Phase 3 Randomized Double-blind Placebo-controlled Study of Avalotcagene Ontaparvovec Gene Transfer in Late-onset Ornithine Transcarbamylase Deficiency
- Trial ID
- 2024-514337-38-00
- Protocol
- DTX301-CL301
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of DTX301, a gene therapy product, in improving the function of **Ornithine Transcarbamylase (OTC)** by maintaining safe plasma ammonia levels in patients with late-onset OTC deficiency. This is clinically relevant as maintaining safe plasma ammonia levels is crucial for preventing the neurological and metabolic complications associated with OTC deficiency.
Secondary objectives include:
- To evaluate the efficacy of DTX301 in three response categories.
- To assess the effect of DTX301 on health outcomes in patients with OTC deficiency.
- To evaluate the effect of DTX301 on the occurrence of hyperammonemic crises (HACs).
- To assess the effect of DTX301 on plasma ammonia levels over time.
- To evaluate the safety of DTX301.
- To characterize the immune response to the OTC protein, specifically the presence of anti-OTC antibodies.
Participants
The clinical trial involves a total of **22 participants** diagnosed with **late-onset Ornithine transcarbamylase (OTC) deficiency**. The study population includes both male and female subjects aged 12 years and older. Participants were selected based on a confirmed clinical diagnosis of late-onset OTC deficiency, with historical documentation through enzymatic, biochemical, or molecular testing. The trial includes individuals who are currently receiving ammonia scavenger therapy and/or adhering to a protein-restricted diet, ensuring they are free from symptomatic hyperammonemia and have not required emergent intervention for hyperammonemia within four weeks prior to screening. Participants must be on a stable dose of ammonia scavenger therapy or a stable protein-restricted diet for at least four weeks before screening. The trial population is characterized by their ability to comply with study procedures, including periodic inpatient hospitalizations and frequent blood and urine collections. The study also includes vulnerable populations, ensuring that minors have a caregiver willing to assist with study requirements. The trial does not specify any particular lifestyle considerations beyond the dietary and therapeutic requirements mentioned.
Plans and Procedures
The clinical trial is a **Phase 3**, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy of **avalotcagene ontaparvovec** in patients with late-onset **Ornithine transcarbamylase (OTC) deficiency**. The primary objective is to assess the improvement of OTC function by maintaining safe plasma ammonia levels. The trial is expected to run until March 2031, with recruitment having commenced in August 2022. Participants will be randomly assigned to receive either the investigational gene therapy or a placebo, with the study employing a double-blind design to ensure unbiased results.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, clinical diagnosis, and current treatment regimen. The trial includes multiple follow-up visits to monitor safety and efficacy, with key assessments occurring at Week 64. The end-of-study visit will conclude the participant's involvement, with the total duration of participation expected to be approximately 64 weeks. Conditions that may lead to early termination from the study include non-compliance with study procedures, adverse events, or withdrawal of consent.
Throughout the trial, participants will be required to adhere to study protocols, including the use of highly effective contraception for those of childbearing potential, and compliance with dietary and medication regimens. The study will measure primary endpoints such as plasma ammonia levels and the percentage of patients achieving a complete response. Secondary endpoints will include changes in plasma ammonia, incidence of adverse events, and development of anti-OTC antibodies. The trial aims to provide comprehensive data on the safety and efficacy of the investigational therapy in managing late-onset OTC deficiency.
Treatment
The clinical trial involves the administration of **Avalotcagene ontaparvovec**, a recombinant adeno-associated virus serotype 8 (AAV8) vector encoding the human ornithine transcarbamylase (OTC) gene. This experimental medication is provided as a **solution for infusion** and is administered via **intravenous infusion**. The maximum daily and total dose is 60 ml, with a treatment period limited to a single day. Avalotcagene ontaparvovec is classified as a structurally diverse substance and is not a paediatric formulation. The product is developed by Ultragenyx Pharmaceutical Inc. and is designated as an orphan drug under the number EU/3/16/1623.
**Prednisolone** is used as a non-experimental treatment in the study, available in two formulations: Prednisolon STADA® 5 mg and 10 mg tablets. Both formulations are administered **orally**. The maximum daily dose for each is 60 mg, with a total dose not exceeding 2230 mg over a treatment period of 58 days. Prednisolone is a chemical substance, and the tablets have been re-encapsulated for blinding purposes and relabeled. The manufacturer of these tablets is Stadapharm GmbH.
