Urea Cycle Disorders, Inborn
Conditions
Keywords
urea cycle disorders
Brief summary
The investigators will study and compare how effectively sodium phenylbutyrate, sodium benzoate, and a combination of the two, help excrete nitrogen in healthy volunteers. Subject participation will require three, separate, four-day study periods at least one week apart. During one study period (also called a treatment arm), subjects will take sodium phenylbutyrate; during another they will take sodium benzoate; during another they will take a combination of the two medications. We expect to find that phenylbutyrate is more effective at removing nitrogen than benzoate or a combination of the two.
Interventions
DRUGSodium Benzoate
Subjects will be instructed to take the study medication with meals (08:00 breakfast; 13:00 lunch; 19:00 dinner) for 3 days.
DRUGSodium Phenylbutyrate
Subjects will be instructed to take the study medication with meals (08:00 breakfast; 13:00 lunch; 19:00 dinner) for 3 days.
Sponsors
Baylor College of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 64 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy volunteers
Exclusion criteria
* Subjects with (a) a history of frequent dietary protein intolerance, (b) a history of chronic or acute liver diseases which may result in altered hepatic synthetic capacity (e.g., hepatitis), (c) acute or chronic disease or on medications that in the opinion of the clinical investigators will interfere with the measurements (e.g., drugs which may have hepatotoxicity as potential side effects), (d) a physical disability that will interfere with their ability to either conform to the dietary regimes or undergo the isotopic infusions, (e) pregnancy or recent (\<6 months)/current lactation, (f) intercurrent evidence of significant hyperammonemia (more than 100 µmol/L), (g) any clinical abnormality of Grade 3 or greater according to the Common Terminology Criteria for Adverse Events v.4.0 (CTCAE), (h) any condition(s) not covered by the CTCAE, or (i) a severe or life-threatening toxicity at screening, will be excluded from the study. Subjects taking ammonia scavenger medications will not be enrolled.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Urinary Hippuric Acid | 4 days per arm | The objective of this protocol is to directly compare the efficacy of benzoate, phenylbutyrate and a combination of the two, to conjugate nitrogenous compounds in healthy volunteers. The nitrogenous compound of interest in each arm would be based on the medication used. This would be hippuric acid in the benzoate arm, phenylacetylglutamine in the phenylbutyrate arm, and hippuric acid AND phenylacetylglutamine in the MIX arm. The mean hippuric acid levels in the phenylbutyrate arm would thus be 0. |
| Urinary PAGN Excretion | 4 days per arm | The objective of this protocol is to directly compare the efficacy of benzoate, phenylbutyrate and a combination of the two, to conjugate nitrogenous compounds in healthy volunteers. The nitrogenous compound of interest in each arm would be based on the medication used. This would be hippuric acid in the benzoate arm, phenylacetylglutamine in the phenylbutyrate arm, and hippuric acid AND phenylacetylglutamine in the MIX arm. The mean phenylacetylglutamine levels in the benzoate arm would thus be 0. |
| Total Nitrogen as a Conjugate of the Drug | 4 days per arm | The objective of this protocol is to directly compare the efficacy of benzoate, phenylbutyrate and a combination of the two, to conjugate nitrogenous compounds in healthy volunteers. The nitrogenous compound of interest in each arm would be based on the medication used. This would be hippuric acid in the benzoate arm, phenylacetylglutamine in the phenylbutyrate arm, and hippuric acid AND phenylacetylglutamine in the MIX arm. |
Countries
United States
Participant flow
Pre-assignment details
There was no washout period prior to enrollment. Individuals who were enrolled in the trial were not on any medications.
Participants by arm
| Arm | Count |
|---|---|
| Sodium Phenylbutyrate->MIX->Sodium Benzoate 1. Sodium phenylbutyrate arm: Participants received ONLY sodium phenylbutyrate at a dose of 7.15 g/m2/day divided into three equal doses per day (maximum dose of 20 g/day) for 3 days. Subjects took the study medication with meals (08:00 breakfast; 13:00 lunch; 19:00 dinner) for 3 days.
