This study has been transitioned to CTIS with ID 2023-508750-25-00 check the CTIS register for the current data. Primary: To evaluate the efficacy of DTX401 to reduce or eliminate dependence on exogenous glucose replacement therapy needed to…
ID
Source
Brief title
Condition
- Congenital and hereditary disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Percent change from Baseline to Week 48 in daily cornstarch intake for the
DTX401 Group compared with the Placebo Group
Secondary outcome
(subject to multiplicity)
• Change from Baseline to Week 48 in number of total daily doses of cornstarch.
• Change from Baseline to Week 48 in 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
• PGIC assessment score at Week 48.
(not subject to multiplicity)
• Change from Baseline to Week 48 in time to hypoglycemia (<54 mg/dL [3.0
mmol/L]) during the CFC
• 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
• 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.
Background summary
DTX401 is a gene therapy that is being developed for the treatment of glycogen
storage disease type Ia (GSDIa). Patients with GSDIa have a deficiency in the
glucose-6-phosphatase protein (G6Pase) enzyme and therefore cannot release
glucose from glycogen storage in the liver during times of fasting (ie, during
the period between meals) and are at risk for severe fasting hypoglycemia.
DTX401 therapy is expected to provide G6Pase activity resulting in efficient
release of glucose from glycogen stores in the liver, thereby reducing the risk
of hypoglycemia during periods of fasting and the long-term complications
associated with GSDIa.
The purpose of this study is to investigate the efficacy and safety of DTX401
in pediatric (8 to <*18 years) and adult (>= 18 years) subjects with GSDIa.
Study objective
This study has been transitioned to CTIS with ID 2023-508750-25-00 check the CTIS register for the current data.
Primary:
To evaluate the efficacy of DTX401 to reduce or eliminate dependence on
exogenous glucose replacement therapy needed to maintain glucose
control
Secondary:
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
Study design
Study DTX401-CL301 is a Phase 3, randomized, double-blind, placebo-controlled
study to determine the efficacy and confirm the safety of DTX401 in patients 8
years and older with GSDIa.
This study includes the following sequential stages:
Screening (Day -122 to Day -10): The site must obtain written informed consent
for participation in the study before performing any study-specific screening
tests or evaluations. (For pediatric subjects, a legal guardian must provide
written informed consent, and the subject must provide age-appropriate assent
to participate.)
During the Screening Period, the subject will be given a continuous glucose
monitoring (CGM) system, a meter for capillary glucose measurements
(self-monitored blood glucose [SMBG]), and the electronic diary (eDiary) to
start collecting baseline data.
Randomization (Day -10 to Day 0): Screening ends when the subject is
randomized. Using the interactive response technology (IRT) system, the site
will randomly assign the subject to DTX401 or placebo treatment and schedule
the investigational product (IP; ie, DTX401 or placebo) infusion at least 10
business days before the IP infusion to allow time for IP and the prophylactic
oral prednisolone/placebo kit to be delivered to the site.
Baseline (Day 0): The day before IP administration (ie, Day 0), the subject
will be admitted to the hospital or research facility for Baseline assessments.
Day 1 IP Administration: On Day 1, subjects randomly assigned to DTX401 will
receive a single, blinded, peripheral intravenous (IV) infusion of DTX401 at
1.0 × 10^13 genome copies (GC)/kg. Subjects randomly assigned to placebo will
receive a single, blinded, peripheral IV infusion of normal saline.
Day 15: Subjects randomly assigned to DTX401 will start an oral prophylactic
prednisolone regimen to minimize or prevent potential vector-induced hepatic
effects (eg, transaminase elevations). Subjects randomly assigned to placebo IP
infusion will receive a matching oral placebo regimen to maintain the study
blind.
The Primary Efficacy Analysis Period (PEAP; Day 1 to Week 48): The PEAP is the
time from Day 1 postdose through the completion of the Week 48 controlled
fasting challenge. The primary endpoint and secondary efficacy endpoints will
be analyzed after the last enrolled subject completes the Week 48 assessments.
Week 48 IP Administration: At Week 48, after all Week 48 assessments are
completed, subjects will receive a second blinded infusion of IP: subjects
randomly assigned to DTX401 at baseline will receive placebo at Week 48, while
eligible subjects randomly assigned to placebo at baseline will receive a
single, blinded, peripheral IV infusion of DTX401 at 1.0 × 10^13 GC/kg at Week
48 (if still eligible for IP infusion).
Subjects will begin an oral prophylactic prednisolone regimen or matching oral
placebo regimen 14 days after the Week 48 IP administration.
Follow-up Period (Week 48 through Week 144): Study assessments during the
Follow-up Period will further characterize the efficacy and safety of DTX401
administration to inform the overall risk-benefit profile.
Upon completion of this study (Week 144 or Early Withdrawal), all subjects who
receive DTX401 will be asked to enroll in a long-term follow-up study (GSDIa
disease monitoring program [DMP]) to evaluate the long-term safety and
effectiveness of DTX401 via the disease DMP for at least 10 years (total
duration from first infusion) after DTX401 administration.
Intervention
Subjects will receive a single IV infusion of DTX401 and placebo (cross-over).
Study burden and risks
Taking part in the study can have these cons:
You may experience the side effects or adverse effects of AAV8 gene therapy
vector, as described in Section 6.
There may be some discomfort from the measurements during the study. For
example: taking a blood sample can be a little painful. Or you could get a
bruise as a result.
Taking part in the study will cost you extra time, for example to complete the
electronic diary.
You will need to wear a CGM monitoring device for a prolonged period of time
During the controlled fasting challenge, you may experience symptoms of
hypoglycemia (dizziness, shakiness, sweating, hunger, inability to concentrate,
confusion, and irritability or moodiness). You will need to inform your study
doctor right away if this happens.
You need to be hospitalised.
You have to comply with the study agreements.
What are the possible discomforts you may experience with checks or
measurements during the study?
There may be discomforts associated with the study procedures, such as
irritation from the sticky pads used during the ECG, or distress due to the
closed space you are in during the MRI. You can read more about the discomforts
and risks associated with the study procedures in Appendix E.
It is possible that an accidental discovery is made during an MRI scan or
during a genetic examination that is not directly related to the research but
does concern your health or that of your family members. If this happens, your
own doctor or specialist will discuss with you what needs to happen next. The
cost of this will fall under your own insurance policy.
Leveroni Court 60
Novato 94949
US
Leveroni Court 60
Novato 94949
US
Listed location countries
Age
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.
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
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 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.
Design
Recruitment
Medical products/devices used
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 |
|---|---|
| EU-CTR | CTIS2023-508750-25-00 |
| EudraCT | EUCTR2020-004184-12-NL |
| CCMO | NL77275.000.21 |