Glycerol-Phenylbutyrate Treatment in Children With MCT Mutation (Allan-Herndon- Dudley Syndrome)

NCT05019417 | Unknown Phase 2 FDA Drug

• 1 other identifier: 0089-19-KMC
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

Rationale: Thyroid hormone (TH) is crucial for normal brain development. The transporter monocarboxlate transporter 8 (MCT8), located at various organs including brain neurons, is crucial for cellular transport of TH, mainly T3 . A defect in this transporter causes Allan-Herndon-Dudley syndrome (AHDS), which characterized by severe motor and cognitive retardation. Serum TH tests typically show low T4, high T3 and mildly elevated TSH. The neurological phenotype entails diminished TH transport into the brain. On the other hand, elevated serum T3 leads to hypermetabolic status in peripheral tissues. Subsequently, AHDS patients have a low body weight and muscle mass. Currently, no effective treatment is available. Over the last decade, several studies focused on the effect of T3 analogues, that their trans-membrane transport is not mediated by MCT8. Two analogues were studied: Diiodothyropropionic acid (DITPA) and tetraiodothyroacetic acid (Triac). Both agents have demonstrated improvement in serum TH levels (mainly T3 and TSH) but no change in the neurocognitive status of the patients. Recently, several studies have demonstrated that sodium phenylbutyrate (PB) acting as a chaperon and increase the expression of MCT8 in the cell membrane. Subsequently, cells transfected with various mutations in MCT8 have shown remarkable improvement in T3 transport into the cytoplasm. We hypothesize that treatment of AHDS patients with glycerol phenylbutyrate (GPB) will improve thyroid function and neurodevelopmental parameters and relieve symptoms resulting from toxic T3 levels in peripheral tissues. Objective: To test safety and efficacy of PB treatment in AHDS patients. Primary objectives: To determine the effect of PB treatment on serum levels of TH. Secondary objective:

1. 1.To determine the effect of PB on T3-associated hyperthyroid state in peripheral tissues.
2. 2.To determine the effects of PB treatment on the neurodevelopmental status. Study design: therapeutic prospective trial. Study population: Up to 6 AHDS patients with genetically proven ADHD. Intervention: all participants will receive an escalating dose of PB in the form of Glycerol-PB (commercial name Ravicti) until individual serum T3 levels have been normalized or dose limiting toxicities occur.

Conditions

Monocarboxylate Transporter 8 Deficiency

Keywords

MCT8; Glycerol phenylbutyrate

Outcome Measures

Primary Outcomes (1)

• Normalization of thyroid function test in response to glycerol phenylbutyrate

  Serum free T4 (ng/dl), Serum total T4 (nmol/L), Serum free T3 (pg/ml), Serum TSH (microIU/ml), Serum thyroglobulin (ng.ml)

  4 months

Secondary Outcomes (3)

• The effect of glycerol phenybutyrat on hematological and biochemical parameters in patients

  4 months

• Height and weight gain in response to glycerol phenylbutyrate treatment

  4 months

• improvement in motor function in response to glycerol phenylbutyrate treatment

  4 months

Study Arms (1)

Glycerol phenylbutyrate treatment

EXPERIMENTAL

Name of the Investigational Medicinal product: Glycerol phenylbutyrate \[GPB\] (Ravicti oral liquid 1.1 gr/1 ml; manufacturer Horizon Pharma USA). Dosage of GPB will follow the dosage in use for children with urea cycle disorder. Initial dose: 5.0 gr (4.5 ml)/ meter square divided by three time a day. An escalating schedule dose of GPB will be used until normal serum T3 levels are reached. Initial dose: 5 gr/square meter body surface area (BSA). Second visit: 10 gr/square meter BSA The dose raising will be stopped if one of the following condition is reaches: 1. Clinically significant side effects 2. Reaching the PAA serum toxic threshold of 500 µg/ml 3. Reaching the maximal dose of GPB that is in use in urea cycle disorder: 12.4 gr (11.2 ml)/ meter square BSA divided by three times a day. Duration of study: 4 months

Drug: Glycerol Phenylbutyrate 1100 MG/ML

Interventions

Glycerol Phenylbutyrate 1100 MG/ML DRUG

Daily adminisitraion of the study drug (three times a day) in escalting dose over 4 months

Also known as: Ravicti (Horizon Pharma USA)

Glycerol phenylbutyrate treatment

Eligibility Criteria

• Age: 6 Months - 20 Years
• Gender Eligibility Details: The disease is X-linked and basically appears only in males
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• AHDS with characteristic clinical phenotype and with genetically confirmed mutation in the MCT8 gene SLC16A2.

You may not qualify if:

• Inability to get the study medication glycerol phenylbutyrate per-os (in cases without gastrotstomy)
• Known contra-indication for glycerol phenylbutyrate
• Patients without confirmed mutation in the MCT8 gene

Sponsors & Collaborators

• Kaplan Medical Center: lead
• Weizmann Institute of Science: collaborator

Study Sites (1)

Pediatric Endocrinology Unit, Kapan Medical Center

Rehovot, 76100, Israel

RECRUITING

MeSH Terms

Conditions

Allan-Herndon-Dudley syndrome

Interventions

glycerol phenylbutyrate

Study Officials

• Amnon Zung, MD

  Kaplan Medical Center, affiliated with the Hebrew University of Jerusalem, Israel

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Amnon Zung, MD

CONTACT

972-8-9441276; amnon_z@clalit.org.il

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Head of Pediatrics, Associate Clinical Profesor, the Hebrew University of Jerusalem, Israel

Study Record Dates

• First Submitted: July 1, 2021
• First Posted: August 24, 2021
• Study Start: June 30, 2021
• Primary Completion: August 30, 2022
• Study Completion: August 30, 2022
• Last Updated: August 24, 2021

Record last verified: 2021-08

Locations

IL (1)