Phase 3 Randomized Double-Blind Placebo-Controlled Trial of Pariglasgene Brecaparvovec in Glycogen Storage Disease Type Ia Patients
- Trial ID
- 2023-508750-25-00
- Protocol
- DTX401-CL301
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 3, randomized, double-blind, placebo-controlled study is to evaluate the **efficacy** of DTX401, an adeno-associated virus serotype 8-mediated gene transfer, in reducing or eliminating the dependence on exogenous glucose replacement therapy required to maintain glucose control in patients with **Glycogen Storage Disease Type Ia (GSDIa)**. This is clinically relevant as it addresses a critical aspect of disease management, potentially reducing the burden of frequent glucose supplementation and improving patient quality of life.
Secondary objectives include:
- To evaluate the effect of DTX401 on reducing the frequency of exogenous glucose replacement therapy.
- To assess the impact of DTX401 on glucose control.
- To evaluate the effect of DTX401 on the subject's experience of the disease.
- To evaluate the safety of DTX401.
Participants
The clinical trial involves a total of **27 participants** diagnosed with **Glycogen Storage Disease Type Ia (GSDIa)**. The study population includes both male and female subjects aged 8 years and older. Participants were selected based on a confirmed diagnosis of GSDIa, either through deficient enzymatic activity identified via liver biopsy or molecular testing of the G6PC gene revealing two pathogenic mutations. The trial includes individuals who are currently on a stable therapeutic regimen of cornstarch or its equivalent, adhering to international guidelines, with consistent nutritional and glycemic status. Participants are required to maintain a stable intake of carbohydrates and demonstrate controlled blood glucose levels, as evidenced by continuous glucose monitoring. The study population is characterized by their ability to comply with study procedures, including frequent blood collection and the use of a continuous glucose monitoring device. Both male and female subjects of childbearing potential are required to use highly effective contraception throughout the study duration. The trial also includes a vulnerable population, ensuring that all participants, or their guardians if under 18, provide informed consent or assent as appropriate.
Plans and Procedures
The clinical trial is a **Phase 3**, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of DTX401 in patients with **Glycogen Storage Disease Type Ia (GSDIa)**. The primary objective is to assess the ability of DTX401 to reduce or eliminate the need for exogenous glucose replacement therapy. The trial is expected to enroll approximately 50 participants, with an estimated recruitment start date of July 15, 2021, and an anticipated end date of December 17, 2025. The study involves the administration of **Pariglasgene brecaparvovec** via intravenous infusion, with a maximum treatment period of one day, and the use of **Prednisolone** in tablet form for blinding purposes.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as age, confirmed diagnosis of GSDIa, and stable clinical status. Following randomization, participants will attend regular follow-up visits to monitor safety and efficacy outcomes, including changes in daily cornstarch intake and glucose levels. The primary endpoint is the percent change from baseline to week 48 in daily cornstarch intake for the DTX401 group compared to the placebo group. Secondary endpoints include changes in the number of daily cornstarch doses, glucose values, and patient-reported outcomes.
The expected length of participant involvement is approximately 48 weeks, with conditions for early termination including adverse events, non-compliance with study procedures, or withdrawal of consent. Participants are required to adhere to study protocols, including the use of continuous glucose monitoring devices, completion of electronic diaries, and compliance with prednisolone/placebo prescriptions. The study is conducted under strict ethical guidelines, ensuring informed consent and the use of effective contraception for participants of childbearing potential throughout the study duration.
Treatment
The clinical trial involves the administration of several treatments, including **Prednisolone** and **Pariglasgene brecaparvovec**, as well as their respective placebos. **Prednisolone** is provided in two dosages: 10 mg and 5 mg, both in tablet form. The 10 mg tablets are marketed under the name "Prednisolon STADA® 10 mg Tabletten" and the 5 mg tablets as "Prednisolon STADA® 5 mg Tabletten." These tablets are administered orally, with a maximum daily dose of 60 mg and a total maximum dose of 2230 mg over a treatment period of up to 58 days. The tablets have been re-encapsulated for blinding purposes and are labeled accordingly. The active substance, **Prednisolone**, is of chemical origin and is manufactured by STADAPHARM GMBH.
The study also includes a placebo group receiving "Prednisolone placebo hard capsule" in both 10 mg and 5 mg dosages. These placebos are designed to match the active treatment in appearance and are used to maintain the double-blind nature of the trial. The placebo capsules do not contain any active substance and are administered in a similar manner to the active treatment.
