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

Phase 2

Not yet recruiting

• Conditions: Pyruvate Dehydrogenase Complex Deficiency Disease
• Interventions: Drug: Glycerol Phenylbutyrate 1100 MG/ML [Ravicti]

• Registration Number: NCT06887777
• Lead Sponsor: Assistance Publique - Hôpitaux de Paris

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.

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 Timeline

• Study First Submitted: 2025-03-10
• Study First Submitted QC: 2025-03-14
• Study First Posted: 2025-03-20
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-29
• Study Start: 2025-05
• Last Update Posted: 2025-05-02
• Primary Completion: 2025-11
• Study Completion: 2026-12

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 15

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
• Male patient with a class 4 or 5 non-sense variant on the PDHA1, PDHB or DLAT gene
• 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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Glycerol phenylbutyrate treatment	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. 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

Primary Outcome Measures

Name	Time	Method
Efficacy on fatigue at 6 months	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.

Secondary Outcome Measures

Name	Time	Method
Efficacy on fatigue at 3 months	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.
Efficacy on polyhandicap	6 months	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.
Efficacy on neurodevelopmental functioning	6 months	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.
Efficacy on epilepsy	6 months	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.
Efficacy on the biological balance	6 months	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.
Efficacy on quality of life	6 months	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.
Treatment tolerance	6 months	Glycerol Phenylbutyrate treatment tolerance assessment at 6 months \[allergy, side effects, amino acid chromatography (glutamine and other amino acid levels) in plasma\].
Treatment compliance	6 months	Glycerol Phenylbutyrate treatment compliance assessment at 6 months.

Trial Locations

Locations (1)

Hôpital Universitaire Necker - Enfants Malades; 🇫🇷 Paris, France