Efficacy and Safety of the Treatment of Pyruvate Dehydrogenase Deficiency Patients With Glycerol Phenylbutyrate (RAVICTI) (PDH-RAVICTI)

A Phase II, Multicentric, Prospective, Non-comparative Clinical Trial to Assess the Efficacy and Safety of the Treatment of Pyruvate Dehydrogenase Deficiency (PDH) Patients With Glycerol Phenybutyrate (RAVICTI®)

This is a phase II, multicenter, prospective, non-comparative clinical trial to assess the efficacy and safety of the treatment of pyruvate dehydrogenase deficiency (PDH) patients with glycerol phenylbutyrate (Ravicti®).

The trial will be conducted with three visits: 3 day hospitalizations including clinical consultations and paramedical procedures at Month 0 (M0), Month 3 (M3), Month 6 (M6).

During all the research, AE/SAE and treatment compliance will be recorded. Patients will keep their usual treatment during the study time: vitamin B1, ketogenic diet, possible anti-epileptic and/or dystonic treatment(s).

The efficacy on fatigue, polyhandicap, neurodevelopmental functioning, quality of life and seizure amount for epileptic patients will be evaluated at 0, 3 and 6 months. Biological balance will be assed with regular quantification of PDH deficiency markers, lactate concentration and amino acid plasma quantification.

Study Overview

• Status: Recruiting
• Conditions: Pyruvate Dehydrogenase Complex Deficiency Disease
• Intervention / Treatment: Drug: Glycerol Phenylbutyrate 1100 MG/ML [Ravicti]

Detailed Description

PDH deficiencies are mainly characterized by primary lactic acidosis associated with neurological disorders. The diagnosis is suspected in the presence of an increase of pyruvate and lactate with a normal or low lactate/pyruvate ratio, especially in postprandial period, in the blood and/or cerebrospinal fluid.

Neurological disorders are explained by the energy deficit associated with the absence of aerobic oxidation of glucose, their preferential energy substrate, which cannot be compensated by the catabolism of fatty acids.

Phenylbutyrate was therefore proposed to increase the enzymatic activity of PDH in PDH deficits, particularly in patient cells and mouse model: it has reduced the phosphorylated form in these models and thus increased the enzymatic activity of the PDH complex. Phenylbutyrate would be more active when the PDH deficit is linked to missense variants, and less effective in the presence of non-meaning variant, with the exception of variants on the PDHX gene which are mostly non-sense variants.

The study plan is to treat these patients with Glycerol Phenylbutyrate (Ravicti®) 1.1 g/mL oral fluid (or in enteral tube or gastrostomy). Sodium Phenylbutyrate and Glycerol Phenylbutyrate are commonly used in inherited metabolic diseases in urea cycle diseases, for chelating ammonia, in children and adults. The expectation is to obtain an improvement of patients' fatigue and neurodevelopmental disability for PDH patients. Phenylbutyrate prevents PDH kinase from phosphorylating the PDH complex, allowing the complex to remain active. It acts on different isoforms of PDH kinase.

• Study Type: Interventional
• Enrollment (Estimated): 15
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Pascale De Lonlay, MD, PhD; Phone Number: +33 01 44 49 58 52; Email: pascale.delonlay@aphp.fr
• Study Contact Backup: Name: Gael Plastow, Project advisor; Phone Number: +33 01 44 38 18 57; Email: gael.plastow@aphp.fr

Study Locations

• France
  • France
    • Paris, France, France, 75015
      • Recruiting
      • Hôpital Universitaire Necker - Enfants Malades
      • Contact: Pascale De Lonlay, MD; Phone Number: +33 01 44 49 58 52; Email: pascale.delonlay@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Child from 2 to 17 years of age Or
• Adult from 18 to 25 years of age

• With a PDH deficiency confirmed by molecular biology:

