Phenylbutyrate for Monogenetic Developmental and Epileptic Encephalopathy

NCT04937062 | Active Not Recruiting Early Phase 1 DMC FDA Drug

• 1 other identifier: 19-10020997
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 2

Brief Summary

This study is to evaluate the use of glycerol phenylbutyrate for monogenetic developmental epileptic encephalopathies (DEEs). DEEs are characterized by epilepsy and developmental delay in early life. Two examples of DEEs are STXBP1 and SLC6A1, though there are dozens of others. STXBP1 Encephalopathy is a severe disease that can cause seizures and developmental delays in infants and children. SLC6A1 neurodevelopmental disorder is characterized by developmental delay and often epilepsy. Both STXBP1 encephalopathy and SLC6A1 neurodevelopmental disorder cause symptoms because there are not enough working proteins made by these genes. It is possible that a medication called phenylbutyrate may help the the remaining proteins work better for STXBP1, SLC6A1, and/or other similar DEEs caused by single genes (i.e. "monogenetic"). This study is to test if glycerol phenylbutyrate is safe and well tolerated in children with monogenetic DEE.

Conditions

STXBP1 Encephalopathy With Epilepsy, SLC6A1 Neurodevelopmental Disorder; Developmental and Epileptic Encephalopathy

Keywords

phenylbutyrate, developmental and epileptic encephalopathy

Outcome Measures

Primary Outcomes (3)

• Short Term Adverse events (i.e., safety)

  The qualitative safety endpoint will describe any adverse events. It will include a description of the incidence, frequency, and severity of adverse events (including known side effects of the medication, changes in vital signs, EKG changes, EEG changes, increase in seizures, changes in clinical laboratory results, and/or changes in physical examination). We will monitor for these adverse events throughout the study, and measure them definitely at the time of the second admission.

  20 weeks

• Long Term Adverse events (i.e., safety)

  The long term qualitative safety endpoint will describe any adverse events. It will include a description of the incidence, frequency, and severity of adverse events (including known side effects of the medication, changes in vital signs, EKG changes, EEG changes, increase in seizures, changes in clinical laboratory results, and/or changes in physical examination). We will monitor for these adverse events throughout the study, and measure them yearly until December 2025.

  through December 2025 (1 - 5 years, depending on participant)

• Percentage of doses taken by participants (i.e., tolerability)

  The tolerability endpoint is quantitative and will measure medication compliance (i.e. what percentage of the doses are taken).

  20 weeks

Secondary Outcomes (1)

• Plasma concentration of phenylbutyrate

  20 weeks

Study Arms (2)

SLC6A1 and STXBP1

EXPERIMENTAL

Each participant will be enrolled for 14 weeks (4 weeks baseline, 8 weeks of drug exposure, and 2 weeks follow-up). After clinical assessment by the investigator if deemed safe and appropriate, and requested by the caregiver, participants may continue to receive the study medication ("extended use"), up to December 2025. Participants who remain on phenylbutyrate therapy will be followed quarterly through video visits, and yearly in-person visit. Participants who do not opt to remain on phenylbutyrate therapy will be weaned off the medication during the 2 week follow-up period.

Drug: Glycerol Phenylbutyrate 1100 MG/ML [Ravicti]

Monogenetic Epileptic Encephalopathy

EXPERIMENTAL

Each participant will be enrolled for 20 weeks (5 weeks baseline, 12 weeks of drug exposure, and 2 weeks follow-up) . After clinical assessment by the investigator if deemed safe and appropriate, and requested by the caregiver, participants may continue to receive the study medication ("extended use"), up to December 2025. Participants who remain on phenylbutyrate therapy will be followed quarterly through video visits, and yearly in-person visit. Participants who do not opt to remain on phenylbutyrate therapy will be weaned off the medication during the 2 week follow-up period.

Drug: Glycerol Phenylbutyrate 1100 MG/ML [Ravicti]

Interventions

Glycerol Phenylbutyrate 1100 MG/ML [Ravicti] DRUG

Glycerol phenylbutyrate (trade name "Ravicti") is an FDA-approved medication used for urea cycle disorders in children and adults. We will titrate to a goal dose of 1.2 mL/m2 (12.4 g/m2) in three equally divided doses given enterally (i.e., by mouth or by g-tube). The dosing is consistent with the dosing guidelines in the FDA approved Medication Guide (https://www.accessdata.fda.gov/drugsatfda\_docs/label/2017/203284s005lbl.pdf).

