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

Condition(s) targeted: Hypoxic Ischemic Encephalopathy (HIE)

Intervention: Clonidine (Drug); Clonidine (Drug)

Phase: Phase 1

Status: Recruiting

Sponsored by: Gauda, Estelle B., M.D.

Official(s) and/or principal investigator(s):
Estelle B Gauda, MD, Principal Investigator, Affiliation: Johns Hopkins Medical Institution

Overall contact:
Estelle B Gauda, MD, Phone: 410-614-0151, Email: egauda@jhmi.edu

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.

Official title: Phase I Clinical Trial to Determine the Safety of Clonidine in Infants With Hypoxic Ischemic Encephalopathy During Therapeutic Hypothermia.

Study design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Cardiovascular parameters

Secondary outcome:

Shivering and cerebrovascular autoregulation

Clonidine Serum levels during the cooling

Detailed 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.

Minimum age: N/A. Maximum age: 36 Hours. Gender(s): Both.

Criteria:

Inclusion Criteria:

- 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 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 ECMO will be withdrawn from the study

Estelle B Gauda, MD, Phone: 410-614-0151, Email: egauda@jhmi.edu

Johns Hopkins Hospital, Baltimore, Maryland 21287, United States; Recruiting
Estelle B Gauda, MD, Phone: 410-614-0151, Email: egauda@jhmi.edu
Tarrah N Ezell, Phone: 410-614-0151, Email: Tezell1@jhmi.edu
Estelle B Gauda, MD, Principal Investigator

Starting date: March 2014
Last updated: September 29, 2014