Anaplerotic Therapy in Propionic Acidemia

NCT00645879 | Completed Phase 1 DMC

• 3 other identifiers: 248061R21DK077415-01A1ANA-PA-001
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Propionic Acidemia

Keywords

Propionic Acidemia; hyperammonemia; hypotonia; glutamine; ornithine alpha ketoglutarate; citrate

Outcome Measures

Primary Outcomes (1)

• 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.

  end of study

Secondary Outcomes (2)

• 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.

  end of study

• Evaluate the effect of investigational products on the developmental quotient and medical complications in patients with propionic acidemia.

  end of study

Study Arms (1)

OKG, Glutamine, and Disodium Citrate

EXPERIMENTAL

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).

Drug: ornithine alpha ketoglutarate; Drug: glutamine; Drug: disodium citrate

Interventions

ornithine alpha ketoglutarate DRUG

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.

Also known as: OKG

OKG, Glutamine, and Disodium Citrate

glutamine DRUG

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.

Also known as: Glutamic Acid

OKG, Glutamine, and Disodium Citrate

disodium citrate DRUG

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.

Also known as: Citric Acid Sodium Salt, Sodium Citrate

OKG, Glutamine, and Disodium Citrate

Eligibility Criteria

• Age: 5 Years - 12 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

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

You may not qualify if:

• Severe illness with cardiac or hepatic compromise that could affect study results
• Use of other investigative therapies
• Inability to comply with study directions

Sponsors & Collaborators

• Nicola Longo: lead
• National Institutes of Health (NIH): collaborator
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

University of Utah, Department of Pediatrics

Salt Lake City, Utah, 84132, United States

Location

Related Publications (6)

• 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.

  PMID: 16602092 BACKGROUND

• 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.

  PMID: 16763906 BACKGROUND

• 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.

  PMID: 15781190 BACKGROUND

• 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.

  PMID: 12122118 BACKGROUND

• 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.

  PMID: 16406646 BACKGROUND

• 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.

  PMID: 28712602 DERIVED

MeSH Terms

Conditions

Propionic Acidemia; Hyperammonemia; Muscle Hypotonia

Interventions

ornithine alpha-ketoglutarate; Glutamine; Glutamic Acid; Sodium Citrate

Condition Hierarchy (Ancestors)

Amino Acid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neuromuscular Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms

Intervention Hierarchy (Ancestors)

Amino Acids, Basic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Diamino; Amino Acids, Neutral; Glutamates; Amino Acids, Acidic; Amino Acids, Dicarboxylic; Excitatory Amino Acids; Citric Acid; Citrates; Tricarboxylic Acids; Acids, Acyclic; Carboxylic Acids; Organic Chemicals

Study Officials

• Nicola Longo, MD, PhD

  University of Utah

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD, Professor, Biochemical Geneticist

Study Record Dates

• First Submitted: March 25, 2008
• First Posted: March 28, 2008
• Study Start: July 1, 2008
• Primary Completion: August 1, 2009
• Study Completion: February 1, 2010
• Last Updated: January 21, 2015

Record last verified: 2015-01

Locations

US (1)