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

NCT06887777 | Recruiting Phase 2

• 2 other identifiers: APHP2308342024-516410-38-00
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Pyruvate Dehydrogenase Complex Deficiency Disease

Keywords

Pyruvate dehydrogenase (PDH); Enzyme; PDH deficiency; Glycerol Phenylbutyrate; Fatigue

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (12)

• Efficacy on fatigue at 3 months

  3 months

• Efficacy on polyhandicap

  6 months

• Efficacy on neurodevelopmental functioning

  6 months

• Efficacy on epilepsy

  6 months

• Efficacy on the biological balance

  3 months

Study Arms (1)

Glycerol phenylbutyrate treatment

EXPERIMENTAL

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]

Interventions

Glycerol Phenylbutyrate 1100 MG/ML [Ravicti] DRUG

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.

Glycerol phenylbutyrate treatment

Eligibility Criteria

• Age: 2 Years - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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)

You may not qualify if:

• 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.
• 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

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead
• URC-CIC Paris Descartes Necker Cochin: collaborator

Study Sites (1)

Hôpital Universitaire Necker - Enfants Malades

Paris, France, 75015, France

RECRUITING

Related Publications (7)

• 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.

  PMID: 11485553 BACKGROUND

• 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.

  PMID: 16097935 BACKGROUND

• Strumilo S. Short-term regulation of the mammalian pyruvate dehydrogenase complex. Acta Biochim Pol. 2005;52(4):759-64. Epub 2005 Jul 11.

  PMID: 16025163 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

• 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

MeSH Terms

Conditions

Pyruvate Dehydrogenase Complex Deficiency Disease; Fatigue

Interventions

glycerol phenylbutyrate

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; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Central Study Contacts

Pascale De Lonlay, MD, PhD

CONTACT

01 44 49 58 52; pascale.delonlay@aphp.fr

Gael Plastow, Project advisor

CONTACT

01 44 38 18 57; gael.plastow@aphp.fr

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 10, 2025
• First Posted: March 20, 2025
• Study Start: October 1, 2025
• Primary Completion: April 1, 2026
• Study Completion (Estimated): April 1, 2027
• Last Updated: March 31, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)