Anaplerotic Therapy in Propionic Acidemia

January 17, 2015 updated by: Nicola Longo

Safety & Efficacy of Investigational Products: Ornithine Alpha-ketoglutarate, Glutamine, or Disodium Citrate on Hyperammonemia in Propionic Acidemia.

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
3

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Utah
      • Salt Lake City, Utah, United States, 84132
        • University of Utah, Department of Pediatrics

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

5 years to 12 years (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

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

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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).
Drug: 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 Names:
  • OKG
Drug: 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 Names:
  • Glutamic Acid
Drug: 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 Names:
  • Citric Acid Sodium Salt, Sodium Citrate

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
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
end of study

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Time Frame
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
end of study
Evaluate the effect of investigational products on the developmental quotient and medical complications in patients with propionic acidemia.
Time Frame: end of study
end of study

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Nicola Longo

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Institutes of Health (NIH)

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Nicola Longo, MD, PhD, University of Utah

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
July 1, 2008

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
August 1, 2009

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
February 1, 2010

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
March 25, 2008

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 27, 2008

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
March 28, 2008

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
January 21, 2015

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 17, 2015

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
January 1, 2015

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant 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

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

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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