This trial is active, not recruiting.

Condition encephalopathy, hypoxic-ischemic
Treatment clonidine (duraclon®)
Phase phase 1/phase 2
Sponsor Estelle B. Gauda, MD
Collaborator University of Maryland
Start date July 2013
End date July 2015
Trial size 13 participants
Trial identifier NCT01862250, HIE-CLON_2012


This research is being done to find out the safety of the investigational study drug,clonidine, in infants who are undergoing whole body cooling for the treatment of hypoxic ischemic encephalopathy (HIE). HIE is the damage that occurs to the cells of the central nervous system (brain and spinal cord) as a result of decreased oxygen supply and blood flow to the fetus due to perinatal asphyxia (inadequate oxygen to the baby during the birth process). HIE is a significant cause of morbidity and mortality in infants. 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 sedative-analgesic medications like morphine are frequently used. Clonidine (Clon), which is another class of sedative-analgesic can be used for the similar purpose but is more effective than morphine 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). Clon (Duraclon®) has been approved by the Food and Drug Administration (FDA)for the treatment of pain in certain cancer patients. It is not approved for treating side effects of therapeutic hypothermia in infants and its use in this study is considered investigational. FDA is allowing for us to use clonidine for this Phase I-II study. In this kind of study clonidine will be started at low dose and slowly increased do determine at what dose the shivering is controlled and the use of clonidine is not associated with any side effects. This means that not all babies in the study will get the same dose of Clon. Doses at the beginning of the study will be lower than doses at the end of the study. Because of the design of the study, some babies may get doses that are too low to have an effect, and other babies will probably might get a doses that could cause side effects. In this Phase I-II study, the investigators will determine the (i) the maximum tolerated dose of clonidine during cooling for HIE, (ii) the effects of clonidine on heart rate, blood pressure, core body temperature and cerebral autoregulation (ability to maintain constant blood flow in the face of blood pressure changes) 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.

United States No locations recruiting
Other countries No locations recruiting

Study Design

Endpoint classification safety/efficacy study
Intervention model single group assignment
Masking open label
Primary purpose treatment
Starting dose of clonidine will be 1µg/kg/dose. The dosing intervals can range from every 4, 6, 8 or 12 hours. The following dose-escalation schema will be employed to define the max tolerated dose. A minimum of 3 infants will be treated at each dosing interval. If no Dose Limiting Toxicity (DLT) is observed among the infants treated at a given dosing interval, then the interval will be shortened. If 1/3 of the infants has a DLT at a given dose then an additional 3 infants will be treated at that interval. If ≥ 2 infants have a DLT at a given interval then the interval will be increased to the previous longer interval. The maximal tolerable dose (MTD) will be defined as the dose level immediately below max administered dose at which 2 or more infants have a DLT. Six infants will be treated at the MTD.
clonidine (duraclon®)
Clonidine at dosing intervals that may be every 4, 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

Primary Outcomes

Maximum-tolerated dose of clonidine
time frame: 6 Day
Clonidine Plasma levels
time frame: 6 days

Secondary Outcomes

Time to onset of shivering after clonidine
time frame: 48hrs
time frame: 36 hrs

Eligibility Criteria

Male or female participants from 35 weeks up to 42 weeks old.

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

Additional Information

Official title Phase I-II Clinical Trial to Determine the Safety of Clonidine in Infants With Hypoxic Ischemic Encephalopathy During Therapeutic Hypothermia
Principal investigator Estelle B Gauda, MD
Description 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 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 [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.
Trial information was received from ClinicalTrials.gov and was last updated in October 2016.
Information provided to ClinicalTrials.gov by Johns Hopkins University.