Phase I Clinical Trial to Determine the Safety of Clonidine in Infants With HIE During Therapeutic Hypothermia.

  • STATUS
    Recruiting
  • participants needed
    55
  • sponsor
    Gauda, Estelle B., M.D.
Updated on 8 November 2020

Summary

Hypoxic ischemic encephalopathy (HIE) occurs in ~ 2-4/1000 term infants and is a major cause of neonatal morbidity and mortality. To date, therapeutic hypothermia started within 6 h of birth is the only intervention known to be effective in reducing the morbidity and mortality of HIE. Hypothermia does not totally reverse the injury in many infants and is associated with side effects that may compromise its effectiveness. Low dose morphine is often used to reduce shivering in infants undergoing therapeutic hypothermia, but escalating doses of sedatives/analgesics are often required. Escalating doses of opioids and benzodiazepines causes respiratory depression and can either cause the need for or prolong mechanical ventilation.Agonists to the central a2 - adrenergic receptors are more effective at reducing postoperative shivering than opioid receptor agonists and provide analgesia and sedation without respiratory depression. The most desirable sedative-analgesic agent used in infants with HIE would: (a) have an excellent safety profile, (b) reduce shivering, (c) provide adequate analgesia and sedation, (d) cause minimal respiratory depression, (e) preserve cerebrovascular autoregulation, and (f) confer neuroprotection.

Description

Hypoxic ischemic encephalopathy (HIE) occurs in ~ 2-4/1000 term infants and is a major cause of neonatal morbidity and mortality. Resulting neurologic deficits include disabling cerebral palsy and abnormalities of speech, vision and intellect in 50-70% of surviving infants. To date, therapeutic hypothermia started within 6 h of birth is the only intervention known to be effective in reducing the morbidity and mortality of HIE. Hypothermia does not totally reverse the injury in many infants and is associated with side effects that may compromise its effectiveness. For example, hypothermia can cause intense shivering which blocks the neuroprotective effect of therapeutic hypothermia in newborn models. Low dose morphine is often used to reduce shivering in infants undergoing therapeutic hypothermia, but escalating doses of sedatives/analgesics are often required. Escalating doses of opioids and benzodiazepines causes respiratory depression and can either cause the need for or prolong mechanical ventilation. Agonists to the central a2 - adrenergic receptors are more effective at reducing postoperative shivering than opioid receptor agonists and provide analgesia and sedation without respiratory depression. More importantly, in newborn and adult animal models of brain injury, a2 - adrenergic receptor agonists provide neuroprotection. Clonidine is an a-2 adrenergic receptor agonist that is broadly used (off-label) for several disorders in infants and children. It is not known which class of sedative-analgesic agents are the most beneficial infants with HIE. Little is known about how immaturity, end organ damage and therapeutic hypothermia affect the pharmacokinetics and pharmacodynamics (PK/PD) of sedatives-analgesics. The most desirable sedative-analgesic agent used in infants with HIE would: (a) have an excellent safety profile, (b) reduce shivering, (c) provide adequate analgesia and sedation, (d) cause minimal respiratory depression, (e) preserve cerebrovascular autoregulation, and (f) confer neuroprotection. Several lines of evidence suggest that the a2-adrenergic receptor agonist class of sedatives-analgesics may have all these properties. We have developed a sensitive assay to measure clonidine plasma levels that will allow us to characterize the population PK/PD parameters of clonidine in these high risk infants. We have the tools, expertise and patient population to conduct a phase I/II trial to test the hypotheses that clonidine is safe and will reduce the incidence of shivering without adversely affecting heart rate, blood pressure, temperature regulation or cerebrovascular autoregulation. Data from this trial will inform the study design of a larger randomized-double-blind trial to determine if clonidine as an adjunct to therapeutic hypothermia will improve neurological outcomes in this high risk population.

Details
Condition Hypoxic Brain Damage
Treatment clonidine
Clinical Study IdentifierNCT02252848
SponsorGauda, Estelle B., M.D.
Last Modified on8 November 2020

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age less than or equal to 1 yrs?
Gender: Male or Female
Do you have Hypoxic Brain Damage?
Infants 35 0/7 weeks gestation with the diagnosis of HIE who meet the criteria and are treated with therapeutic hypothermia
Informed parental consent

Exclusion Criteria

Infants who are considered moribund and the clinical team is considering withdrawal of support
Infants who need > 20 g/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 ECMO will be withdrawn from the study
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