Type 1 Primary Hyperoxaluria
Conditions
Brief summary
This study is a single-arm, open-label, single-dose, dose-escalation trial, aiming to evaluate the safety and tolerability of YOLT-203 in the Chinese population with type 1 primary hyperoxaluria (PH1); and to preliminarily assess the effect of a single dose of YOLT-203 on the plasma oxalate level.In this study, the maximum screening period of the main study is 60 days, the treatment day is Day 1 (D1), and the safety follow-up period is up to Week 52 after administration. In addition, subjects within the first dose group can voluntarily receive a second treatment with the test drug at the effective dose level. After the end of the main study, the subjects will undergo long-term followup. According to the requirements of the Technical Guidelines for Long-Term Follow-up Clinical Studies of Gene Therapy Products (Trial) issued by the CDE, the long-term follow-up is up to 15 years after administration. The most updated protocol is V1.2 , 22 Jan 2025
Interventions
DRUGYOLT-203
The IP is administered intravenously at the predetermined dose.
Sponsors
Guangzhou Women and Children's Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
0.45mg/kg
Eligibility
Sex/Gender
ALL
Age
2 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
* The age is 2≤ years \<18 years old at the time of signing the informed consent. * Have AGXT gene mutations and be diagnosed with primary hyperoxaluria (PH1); eGFR ≥ 30 ml/min/1.73m2. * At least 2 times of 24-hour urinary oxalate excretion ≥ 0.7 mmol/1.73m2/ day or the ratio of urinary oxalate to creatinine in a single urine collection must be higher than the upper limit of normal (ULN) for the corresponding age. * If treated with vitamin B6, the treatment has been stable for 90 days before enrollment in the study and is willing to maintain the stable treatment plan unchanged during the study. * The patient himself/herself or the guardian voluntarily signs the informed consent.
Exclusion criteria
* The investigator judges that there is clinical evidence of systemic extrarenal oxalate deposition. * Have any of the following laboratory parameter assessment results at screening: 1. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 2 x the upper limit of normal (ULN). 2. Total bilirubin \> 1.5 x ULN. If the increase in total bilirubin is caused by diagnosed Gilbert's syndrome and the total bilirubin \< 2 x ULN, it is eligible. 3. International normalized ratio (INR) \> 1.5 (Patients on oral anticoagulants \[such as warfarin\] and with INR \< 3.5 will be allowed to participate). * Known to have active human immunodeficiency virus (HIV) infection; or have evidence of current or chronic hepatitis C virus (HCV) or hepatitis B virus (HBV) infection. * The estimated glomerular filtration rate (GFR) at screening is less than 30 mL/min/1.73m² (For patients ≥ 18 years old, it will be calculated according to the Modification of Diet in Renal Disease \[MDRD\] formula; for patients \< 18 years old, it will be calculated according to the Schwartz bedside formula). See the attachment. * Have received an investigational drug within the last 30 days or 5 halflives (whichever is longer) before the first administration of the study drug, or have participated in the follow-up of another clinical study before randomization. * Have a history of kidney or liver transplantation. * According to the investigator's opinion, have other medical conditions or comorbidities that may interfere with study compliance or data interpretation. * Page 4 of 5 \[DRAFT\] - * Have a history of multiple drug allergies or allergic reaction history to oligonucleotides or LNP. * Have a history of subcutaneous injection intolerance. * Unwilling to comply with contraceptive requirements throughout the study participation period until 6 months after the end of the main study trial. * Female patients are pregnant, planning to become pregnant or breastfeeding. * Unwilling or unable to limit alcohol consumption throughout the study. Alcohol consumption during the study exceeds 2 units per day (1 unit: approximately 125 ml of wine = approximately 29 ml of spirits = approximately 284 ml of beer, will be excluded. * The investigator believes that there is a history of alcohol abuse within 12 months before screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment-Emergent Adverse events | through week 52 | An Adverse Event(AE) is any untoward medical occurrence in a participant or clinical investigational participant adminstered a medicinal product and which does not necessarily have a casual relationship with this treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area under the plasma concentration versus time curve (AUC)of YOLT-203 | through Day 14 | Area under the plasma concentration versus time curve (AUC). 0.5 predose,6,24,48,144,and312 hours after treatment |
| Time to Maximum Plasma Concentration (Tmax)of YOLT-203 | through Day 14 | Tmax is the time it takes for YOLT-203 to reach the maximun concentration (Tmax) after administration |
| Drug half-life (T1/2)of YOLT-203 | through Day 14 | The amount of time it takes for the plasma YOLT-203 drug concentration to drop to half |
| The Peak Plasma Concentration (Cmax) of YOLT-203 | through Day 14 | The Peak Plasma Concentration (Cmax) of YOLT-203 in the plasma after a dose is given |
| The changes in 24-hour urinary oxalic acid excretion | through week 52 | After medication, at 1,2,4, 8, 16, 24, 36and 52 weeks, the changes in 24-hour urinary oxalic acid excretion compared to the baseline value. |
| The changes in 24-hour urinary glycolic acid excretion | through week 52 | After medication, at 1, 2, 4, 8, 16, 24, 36, and 52 weeks, the changes in 24-hour urinary glycolic acid excretion |
| The changes in eGFR | through week 52 | After medication, at 1, 2, 4, 8, 16, 24, 36, and 52 weeks, the changes in eGFR. |
| The changes in blood glycolic acid levels | through week 52 | After medication, at 1, 2, 4, 8, 16, 24, 36, and 52 weeks, the changes in blood glycolic acid levels |
Countries
China
Outcome results
None listed