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

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

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

Conditions
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Pyruvate Dehydrogenase Complex Deficiency

Intervention / Treatment
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* Drug: sodium phenylbutyrate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 3 Months
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: open label<br>sodium phenylbutyrate | Drug: sodium phenylbutyrate<br>* Enrolled subjects will receive a four-week period of treatment with sodium phenylbutyrate (oral use)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy: blood pyruvate (mmol/L) | blood pyruvate (mmol/L) | two weeks after starting therapy | 
| Efficacy:urinary lactate (mmol/mol crea) | urinary lactate (mmol/mol crea) | two weeks after starting therapy | 
| Efficacy: blood pyruvate (mmol/L) | blood pyruvate (mmol/L) | four weeks after starting therapy | 
| Efficacy: urinary lactate (mmol/mol crea) | 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 | Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | two weeks after starting therapy | 
| 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 |