Use of Phenylbutyrate Therapy for Patients With Pyruvate Dehydrogenase Complex Deficiency.

NCT03734263 | Completed Phase 2

• 1 other identifier: TIGEM2-PDH
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

Brief Summary

In this study phenylbutyrate is used for patients with pyruvate dehydrogenase complex deficiency. The aim of the study is to investigate the safety and efficacy of therapy.

Conditions

Pyruvate Dehydrogenase Complex Deficiency

Outcome Measures

Primary Outcomes (2)

• Efficacy: blood lactate (mmol/L)

  blood lactate (mmol/L)

  two weeks after starting therapy

• Efficacy: blood lactate (mmol/L)

  blood lactate (mmol/L)

  four weeks after starting therapy

Secondary Outcomes (6)

• Efficacy: blood pyruvate (mmol/L)

  two weeks after starting therapy

• Efficacy:urinary lactate (mmol/mol crea)

  two weeks after starting therapy

• Efficacy: blood pyruvate (mmol/L)

  four weeks after starting therapy

• Efficacy: urinary lactate (mmol/mol crea)

  four weeks after starting therapy

• Safety and tolerability:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

  two weeks after starting therapy

Study Arms (1)

open label

EXPERIMENTAL

sodium phenylbutyrate

Drug: sodium phenylbutyrate

Interventions

sodium phenylbutyrate DRUG

Enrolled subjects will receive a four-week period of treatment with sodium phenylbutyrate (oral use)

open label

Eligibility Criteria

• Age: 3 Months - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Subject must be older than 3 months old and younger than 18 years old.
• Clinical diagnosis of PDC deficiency confirmed by DNA testing showing a missense mutation in the PDHA1 gene.
• Lactate concentration ≥ 2.5 mmol/l or ≥ 2 mmol/l, respectively in venous or arterial blood samples.
• Provision of signed and dated informed consent form by the parents/legal guardians of the patient
• Negative pregnancy test for women of childbearing potential, and agree to use effective form of contraception until 6 weeks post treatment.

You may not qualify if:

• Frameshift or nonsense mutations of the PDHA1 gene.
• Defects affecting any gene encoding PDC subunits other than PDHA1
• Secondary forms of lactic acidosis (e.g. impaired oxygenation or circulation).
• Tracheostomy or requirement for artificial ventilation.
• Hyperlactatemia or organic acidosis associated with other metabolic disorders (e.g. biotinidase deficiency, primary disorders of gluconeogenesis, organic acidurias, primary defects of fatty acids oxidation)
• Evidence of hepatic insufficiency, renal insufficiency, edema with sodium retention, cardiac arrhythmia, congenital heart defects, hypertension, blood dyscrasia, symptomatic pancreatitis, or inflammatory bowel disease.
• Any clinical condition or medications known to significantly affect renal clearance.
• Any other condition that, in the opinion of the Investigator, may compromise the safety or compliance of the patient or would preclude the patient from successful completion of the study.
• Known allergic reactions to components of the study agent.
• Treatment with another investigational drug or other intervention (including DCA) or participation in a clinical study with an investigational drug within 6 months prior to enrolment.
• Pregnancy or lactation.

Sponsors & Collaborators

• Fondazione Telethon: lead

Study Sites (1)

Federico II University

Napoli, 80131, Italy

Location

Related Publications (4)

• Ferriero R, Manco G, Lamantea E, Nusco E, Ferrante MI, Sordino P, Stacpoole PW, Lee B, Zeviani M, Brunetti-Pierri N. Phenylbutyrate therapy for pyruvate dehydrogenase complex deficiency and lactic acidosis. Sci Transl Med. 2013 Mar 6;5(175):175ra31. doi: 10.1126/scitranslmed.3004986.

  PMID: 23467562 BACKGROUND

• Ferriero R, Brunetti-Pierri N. Phenylbutyrate increases activity of pyruvate dehydrogenase complex. Oncotarget. 2013 Jun;4(6):804-5. doi: 10.18632/oncotarget.1000. No abstract available.

  PMID: 23868807 BACKGROUND

• Ferriero R, Boutron A, Brivet M, Kerr D, Morava E, Rodenburg RJ, Bonafe L, Baumgartner MR, Anikster Y, Braverman NE, Brunetti-Pierri N. Phenylbutyrate increases pyruvate dehydrogenase complex activity in cells harboring a variety of defects. Ann Clin Transl Neurol. 2014 Jul;1(7):462-70. doi: 10.1002/acn3.73. Epub 2014 Jun 19.

  PMID: 25356417 BACKGROUND

• Ferriero R, Iannuzzi C, Manco G, Brunetti-Pierri N. Differential inhibition of PDKs by phenylbutyrate and enhancement of pyruvate dehydrogenase complex activity by combination with dichloroacetate. J Inherit Metab Dis. 2015 Sep;38(5):895-904. doi: 10.1007/s10545-014-9808-2. Epub 2015 Jan 20.

  PMID: 25601413 BACKGROUND

MeSH Terms

Conditions

Pyruvate Dehydrogenase Complex Deficiency Disease

Interventions

4-phenylbutyric acid

Condition Hierarchy (Ancestors)

Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; X-Linked Intellectual Disability; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Heredodegenerative Disorders, Nervous System; Metabolism, Inborn Errors; Pyruvate Metabolism, Inborn Errors; Carbohydrate Metabolism, Inborn Errors; Metabolic Diseases; Nutritional and Metabolic Diseases; Mitochondrial Diseases

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: Principal Investigator

Model Details: An open-label, uncontrolled, multicentric clinical trial will be performed on pediatric patients with PDC deficiency. Enrolled subjects will receive a four-week period of treatment with NaPB; primary and secondary endpoints will be evaluated at defined time points. Before NaPB treatment, all patients will undergo a four-week period of observation during which the same parameters will be analyzed at different time points, with the aim of evaluating basal conditions in the absence of treatment.

Study Record Dates

• First Submitted: October 25, 2018
• First Posted: November 7, 2018
• Study Start: October 1, 2018
• Primary Completion: July 30, 2019
• Study Completion: December 30, 2020
• Last Updated: October 13, 2021

Record last verified: 2021-10

Locations

IT (1)