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

• ClinicalTrials.gov Identifier: NCT01624311
• Recruitment Status: Completed
• First Posted: June 20, 2012
• Last Update Posted: June 1, 2015
• Sponsor: Uta Lichter-Konecki
• Collaborators: Children's National Research Institute; Medical College of Wisconsin
• Information provided by (Responsible Party): Uta Lichter-Konecki, Columbia University

Study Description

Brief Summary:

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 or disease	Intervention/treatment	Phase
Urea Cycle Disorders; Organic Acidemias	Other: Therapeutic Hypothermia; Other: Standard of Care Therapy	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 5 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Hypothermia Treatment in Hyperammonemia and Encephalopathy
• Study Start Date: August 2007
• Actual Primary Completion Date: May 2015
• Actual Study Completion Date: May 2015

Arms and Interventions

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; 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; CVVHD

Outcome Measures

Primary Outcome Measures :

1. 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 ]
   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.
2. Feasibility of hypothermia therapy as adjunct therapy to the complex standard of care therapy [ Time Frame: During the first 72h of treatment ]
   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 :

1. Time to normalization of ammonia level [ Time Frame: During the first 72 hours of treatment ]
   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.

Eligibility Criteria

• Ages Eligible for Study: up to 30 Days (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

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 National Research Institute

Medical College of Wisconsin

Investigators

• Principal Investigator: Uta Lichter-Konecki, MD, PhD; Columbia University

More Information

Additional Information:

National Urea Cycle Disorders Foundation (Family Organisation) 

• Responsible Party: Uta Lichter-Konecki, MD, Columbia University
• ClinicalTrials.gov Identifier: NCT01624311
• Other Study ID Numbers: AAAN6104
• First Posted: June 20, 2012
• Last Update Posted: June 1, 2015
• Last Verified: May 2015

Keywords provided by Uta Lichter-Konecki, Columbia University:

High ammonia level; Hyperammonemia; Poor suck; Lethargy; Coma; Encephalopathy; Seizures; Brain edema; Urea Cycle Disorder; Ornithine Transcarbamylase Deficiency; Carbamoyl Phosphate Synthetase Deficiency; Citrullinemia; Argininosuccinic Aciduria; Organic Acidemia; Propionic Aciduria; Methylmalonic Aciduria; Isovaleric Aciduria

Additional relevant MeSH terms:

Brain Diseases; Urea Cycle Disorders, Inborn; Hypothermia; Hyperammonemia; Central Nervous System Diseases; Nervous System Diseases; Body Temperature Changes; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Amino Acid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Pathologic Processes