Followed by a Washout period of at least 7 days
2. MIX arm: Participants received a combination of Sodium Phenylbutyrate 3.575 g/m2/day and Sodium Benzoate 2.75 g/m2/day were given in three equal doses per day for 3 days. Subjects took the study medications with meals (08:00 breakfast; 13:00 lunch; 19:00 dinner) for 3 days.
Followed by a Washout period of at least 7 days
3. Sodium benzoate: Participants received ONLY Sodium Benzoate at a dose of 5.5 g/m2/day divided into three equal doses per day (maximum dose 12 g/day) for 3 days. Subjects took the study medications with meals (08:00 breakfast; 13:00 lunch; 19:00 dinner) for 3 days. | 3 |
| Sodium Benzoate->MIX-> Sodium Phenylbutyrate 1. Sodium benzoate: Participants received ONLY Sodium Benzoate at a dose of 5.5 g/m2/day divided into three equal doses per day (maximum dose 12 g/day) for 3 days. Subjects took the study medications with meals (08:00 breakfast; 13:00 lunch; 19:00 dinner) for 3 days.
Followed by a Washout period of at least 7 days
2. MIX arm: Participants received a combination of Sodium Phenylbutyrate 3.575 g/m2/day and Sodium Benzoate 2.75 g/m2/day were given in three equal doses per day for 3 days. Subjects took the study medications with meals (08:00 breakfast; 13:00 lunch; 19:00 dinner) for 3 days.
Followed by a Washout period of at least 7 days
3. Sodium phenylbutyrate arm: Participants received ONLY sodium phenylbutyrate at a dose of 7.15 g/m2/day divided into three equal doses per day (maximum dose of 20 g/day) for 3 days. Subjects took the study medication with meals (08:00 breakfast; 13:00 lunch; 19:00 dinner) for 3 days. | 2 |
| MIX->Sodium Benzoate-> Sodium Phenylbutyrate 1. MIX arm: Participants received a combination of Sodium Phenylbutyrate 3.575 g/m2/day and Sodium Benzoate 2.75 g/m2/day were given in three equal doses per day for 3 days. Subjects took the study medications with meals (08:00 breakfast; 13:00 lunch; 19:00 dinner) for 3 days.
Followed by a Washout period of at least 7 days
2. Sodium benzoate: Participants received ONLY Sodium Benzoate at a dose of 5.5 g/m2/day divided into three equal doses per day (maximum dose 12 g/day) for 3 days. Subjects took the study medications with meals (08:00 breakfast; 13:00 lunch; 19:00 dinner) for 3 days.
Followed by a Washout period of at least 7 days
3. Sodium phenylbutyrate arm: Participants received ONLY sodium phenylbutyrate at a dose of 7.15 g/m2/day divided into three equal doses per day (maximum dose of 20 g/day) for 3 days. Subjects took the study medication with meals (08:00 breakfast; 13:00 lunch; 19:00 dinner) for 3 days. | 1 |
| MIX-> Sodium Phenylbutyrate-> Sodium Benzoate 1. MIX arm: Participants received a combination of Sodium Phenylbutyrate 3.575 g/m2/day and Sodium Benzoate 2.75 g/m2/day were given in three equal doses per day for 3 days. Subjects took the study medications with meals (08:00 breakfast; 13:00 lunch; 19:00 dinner) for 3 days.
Followed by a Washout period of at least 7 days
2. Sodium phenylbutyrate arm: Participants received ONLY sodium phenylbutyrate at a dose of 7.15 g/m2/day divided into three equal doses per day (maximum dose of 20 g/day) for 3 days. Subjects took the study medication with meals (08:00 breakfast; 13:00 lunch; 19:00 dinner) for 3 days.
