Maple Syrup Urine DiseasePhase 2/3MSUDNCT01529060
Phenylbutyrate Therapy for Maple Syrup Urine Disease
A Phase 2/3 study testing Phenylbutyrate in people with Maple Syrup Urine Disease, run by Brendan Lee at 1 site in United States.
Trial summary
The investigators have learned in past research that the drug phenylbutyrate can decrease the amounts of branched chain amino acids and their byproducts in the bloodstreams of healthy volunteer patients and also patients with certain disorders of protein breakdown including maple syrup urine disease. Read more about this study
- Who is it for?
- Ages 3 years and older
- Conditions the study is for
- Maple Syrup Urine Disease
- What is being tested?
- Phenylbutyrate
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 20 participants
- Where
- 1 siteUnited States
- Study dates
- Feb 2013to Dec 2017
- Phase
- Phase 2/3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 3 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Must be 3 years or older at enrollment.
- Must have a diagnosis of maple syrup urine disease (MSUD) confirmed by the presence of plasma alloisoleucine (>5 micromol/L) and/or genetic testing showing mutations in both alleles of any subunit of BCKDHA (E1alpha subunit gene, MSUD type 1A), BCKDHB (E1beta subunit gene, MSUD type 1B), or DBT (E2 subunit gene, MSUD type 2).
- Participants must have a history of compliance to diet and treatment.
- Signed informed consent by subject and/or subject's legally acceptable representative.
- Must be capable of completing study procedures, including taking oral or G- tube medication.
- Negative pregnancy test for all females of childbearing potential.
- All females of childbearing potential and all sexually active males must agree to use an acceptable method of contraception throughout the study. Appropriate contraceptive methods include hormonal contraceptives (oral, injected, implanted, or transdermal), tubal ligation, intrauterine device, hysterectomy, vasectomy, or double barrier methods. Abstinence is an acceptable form of birth control, though appropriate contraception must be used if the subject becomes sexually active.
Who cannot join
- May not have used sodium phenylbutyrate within 30 days of Visit 1.
- May not have an active infection (viral or bacterial) or any condition which may exacerbate their MSUD causing metabolic decompensation.
- Cannot have any clinical or laboratory abnormality of Grade 3 or greater according to the Common Terminology Criteria for Adverse Events v3.0 (CTCAE) (or for conditions not covered by the CTCAE, a severe or life-threatening toxicity).
- May not have taken any medications known to significantly affect renal clearance or to increase protein catabolism within the 24 hours prior to Visit 1.
- May not participate if they have a known hypersensitivity to phenylacetate or phenylbutyrate or creatinine levels 1.5 times or more ULN.
- Since a total of 53 mL will be drawn over Days 14 and 15 of both treatment periods, only subjects weighing more than 30 pounds can be enrolled.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Double-Blind, Randomized, Placebo-Controlled, Crossover Trial of Phenylbutyrate in the Treatment of Maple Syrup Urine Disease
The investigators have learned in past research that the drug phenylbutyrate can decrease the amounts of branched chain amino acids and their byproducts in the bloodstreams of healthy volunteer patients and also patients with certain disorders of protein breakdown including maple syrup urine disease. Through this study, the investigators will try to find out how well phenylbutyrate (NaPBA), also known by name brand "Buphenyl-TM", decreases BCAA and branched chain keto chain acids in the blood of patients with MSUD. The investigators hope is that through this research the investigators will be better able to treat these patients.
Subjects with MSUD will take phenylbutyrate (NaPBA) in powder form for a two-week treatment period and powder placebo, a substance with no effect on the body, for a two-week treatment period. They will be given the same amount of powder and undergo the same laboratory testing during both of the two-week treatment periods. The results will be compared once the study is over.
Read the detailed description
Maple syrup urine disease is a severe inborn error of amino acid metabolism caused by deficiency of the mitochondrial branched-chain alpha-ketoacid dehydrogenase complex (BCKDC) resulting in the accumulation of branched-chain amino acids (BCAA) (isoleucine, leucine, and valine) and their corresponding branched-chain alpha-ketoacids (BCKA) [alpha-keto-beta-methylvalerate (KMV), alpha-ketoisocaproate (KIC), and alpha-ketoisovalerate(KIV)] in tissues and plasma. The disorder typically manifests with potentially lethal episodes of intoxication presenting with acute neurological deterioration, feeding problems, weight loss, and a maple syrup odor to the urine. Current treatment is based on dietary manipulations with protein restriction and a synthetic formula with reduced BCAA content. However, mental and social impairment are still present in the majority of these patients in spite of dietary management.
