Primary Objective: To determine the safety of single intravenous (IV) doses of DTX401 in adultswith GSDIa, including the incidence of dose-limiting toxicities (DLTs).Secondary Objective:To establish a dose of DTX401 that achieves symptom-free…
ID
Source
Brief title
Condition
- Congenital and hereditary disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoints:
The incidence of adverse events (AEs), including the incidence of DLTs at
each dose level, treatment-emergent adverse events (TEAEs), and serious
adverse events (SAEs) for each dosing cohort, assessed by severity and
relationship to study product.
Secondary outcome
Secondary Endpoints:
The change from baseline in time (in minutes) to first hypoglycemic event
(defined as glucose <60 mg/dL [<3.33 mmol/L]) during a controlled fasting
challenge at 6, 12, 24, and 52 weeks after IV administration of DTX401.
Background summary
Previous animal studies demonstrated long-term correction of the disease
sequelae, including correction of fasting
hypoglycemia; reduction of uric acid, triglycerides, and cholesterol; improved
growth; reduction in
hepatomegaly and nephromegaly; and a reduction in lactic acidosis (canine
model). Histologically,
there was also a reduction in glycogen deposition in the liver, and recent data
demonstrated
prevention of both HCAs and HCCs.
Glucose-6-phosphatase gene transfer is expected to be effective for the
treatment of GSDIa because
the disease is caused by mutations within a single gene. Currently,
no gene transfer product has been approved for the treatment of GSDIa. Based on
previous clinical
experience with AAV8, DTX401 is expected to result in sustained (at least 3
years following vector
infusion) expression of G6PC. Therefore, unlike current treatment
options (ie, dietary supplementation), G6PC gene transfer offers the potential
to correct the
underlying deficiency for a prolonged period of time with a single IV infusion.
Furthermore,
increasing G6Pase activity should allow patients with GSDIa to avoid
hypoglycemic episodes and
long-term complications associated with GSDIa, which should greatly improve
their quality of life
(QoL).
Study objective
Primary Objective:
To determine the safety of single intravenous (IV) doses of DTX401 in adults
with GSDIa, including the incidence of dose-limiting toxicities (DLTs).
Secondary Objective:
To establish a dose of DTX401 that achieves symptom-free euglycemia
(glucose >=60 mg/dL [>=3.33 mmol/L]) in a setting of a controlled fasting
challenge to allow further clinical development.
Study design
This is a Phase 1/2, open-label, single-arm, multicenter, safety and
dose-finding
study of DTX401 in adults with GSDIa. The primary objective of the study is to
determine the safety of single IV doses of DTX401, including the incidence of
DLTs. The secondary objective of the study is to identify the optimal
biological dose (OBD) of DTX401 by assessing the time (in minutes) to first
hypoglycemic
event (defined as glucose <60 mg/dL [<3.33 mmol/L]) during a controlled fasting
challenge, which will end when either hypoglycemia occurs or 15 hours is
reached.
Eligible subjects will receive a single IV infusion of DTX401. Three subjects
will
be enrolled in Cohort 1 and in each subsequent cohort. After the third patient
in a
cohort reaches the 12-week time point, the continual reassessment method (CRM)
will propose a dose for the next cohort using the collected data from the
previous
cohort. The decision to proceed will be made after the data monitoring committee
(DMC) has evaluated at least 12 weeks of safety data for all subjects in a
dosing
cohort.
Subjects enrolled in Study 401GSDIA01 will be monitored for 52 weeks. During
the informed consent process for this study, subjects will be informed of the
long-term 4-year follow-up study in order to maximize subject retention into
this
extension study.
Intervention
Subjects will receive a single IV infusion of DTX401.
