Safety of Clonidine in Infants With Hypoxic Ischemic Encephalopathy During Therapeutic Hypothermia

Condition(s) targeted: Encephalopathy, Hypoxic-Ischemic

Intervention: Clonidine (Duraclon®) (Drug)

Phase: Phase 1/Phase 2

Status: Not yet recruiting

Sponsored by: Estelle B. Gauda, MD

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

Overall contact:
Tarrah N Ezell, Phone: 410.614.0151, Email: Tezell1@jhmi.edu

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.

Official title: Phase I-II 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:

Maximum-tolerated dose of clonidine

Clonidine Plasma levels

Secondary outcome:

Time to onset of shivering after clonidine

shivering

Detailed 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.

Minimum age: 35 Weeks. Maximum age: 42 Weeks. Gender(s): Both.

Criteria:

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

Tarrah N Ezell, Phone: 410.614.0151, Email: Tezell1@jhmi.edu

Johns Hopkins Hospital, Baltimore, Maryland 21287, United States; Recruiting
Tarrah N Ezell, Phone: 410-614-0151, Email: Tezell1@jhmi.edu
Estelle B Gauda, MD, Phone: 410.614.0151, Email: egauda1@jhmi.edu

Related publications:

Agthe AG, Kim GR, Mathias KB, Hendrix CW, Chavez-Valdez R, Jansson L, Lewis TR, Yaster M, Gauda EB. Clonidine as an adjunct therapy to opioids for neonatal abstinence syndrome: a randomized, controlled trial. Pediatrics. 2009 May;123(5):e849-56. doi: 10.1542/peds.2008-0978. Epub 2009 Apr 27.

Angeles DM, Wycliffe N, Michelson D, Holshouser BA, Deming DD, Pearce WJ, Sowers LC, Ashwal S. Use of opioids in asphyxiated term neonates: effects on neuroimaging and clinical outcome. Pediatr Res. 2005 Jun;57(6):873-8. Epub 2005 Mar 17.

Róka A, Melinda KT, Vásárhelyi B, Machay T, Azzopardi D, Szabó M. Elevated morphine concentrations in neonates treated with morphine and prolonged hypothermia for hypoxic ischemic encephalopathy. Pediatrics. 2008 Apr;121(4):e844-9. doi: 10.1542/peds.2007-1987.

Zhang Y. Clonidine preconditioning decreases infarct size and improves neurological outcome from transient forebrain ischemia in the rat. Neuroscience. 2004;125(3):625-31.

Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, Fanaroff AA, Poole WK, Wright LL, Higgins RD, Finer NN, Carlo WA, Duara S, Oh W, Cotten CM, Stevenson DK, Stoll BJ, Lemons JA, Guillet R, Jobe AH; National Institute of Child Health and Human Development Neonatal Research Network. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005 Oct 13;353(15):1574-84.

Starting date: July 2013
Last updated: May 23, 2013