Our study seeks to investigate the potential small molecule inhibition of the kinase that regulates BCKDC by applying a novel activity of sodium phenylbutyrate (NaPBA), in MSUD. Sodium phenylbutyrate is has been used to treat patients with urea cycle disorders (UCDs). In our extensive studies with UCDs, we noted that patients on therapy with NaPBA had decreased plasma levels of BCAA. This led us to hypothesize that NaPBA has effects on BCAA metabolism.
This will be a single-site, randomized, active-controlled, double-blind, cross-over study designed to enroll subjects with MSUD. Subjects will be randomly assigned to receive either sodium phenylbutyrate (PB) or placebo for 2 weeks, and then crossed over to receive the other treatment for 2 weeks.
If study findings show sodium phenylbutyrate lowers BCAA and BCKA levels in these patients, it may prove to be an effective adjunct treatment for these patients. A treatment option that could prevent or decrease the accumulation of BCAA and BCKA during states of catabolism induced by fasting or intercurrent illnesses, and thereby minimize or prevent the neurologic sequelae and loss of human potential that result, would greatly benefit society.
- Conditions
- Maple Syrup Urine Disease
- Being tested
- Phenylbutyrate, Placebo powder
- Keywords
- phenylbutyrate, MSUD, Buphenyl-TM
- Medical subject headings
- Maple Syrup Urine Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PhenylbutyrateDrug
Also called Buphenyl-TM
Dosage of phenylbutyrate powder will be 500 mg/kg/day in patients weighing less than 20kg and 10 g/m2/day in larger patients in four divided doses per day, the standard UCD dose studied in our preliminary studies, for 14 days.
Placebo powderDrug
Dosage of inactive placebo powder will be 500 mg/kg/day in patients weighing less than 20kg and 10 g/m2/day in larger patients in four divided doses per day for 14 days. Subjects will receive the same amount of powder for each arm of the study.
| Study group | Role | What they receive |
|---|---|---|
| Phenylbutyrate | Active comparator | Study Drug Receives: Drug: Phenylbutyrate |
| Inactive Powder | Placebo comparator | Placebo powder Receives: Drug: Placebo powder |
What is being measured
The primary outcome is the main question the study is designed to answer.
0-24 Hour AUC Leucine (Samples Collected at 0, 2, 4, 8, 12, 16, 20, and 24 Hours)
Total Leucine exposure over 24 hours was calculated by serial blood draws at times 0, 2, 4, 8, 12, 16, 20, and 24 hours
Measured: 24 Hours
Leucine CMax 0-24 Hours
Maximal leucine concentration in 0-24 hours
Measured: 24 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Feb 2012 (estimated)
- Study startFeb 2013
- Primary completion2 Sep 2017
- Study completionDec 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Maple Syrup Urine DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 20 participants (actual)
Sponsor and investigators
- Lead sponsor
- Brendan Lee
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Brendan Lee, Baylor College of Medicine
- Investigators
- Brendan Lee, M.D., Ph.D., Principal investigator, Baylor College of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01529060
- Sponsor's protocol ID
- H-28463
- Acronym
- MSUD
- Status last verified
- Mar 2019
- First submitted
- 6 Feb 2012
- Last updated
- 19 Mar 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 19 Mar 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Double-Blind, Randomized, Placebo-Controlled, Crossover Trial of Phenylbutyrate in the Treatment of Maple Syrup Urine Disease
- ClinicalTrials.gov ID
- NCT01529060
- Acronym / sponsor ID
- MSUD / H-28463
- Conditions
- Maple Syrup Urine Disease
- Keywords
- phenylbutyrate, MSUD, Buphenyl-TM
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 20 participants (actual)
- Lead sponsor
- Brendan LeeUniversity, hospital or other
- Study start
- Feb 2013
- Primary completion
- 2 Sep 2017 (actual)
- Study completion
- Dec 2017 (actual)
- First posted
- 8 Feb 2012 (estimated)
- Results
- Posted 6 Mar 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The investigators have learned in past research that the drug phenylbutyrate can decrease the amounts of branched chain amino acids and their byproducts in the bloodstreams of healthy volunteer patients and also patients with certain disorders of protein breakdown including maple syrup urine disease. Through this study, the investigators will try to find out how well phenylbutyrate (NaPBA), also known by name brand "Buphenyl-TM", decreases BCAA and branched chain keto chain acids in the blood of patients with MSUD. The investigators hope is that through this research the investigators will be better able to treat these patients.
Subjects with MSUD will take phenylbutyrate (NaPBA) in powder form for a two-week treatment period and powder placebo, a substance with no effect on the body, for a two-week treatment period. They will be given the same amount of powder and undergo the same laboratory testing during both of the two-week treatment periods. The results will be compared once the study is over.