**Normal Saline** is utilized as an auxiliary treatment in the trial. It serves as a standard diluent or placebo in various clinical settings. However, specific details regarding its pharmaceutical form, route of administration, and dosing schedule are not provided in the trial documentation.
**[1-13C]Sodium Acetate** is included as an auxiliary treatment, functioning as a chemical isotopic tracer. It is provided as an **oral solution** and administered **orally**. The maximum daily dose is 50 ml, with a total dose of 300 ml over a 64-day treatment period. This product is also developed by Ultragenyx Pharmaceutical Inc.
A **Prednisolone placebo** is employed in the study to maintain the double-blind design. It is available in the form of hard capsules and tablets. Specific details regarding its pharmaceutical form, route of administration, and dosing schedule are not disclosed in the trial documentation.
Efficacy
The efficacy of the investigational product **Avalotcagene ontaparvovec** in the treatment of late-onset ornithine transcarbamylase (OTC) deficiency will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoint is the measurement of plasma ammonia levels, specifically the 24-hour ammonia area under the curve (AUC0-24) at Week 64. This will be evaluated using the geometric mean ratio to test for noninferiority between the treatment group receiving DTX301 and the placebo group. Additionally, the percentage of patients achieving a complete response at Week 64 will be assessed for superiority.
Secondary endpoints include the percentage of patients achieving complete response, response, or no response at Week 64, as well as the PGIC-Overall Change score at the same time point. The rate of hyperammonemic crises (HACs) from baseline to Week 64 will be compared to the 15-month pre-enrollment period. Changes in plasma ammonia (AUC0-24) from baseline to Week 64 will also be analyzed, along with the incidence of treatment-emergent adverse events (TEAEs), serious adverse events (TESAEs), and the development of anti-OTC antibodies. Clinically significant changes in laboratory values, physical examination results, and vital sign measurements will be monitored throughout the study.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female patient 12 years of age or older at the time of signed informed consent.
- Provide informed consent after the nature of the study has been explained, and prior to any research-related procedures. If a minor, be willing and able (if possible) to provide assent and have a legally authorized representative provide informed consent after the nature of the study has been explained and prior to any research-related procedures.
- Confirmed clinical diagnosis of late-onset OTC deficiency with historical documentation by enzymatic (ie, liver biopsy), biochemical (ie, hyperammonemia in the presence of elevated plasma glutamine, low citrulline, and elevated spot urine orotic acid), or molecular testing (ie, OTC analysis).
- Documented history of ≥ 1 symptomatic hyperammonemia episode with ammonia level ≥ 100 μmol/L for confirmation of clinical disease.
- Patient is currently receiving ammonia scavenger therapy and/or protein-restricted diet, is free from symptomatic hyperammonemia, and has not required emergent active intervention for hyperammonemia within 4 weeks before screening/baseline.
- Plasma 24-hour ammonia (AUC0-24) is ≤ 4800 μmol*h/L at screening. If the ammonia AUC0-24 is inconsistent with the patient’s clinical status, the assessment may be repeated to ensure accurate results.
- If on ongoing daily ammonia scavenger therapy, must be at stable daily dose(s) for ≥ 4 weeks prior to screening
- If on a protein-restricted diet, must be on a stable protein-restricted diet as evidenced by a stable amount of total protein intake (ie, daily protein intake in grams per day does not vary more than 20%) for ≥ 4 weeks prior to screening.
- Willing and able to comply with study procedures and requirements, including periodic inpatient hospitalizations, frequent blood and urine collections, blood collections over a 24-hour period, questionnaires, cognitive assessments, and patient/caregiver reported outcome assessments. If a minor, must have a caregiver(s) willing and able to assist in all applicable study requirements.
- From the time written informed consent is provided through Week 28, females of childbearing potential and fertile males must consent to use highly effective contraception as defined by the United States Food and Drug Administration (FDA) and Clinical Trial Facilitation Coordination Group (CTFG) Recommendations Related to Contraception and Pregnancy in Clinical Trials. If female, agree not to become pregnant. If male, agree to not father a child or donate sperm.
Exclusion Criteria
- Liver transplant, including hepatocyte cell therapy/transplant.
