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

NCT01862250 | Completed Phase 1 Results DMC

• 1 other identifier: ID: NA_00072308
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 1

Brief Summary

This research is being done to find out the safety of the investigational study drug, Clonidine Hydrochloride ( CLON). , in infants who are undergoing whole body cooling for the treatment of hypoxic ischemic encephalopathy (HIE). 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 morphine is frequently used. CLON is very effective 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)..This is a Phase I-II to determine if low dose CLON will reduce the incidence of shivering and whether it has short term cardiovascular safety. In this Phase I-II study, the investigators will determine the (i) the maximum tolerated dose of CLON during cooling for HIE, (ii) the effects of CLON on heart rate, blood pressure, core body temperature and cerebral autoregulation (ability to maintain constant blood flow to the brain) 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.

Conditions

Encephalopathy, Hypoxic-Ischemic

Outcome Measures

Primary Outcomes (2)

• Steady State Clonidine Blood Levels During Hypothermia

  Trough clonidine blood levels were measured after 4-7 doses of clonidine were given intravenously with a dosing interval of every 8 hrs. Mean and standard deviation (SD) of the number of doses given prior to levels being drawn was 5.3 (mean) and 0.37 (SD). Time after last dose before measurement was 9hrs (mean) and 2.7hrs (SD).

  3 days

• Amount of Morphine Given

  Intravenous morphine (mg/kg) was given. The standard dose is 0.05 mg/kg per dose

  Up to 2 days

Secondary Outcomes (2)

• Presence of Shivering After Clonidine

  48hrs

• Time to Passive Rewarming

  Beginning at 72 hours up to 12 hours

Study Arms (1)

Clonidine infants with HIE

EXPERIMENTAL

Infants in this group will receive Intravenous clonidine at 1µg/kg/dose either every 6 or 8 hrs from the start of cooling to the end of re-warming

Drug: Clonidine (Duraclon®)

Interventions

Clonidine (Duraclon®) DRUG

Clonidine at dosing intervals of 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

Clonidine infants with HIE

Eligibility Criteria

• Age: 35 Weeks - 42 Weeks
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Johns Hopkins University: lead
• University of Maryland: collaborator

Study Sites (1)

Johns Hopkins Hospital

Baltimore, Maryland, 21287, United States

Location

Related Publications (5)

• 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.

  PMID: 19398463 BACKGROUND

• 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. doi: 10.1203/01.PDR.0000157676.45088.8C. Epub 2005 Mar 17.

  PMID: 15774841 BACKGROUND

• Roka A, Melinda KT, Vasarhelyi B, Machay T, Azzopardi D, Szabo 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.

  PMID: 18381513 BACKGROUND

• Zhang Y. Clonidine preconditioning decreases infarct size and improves neurological outcome from transient forebrain ischemia in the rat. Neuroscience. 2004;125(3):625-31. doi: 10.1016/j.neuroscience.2004.02.011.

  PMID: 15099676 BACKGROUND

• 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. doi: 10.1056/NEJMcps050929.

  PMID: 16221780 BACKGROUND

MeSH Terms

Conditions

Hypoxia-Ischemia, Brain

Interventions

Clonidine

Condition Hierarchy (Ancestors)

Brain Ischemia; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hypoxia, Brain; Vascular Diseases; Cardiovascular Diseases; Hypoxia; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Imidazolines; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Estelle B. Gauda
• Organization: University of Toronto

estelle.gauda@sickkids.ca

416-813-4908

Study Officials

• Estelle B Gauda, MD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 1, 2013
• First Posted: May 24, 2013
• Study Start: October 3, 2013
• Primary Completion: April 14, 2015
• Study Completion: April 14, 2015
• Last Updated: January 5, 2018
• Results First Posted: January 5, 2018

Record last verified: 2017-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)