Detailed description
Maple syrup urine disease is a severe inborn error of amino acid metabolism caused by deficiency of the mitochondrial branched-chain alpha-ketoacid dehydrogenase complex (BCKDC) resulting in the accumulation of branched-chain amino acids (BCAA) (isoleucine, leucine, and valine) and their corresponding branched-chain alpha-ketoacids (BCKA) [alpha-keto-beta-methylvalerate (KMV), alpha-ketoisocaproate (KIC), and alpha-ketoisovalerate(KIV)] in tissues and plasma. The disorder typically manifests with potentially lethal episodes of intoxication presenting with acute neurological deterioration, feeding problems, weight loss, and a maple syrup odor to the urine. Current treatment is based on dietary manipulations with protein restriction and a synthetic formula with reduced BCAA content. However, mental and social impairment are still present in the majority of these patients in spite of dietary management.
Our study seeks to investigate the potential small molecule inhibition of the kinase that regulates BCKDC by applying a novel activity of sodium phenylbutyrate (NaPBA), in MSUD. Sodium phenylbutyrate is has been used to treat patients with urea cycle disorders (UCDs). In our extensive studies with UCDs, we noted that patients on therapy with NaPBA had decreased plasma levels of BCAA. This led us to hypothesize that NaPBA has effects on BCAA metabolism.
This will be a single-site, randomized, active-controlled, double-blind, cross-over study designed to enroll subjects with MSUD. Subjects will be randomly assigned to receive either sodium phenylbutyrate (PB) or placebo for 2 weeks, and then crossed over to receive the other treatment for 2 weeks.
If study findings show sodium phenylbutyrate lowers BCAA and BCKA levels in these patients, it may prove to be an effective adjunct treatment for these patients. A treatment option that could prevent or decrease the accumulation of BCAA and BCKA during states of catabolism induced by fasting or intercurrent illnesses, and thereby minimize or prevent the neurologic sequelae and loss of human potential that result, would greatly benefit society.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Phenylbutyrate | Active comparator | Drug: PhenylbutyrateStudy Drug |
| Inactive Powder | Placebo comparator | Drug: Placebo powderPlacebo powder |
Who may qualify
- Ages
- 3 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (7 listed)
- Must be 3 years or older at enrollment.
- Must have a diagnosis of maple syrup urine disease (MSUD) confirmed by the presence of plasma alloisoleucine (>5 micromol/L) and/or genetic testing showing mutations in both alleles of any subunit of BCKDHA (E1alpha subunit gene, MSUD type 1A), BCKDHB (E1beta subunit gene, MSUD type 1B), or DBT (E2 subunit gene, MSUD type 2).
- Participants must have a history of compliance to diet and treatment.
- Signed informed consent by subject and/or subject's legally acceptable representative.
- Must be capable of completing study procedures, including taking oral or G- tube medication.
Key exclusion criteria (6 listed)
- May not have used sodium phenylbutyrate within 30 days of Visit 1.
- May not have an active infection (viral or bacterial) or any condition which may exacerbate their MSUD causing metabolic decompensation.
- Cannot have any clinical or laboratory abnormality of Grade 3 or greater according to the Common Terminology Criteria for Adverse Events v3.0 (CTCAE) (or for conditions not covered by the CTCAE, a severe or life-threatening toxicity).
- May not have taken any medications known to significantly affect renal clearance or to increase protein catabolism within the 24 hours prior to Visit 1.
- May not participate if they have a known hypersensitivity to phenylacetate or phenylbutyrate or creatinine levels 1.5 times or more ULN.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PhenylbutyrateAlso: Buphenyl-TMDosage of phenylbutyrate powder will be 500 mg/kg/day in patients weighing less than 20kg and 10 g/m2/day in larger patients in four divided doses per day, the standard UCD dose studied in our preliminary studies, for 14 days. | Drug | Phenylbutyrate |
| Placebo powderDosage of inactive placebo powder will be 500 mg/kg/day in patients weighing less than 20kg and 10 g/m2/day in larger patients in four divided doses per day for 14 days. Subjects will receive the same amount of powder for each arm of the study. | Drug | Inactive Powder |
Primary outcome
0-24 Hour AUC Leucine (Samples Collected at 0, 2, 4, 8, 12, 16, 20, and 24 Hours)
Time frame: 24 Hours
Total Leucine exposure over 24 hours was calculated by serial blood draws at times 0, 2, 4, 8, 12, 16, 20, and 24 hours
Leucine CMax 0-24 Hours
Time frame: 24 hours
Maximal leucine concentration in 0-24 hours
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Mar 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Baylor College of Medicine WebsiteLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Brendan Lee, M.D., Ph.D. principal investigator
Baylor College of Medicine
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Phenylbutyrate in people with Maple Syrup Urine Disease, run by Brendan Lee at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Mar 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 6 Mar 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
0-24 Hour AUC Leucine (Samples Collected at 0, 2, 4, 8, 12, 16, 20, and 24 Hours) (time frame: 24 Hours). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Mar 2019.