A Clinical Study of Glycerol Phenylbutyrate in Chinese Patients With Urea Cycle Disorders

Urea cycle disorders (UCD) are rare diseases in China, would lead to high mortality and disability, which require long-term management due to the recurrent symptoms. This multi-center, prospective, single-arm study was designed to assess the efficacy and safety of Glycerol Phenylbutyrate for Chinese pediatric patients with UCD, to provide the additional references and treatment options for Chinese UCD patients, and enhance the clinical management of UCD in China. This study primarily observes patients with UCD who are on long-term treatment with glyceryl phenylbutyrate, the total planned observation period is 5 years.

The duration of treatment with GPB in this study was 5 years. Forty participants aged 0-18 years with a diagnosis of UCD, including carbamoyl phosphate synthetase I deficiency, ornithine carbamoyltransferase deficiency, citrullinemia type I, argininosuccinic aciduria, argininemia, or hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, and who plan to use and have not used glycerol phenylbutyrate in the previous 3 months (including 3 months) were enrolled. Participants should return to clinic visits at 1 month and 3 months after enrollment. They were queried about any adverse events (AEs), dosage change of the study drug or hyperammonemic crises (HACs) that occurred since the last visit, and blood samples were collected for the analysis of ammonia and blood biochemistry. Then the detailed information on AEs, dosage change of the study drug, HACs, and data about ammonia, routine clinical laboratory safety tests and neurocognitive outcomes that have been actually completed in the clinical practice of the patients will be collected every 6 months until 5 years. Height, weight and/or head circumference data were also collected at each visit. The assessments would be conducted at 1, 3, and 6 months, and subsequently on a semi-annual basis. The evaluation of ammonia levels, frequency of HACs, dosage of the study drug, AEs, serious AEs, and concomitant medications were included. The neurocognitive outcomes, growth and development of the participants would be described at the end.

Eligibility Criteria:
Inclusion Criteria:

1. Male or female aged 0-18 years;
2. Subject and/or subject's legally authorized representative willing to follow the therapeutic regimen, dietary management and visit plan of the study, and voluntarily signing informed consent form;
3. Patients with the following subtypes of UCD: Carbamoyl phosphate synthetase I deficiency, Ornithine translocase deficiency, citrullinemia type I, argininosuccinic aciduria, argininemia, and hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome;
4. Patients planned to use glycerol phenylbutyrate who have not used it in past 3 months (including at the time of 3 months);
5. Men with fertility and women of childbearing potential (with menstruation) who are willing to take effective contraceptive measures during the period from the date of signing the informed consent to 1 months after the last dose of the study drug, such as abstinence, condoms, intra-uterine contraceptive devices, and double barrier methods (such as condoms + contraceptive diaphragms). Pregnancy test results must be negative for women of childbearing age within ≤ 7 days before the initial administration of study drug.

Exclusion Criteria:

1. Hypersensitivity to any of the active ingredient, including phenylbutyrate (PBA), phenylacetate acid (PAA) and phenylacetyl glutamine (PAGN), or excipients;
2. Use of any drug known to significantly affect renal clearance (such as probenecid) or increase protein catabolism (such as corticosteroids) or other drugs known to increase blood ammonia levels (such as valproate) within 24 h before the first administration;
3. Use of other nitrogen-scavenging agent at the same time after enrollment, such as sodium phenylbutyrate and sodium benzoate;
4. Pregnant or breastfeeding females.
5. Other reasons, in the opinion of the investigator, that may affect the patient's compliance and safety in participating in the study.