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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Glycerol phenylbutyrate cohort | Glycerol Phenylbutyrate was used. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Glycerol phenylbutyrate Oral Liquid | Drug | 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:
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| Measure | Description | Time Frame |
|---|---|---|
| Mean blood ammonia levels at month 3 after enrollment. | The average of blood ammonia levels at months 3 after enrollment. | months 3 |
| Measure | Description | Time Frame |
|---|---|---|
| Mean blood ammonia levels | The average of blood ammonia levels at period of baseline, month 1, month 6, and every 6 months thereafter (1-5 years) | Baseline, Month 1, Month 6, and every 6 months thereafter (1-5 years) |
| Maximum blood ammonia levels |
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Inclusion Criteria:
Exclusion Criteria:
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Long term treatment for pediatric patients with UCD, aged 0-18 years, who cannot be managed with protein restriction and/or amino acid supplementation alone, including carbamoyl phosphate synthetase I deficiency, ornithine carbamoyltransferase deficiency, citrullinemia type I, argininosuccinic aciduria, argininemia, and hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome.
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Xiaoping Luo, M.D. | Contact | 027-83662640 | xpluo@tjh.tjmu.edu.cn |
| Name | Affiliation | Role |
|---|---|---|
| Xiaoping Luo, M.D. | Tongji Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Peking University First Hospital | Recruiting | Beijing | Beijing Municipality | 100034 | China |
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| ID | Term |
|---|---|
| D056806 | Urea Cycle Disorders, Inborn |
| ID | Term |
|---|---|
| D020739 | Brain Diseases, Metabolic, Inborn |
| D001928 | Brain Diseases, Metabolic |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
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| ID | Term |
|---|---|
| C570223 | glycerol phenylbutyrate |
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The maximum blood ammonia levels at period of baseline, month 1, month 3, month 6, and every 6 months thereafter (1-5 years)
| Baseline, Month 1, Month 3, Month 6, and every 6 months thereafter (1-5 years) |
| Frequency of hyperammonaemic crisis | The frequency of hyperammonaemic crisis at period of baseline, month 1, month 3, month 6, and every 6 months thereafter (1-5 years) | Baseline, Month 1, Month 3, Month 6, and every 6 months thereafter (1-5 years) |
| Height | The change of height to the baseline in children aged 0-18 years old, and the proportion of weight in the upper, upper-middle, middle, lower-middle, and lower categories for each age group, according to the growth standards for children under 7 years old (WS/T 423-2022) and standard for height level classification among children and adolescents aged 7~18 years (WS/T 612-2018）issued by the National Health Commission of the People's Republic of China. | Baseline, Month 1, Month 3, Month 6, and every 6 months thereafter (1-5 years). |
| Weight | The change of weight to the baseline in children aged 0-7 years old, and the proportion of weight in the upper, upper-middle, middle, lower-middle, and lower categories for each age group, according to the growth standards for children under 7 years old issued by the National Health Commission of the People's Republic of China (WS/T 423-2022). | Baseline, Month 1, Month 3, Month 6, and every 6 months thereafter (1-5 years) |
| Head circumference | The change of head circumference to the baseline in children aged 0-3 years old, and the proportion of head circumference in the upper, upper-middle, middle, lower-middle, and lower categories for each age group, according to the growth standards for children under 7 years old issued by the National Health Commission of the People's Republic of China (WS/T 423-2022). | Baseline, Month 1, Month 3, Month 6, and every 6 months thereafter (1-5 years) |
| Dose adjustment changes | The changes of dose adjustment in glycerol phenylbutyrate throughout the study | 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 | The neonatal behavioral neurological assessment (NBNA) scale was used for newborn participants who were at least 2 months of age, consisting of 20 items, with a maximum score of 40 points. The total scores of the NBNA are derived from the cumulative sum of the scores obtained in behavioral ability (6 items), passive muscle tone (4 items), active muscle tone (4 items), primitive reflexes (3 items), and general assessment (3 items), which are collected according to the scales have been actually completed by the subjects in the clinical practice. The total scores greater than 37 is considered normal, while a score less than or equal to 37 is considered abnormal. | Month 6, every year thereafter (1-5 years) |