  • a class 4 or 5- missense variant on the PDHA1 gene or
  • one homozygous variant or two mixed heterozygous variants of class 4 or 5 that are missense variants on PDHB or DLAT genes or
  • one homozygous variant or two mixed heterozygous variants of class 4 or 5 on PDHX genes (including non-sense and frameshift variants, and intragenic deletions
• For females of childbearing potential, negative bHCG and effective method of contraception (sexual abstinence, hormonal contraception containing ethinylestradiol and levonorgestrel, intrauterine device or hormone-releasing system, cap, diaphragm or sponge with spermicide, condom) until 30 days after the end of study. For male, an effective method of contraception (sexual abstinence, condom) until 30 days after the end of study
• Signature of consent by the legal representative
• Beneficiary of a social security coverage (affiliated or entitled)

Exclusion Criteria:

• Patient with E3 deficiency due to pathogenic mutation in DLD gene
• Patient with non-sense mutation on PDHB or DLAT gene, and male patient with non-sense mutation or PDHA1 gene.
• Patient with planned hip or scoliosos surgery during the study timeframe.
• Patient whose parents / legal representative refuse flu vaccine.
• Treatment change during the last 3 months prior inclusion (ketogenic diet and/or B1 vitamin)
• Hypersensitivity to Glycerol Phenylbutyrate or to any of the excipients
• No disease requiring Glycerol Phenylbutyrate (Hyperammonemia due to urea cycle disease or other aetiology)
• Pregnant or breastfeeding women
• Participation to another clinical trial on medicinal products for human use

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Glycerol phenylbutyrate treatment; The patients will orally take a dose of 200 mg/kg/day three times a day during meals: breakfast, lunch or afternoon snack and diner for 6 months. Questionnaires will be answered by parents or the patient's legal guardian. An additional hospital visit à 3 months following treatment start will be conducted with 6 blood drawing	Drug: Glycerol Phenylbutyrate 1100 MG/ML [Ravicti]; The patients will orally take a dose of 200 mg/kg/day three times a day during meals: breakfast, lunch or afternoon snack and diner for 6 months.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy on fatigue at 6 months	The efficacy of Glycerol Phenylbutyrate treatment on fatigue at 6 months will be evaluated by the Pediatric Quality of Life Multidimensional Fatigue Scale (PedsQL MFS) at Month 0 and Month 6. Results range from 0 to 72.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy on the biological balance	Evaluation of the efficacy of Glycerol Phenylbutyrate treatment on the biological balance by quantification of the decrease in pyruvate concentration, marker of PDH deficiency, and lactate concentration (points Redox performed before and after 3 meals), and the quantification of amino acids in plasma notably alanine and proline (markers of hyperlactatemia) (aminoacid chromatography) at 3 months.	3 months
Efficacy on the biological balance	Evaluation of the efficacy of Glycerol Phenylbutyrate treatment on the biological balance by quantification of the decrease in pyruvate concentration, marker of PDH deficiency, and lactate concentration (points Redox performed before and after 3 meals), and the quantification of amino acids in plasma notably alanine and proline (markers of hyperlactatemia) (aminoacid chromatography) at 6 months.	6 months
Treatment tolerance	Glycerol Phenylbutyrate treatment tolerance assessment at 3 months [allergy, side effects, amino acid chromatography (glutamine and other amino acid levels) in plasma].	3 months
Treatment tolerance	Glycerol Phenylbutyrate treatment tolerance assessment at 6 months [allergy, side effects, amino acid chromatography (glutamine and other amino acid levels) in plasma].	6 months
Treatment compliance	Glycerol Phenylbutyrate treatment compliance assessment at 3 months.	3 months
Treatment compliance	Glycerol Phenylbutyrate treatment compliance assessment at 6 months.	6 months
Efficacy on fatigue at 3 months	The efficacy of Glycerol Phenylbutyrate treatment on fatigue at 3 months will be evaluated by the Pediatric Quality of Life Multidimensional Fatigue Scale (PedsQL MFS) at Month 0 and Month 3. Results range from 0 to 72.	3 months
Efficacy on polyhandicap	The efficacy of Glycerol Phenylbutyrate treatment on polyhandicap, will be evaluated by the Polyhandicap severity scale at Month 0 and Month 6, performed by a psychomotrician, a physiotherapist or a medical physician. Results range from 0 to 93.	6 months
Efficacy on neurodevelopmental functioning	The efficacy of Glycerol Phenylbutyrate treatment on neurodevelopmental functions will be evaluated by a semi-structured interview with the Vineland Adaptive Behavior Scales second edition (VABS-II) 20 at Month 0 and Month 6. Results range from 0 to 160.	6 months
Efficacy on epilepsy	The efficacy of Glycerol Phenylbutyrate treatment on the number of seizures during the last 3 months using patient diary, and electroencephalogram (EEG) for epileptic patients at Month 6 compared to Month 0.	6 months
Efficacy on quality of life	Evaluation of the efficacy of Glycerol Phenylbutyrate treatment on quality of life of persons with polyhandicap at 3 months assessed by using the PolyQol questionnaire 22 at Month 0 and Month 3. Results range from 20 to 100.	3 months
Efficacy on quality of life	Evaluation of the efficacy of Glycerol Phenylbutyrate treatment on quality of life of persons with polyhandicap at 6 months assessed by using the PolyQol questionnaire at Month 0 and Month 6. Results range from 20 to 100.	6 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: URC-CIC Paris Descartes Necker Cochin
• Investigators: Principal Investigator: Pascale De Lonlay, MD, PhD, Hôpital Universitaire Necker - Enfants Malades; Study Director: Elise LEBIGOT, MD, PhD, CHU Bicêtre - GHU APHP Paris Saclay; Study Director: Marie HULLY, MD, PhD, Hôpital Universitaire Necker - Enfants Malades

