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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Encephalopathy, Hypoxic-Ischemic

Intervention / Treatment
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* Drug: Clonidine (Duraclon®)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 35 Weeks
Maximum Age: 42 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Clonidine infants with HIE<br>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®)<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Steady State Clonidine Blood Levels During Hypothermia | 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 | 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 |
| --- | --- | --- |
| Time to Passive Rewarming | 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 | 
| Presence of Shivering After Clonidine | Babies were assessed after administration of clonidine for the presence or absence of shivering. | 48hrs |