Phase II Multicentric Trial Assessing Efficacy and Safety of Glycerol Phenylbutyrate in Pyruvate Dehydrogenase Deficiency Patients

The primary objective of this clinical trial is the evaluation of the efficacy of **Glycerol Phenylbutyrate** treatment on fatigue at 6 months in patients with **Pyruvate Dehydrogenase Deficiency**. This objective is clinically relevant as fatigue is a significant symptom impacting the quality of life in these patients, and effective management could lead to improved daily functioning and overall well-being.

Secondary objectives include:

• Evaluation of the efficacy of Glycerol Phenylbutyrate treatment on fatigue at 3 months.
• Assessment of its efficacy on polyhandicap at 6 months.
• Evaluation of its impact on neurodevelopmental functioning symptoms, including behavior and learning capacity, at 6 months.
• Assessment of its efficacy on the number of seizures in epileptic patients at 6 months.
• Evaluation of its impact on the quality of life for individuals with polyhandicap at 3 and 6 months.
• Assessment of its efficacy on biological balance by quantifying the decrease in pyruvate and lactate concentrations, and amino acids in plasma at 3 and 6 months.
• Evaluation of treatment tolerance at 3 and 6 months, including allergy, side effects, and amino acid levels in plasma.
• Assessment of treatment compliance by measuring 4-phenylbutyrate levels in plasma at 3 and 6 months.

The clinical trial focuses on evaluating the efficacy of Glycerol Phenylbutyrate treatment on fatigue in individuals with **Pyruvate dehydrogenase deficiency**. The study population includes both male and female participants, ranging from children aged 2 to 17 years and adults aged 18 to 25 years. Participants are required to have a confirmed diagnosis of PDH deficiency through molecular biology, specifically involving certain genetic variants on the PDHA1, PDHB, DLAT, or PDHX genes. The trial includes a vulnerable population, and both genders are represented. Lifestyle considerations such as effective contraception methods are mandated for participants of childbearing potential. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is a **Phase II**, multicentric, prospective, non-comparative study designed to evaluate the efficacy and safety of **glycerol phenylbutyrate** in patients with **pyruvate dehydrogenase deficiency**. The trial will involve participants aged 2 to 25 years, with confirmed genetic mutations associated with the condition. The study will assess the impact of the treatment on fatigue over a period of six months, using the Pediatric Quality of Life Inventory™ Multidimensional Fatigue Scale. The trial is expected to commence recruitment on May 1, 2025, and conclude by November 9, 2026.

Participants will be required to attend several study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific genetic criteria and other inclusion requirements. This will be followed by regular follow-up visits to monitor treatment efficacy and safety, with the primary endpoint being the improvement in fatigue scores by 20% from baseline to six months. The end-of-study visit will mark the completion of the participant's involvement, which is anticipated to last for six months. Conditions that may lead to early termination from the study include non-compliance with the study protocol or withdrawal of consent by the participant or their legal representative.

The trial will utilize **RAVICTI 1.1 g/ml oral liquid**, administered via oral, nasogastric tube, or percutaneous endoscopic gastrostomy tube routes. The maximum daily dose is set at 12 grams, with a total maximum dose of 2196 grams over the treatment period. The study is not classified as low intervention, and it does not include a control group, as it is non-comparative in nature. The trial's primary objective is to evaluate the treatment's efficacy on fatigue, with no secondary endpoints specified. Participants must adhere to effective contraception methods during the study and for seven days after its conclusion.

The clinical trial involves the administration of **RAVICTI 1.1 g/ml oral liquid**, which contains the active substance **glycerol phenylbutyrate**. This experimental medication is provided in an oral liquid pharmaceutical form and is intended for use in the treatment of patients with **pyruvate dehydrogenase deficiency**. The medication can be administered orally, or via a nasogastric tube or percutaneous endoscopic gastrostomy tube. The maximum daily dose is 12 grams, with a total maximum dose of 2196 grams over the course of the treatment period, which is set at a maximum of 6 months. The medication is produced by IMMEDICA PHARMA AB and is classified under the ATC code A16AX09.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The trial is designed to evaluate the efficacy and safety of glycerol phenylbutyrate as a standalone treatment. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial's main objective is to assess the impact of glycerol phenylbutyrate on fatigue in patients over a 6-month period.

The efficacy of Glycerol Phenylbutyrate treatment in patients with **Pyruvate Dehydrogenase Deficiency (PDH)** will be assessed using the Pediatric Quality of Life Inventory™ Multidimensional Fatigue Scale (PedsQL™ MFS). This scale will be utilized to evaluate the primary endpoint, which is the change in fatigue levels over a 6-month period. The efficacy assessment will involve calculating the difference in the total PedsQL™ MFS score between the baseline (M0) and the 6-month mark (M6). A 20% improvement in the overall score from M0 to M6 will be considered indicative of a successful treatment outcome, reflecting a positive impact on fatigue.