, 2) provide adequate analgesia and sedation, 3) reduce shivering, 4) cause minimal respiratory depression, 5) preserve cerebrovascular autoregulation, and 6) confer neuroprotection. Several lines of evidence suggest alpha 2 adrenergic receptor agonist class of sedatives-analgesics may have all these properties. The investigators have recently developed a sensitive assay to measure clonidine levels which will allow us to perform population Pharmacokinetic (PK)/Pharmacodynamic (PD) analyses of clonidine in sick newborns. Thus, this phase I/II trial is designed to test the hypothesis clonidine , an alpha- 2 adrenergic receptor agonist, will reduce the incidence of shivering without adversely affecting heart rate (HR), blood pressure (BP), temperature regulation or cerebrovascular autoregulation.

Essentially all classes of sedative-analgesic agents affect mean arterial blood pressure (MAP) which can alter cerebral perfusion and affect cerebrovascular autoregulation. Cerebrovascular autoregulation is when blood flow to the brain is held relatively constant over a wide range of MAPs; it ensures a steady supply of oxygenated blood to the brain, and is only functional within a specific range of MAP's. When MAP deviates from this range and drops below the lower limit of autoregulation, blood flow becomes passive to MAP and the brain is placed at risk for ischemic injury. Brain injury alters cerebrovascular autoregulation in the region of injury, and together with sub-optimal MAP after hypoxic brain injury could cause more brain ischemia leading to poor outcomes, seizures, and permanent neurologic injuries. Little information is available on the effect of HIE alone or in combination with hypothermia on cerebrovascular autoregulation, and no information is published on the direct effect of sedative-analgesics on alterations in hemodynamic parameters and subsequent indirect or direct effects on cerebrovascular autoregulation in newborns with HIE. Thus, this study will establish the safety of clonidine, a commonly used sedative-analgesic in infants and children, in a population of infants with HIE undergoing therapeutic hypothermia. A secondary exploratory outcome is to determine the efficacy of clonidine in reducing shivering during the cooling phase of the therapeutic hypothermia protocol.

Study Type

Interventional

Enrollment (Actual)

13

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Baltimore, Maryland, United States, 21287
        • Johns Hopkins Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

8 months to 6 months (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Infants ≥35 0/7 weeks gestation with the diagnosis of HIE who are being treated with therapeutic hypothermia, who have indwelling arterial lines
  • Informed parental consent

Exclusion Criteria:

  • Infants who are considered moribund and the clinical team is considering withdrawal of support
  • Infants who need > 20 µg/kg/min of dopamine or the addition of epinephrine or dobutamine to maintain a mean arterial pressure (MAP) ≥ 45 mmHg, or milrinone for cardiovascular support
  • Baseline heart rate (HR) <80 bpm during hypothermia
  • Infants suspected of major chromosomal anomalies, except trisomy 21
  • Infants with major cardiovascular anomalies
  • Infants with severe persistent pulmonary hypertension of the newborn who are enrolled and who then need Extracorporal Membrane Oxygenation (ECMO) will be withdrawn from the study

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Clonidine infants with HIE
Infants in this group will receive Intravenous clonidine at 1µg/kg/dose either every 6 or 8 hrs from the start of cooling to the end of re-warming
Drug: Clonidine (Duraclon®)

Clonidine at dosing intervals of 6, 8, 12, 18 or 24 hours. If the following is observed the event will be recorded, and no additional clonidine will be given and blood will be drawn to measure plasma level of clondine.

  • 10 mm Hg reduction in MAP or MAP ≤ 40 mm Hg sustained for ≥30 min after administration
  • 20% drop in HR from the infant's baseline, sustained for ≥30 min after administration
  • HR ≤70/min, sustained for ≥30 min after administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Steady State Clonidine Blood Levels During Hypothermia
Time Frame: 3 days

Trough clonidine blood levels were measured after 4-7 doses of clonidine were given intravenously with a dosing interval of every 8 hrs. Mean and standard deviation (SD) of the number of doses given prior to levels being drawn was 5.3 (mean) and 0.37 (SD).

Time after last dose before measurement was 9hrs (mean) and 2.7hrs (SD).
3 days
Amount of Morphine Given
Time Frame: Up to 2 days
Intravenous morphine (mg/kg) was given. The standard dose is 0.05 mg/kg per dose
Up to 2 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Presence of Shivering After Clonidine
Time Frame: 48hrs
Babies were assessed after administration of clonidine for the presence or absence of shivering.
48hrs
Time to Passive Rewarming
Time Frame: Beginning at 72 hours up to 12 hours
Following 2 hours of therapeutic hypothermia, the temperature of the thermo-blanket is adjusted up half degree per hour allowing passive rewarming until 36.5 degrees is reached
Beginning at 72 hours up to 12 hours

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Johns Hopkins University

Collaborators

University of Maryland

Investigators

  • Principal Investigator: Estelle B Gauda, MD, Johns Hopkins University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 3, 2013

Primary Completion (Actual)

April 14, 2015

Study Completion (Actual)

April 14, 2015

Study Registration Dates

First Submitted

April 1, 2013

First Submitted That Met QC Criteria

May 23, 2013

First Posted (Estimate)

May 24, 2013

Study Record Updates

Last Update Posted (Actual)

January 5, 2018

Last Update Submitted That Met QC Criteria

December 4, 2017

Last Verified

December 1, 2017

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ID: NA_00072308

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Encephalopathy, Hypoxic-Ischemic

Clinical Trials on Clonidine (Duraclon®)

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Cote d'Ivoire

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe