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

Pyruvate Dehydrogenase Complex Deficiency Clinical Trial

— TIGEM2-PDH  

Official title:

Pilot Clinical Trial to Investigate the Safety and Efficacy of Phenylbutyrate Therapy for Patients With Pyruvate Dehydrogenase Complex Deficiency.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03734263
• Other study ID #: TIGEM2-PDH
• Status: Completed
• Phase: Phase 2
• Start date: October 1, 2018
• Est. completion date: December 30, 2020

Study information

• Verified date: October 2021
• Source: Fondazione Telethon
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

The Investigator will evaluate the safety and efficacy of a 4-weeks treatment with sodium phenylbutyrate in patients with pyruvate dehydrogenase complex deficiency. Efficacy will be evaluated based on biochemical endpoints (blood lactate and pyruvate).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1
• Est. completion date: December 30, 2020
• Est. primary completion date: July 30, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Months to 18 Years

Eligibility

Inclusion Criteria:

1. Subject must be older than 3 months old and younger than 18 years old.

2. Clinical diagnosis of PDC deficiency confirmed by DNA testing showing a missense mutation in the PDHA1 gene.

3. Lactate concentration = 2.5 mmol/l or = 2 mmol/l, respectively in venous or arterial blood samples.

4. Provision of signed and dated informed consent form by the parents/legal guardians of the patient

5. Negative pregnancy test for women of childbearing potential, and agree to use effective form of contraception until 6 weeks post treatment.

Exclusion Criteria:

1. Frameshift or nonsense mutations of the PDHA1 gene.

2. Defects affecting any gene encoding PDC subunits other than PDHA1

3. Secondary forms of lactic acidosis (e.g. impaired oxygenation or circulation).

4. Tracheostomy or requirement for artificial ventilation.

5. 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)

6. Evidence of hepatic insufficiency, renal insufficiency, edema with sodium retention, cardiac arrhythmia, congenital heart defects, hypertension, blood dyscrasia, symptomatic pancreatitis, or inflammatory bowel disease.

7. Any clinical condition or medications known to significantly affect renal clearance.

8. 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.

9. Known allergic reactions to components of the study agent.

10. 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.

11. Pregnancy or lactation.

Related Conditions & MeSH terms

• Pyruvate Dehydrogenase Complex Deficiency
• Pyruvate Dehydrogenase Complex Deficiency Disease

Intervention

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

Locations

Country	Name	City	State
Italy	Federico II University	Napoli

Sponsors (1)

Lead Sponsor	Collaborator
Fondazione Telethon

Country where clinical trial is conducted

Italy, 

References & Publications (4)

Ferriero R, Boutron A, Brivet M, Kerr D, Morava E, Rodenburg RJ, Bonafé 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. — View Citation

Ferriero R, Brunetti-Pierri N. Phenylbutyrate increases activity of pyruvate dehydrogenase complex. Oncotarget. 2013 Jun;4(6):804-5. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Efficacy: blood lactate (mmol/L)	blood lactate (mmol/L)	two weeks after starting therapy
Primary	Efficacy: blood lactate (mmol/L)	blood lactate (mmol/L)	four weeks after starting therapy
Secondary	Efficacy: blood pyruvate (mmol/L)	blood pyruvate (mmol/L)	two weeks after starting therapy
Secondary	Efficacy:urinary lactate (mmol/mol crea)	urinary lactate (mmol/mol crea)	two weeks after starting therapy
Secondary	Efficacy: blood pyruvate (mmol/L)	blood pyruvate (mmol/L)	four weeks after starting therapy
Secondary	Efficacy: urinary lactate (mmol/mol crea)	urinary lactate (mmol/mol crea)	four weeks after starting therapy
Secondary	Safety and tolerability:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0	Number of participants with treatment-related adverse events as assessed by CTCAE v4.0	two weeks after starting therapy
Secondary	Safety and tolerability: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0	Number of participants with treatment-related adverse events as assessed by CTCAE v4.0	four weeks after starting therapy