Followed by a Washout period of at least 7 days
3. Sodium benzoate: Participants received ONLY Sodium Benzoate at a dose of 5.5 g/m2/day divided into three equal doses per day (maximum dose 12 g/day) for 3 days. Subjects took the study medications with meals (08:00 breakfast; 13:00 lunch; 19:00 dinner) for 3 days. | 1 |
| Total | 7 |
Baseline characteristics
| Characteristic | Sodium Phenylbutyrate->MIX->Sodium Benzoate | Sodium Benzoate->MIX-> Sodium Phenylbutyrate | MIX->Sodium Benzoate-> Sodium Phenylbutyrate | MIX-> Sodium Phenylbutyrate-> Sodium Benzoate | Total |
|---|---|---|---|---|---|
| Age, Continuous | 26 years | 42.5 years | 28 years | 33 years | 28 years |
| Region of Enrollment United States | 3 participants | 2 participants | 1 participants | 1 participants | 7 participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 1 Participants | 0 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 7 | 0 / 7 |
| other Total, other adverse events | 3 / 7 | 5 / 7 | 3 / 7 |
| serious Total, serious adverse events | 0 / 7 | 0 / 7 | 0 / 7 |
Outcome results
Primary
Total Nitrogen as a Conjugate of the Drug
The objective of this protocol is to directly compare the efficacy of benzoate, phenylbutyrate and a combination of the two, to conjugate nitrogenous compounds in healthy volunteers. The nitrogenous compound of interest in each arm would be based on the medication used. This would be hippuric acid in the benzoate arm, phenylacetylglutamine in the phenylbutyrate arm, and hippuric acid AND phenylacetylglutamine in the MIX arm.
Time frame: 4 days per arm
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sodium Benzoate Arm | Total Nitrogen as a Conjugate of the Drug | 16.4 mmol/24 hours | Standard Deviation 3.1 |
| Sodium Phenylbutyrate Arm | Total Nitrogen as a Conjugate of the Drug | 29 mmol/24 hours | Standard Deviation 3.3 |
| Mix Arm | Total Nitrogen as a Conjugate of the Drug | 30.7 mmol/24 hours | Standard Deviation 4.5 |
Primary
Urinary Hippuric Acid
The objective of this protocol is to directly compare the efficacy of benzoate, phenylbutyrate and a combination of the two, to conjugate nitrogenous compounds in healthy volunteers. The nitrogenous compound of interest in each arm would be based on the medication used. This would be hippuric acid in the benzoate arm, phenylacetylglutamine in the phenylbutyrate arm, and hippuric acid AND phenylacetylglutamine in the MIX arm. The mean hippuric acid levels in the phenylbutyrate arm would thus be 0.
Time frame: 4 days per arm
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sodium Benzoate Arm | Urinary Hippuric Acid | 16.4 mmol/24 hours | Standard Deviation 3.1 |
| Sodium Phenylbutyrate Arm | Urinary Hippuric Acid | 0 mmol/24 hours | Standard Deviation 0 |
| Mix Arm | Urinary Hippuric Acid | 10.5 mmol/24 hours | Standard Deviation 1.7 |
Primary
Urinary PAGN Excretion
The objective of this protocol is to directly compare the efficacy of benzoate, phenylbutyrate and a combination of the two, to conjugate nitrogenous compounds in healthy volunteers. The nitrogenous compound of interest in each arm would be based on the medication used. This would be hippuric acid in the benzoate arm, phenylacetylglutamine in the phenylbutyrate arm, and hippuric acid AND phenylacetylglutamine in the MIX arm. The mean phenylacetylglutamine levels in the benzoate arm would thus be 0.
Time frame: 4 days per arm
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sodium Benzoate Arm | Urinary PAGN Excretion | 0 mmol/24 hours | Standard Deviation 0 |
| Sodium Phenylbutyrate Arm | Urinary PAGN Excretion | 15.3 mmol/24 hours | Standard Deviation 2.3 |
| Mix Arm | Urinary PAGN Excretion | 9.3 mmol/24 hours | Standard Deviation 0.8 |