- History of liver disease as evidenced by any of the following: portal hypertension, ascites, splenomegaly, esophageal varices, hepatic encephalopathy, or a liver biopsy with evidence of stage 3 fibrosis.
- Significant hepatic inflammation or cirrhosis as evidenced by imaging or any of the following laboratory abnormalities: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 × ULN, total bilirubin > 1.5 × ULN (except if patient has a diagnosis of Gilbert’s syndrome), alkaline phosphatase > 2.5 × ULN. Note: Any of the LFTs may be retested.
- Estimated glomerular filtration rate < 60 mL/min/1.73 m2 at screening by the CKD-EPI 2021 creatinine-based formula (Inker et al., 2021) for patients ≥ 18 years of age or the Schwartz bedside formula (Schwartz and Work, 2009) for patients < 18 years of age.
- Evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection documented by current use of antiviral therapy for HBV or HCV or by hepatitis B surface antigen (HBsAg) or HCV RNA positivity. Note: Patients with a history of HCV infection must have documentation of 2 negative viral assays by PCR collected at least 6 months apart to be considered negative for HCV. Patients with a history of HCV infection who test positive for HCV RNA at screening can be rescreened once after they have been treated and have documentation of at least 2 negative samples collected at least 6 months apart.
- History of human immunodeficiency virus (HIV) infection AND any of the following: CD4+ cell count < 350 cells/mm3, change in antiretroviral therapy regimen within 6 months prior to Baseline (Day 0), or plasma viral load > 200 copies/mL, documented on 2 separate occasions, as measured by PCR.
- Active infection (viral or bacterial).
- Detectable pre-existing antibodies to the AAV8 capsid.
- History of a malignancy for which the patient has received treatment in the past 2 years, except for prostate cancer treated with watchful waiting or surgically removed nonmelanoma skin cancer.
- Any of the following that, in the judgment of the Investigator, places the patient at increased risk for adverse effects: - Known hypersensitivity to DTX301, its excipients, or its placebo - Known hypersensitivity to prednisolone, its excipients, or its placebo
- Chronic use of inhibitors of urea synthesis (eg, valproic acid) or drugs that significantly affect renal clearance (eg, probenecid).
- Presence or history of any condition that, in the view of the Investigator, would interfere with participation, pose undue risk, or confound interpretation of results, including but not limited to: - Underlying conditions that may require systemic corticosteroids if the condition worsens (eg, autoimmune disorders) - Patients in a catabolic state (eg, due to current infection), or in whom a catabolic state may be reasonably foreseeable (eg, due to planned procedures) - Patient is considered vulnerable by local regulations (eg, imprisoned or institutionalized)
- Marked neurological deficit or compromise that, in the Investigator’s opinion, would interfere with the patient’s safety or ability to participate in the study.
- Pregnant or breastfeeding or planning to become pregnant within 64 weeks after receiving DTX301 (ie, through Visit 28 of this study).
- Participation (current or previous) in another gene transfer study.
- Use of any investigational product within 3 months prior to screening, or during the study.
- Patients who meet any of the following criteria are not eligible to undergo the URT: - Unable to fast safely for 12 hours - History of HAC triggered by minimal vomiting - Age < 18 years at screening Note: Any patient < 18 years of age at screening will not undergo ureagenesis rate testing for the duration of study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 25 Aug 2022 | 4 |
 Germany | Not Recruiting | 25 Aug 2022 | 8 |
 Italy | Not Recruiting | 25 Aug 2022 | 6 |
 The Netherlands | Not Recruiting | 25 Aug 2022 | — |
 Portugal | Not Recruiting | 25 Aug 2022 | 4 |
 Spain | Not Recruiting | 25 Aug 2022 | 3 |
| Netherlands | — | — | 7 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Prednisolon STADA® 5 mg Tabletten | Other | TABLETTEN | ORAL | 60 | 58 | PRD514378 |
Prednisolone placebo hard capsule and tablet | Placebo | N/A | — | — | — | N/A |
Normal Saline | Placebo | N/A | — | — | — | N/A |
Prednisolon STADA® 10 mg Tabletten | Other | TABLETTEN | ORAL | 60 | 58 | PRD394471 |
[1-13C]SODIUM ACETATE | Test | ORAL SOLUTION | ORAL | 50 | 64 | PRD10066517 |
Avalotcagene ontaparvovec | Test | SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 60 | 1 | PRD7389680 |