**Pariglasgene brecaparvovec** is another experimental treatment used in this trial. It is provided as a solution for infusion and is administered intravenously. The product is identified by the sponsor product code "DTX401, AAV8G6PC" and is manufactured by Ultragenyx Pharmaceutical Inc. The maximum daily and total dose is 32 ml, with a treatment period limited to a single administration. This gene therapy product is an adeno-associated viral vector serotype 8 containing the human glucose-6-phosphatase gene, designed to address Glycogen Storage Disease Type Ia.
Additionally, a placebo for the **Pariglasgene brecaparvovec** treatment is included in the study, referred to as "Normal Saline." This placebo is used to ensure the integrity of the double-blind study design and is administered in the same manner as the active infusion.
Efficacy
The efficacy of the investigational product, **DTX401**, in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the percent change from baseline to week 48 in daily cornstarch intake for the DTX401 group compared with the placebo group. This endpoint is designed to evaluate the reduction or elimination of dependence on exogenous glucose replacement therapy in patients with Glycogen Storage Disease Type Ia (GSDIa).
Secondary endpoints include several measures to further assess the efficacy of DTX401. These include the change from baseline to week 48 in the number of total daily doses of cornstarch, and the change in the percentage of glucose values in the hypoglycemic range (<70 mg/dL), which will be assessed for non-inferiority and, if established, tested for superiority. Additionally, the Patient Global Impression of Change (PGIC) assessment score at week 48 will be evaluated. Other secondary endpoints involve the change from baseline to week 48 in time to hypoglycemia (<54 mg/dL) during the controlled fasting challenge (CFC), and the change in the percentage of glucose values in the range of 70-120 mg/dL, also assessed for non-inferiority and potential superiority. The incidence, severity, and relationship to the investigational product of treatment-emergent adverse events (TEAEs), serious TEAEs, and discontinuations due to adverse events will also be monitored.
These efficacy parameters will be measured and collected at specified time points, with the primary endpoint evaluated at week 48. The use of continuous glucose monitoring (CGM) and self-monitoring of blood glucose (SMBG) will be employed to corroborate glucose levels, ensuring accurate and reliable data collection throughout the study. The analysis of these endpoints will provide comprehensive insights into the efficacy of DTX401 in managing GSDIa.
Inclusion and Exclusion Criteria
Inclusion Criteria
- "1. Male and female patients ≥ 8 years of age at time of informed consent or assent. 2. Subject has a diagnosis of GSDIa confirmed by deficient enzymatic activity (on liver biopsy), or by molecular testing of G6PC gene revealing 2 pathogenic mutations. In the case where only a single pathogenic mutation is identified, clinical diagnosis is compatible with GSDIa and absence of characteristic features of GSDIb (ie, chronic neutropenia, inflammatory bowel disease). 3. Subject is currently receiving a therapeutic regimen of cornstarch (or equivalent), following international guidance/recommendations (Appendix 1) with stable nutrition, glycemic, and clinical status as evidenced by: a. no more than a 10% variation in weekly average daily cornstarch (or equivalent) intake over the last 4 weeks. b. no more than a 25% variation in weekly average daily non-cornstarch carbohydrate over the last 4 weeks. c. No more than 15% variation in weekly percentage of values in the target blood glucose range (60-120 mg/dL) over the last 4 weeks as measured by CGM and corroborated by SMBG. If adequate corroboration is not observed, this assessment should be made by SMBG. d. No hospitalization for hypoglycemia and no severe hypoglycemic event (SHE) during the 4-week period preceding randomization and dosing (see Section 10.4.2 for more detail on SHE), notwithstanding events of hypoglycemia due to unavoidable and unforeseeable events (eg, infection, trauma) that transiently prevent the subject from tolerating enteral intake or acutely change the subject's metabolic demands, provided that the subject quickly returns to their prior physiologic state. 4. Subject is willing 4. Subject is willing and able to comply with study procedures, requirements, and study medication, including periodic inpatient hospitalization or admission in a research facility; CFC studies; frequent blood collection; wearing a CGM device for the duration of the study (and excluding the use of any non-study CGM or flash glucose device); performing capillary glucose measurements according to the protocol using a study approved glucometer (and excluding the use of any other glucometer); completing an eDiary to track daily cornstarch, diet intake, and reasons for doing SMBG routinely throughout the study as required by the protocol; and completing patient-reported questionnaires. Subject must strictly comply with prednisolone/placebo prednisolone prescription including changes in prescription that may be implemented during the study by the Investigator, if needed. (See Section 9.2, Prednisolone Taper.) If < 18 years (or as required by region), has a parent or legal guardian willing and able to assist with study requirements. 5. From the period following informed consent through the duration of participation in the study, female subjects of childbearing potential and fertile male subjects must consent to use highly effective contraception as defined by the Food and Drug Administration (FDA) and Clinical Trial Facilitation Group Recommendations Related to Contraception and Pregnancy Testing in Clinical Trials (Version 1.1 dated 21 Sep 2020). Female subjects must agree not to become pregnant and male subjects must agree not father a child or donate sperm for at least 48 weeks after the last dose of IP if they decide to withdraw early from the study. 6. Subject is willing and able to provide written informed consent after the study has been explained and before any study-related procedures are performed. If < 18 years (or as required by region), willing and able to provide written assent and have a parent or legal guardian willing and able to provide written informed consent after the study has been explained and before any study-related procedures are performed."
Exclusion Criteria
- "1. Detectable pre-existing antibodies to the AAV8 capsid during Sceening. 2. History of liver transplant, including hepatocyte cell therapy/transplant. 3. History of severe hepatic fibrosis or cirrhosis as evidenced by any of the following: portal hypertension, ascites, splenomegaly, esophageal varices, hepatic encephalopathy, or a liver biopsy with evidence of stage III fibrosis. 4. Presence of liver adenoma > 5 cm in size or presence of liver adenoma > 3 cm and ≤ 5 cm in size with a documented annual growth rate of ≥ 0.5 cm per year. 5. Significant hepatic injury or dysfunction as evidenced by imaging or any of the following laboratory abnormalities from 2 consecutive samples (collected at least 4 weeks apart). Liver function tests may be repeated during Screening at the Investigator's discretion; those with initially abnormal values may be retested and the subject will qualify for this criterion if the most recent results during Screening are within the allowed range: − ALT or aspartate aminotransferase > 2.5 × the ULN − Total bilirubin > ULN (unless the subject has Gilbert syndrome) − Alkaline phosphatase > ULN, with gamma-glutamyl transferase > ULN 6. Presence or history of hepatitis B virus infection, hepatitis C virus infection, or both. 7. Non-fasting triglycerides ≥ 1000 mg/dL. For the purposes of this study, non-fasting refers to the longest fasting period that each individual subject is able to tolerate. Depending on the meal and cornstarch schedule, the blood draw could occur in the morning before breakfast or before the first dose of cornstarch. 8. Human immunodeficiency virus infection AND any of the following: CD4+ cell count < 350 cells/mm3, change in antiretroviral therapy regimen within 6 months before baseline, or plasma viral load > 200 copies/ml on 2 separate occasions as measured by polymerase chain reaction. 9. Presence or history of any disease or condition that, in the Investigator's opinion, would interfere with the subject's safety or ability to participate in the study or would significantly affect interpretation of study results. This includes any intercurrent febrile or nonfebrile illness including common viral infections, epidemic influenza, and other viral illnesses, and Coronavirus disease 2019 (COVID-19) until full clinical recovery. 10. Female subjects of childbearing potential who have a positive pregnancy test who are unwilling to use contraception, or are unwilling to have additional pregnancy tests during the study. 11. Pregnant, breastfeeding, or planning to become pregnant (self or partner) at any time during the study. 12. Presence or history of any hypersensitivity to the excipients of DTX401 or placebo or to prednisolone, or inability to swallow capsules that, in the judgment of the Investigator, places the subject at increased risk for adverse effects. 13. Current or previous participation in another gene transfer study. 14. Use of any IP or investigational medical device within 3 months preceding screening or planning to use at any time during the study. 15. History of illicit drug use within 60 days prior to Screening or positive results from a 9-panel urine drug screen prior to dosing and completed at 2 time points at least 4 weeks apart. Positive results that are due to a prescribed medication may be allowed if not impacting glycemic control and liver function and after agreement with the Sponsor. For the purposes of this protocol, the use of recreational cannabis products is not allowed, even if legal in the region where the patient lives."
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Denmark | Not Recruiting | 15 Jul 2021 | 7 |
 Germany | Not Recruiting | 15 Jul 2021 | 5 |
 Italy | Not Recruiting | 15 Jul 2021 | 8 |
 The Netherlands | Not Recruiting | 15 Jul 2021 | — |
 Spain | Not Recruiting | 15 Jul 2021 | 4 |
| Netherlands | — | — | 6 |
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 USE | 60 | 58 | PRD514378 |
Prednisolone placebo hard capsule, 10 mg | Placebo | N/A | — | — | — | N/A |
Prednisolone Placebo hard capsule, 5mg | Placebo | N/A | — | — | — | N/A |
Prednisolon STADA® 10 mg Tabletten | Other | TABLETTEN | ORAL USE | 60 | 58 | PRD394471 |
Pariglasgene brecaparvovec | Test | SOLUTION FOR INFUSION | INTRAVENOUS | 32 | 1 | PRD7389681 |
Normal Saline | Placebo | N/A | — | — | — | N/A |