Publications and helpful links

General 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. doi: 10.18632/oncotarget.1000. No abstract available.
• 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.
• 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.
• Kolobova E, Tuganova A, Boulatnikov I, Popov KM. Regulation of pyruvate dehydrogenase activity through phosphorylation at multiple sites. Biochem J. 2001 Aug 15;358(Pt 1):69-77. doi: 10.1042/0264-6021:3580069.
• Strumilo S. Short-term regulation of the alpha-ketoglutarate dehydrogenase complex by energy-linked and some other effectors. Biochemistry (Mosc). 2005 Jul;70(7):726-9. doi: 10.1007/s10541-005-0177-1.
• Strumilo S. Short-term regulation of the mammalian pyruvate dehydrogenase complex. Acta Biochim Pol. 2005;52(4):759-64. Epub 2005 Jul 11.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2025
• Primary Completion (Estimated): April 1, 2026
• Study Completion (Estimated): April 1, 2027

Study Registration Dates

• First Submitted: March 10, 2025
• First Submitted That Met QC Criteria: March 14, 2025
• First Posted (Actual): March 20, 2025

Study Record Updates

• Last Update Posted (Actual): March 31, 2026
• Last Update Submitted That Met QC Criteria: March 30, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Fatigue; Enzyme; PDH deficiency; Glycerol Phenylbutyrate; Pyruvate dehydrogenase (PDH)
• Additional Relevant MeSH Terms: Neurologic Manifestations; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Neurobehavioral Manifestations; Heredodegenerative Disorders, Nervous System; Intellectual Disability; Genetic Diseases, X-Linked; Carbohydrate Metabolism, Inborn Errors; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Pyruvate Metabolism, Inborn Errors; Mitochondrial Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; X-Linked Intellectual Disability; Fatigue; Pyruvate Dehydrogenase Complex Deficiency Disease; Antineoplastic Agents; Physiological Effects of Drugs; Protective Agents; Cryoprotective Agents; glycerol phenylbutyrate
• Other Study ID Numbers: APHP230834; 2024-516410-38-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No