An Phase 3 clinical study comparing a vector transferring the gene for Glucose-6-Phosphatase with placebo in adults with Glycogen Storage Disease Type Ia.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ultragenyx Pharmaceutical Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

Trial duration

11 Jan 2022 → 20 Feb 2026

Decision date (initial)

2024-05-17

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Ultragenyx Pharmaceutical Inc.

External identifiers

EU CT number

2023-508750-25-00

EudraCT number

2020-004184-12

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

To evaluate the efficacy of DTX401 to reduce or eliminate dependence on exogenous glucose replacement therapy needed to maintain glucose control.

Secondary objectives 1

1. "subject to multiplicity: •To evaluate the effect of DTX401 on reducing the frequency of exogenous glucose replacement therapy •To evaluate the effect of DTX401 on glucose control •To evaluate the effect of DTX401 on subject experience of disease not subject to multiplicity: •To evaluate the effect of DTX401 on glucose control •To evaluate the safety of DTX401"

Conditions and MedDRA coding

Glycogen Storage Disease Type Ia (GSDIa)

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-002734-PIP01-19

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. "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

1. "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."

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. "Percent change from Baseline to Week 48 in daily cornstarch intake for the DTX401 Group compared with the Placebo Group."

Secondary endpoints 3

1. "1. Change from Baseline to Week 48 in number of total daily doses of cornstarch 2. Change from Baseline to Week 48 in the percentage of glucose values in hypoglycemic range (<70 mg/dL [3.9 mmol/L]), assessed for noninferiority; if non-inferiority is established, the endpoint will be tested for superiority. 3. PGIC assessment score at Week 48. "
2. "4. Change from Baseline to Week 48 in time to hypoglycemia (<54 mg/dL [3.0 mmol/L]) during the CFC. 5. Change from Baseline to Week 48 in percentage of glucose values in the range of 70-120 mg/dL [3.9-6.7 mmol/L], assessed for noninferiority; if non-inferiority is established, the endpoint will be tested for superiority."
3. 6. Incidence, severity, and relationship to investigational product of TEAEs, TEAEs of special interest, serious TEAEs, related TEAEs, discontinuations from study or investigational product due to AEs, and fatal AEs.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 3

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ultragenyx Pharmaceutical Inc.

Sponsor organisation

Ultragenyx Pharmaceutical Inc.

Address

60 Leveroni Court Suite 200

City

Novato

Postcode

94949-5746

Country

United States

Scientific contact point

Organisation

Ultragenyx Pharmaceutical Inc.

Contact name

Medical Information

Public contact point

Organisation

Ultragenyx Pharmaceutical Inc.

Contact name

Ultragenyx trial information group

Third parties 14

Locations

5 EU/EEA countries · 7 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 12 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications