A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study of Adeno-Associated Virus Serotype 8-Mediated Gene Transfer of Glucose-6-Phosphatase in Patients with Glycogen Storage Disease Type Ia

Phase 3

Recruiting

Conditions: GSDI
Von Gierke disease
10027664

Registration Number: NL-OMON56166

Lead Sponsor: ltragenyx Pharmaceutical Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Recruiting

Sex: Not specified

Target Recruitment: 6

Inclusion Criteria

1. Males and females >=*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 case of a single pathogenic mutation, 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 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.
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Exclusion Criteria

Detectable pre-existing antibodies to the AAV8 capsid during Screening.

History of liver transplant, including hepatocyte cell therapy/transplant.

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.

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.

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*s syndrome)
- Alkaline phosphatase >*ULN, with gamma-glutamyl transferase > ULN

Presence or history of hepatitis*B virus infection, hepatitis*C virus
infection, or both.

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.

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.

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.

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.

Pregnant, breastfeeding, or planning to become pregnant (self or partner) at
any time during the study.

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.

Current or previous participation in another gene transfer study.

Use of any IP or investigational medical device within 3*months preceding
screening or planning to use at any time during the study.

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 medic