Monogenetic Epileptic Encephalopathy; SLC6A1 and STXBP1

Eligibility Criteria

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

You may qualify if:

• Diagnosed with STXBP1-E or SLC6A1-NDD; confirmed by laboratory report (i.e., a genetic test with a pathogenic or likely pathogenic mutation of STXBP1 or SLC6A1-NDD and a clinical picture consistent with the disorder, as determined by the Investigator). Patients with the appropriate clinical picture, a de novo variant of uncertain significance in STXBP1 or SLC6A1-NDD will also be eligible for enrollment, at the discretion of the Investigator.
• Is between 2 months and 17 years of age, inclusive.
• For children with STXBP1-E, the child must have had at least one seizure in the past 30 days prior to enrollment. If there is high demand for the study and we have several subjects to choose, we will prefer to enroll children with a high number of seizures in the past month.
• For SLC6A1-NDD, seizures occur later in the course (typically middle of 1st decade) and so seizures will not be an entry criteria.
• Is in general good health, aside from neurological consequences of STXBP1-E or SLC6A1-NDD, as determined by having no concurrent medical illness, in the opinion of the site investigator, that places the subject at increased risk of adverse drug reactions or that will interfere with study follow-up.
• Has normal laboratory test results (≤ 1.5 × upper limit of normal \[ULN\]) for serum aminotransferase (aspartate aminotransferas \[AST\] and alanine aminotransferase \[ALT\]) concentrations and ammonia at Screening.
• Has normal renal function, with estimated glomerular filtration rate \> 90 mL/minute/1.73 m2 at Screening (using the Chronic Kidney Disease Epidemiology Collaboration equation).
• Has a platelet count \> 150 × 103/μL at Screening.
• Has a QT interval corrected with Fridericia's formula (QTcF) \< 450 msec on the Screening EKG.
• Parent or guardian is able to comprehend and willing to sign an informed consent form (ICF).

You may not qualify if:

• Has participated in another investigational study within 30 days or 5 half-lives of the test drug's biologic activity (whichever is longer) before the first study drug dose.
• Has a QT interval corrected with Fridericia's formula (QTcF) ≥ 450 msec on the Screening EKG.
• Has an active medical illness that would preclude participation in the study (as determined by the Investigator).
• Has a clinical laboratory evaluation outside of the test laboratory reference range, unless deemed not clinically significant by the Investigator and the Sponsor.
• Is unable to comply with the study protocol.
• Has poor venous access and/or cannot tolerate venipuncture.
• Is pregnant
• Is a female of child-bearing age (12 years old or older) and known to be sexually active (for example, as determined through a confidential HEADDSSS history), and not taking medication for contraception. This will be assessed confidentially as per good general pediatrics practice
• Known hypersensitivity to phenylbutyrate. Signs of hypersensitivity include wheezing, dyspnea, coughing, hypotension, flushing, nausea, and rash.
• Taking alfentanil, quinidine, cyclosporine, or probenecid (known interactions with phenylbutyrate). For subjects who had taken any of these medications in the past, the last dose must have been taken at least 1 week prior to enrollment into the study.
• Inborn errors of beta oxidation.
• Pancreatic insufficiency or intestinal malabsorption
• Diagnosed with a monogenic developmental and epileptic encephalopathy; confirmed by laboratory report (i.e., a genetic test with a pathogenic or likely pathogenic mutation of a monogenic developmental and epileptic encephalopathy and a clinical picture consistent with the disorder, as determined by the Investigator). Children with the appropriate clinical picture, a de novo variant of uncertain significance in a monogenic developmental and epileptic encephalopathy will also be eligible for enrollment, at the discretion of the Investigator. If the mutant is classified as definitively non-pathogenic, we would not enroll the child. "Appropriate clinical picture" is at the discretion of the Investigator.
• Is between 0 months and 15 years of age, inclusive.
• The child must have had at least one seizure in the past 30 days prior to enrollment. (If there is high demand for the study and we have several subjects to choose, we will prefer to enroll children with a high number of seizures in the past month.)

Sponsors & Collaborators

• Weill Medical College of Cornell University: lead
• Children's Hospital Colorado: collaborator
• SLC6A1 Connect: collaborator
• STXBP1 Foundation: collaborator
• Clara Inspired: collaborator
• Horizon Therapeutics: collaborator
• University of Pennsylvania Orphan Disease Center: collaborator

Study Sites (2)

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Weill Cornell Medicine

New York, New York, 10065, United States

Location

Related Publications (35)

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MeSH Terms

Conditions

Epileptic Encephalopathy, Early Infantile, 4

Interventions

glycerol phenylbutyrate

Study Officials

• Zachary Grinspan, MD

  Weill Medical College of Cornell University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a pilot, single treatment, multiple-dose, open label, study to be conducted in up to 10 children with STXBP1-E, and 10 with SLC6A1-NDD, and 30 children with monogenetic developmental and epileptic encephalopathy.

Study Record Dates

• First Submitted: June 10, 2021
• First Posted: June 23, 2021
• Study Start: March 1, 2021
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: January 22, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)