| Mean Bayley Scale of Infant Development Scores: mental scale, motor scale | The Bayley Scale of Infant Development was used for infant participants whose ages range from 2 months to 30 months, consisting of 244 behavioral items, including 163 items on the mental scale and 81 items on the motor scale. The scores of each infant on the mental and motor scales are converted into standard scores with a mean of 100 and a standard deviation of 16 according to age groups, thereby calculating the Mental Development Index (MDI) and the Psychomotor Development Index (PDI). A total score of MDI and PDI, which are collected according to the scales have been actually completed by the subjects in the clinical practice, are less than 70 indicates developmental delay, 70-79 indicates a borderline state, 80-89 indicates low average, 90-109 indicates average, 110-119 indicates high average, 120-129 indicates superior, and a score of 130 or above indicates very superior. | Month 6, every year thereafter (1-5 years) |
| Mean Gesell Developmental Diagnosis Scale Scores | The assessment for Gesell Developmental Diagnosis Scale Scores was used for participants whose ages range from 30 months to 6 years, including five areas: gross motor skills, fine motor skills, adaptive behavior, language, and personal-social behavior. The observed behavioral patterns are identified based on the standard of normal behavioral patterns and are expressed in terms of age. This age is then compared with the actual age to calculate the Developmental Quotient (DQ), which is DQ = Developmental Age / Actual Age × 100, and the values of DQ are collected according to the scales have been actually completed by the subjects in the clinical practice. A DQ of 85 or above is considered normal for the nervous system, a DQ between 75 and 85 (inclusive of 75 but exclusive of 85) indicates a borderline level of nervous system impairment, and a DQ below 75 indicates nervous system damage. | 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 | The Chinese - Wechsler Preschool and Primary Scale of Intelligence (C - WYCSI) was used for children participants whose ages range from 4 to 6 years. The Verbal Intelligence Quotient (VIQ) test includes five subtests: Information, Picture Vocabulary, Arithmetic, Picture Comprehension, and Comprehension. The Performance Intelligence Quotient (PIQ) test includes five subtests: Animal Hatching, Picture Completion, Mazes, Geometric Shapes, and Block Design. The intelligence quotient (IQ) score obtained from the 10 subtests of VIQ and PIQ is the Full Intelligence Quotient (FIQ). The values for VIQ, PIQ and FIQ are collected according to the scales have been actually completed by the subjects in the clinical practice. FIQ is divided into five levels: ≥130 is superior, 116 - 129 is above average, 85 - 115 is average, 70 - 84 is below average, and < 70 is intellectual disability. | Month 6, every year thereafter (1-5 years) |
| Mean Wechsler Intelligence Scale for Children Scores: The Verbal Intelligence Quotient, the Performance Intelligence Quotient | The Chinese-Wechsler intelligence scale of children (C-WISC）was used for participants whose ages range from 7 to 18 years. This scale consists of 11 subtests. The Verbal Intelligence Quotient (VIQ) test includes Information, Comprehension, Similarities, Arithmetic, Digit Span, and Vocabulary. The Performance Intelligence Quotient (PIQ) test includes Picture Completion, Picture Arrangement, Block Design, Object Assembly, and Coding. First, the raw score is calculated based on the test results of the examinee. Then, the corresponding age-specific scale score coefficient is checked and converted into a scale score. The sum of the VIQ and PIQ scale scores is the full intelligence quotient (FIQ) score, which are collected according to the scales have been actually completed by the subjects in the clinical practice. A FIQ of ≥120 is classified as high intelligence, 90-119 is classified as normal intelligence, and a score < 90 is classified as low intelligence. | Month 6, every year thereafter (1-5 years) |
| Guangzhou Women and Children's Medical Center | Recruiting | Guangzhou | Guangdong | 510000 | China |
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| Tongji Hosipital | Recruiting | Wuhan | Hubei | 430030 | China |
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| Xinhua Hospital, Shanghai Jiao Tong University School of Medicine | Recruiting | Shanghai | Shanghai Municipality | 200092 | China |
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| Children's Hospital of Zhejiang University School of Medicine | Recruiting | Hangzhou | Zhejiang | China |
|
| D009422 | Nervous System Diseases |
| D000592 | Amino Acid Metabolism, Inborn Errors |
| D008661 | Metabolism, Inborn Errors |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |