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Sponsors and Collaborators: |
University of Utah National Institutes of Health (NIH) |
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Information provided by: | University of Utah |
ClinicalTrials.gov Identifier: | NCT00645879 |
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 |
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Propionic Acidemia |
Dietary Supplement: ornithine alpha ketoglutarate Dietary Supplement: glutamine Dietary Supplement: disodium citrate |
Phase I Phase II |
Study Type: | Interventional |
Study Design: | Treatment, Open Label, Uncontrolled, Single Group Assignment, Safety/Efficacy Study |
Official Title: | Safety & Efficacy of Investigational Products: Ornithine Alpha-Ketoglutarate, Glutamine, or Disodium Citrate on Hyperammonemia in Propionic Acidemia. |
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 |
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1: Experimental
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.
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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.
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.
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.
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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.
Ages Eligible for Study: | 5 Years to 12 Years |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Exclusion Criteria:
Contact: Carrie L Bailey, BS, CCRC | 801-587-3605 | carrie.bailey@hsc.utah.edu |
Contact: Sharon L Ernst, MPH, RD, CD | 801-581-8738 | sharon.ernst@hsc.utah.edu |
United States, Utah | |
University of Utah, Department of Pediatrics | Recruiting |
Salt Lake City, Utah, United States, 84132 | |
Contact: Carrie L Bailey, BS, CCRC 801-587-3605 carrie.bailey@hsc.utah.edu | |
Contact: Nicola Longo, MD, PhD 801-585-2457 nicola.longo@hsc.utah.edu | |
Principal Investigator: Nicola Longo, MD, PhD | |
Sub-Investigator: Sharon L Ernst, MPH, RD, CD | |
Sub-Investigator: Eduard Gappmaier, PhD | |
Sub-Investigator: Marzia Pasquali, PhD | |
Sub-Investigator: Lorenzo Botto, MD |
Principal Investigator: | Nicola Longo, MD, PhD | University of Utah |
Responsible Party: | University of Utah, Department of Pediatrics ( Nicola Longo, MD, PhD ) |
Study ID Numbers: | 24806, NIH #:1R21DK077415 - 01A1, ANA-PA-001 |
Study First Received: | March 25, 2008 |
Last Updated: | January 27, 2009 |
ClinicalTrials.gov Identifier: | NCT00645879 |
Health Authority: | United States: Food and Drug Administration |
Propionic Acidemia hyperammonemia hypotonia |
glutamine ornithine alpha ketoglutarate citrate |
Citric Acid Muscle Hypotonia Hyperammonemia |
Anticoagulants Pathologic Processes Molecular Mechanisms of Pharmacological Action Therapeutic Uses |
Hematologic Agents Chelating Agents Pharmacologic Actions |