Study burden and risks
This study is the first time that DTX401 will be given to humans. All of the
side effects and discomforts associated with DTX401 that may occur in humans
are not yet known. It is possible that you may experience inflammation of the
liver if your immune system reacts to the AAV vector. Side effects associated
with oral steroid use may include (but are not limited to) agitation, headache,
increased blood sugar, irritability, and weight gain. In people with GSDIa,
there may also be an increased risk of elevated blood levels of lactate and
triglycerides that may lead to stomach pain (pancreatitis) and/or vomiting.
There are also Potential Risks Associated with Study Procedures.
For this research it is necessary that patients will visit the site 8 times.
Patients will be hospitalized for 5 times for 24 hours at the site (fasting
challenge, max 15 hours). Besides 3 site visits will take place.
In a period of 12 weeks a (home) visit will take place every 4 or 5 days (18
visits in total). There are less alternatives for the patients available.
Memorial drive 840
Cambridge MA 02139
US
Memorial drive 840
Cambridge MA 02139
US
Listed location countries
Age
Inclusion criteria
1. Willing and able to provide written informed consent.
2. Males and females >= 18 years of age.
3. Documented GSDIa with confirmation by molecular testing.
4. Documented history of >= 1 hypoglycemic event with glucose <60 mg/dL
(<3.33 mmol/L).
5. Subject*s GSDIa disease is stable as evidenced by no hospitalization for
severe hypoglycemia during the 4-week period preceding the screening visit.
6. Hematology and coagulation panel results are within the normal range or, if
outside the normal range, are deemed not clinically significant in the opinion
of the investigator.
7. No known allergic reaction to any component of DTX401.
8. Willing and able to comply with study procedures and requirements,
including periodic inpatient hospitalization, frequent blood collections, and
24-hour urine collection.
9. Males and females of childbearing potential must be willing to use effective
contraception at the time of administration of DTX401 and for 52 weeks
following administration of DTX401 to prevent the potential transmission of
the AAV vector (Section 9.2.1).
Exclusion criteria
1. Screening or Baseline (Day 0) glucose level <60 mg/dL (<3.33 mmol/L);
subjects may be rescreened after glucose is controlled and stable, at the
discretion of the investigator.
2. Liver transplant, including hepatocyte cell therapy/transplant.
3. Presence of liver adenoma >5 cm in size.
4. Presence of liver adenoma >3 cm and >5 cm in size that has a documented
annual growth rate of >= 0.5 cm per year.
5. Significant hepatic inflammation or cirrhosis as evidenced by imaging or any
of the following laboratory abnormalities: alanine aminotransferase (ALT) or
aspartate aminotransferase > the upper limit of normal (ULN), total bilirubin
>1.5 × ULN, or alkaline phosphatase >2.5 × ULN. Liver function tests may
be repeated during the screening period at the investigator*s discretion.
6. Serum creatinine >2.0 mg/dL.
7. Triglycerides >=1000 mg/dL at the time of the screening visit.
8. Presence of active, or history of treatment for, hepatitis B virus or
hepatitis C
virus infection.
9. History of human immunodeficiency virus infection AND any of the
following: CD4+ cell count <350 cells/mm3, change in antiretroviral therapy
regimen within 6 months prior to Day 0, or viral load >200 copies/mL, on
2 separate occasions, as measured by polymerase chain reaction.
10. History of a malignancy for which the subject has received treatment in the
past 2 years except for prostate cancer treated with watchful waiting or
surgically removed nonmelanoma skin cancer.
11. Active infection (viral or bacterial).
12. Anti-AAV8 neutralizing antibody titer >=1:5.
13. Participation (current or previous) in another gene transfer study.
14. Participation in another investigational product study within 3 months of
Screening.
15. Has a positive serum pregnancy test at Screening (females of childbearing
potential only), a positive urine pregnancy test at Baseline (Day 0; females of
childbearing potential only), or is nursing.
16. Has any other significant medical condition that the investigator feels
would
be a risk to the subject or would impede the study.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-003023-30-NL |
| ClinicalTrials.gov | NCT03517085 |
| CCMO | NL65556.000.18 |