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

Official title

A Single-arm, Prospective, Multi-center Post-market Clinical Study of Glycerol Phenylbutyrate in Chinese Patients With Urea Cycle Disorders

Overview

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.

Detailed description

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.

Interventions

• Drug Glycerol phenylbutyrate Oral Liquid
  Administration and dosage: The recommended total daily dose of glycerol phenylbutyrate is calculated based on the patient's body surface area, ranging from 4.5 mL/m2/d to 11.2 mL/m2/d: 1. Recommended initial dose in phenylbutyrate-naïve patients * Patients with body surface area (BSA) \< 1.3 m2: 8.5 mL/m2/day * Patients with body surface area (BSA) ≥ 1.3 m2: 7 mL/m2/day 2. Initial dose for patients switching from sodium phenylbutyrate to glycerol phenylbutyrate: Total daily dose of glyce

Primary outcome measures

• Mean blood ammonia levels at month 3 after enrollment. [Time frame: months 3]

Secondary outcome measures (12)

• Mean blood ammonia levels [Time frame: Baseline, Month 1, Month 6, and every 6 months thereafter (1-5 years)]
• Maximum blood ammonia levels [Time frame: Baseline, Month 1, Month 3, Month 6, and every 6 months thereafter (1-5 years)]
• Frequency of hyperammonaemic crisis [Time frame: Baseline, Month 1, Month 3, Month 6, and every 6 months thereafter (1-5 years)]
• Height [Time frame: Baseline, Month 1, Month 3, Month 6, and every 6 months thereafter (1-5 years).]
• Weight [Time frame: Baseline, Month 1, Month 3, Month 6, and every 6 months thereafter (1-5 years)]
• Head circumference [Time frame: Baseline, Month 1, Month 3, Month 6, and every 6 months thereafter (1-5 years)]
• Dose adjustment changes [Time frame: Baseline, Month 1, Month 3, Month 6, and every 6 months thereafter (1-5 years)]
• Mean Neonatal Behavioral Neurological Assessment Scores: Behavioral ability, passive muscle tone, active muscle tone, primitive reflexes, and general assessment [Time frame: Month 6, every year thereafter (1-5 years)]
• Mean Bayley Scale of Infant Development Scores: mental scale, motor scale [Time frame: Month 6, every year thereafter (1-5 years)]
• Mean Gesell Developmental Diagnosis Scale Scores [Time frame: Month 6, every year thereafter (1-5 years)]
• Mean Wechsler Preschool and Primary Scale of Intelligence Scores: The Verbal Intelligence Quotient, the Performance Intelligence Quotient [Time frame: Month 6, every year thereafter (1-5 years)]
• Mean Wechsler Intelligence Scale for Children Scores: The Verbal Intelligence Quotient, the Performance Intelligence Quotient [Time frame: Month 6, every year thereafter (1-5 years)]

Eligibility criteria

Inclusion criteria

• Male or female aged 0-18 years;
• 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;
• 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;
• Patients planned to use glycerol phenylbutyrate who have not used it in past 3 months (including at the time of 3 months);
• 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

• Hypersensitivity to any of the active ingredient, including phenylbutyrate (PBA), phenylacetate acid (PAA) and phenylacetyl glutamine (PAGN), or excipients;
• 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;
• Use of other nitrogen-scavenging agent at the same time after enrollment, such as sodium phenylbutyrate and sodium benzoate;
• Pregnant or breastfeeding females.
• Other reasons, in the opinion of the investigator, that may affect the patient's compliance and safety in participating in the study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

China · 5 centers

• Peking University First Hospital — Beijing
• Guangzhou Women and Children's Medical Center — Guangzhou
• Tongji Hosipital — Wuhan
• Xinhua Hospital, Shanghai Jiao Tong University School of Medicine — Shanghai
• Children's Hospital of Zhejiang University School of Medicine — Hangzhou

Identifiers

NCT: NCT06904027 · WH002A401

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