- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00645879
Anaplerotic Therapy in Propionic Acidemia
Safety & Efficacy of Investigational Products: Ornithine Alpha-ketoglutarate, Glutamine, or Disodium Citrate on Hyperammonemia in Propionic Acidemia.
Study Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
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Utah
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Salt Lake City, Utah, United States, 84132
- University of Utah, Department of Pediatrics
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: OKG, Glutamine, and Disodium Citrate
Ornithine Alpha Ketoglutarate for 4 weeks, followed by 2 week washout period.
4 weeks Glutamine, followed by 2 week washout period.
4 weeks Disodium Citrate, followed by 2 to 12 week washout period.
Then continue an additional 30 weeks on Disodium Citrate (drug producing the best increment in plasma glutamine levels).
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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 Names:
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 Names:
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 Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
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
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end of study
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Secondary Outcome Measures
Outcome Measure |
Time Frame |
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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
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end of study
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Evaluate the effect of investigational products on the developmental quotient and medical complications in patients with propionic acidemia.
Time Frame: end of study
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end of study
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Nicola Longo, MD, PhD, University of Utah
Publications and helpful links
General Publications
- Deodato F, Boenzi S, Santorelli FM, Dionisi-Vici C. Methylmalonic and propionic aciduria. Am J Med Genet C Semin Med Genet. 2006 May 15;142C(2):104-12. doi: 10.1002/ajmg.c.30090.
- Dionisi-Vici C, Deodato F, Roschinger W, Rhead W, Wilcken B. 'Classical' organic acidurias, propionic aciduria, methylmalonic aciduria and isovaleric aciduria: long-term outcome and effects of expanded newborn screening using tandem mass spectrometry. J Inherit Metab Dis. 2006 Apr-Jun;29(2-3):383-9. doi: 10.1007/s10545-006-0278-z.
- Mochel F, DeLonlay P, Touati G, Brunengraber H, Kinman RP, Rabier D, Roe CR, Saudubray JM. Pyruvate carboxylase deficiency: clinical and biochemical response to anaplerotic diet therapy. Mol Genet Metab. 2005 Apr;84(4):305-12. doi: 10.1016/j.ymgme.2004.09.007.
- Roe CR, Sweetman L, Roe DS, David F, Brunengraber H. Treatment of cardiomyopathy and rhabdomyolysis in long-chain fat oxidation disorders using an anaplerotic odd-chain triglyceride. J Clin Invest. 2002 Jul;110(2):259-69. doi: 10.1172/JCI15311.
- Filipowicz HR, Ernst SL, Ashurst CL, Pasquali M, Longo N. Metabolic changes associated with hyperammonemia in patients with propionic acidemia. Mol Genet Metab. 2006 Jun;88(2):123-30. doi: 10.1016/j.ymgme.2005.11.016. Epub 2006 Jan 10.
- Longo N, Price LB, Gappmaier E, Cantor NL, Ernst SL, Bailey C, Pasquali M. Anaplerotic therapy in propionic acidemia. Mol Genet Metab. 2017 Sep;122(1-2):51-59. doi: 10.1016/j.ymgme.2017.07.003. Epub 2017 Jul 12.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Pathologic Processes
- Metabolic Diseases
- Genetic Diseases, Inborn
- Metabolism, Inborn Errors
- Amino Acid Metabolism, Inborn Errors
- Acid-Base Imbalance
- Acidosis
- Propionic Acidemia
- Hyperammonemia
- Molecular Mechanisms of Pharmacological Action
- Anticoagulants
- Chelating Agents
- Sequestering Agents
- Calcium Chelating Agents
- Citric Acid
- Sodium Citrate
Other Study ID Numbers
- 24806
- 1R21DK077415-01A1 (U.S. NIH Grant/Contract)
- ANA-PA-001 (Other Identifier: University of Utah)
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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