Use of Phenylbutyrate Therapy for Patients With Pyruvate Dehydrogenase Complex Deficiency. (TIGEM2-PDH)

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
Pyruvate Dehydrogenase Complex Deficiency	Drug: sodium phenylbutyrate	Phase 1; Phase 2

Detailed 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).

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	10 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Pilot Clinical Trial to Investigate the Safety and Efficacy of Phenylbutyrate Therapy for Patients With Pyruvate Dehydrogenase Complex Deficiency.
Actual Study Start Date :	October 1, 2018
Estimated Primary Completion Date :	October 1, 2019
Estimated Study Completion Date :	October 1, 2019

Arms and Interventions

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Arm	Intervention/treatment
Experimental: open label; sodium phenylbutyrate	Drug: sodium phenylbutyrate; Enrolled subjects will receive a four-week period of treatment with sodium phenylbutyrate (oral use)

Outcome Measures

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Primary Outcome Measures :

1. Efficacy: blood lactate (mmol/L) [ Time Frame: two weeks after starting therapy ]
   blood lactate (mmol/L)
2. Efficacy: blood lactate (mmol/L) [ Time Frame: four weeks after starting therapy ]
   blood lactate (mmol/L)

Secondary Outcome Measures :

1. Efficacy: blood pyruvate (mmol/L) [ Time Frame: two weeks after starting therapy ]
   blood pyruvate (mmol/L)
2. Efficacy:urinary lactate (mmol/mol crea) [ Time Frame: two weeks after starting therapy ]
   urinary lactate (mmol/mol crea)
3. Efficacy: blood pyruvate (mmol/L) [ Time Frame: four weeks after starting therapy ]
   blood pyruvate (mmol/L)
4. Efficacy: urinary lactate (mmol/mol crea) [ Time Frame: four weeks after starting therapy ]
   urinary lactate (mmol/mol crea)
5. Safety and tolerability:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: two weeks after starting therapy ]
   Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
6. Safety and tolerability: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: four weeks after starting therapy ]
   Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Eligibility Criteria

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Ages Eligible for Study:	3 Months to 18 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

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Contacts

Contact: Nicola Brunetti-Pierri, MD	+390817463288	brunetti@tigem.it

Locations

Italy
Federico II University	Recruiting
Napoli, Italy, 80131
Contact: Nicola Brunetti-Pierri +390817463288 brunetti@tigem.it

Sponsors and Collaborators

Fondazione Telethon

More Information

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Publications:

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.

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

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.

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.

Responsible Party:	Nicola Brunetti-Pierri, Principal Investigator, Fondazione Telethon
ClinicalTrials.gov Identifier:	NCT03734263 History of Changes
Other Study ID Numbers:	TIGEM2-PDH
First Posted:	November 7, 2018
Last Update Posted:	November 7, 2018
Last Verified:	October 2018

Studies a U.S. FDA-regulated Drug Product:		No
Studies a U.S. FDA-regulated Device Product:		No

Additional relevant MeSH terms:

Pyruvate Dehydrogenase Complex Deficiency Disease; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Retardation, X-Linked; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations	Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Heredodegenerative Disorders, Nervous System; Metabolism, Inborn Errors; Pyruvate Metabolism, Inborn Errors; Carbohydrate Metabolism, Inborn Errors; Metabolic Diseases; Mitochondrial Diseases; 4-phenylbutyric acid; Antineoplastic Agents