Anaplerotic Therapy in Propionic Acidemia

The recruitment status of this study is unknown because the information has not been verified recently.
Verified July 2009 by University of Utah.
Recruitment status was  Active, not recruiting
Sponsor:
Collaborator:
Information provided by:
University of Utah
ClinicalTrials.gov Identifier:
NCT00645879
First received: March 25, 2008
Last updated: July 17, 2009
Last verified: July 2009
  Purpose

The objective of this project is to define whether nutritional supplements (ornithine alpha-ketoglutarate, glutamine, or citrate) capable of filling-up the citric acid cycle (anaplerotic therapy) can improve hyperammonemia, glutamine levels, and outcome in patients with propionic acidemia. Ornithine alpha-ketoglutarate, glutamine, and citrate are commonly used as nutritional supplements specially by athletes to increase muscle strength. They can be mixed with formula or other foods.


Condition Intervention Phase
Propionic Acidemia
Dietary Supplement: ornithine alpha ketoglutarate
Dietary Supplement: glutamine
Dietary Supplement: disodium citrate
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Safety & Efficacy of Investigational Products: Ornithine Alpha-ketoglutarate, Glutamine, or Disodium Citrate on Hyperammonemia in Propionic Acidemia.

Resource links provided by NLM:


Further study details as provided by University of Utah:

Primary Outcome Measures:
  • Define safety and efficacy of nutritional therapy with these investigational products: L-Ornithine alpha-ketoglutarate, Glutamine, or disodium citrate (anaplerotic therapy) on hyperammonemia and outcome in patients with propionic acidemia. [ Time Frame: end of study ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Define the effect of citrate, alpha-ketoglutarate and glutamine on plasma amino acids, acylcarnitines, ammonia, lactic acid and urine organic acids in patients with propionic acidemia. [ Time Frame: end of study ] [ Designated as safety issue: Yes ]
  • Evaluate the effect of investigational products on the developmental quotient and medical complications in patients with propionic acidemia. [ Time Frame: end of study ] [ Designated as safety issue: No ]

Estimated Enrollment: 4
Study Start Date: July 2008
Estimated Study Completion Date: December 2009
Estimated Primary Completion Date: August 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
Subjects will take Ornithine Alpha Ketoglutarate for 4 weeks, followed by two week washout period. Followed by 4 weeks Glutamine, followed by two week washout period. Followed by 4 weeks Citrate, followed by two to twelve week washout period. Subjects will then be continued an additional 30 weeks on the drug producing the best increment in plasma glutamine levels.
Dietary Supplement: ornithine alpha ketoglutarate
A dose of 400 mg/kg up to 16 g per day was selected. Split into 2 doses taken for 4 weeks. If determined the drug with the best effect, drug will be taken for 30 weeks.
Other Name: OKG
Dietary Supplement: glutamine
A dose of 400 mg/kg up to 16 g per day was selected. Split into 2 doses taken for 4 weeks. If determined the drug with the best effects, drug will be taken for 30 weeks.
Other Name: Glutamic Acid
Dietary Supplement: disodium citrate
Dose: 7.5 mEq/Kg or 658 mg/kg up to 16 g per day Split into 2 doses taken for 4 weeks. If determined the drug with the best effects, drug will be taken for 30 weeks.
Other Name: Citric Acid Sodium Salt, Sodium Citrate

Detailed Description:

Propionic acidemia is caused by deficiency of propionyl CoA carboxylase that impairs the supply of succinyl CoA to the citric acid (Krebs) cycle. The Krebs cycle is responsible for obtaining energy from food in the form of ATP. ATP is essential for muscle contraction and correct functioning of all organs including the hearth, the kidney, and the pancreas.

Patients with propionic acidemia develop hyperammonemia at birth that recurs during episodes of metabolic decompensation. We found that plasma levels of the amino acids glutamine/glutamate are reduced in patients with propionic acidemia and decrease, rather than increase (like in urea cycle defects or other types of hyperammonemia) with hyperammonemia. Since alpha-ketoglutarate is the main source of endogenous glutamate/glutamine synthesis, our hypothesis is that chronic hyperammonemia and progressive dysfunction of multiple organs in patients with propionic acidemia is due to a functional insufficiency of the citric acid (Krebs) cycle with defective production of alpha-ketoglutarate. The basic deficiency of intermediates of the Krebs cycle can decrease production of ATP and explain the low muscle tone, progressive organ dysfunction, and poor long-term outcome of patients with propionic acidemia.

To test this hypothesis, we will test whether dietary supplementation with alpha ketoglutarate precursors (in the form of ornithine alpha ketoglutarate, glutamine or citrate) can improve plasma ammonia and overall outcome in patients with propionic acidemia. In this study, a limited number of patients (3) with propionic acidemia will be given the 3 different nutritional supplements and studied at regular intervals to see whether their glutamine/glutamate levels improve and if they have fewer episodes of hyperammonemia or acute decompensation. The supplement that produces the best increase in plasma glutamine levels will be tested for an additional 30 weeks. Children's development and motor skills will be tested before and after therapy to see if there is any improvement. The study will be conducted on outpatients at the University of Utah Clinical Research Center. If the initial trial is successful, we will try to launch a national trial involving multiple centers in the US and abroad to involve the largest number of patients possible.

The current therapy of propionic acidemia is based on restriction of precursors of propionic acid (methionine, valine, isoleucine, threonine, odd chain fatty acids, cholesterol) and administration of carnitine to help remove toxic organic acids. This therapy is not effective in preventing the long-term complications of the disease, even in children identified at birth by newborn screening. This research will test a completely new way of treating patients with severe and disabling metabolic disorders using replacement of downstream products involved in the generation of energy (ATP). This approach, if effective, could be extended to a number of other diseases, including other organic acidemias and mitochondrial disorders.

  Eligibility

Ages Eligible for Study:   5 Years to 12 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Confirmed diagnosis of propionic acidemia (propionyl CoA carboxylase deficiency)

Exclusion Criteria:

  • Severe illness with cardiac or hepatic compromise that could affect study results
  • Use of other investigative therapies
  • Inability to comply with study directions
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00645879

Locations
United States, Utah
University of Utah, Department of Pediatrics
Salt Lake City, Utah, United States, 84132
Sponsors and Collaborators
University of Utah
Investigators
Principal Investigator: Nicola Longo, MD, PhD University of Utah
  More Information

Publications:
Responsible Party: Nicola Longo, MD, PhD, University of Utah, Department of Pediatrics
ClinicalTrials.gov Identifier: NCT00645879     History of Changes
Other Study ID Numbers: 24806, NIH #:1R21DK077415 - 01A1, ANA-PA-001
Study First Received: March 25, 2008
Last Updated: July 17, 2009
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Utah:
Propionic Acidemia
hyperammonemia
hypotonia
glutamine
ornithine alpha ketoglutarate
citrate

Additional relevant MeSH terms:
Hyperammonemia
Propionic Acidemia
Pathologic Processes
Amino Acid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
Citric Acid
Anticoagulants
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions
Chelating Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 29, 2014