Pilot Study For Hypothermia Treatment In Hyperammonemic Encephalopathy In Neonates And Very Young Infants

This study has been completed.
Children's Research Institute
Medical College of Wisconsin
Information provided by (Responsible Party):
Uta Lichter-Konecki, Columbia University
ClinicalTrials.gov Identifier:
First received: June 13, 2012
Last updated: May 28, 2015
Last verified: May 2015

This is a pilot study which will test the safety and feasibility of hypothermia treatment as adjunct therapy to conventional treatment of hyperammonemic encephalopathy (HAE) in neonates versus conventional treatment (dialysis, nutritional therapy, and ammonia scavenging drugs) only. The endpoint of the pilot study will be reached when either 24 patients have been enrolled and no serious adverse events were observed, when no patient has been enrolled in 5 years, or when serious adverse events occur which are clearly linked to the use of hypothermia. These would be serious complications not seen in patients on conventional therapy (dialysis , nutritional therapy, ammonia scavenging drugs) for HAE.

Condition Intervention Phase
Urea Cycle Disorders
Organic Acidemias
Other: Therapeutic Hypothermia
Other: Standard of Care Therapy
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Hypothermia Treatment in Hyperammonemia and Encephalopathy

Resource links provided by NLM:

Further study details as provided by Columbia University:

Primary Outcome Measures:
  • Number of Participants with unexpected Serious Adverse Events as a Measure of Safety and Tolerability [ Time Frame: Participants will be followed for the duration of the hospital stay, an expected average of 5 weeks ] [ Designated as safety issue: Yes ]
    The DSMB meets within 3 weeks of each case, no later than 5 weeks after initiation of hypothermia therapy and assesses the safety and feasibility of adjunct hypothermia treatment in this patient group. The treatment of neonates and very young infants in hyperammonemic coma is very complex and adding hypothermia therapy to this treatment could not be feasible, the pilot study therefore also assesses the feasibility of adding hypothermia therapy to the standard of care treatment.

  • Feasibility of hypothermia therapy as adjunct therapy to the complex standard of care therapy [ Time Frame: During the first 72h of treatment ] [ Designated as safety issue: No ]
    The standard of care therapy is very complex. It includes renal replacement therapy, metabolic diet intervention, and ammonia scavenger use. The pilot study will assess primarily for the first 72 hours of treatment and secondarily for the duration of the hospital stay, an expected average of 5 weeks, whether adding hypothermia to this already complex treatment is feasible.

Secondary Outcome Measures:
  • Time to normalization of ammonia level [ Time Frame: During the first 72 hours of treatment ] [ Designated as safety issue: No ]
    One of the effects of hypothermia treatment is an overall slowing of metabolism which should cause less ammonia to be produced. If this is correct this should lead to a faster normalization of the ammonia level by renal replacement therapy.

Enrollment: 5
Study Start Date: August 2007
Study Completion Date: May 2015
Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Adjunct Hypothermia Arm
Patients that receive adjunct therapeutic hypothermia in addition to standard of care therapy
Other: Therapeutic Hypothermia
After obtaining written consent, patients are cooled to 33.5°C (+/- 1°C ) for 72 hours and and then rewarmed by 0.5°C per every 3 hours over 18 hours.
Other Names:
  • Hypothermia
  • Hypothermia Therapy
  • Cooling
Historic Controls
Patients that were treated with standard of care therapy for the same conditions at the sponsoring institution over the past 10 years.
Other: Standard of Care Therapy
Patients with hyperammonemia and encephalopathy requiring renal replacement therapy due to a urea cycle disorder or organic acidemia that were treated at Children's National Medical Center over the past 10 years.
Other Names:
  • Dialysis
  • Hemodialysis
  • CVVH

Detailed Description:

Children with neonatal onset Urea Cycle Disorders or Organic Acidemias develop hyperammonemia (high ammonia levels) and fall into coma often causing brain damage. For these children to be able to benefit maximally from available long-term treatment and solid organ transplant, outcome of the neonatal onset crisis must be improved. Animal experiments and small clinical trials have indicated that hypothermia protects the brain during hyperammonemia. This pilot study investigates whether adjunct hypothermia therapy in addition to standard of care treatment is feasible and safe in babies with high ammonia levels in coma.


Ages Eligible for Study:   up to 30 Days
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Newborns >36 wks gestation and ≥2200g birth weight without co-morbidity (see exclusion criteria) that have clinical signs and symptoms of an Urea Cycle Disorders or Propionic , Methylmalonic, or Isovaleric acidemia and hyperammonemia and encephalopathy requiring renal replacement therapy.

Exclusion Criteria:

  • Patients with hyperammonemia that have clinical signs and symptoms of lysinuric protein intolerance, mitochondrial disorders, congenital lactic acidosis, and fatty acid oxidation disorders, patients with rare and unrelated serious comorbidities and other genetic diseases, e.g., Down syndrome, intraventricular hemorrhage in the newborn period, traumatic brain injury, and low birth weight (<2,200 g at >36 wks gestation).
  • Infants in extremis for which no additional intensive therapy will be offered by the attending neonatologist.
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01624311

United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20010
United States, New York
Columbia University, Morgan Stanley Children's Hospital
New York, New York, United States, 10027
United States, Wisconsin
Medical College Wisconsin
Milwaukee, Wisconsin, United States, 53226
Sponsors and Collaborators
Uta Lichter-Konecki
Children's Research Institute
Medical College of Wisconsin
Principal Investigator: Uta Lichter-Konecki, MD, PhD Columbia University
  More Information

Additional Information:
No publications provided

Responsible Party: Uta Lichter-Konecki, MD, Columbia University
ClinicalTrials.gov Identifier: NCT01624311     History of Changes
Other Study ID Numbers: AAAN6104
Study First Received: June 13, 2012
Last Updated: May 28, 2015
Health Authority: United States: Institutional Review Board

Keywords provided by Columbia University:
Argininosuccinic Aciduria
High ammonia level
Poor suck
Brain edema
Urea Cycle Disorder
Ornithine Transcarbamylase Deficiency
Carbamoyl Phosphate Synthetase Deficiency
Organic Acidemia
Propionic Aciduria
Methylmalonic Aciduria
Isovaleric Aciduria

Additional relevant MeSH terms:
Amino Acid Metabolism, Inborn Errors
Urea Cycle Disorders, Inborn
Body Temperature Changes
Brain Diseases
Brain Diseases, Metabolic
Brain Diseases, Metabolic, Inborn
Central Nervous System Diseases
Genetic Diseases, Inborn
Metabolic Diseases
Metabolism, Inborn Errors
Nervous System Diseases
Signs and Symptoms

ClinicalTrials.gov processed this record on October 02, 2015