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

Phase 1/Phase 2
35 Weeks
42 Weeks
Not Enrolling
Encephalopathy, Hypoxic-Ischemic

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Trial Information

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

Hypoxic ischemic encephalopathy (HIE) or birth asphyxia occurs in ~ 2-4/1000 term infants
and is a significant cause of neonatal morbidity and mortality. Morbidity includes cerebral
palsy and abnormalities of speech, vision and intellect in 50-70% of surviving infants. In
both animal and humans mild hypothermia provides protection against ischemia brain damage.
Hypothermia is the only therapeutic intervention known to be effective in reducing the
morbidity and mortality associated with HIE. However even mild hypothermia triggers strong
thermoregulatory defenses, such as shivering which is associated with a stress response.
Failure to block shivering obviates the neuroprotective properties of hypothermia.
Furthermore, newborns who have HIE are often mechanically ventilated, and thus, are often
treated with analgesic-sedatives to reduce the stress response, provide anxiolysis,
facilitate ventilatory support, and optimize pain control. Currently, there is a
significant gap in knowledge and lack of evidence as to what class of sedative-analgesic
agents may be most beneficial for this group of infants who are already at extremely high
risk for poor neurological outcome. Furthermore, essentially nothing is known about how
immaturity, end organ damage and therapeutic hypothermia affect the pharmacokinetics and
pharmacodynamics (PK/PD) of sedatives-analgesics. While some sedative-analgesics and
anesthetics, including opiates, are known to induce apoptosis in the brain, other classes of
sedatives-analgesics may have neuroprotective properties especially in the setting of brain
injury in newborn models. 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 PK/PD analyses of clonidine in sick newborns. Thus,
this phase I/II trial is designed to test the hypothesis clonidine clonidine, an α-2
adrenergic receptor agonist, will reduce the incidence of shivering without adversely
affecting heart rate (HR), blood pressure (BP), temperature regulation or cerebrovascular

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 [4], 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.

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

Type of Study:


Study Design:

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

Outcome Measure:

Maximum-tolerated dose of clonidine

Outcome Description:

In Cohort 1 we will determine the maximum-tolerated dose (MTD) of clonidine and secondarily, explore the efficacy of clonidine for reducing shivering in infants who are undergoing therapeutic hypothermia for treatment of HIE. In Cohort 2 we will characterize population PK/PD of clonidine using non-linear mixed effects analysis to estimate the exposure-response relationship of clonidine on changes in cardiovascular parameters (heart rate and blood pressure), core body temperature, and cerebrovascular autoregulation during the cooling and rewarming phases of therapeutic hypothermia.

Outcome Time Frame:

6 Day

Safety Issue:


Principal Investigator

Estelle B Gauda, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Johns Hopkins Medical Institutions


United States: Food and Drug Administration

Study ID:




Start Date:

July 2013

Completion Date:

July 2015

Related Keywords:

  • Encephalopathy, Hypoxic-Ischemic
  • Brain Ischemia
  • Hypothermia
  • Ischemia
  • Brain Damage, Chronic
  • Delirium
  • Encephalitis
  • Hepatic Encephalopathy
  • Neurotoxicity Syndromes
  • Hypoxia-Ischemia, Brain
  • Hypoxia, Brain



Johns Hopkins Hospital Baltimore, Maryland  21287