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

Hypothermia Treatment in Hyperammonemia and Encephalopathy

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.

Study Overview

• Status: Completed
• Conditions: Urea Cycle Disorders; Organic Acidemias
• Intervention / Treatment: Other: Therapeutic Hypothermia; Other: Standard of Care Therapy

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.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • New York
    • New York, New York, United States, 10027
      • Columbia University, Morgan Stanley Children's Hospital
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 1 month (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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; Cooling; Hypothermia Therapy
OTHER: 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: Hemodialysis; CVVHD; Dialysis; CVVH

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with unexpected Serious Adverse Events as a Measure of Safety and Tolerability	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.	Participants will be followed for the duration of the hospital stay, an expected average of 5 weeks
Feasibility of hypothermia therapy as adjunct therapy to the complex standard of care therapy	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.	During the first 72h of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to normalization of ammonia level	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.	During the first 72 hours of treatment

Collaborators and Investigators

• Sponsor: Uta Lichter-Konecki
• Collaborators: Medical College of Wisconsin; Children's National Research Institute
• Investigators: Principal Investigator: Uta Lichter-Konecki, MD, PhD, Columbia University

Publications and helpful links

Helpful Links

• National Urea Cycle Disorders Foundation (Family Organisation)

Study record dates

Study Major Dates

• Study Start: August 1, 2007
• Primary Completion (ACTUAL): May 1, 2015
• Study Completion (ACTUAL): May 1, 2015

Study Registration Dates

• First Submitted: June 13, 2012
• First Submitted That Met QC Criteria: June 18, 2012
• First Posted (ESTIMATE): June 20, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): June 1, 2015
• Last Update Submitted That Met QC Criteria: May 28, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Keywords: Seizures; Encephalopathy; Coma; Citrullinemia; Organic Acidemia; Propionic Aciduria; Urea Cycle Disorder; Ornithine Transcarbamylase Deficiency; Hyperammonemia; Brain edema; High ammonia level; Poor suck; Lethargy; Carbamoyl Phosphate Synthetase Deficiency; Argininosuccinic Aciduria; Methylmalonic Aciduria; Isovaleric Aciduria
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Amino Acid Metabolism, Inborn Errors; Body Temperature Changes; Brain Diseases; Hypothermia; Urea Cycle Disorders, Inborn; Hyperammonemia
• Other Study ID Numbers: AAAN6104