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

Hypoxic Ischemic Encephalopathy (HIE) Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02252848
• Other study ID #: NA_00072308
• Status: Recruiting
• Phase: Phase 1
• First received: September 25, 2014
• Last updated: September 4, 2015
• Start date: March 2014
• Est. completion date: August 2016

Study information

• Verified date: September 2015
• Source: Gauda, Estelle B., M.D.
• Contact: Estelle B Gauda, MD
• Phone: 410-614-0151
• Email: egauda[@]jhmi.edu
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 55
• Est. completion date: August 2016
• Est. primary completion date: March 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 36 Hours

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

• Brain Diseases
• Brain Ischemia
• Hypothermia
• Hypoxia-Ischemia, Brain
• Hypoxic Ischemic Encephalopathy (HIE)

Intervention

Drug:
• Clonidine
Determining 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
• Clonidine
Characterizing 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.

Locations

Country	Name	City	State
United States	Johns Hopkins Hospital	Baltimore	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
Gauda, Estelle B., M.D.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cardiovascular parameters	Measuring changes in BP, HR and CBT within 30 minutes after each clonidine administration	3 days	Yes
Secondary	Shivering and cerebrovascular autoregulation	Pharmacodynamic of clonidine on physiological parameters: shivering and cerebrovascular autoregulation. Observe the progression of shivering in infants who are being cooled and treated with IV clondine (no shivering, moderate localized shivering and shivering involving the gross movements upper and lower extremities)	6 days	No
Secondary	Clonidine Serum levels during the cooling	Pharmacokinetic of clonidine during the cooling and re-warming phase. Intervals measured are 0 hr,4 hr, 8 hr, 12 hr, 24 hr, 48 hr, 72 hr and 96 hr on the cooling protocol	72 hours	No