Open-Label Study of Uridine Triacetate in Pediatric Patients With Hereditary Orotic Aciduria

Study Overview
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Brief Summary
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This protocol has two parts - the Main Study which is 42 days in length and the Treatment Extension which allows the patients who complete the Main Study to continue receiving treatment with uridine triacetate. The purpose of this study is to replace oral administration of uridine with oral administration of uridine triacetate in patients with hereditary orotic aciduria who have received (or would reasonably be expected to receive) clinical benefit from treatment with exogenous uridine. It is also to document the continued clinical benefit of exogenous uridine when patients are switched from oral administration of uridine to oral administration of uridine triacetate.

Detailed Description
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Data to be collected during the Main Study include demographic, baseline disease information and medical history including all prior disease-directed therapy. In addition, vital signs, laboratory values and adverse events information will be collected and recorded. Urine samples will be obtained and measured for orotic acid and orotidine levels. Systemic levels of uridine will be evaluated from plasma samples collected at set timepoints. Upon successful completion of the Main Study and entry into the Treatment Extension, physical exams and vital signs will be performed every six (6) months. Additionally, plasma samples to measure systemic levels of uridine and urine samples to measure levels of orotic acid and orotidine will be collected every (6) six months.

Official Title
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Open-Label Study of Uridine Triacetate in Pediatric Patients With Hereditary Orotic Aciduria

Conditions
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Hereditary Orotic Aciduria

Intervention / Treatment
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* Drug: uridine triacetate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (Main Study): Patients with diagnosed hereditary orotic aciduria Judged by the investigator to have the initiative and means to be compliant with the protocol Able to take oral medications Able to provide written informed consent (patient or legally authorized representative) Females of childbearing potential must have a negative pregnancy test at screening Females of childbearing potential or males with partners of childbearing potential are to use one of the following acceptable birth control methods: Surgically sterile or partner is surgically sterile Using adequate contraception (hormonal contraceptives, double barrier methods, or intra-uterine devices) Patients who claim to be sexually inactive agree to use an acceptable method of contraception should she or he become sexually active from 14 days prior to first dosing, throughout the study and for 14 days after the last dose administration Exclusion Criteria (Main Study): Has a known allergy to uridine triacetate or any of its excipients Known to have ornithine transcarbamoylase deficiency Unable to have the initiative and means to be compliant with the protocol Unable to be compliant with taking oral medications Unable to provide written informed consent (patient or legally authorized representative) Female who is pregnant or lactating Inclusion Criteria (Treatment Extension) Patient successfully completed the Main Study Exclusion Criteria (Treatment Extension) Patient did not successfully complete the Main Study

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Uridine Triacetate to Replace Uridine<br>Replacement therapy for oral uridine with oral administration of uridine triacetate in patients with hereditary orotic aciduria who have received (or would reasonably be expected to receive) clinical benefit from treatment with exogenous uridine. The starting dose of uridine triacetate will be 60 mg/kg/day which may be escalated to 300 mg/kg/day of oral uridine triacetate. The dose may be given once a day or as equally divided doses twice a day. | Drug: uridine triacetate<br> <br> * Other names: 2',3',5'-tri-O-acetyluridine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients With Stable Predetermined Principal Hematologic Parameters | Hereditary orotic aciduria patients will be taking uridine triacetate as replacement therapy for uridine. The primary outcome measure will be based on predetermined principal hematologic parameter(s) based on the patient's response(s) to oral uridine when dosing is switched from oral uridine to oral uridine triacetate. The primary outcome measure in patients not previously receiving uridine replacement therapy will be improvement in the patient's principal affected hematologic parameter(s) on Days 28 and 42 compared to baseline (Day 0) of the Main Study. | Days 28 and 42 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients With Stable or Improved Orotic Acid and Orotidine Levels | Significantly elevated urine orotic acid levels are characteristic of patients with HOA. Therefore, urinary orotic acid and orotidine levels were assessed in patients at baseline (on uridine or uridine naïve) and on Day 28 and Day 42 following the switch to uridine triacetate. The table below shows the number of participants with stable or improved orotic acid and orotidine levels at Day 28 and Day 42 compared to baseline. | Days 28 and 42 | 
| Patients With Levels of Uridine in the Plasma Consistent With Expected Therapeutic Benefit | HOA is principally a chronic uridine deficiency disorder. The purpose of uridine triacetate administration is to provide an exogenous source of uridine. Therefore, plasma uridine levels were assessed at various time points (prior to dosing, 30 min, 1 hour, 2 hours, 4 hours, 6 hours and 8 hours) following uridine triacetate dosing to ensure levels of uridine consistent with previously observed symptomatic improvement from administration of uridine were achieved. The table below shows the number of participants with uridine levels consistent with or exceeding previously observed symptomatic improvements. | Days 1 and 28 |