This study has been transitioned to CTIS with ID 2024-514337-38-00 check the CTIS register for the current data. PrimaryTo evaluate the efficacy of DTX301 on the improvement of OTC function by maintaining safe plasma ammonia levelsSecondaryTo…
ID
Source
Brief title
Condition
- Endocrine disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Plasma ammonia as measured by 24-hour ammonia (AUC0 24) at Week 64 for all
patients as assessed by the geometric mean ratio (Modified Intention-to-Treat
[mITT], DTX301 vs Placebo, test for noninferiority)
• Percentage of patients at Week 64 who have achieved complete response (mITT,
DTX301 vs Placebo, test for superiority)a
Secondary outcome
• Percentage of patients at Week 64 who have achieved complete response,
response, or no response (mITT, DTX301 vs Placebo, test for superiority)a
• PGIC-Overall Change score (DTX301 vs Placebo) at Week 64
• Rate of HACs from baseline to Week 64 compared to the 15-month pre-enrollment
period (DTX301 vs Placebo)
• Change in plasma ammonia (AUC0 24) after 64 weeks of DTX301 exposure
(comparison between those who had a reduction of baseline disease management vs
not)
• Change in plasma ammonia (AUC0-24) from baseline to Week 64 for all patients
(DTX301 vs Placebo)
• Incidence of TEAEs, TESAEs, treatment-related TEAEs, treatment-related
TESAEs, and AESIs
• Clinically significant changes in laboratory values, physical examination
results, and vital sign measurements
• Development of anti-OTC antibodies
Background summary
OTC deficiency is caused by a change in the OTC gene. A gene contains the
instructions of making proteins in your body, much like a cookbook recipe. When
the OTC gene is changed, your body can no longer break down ammonia. The high
levels of ammonia are toxic for your body.
DTX301 is an experimental gene transfer product. This means that DTX301 aims to
deliver working copies of the OTC gene. The cells in your liver will now
receive the correct instructions and should be able to break down ammonia.
To get the OTC gene to your liver, a transporter or *vector* is used. You can
think of this vector as a car and the gene as a passenger in the car. The
vector is made from a virus called adeno-associated virus serotype 8 (AAV8).
The AAV8 vector used in DTX301 has been changed in the laboratory so it should
not cause any infection or disease. Before receiving DTX301, your blood will be
checked for the presence of pre-existing antibodies to AAV8. Antibodies are
produced in response to infections or other foreign materials in your body.
They are part of your body's natural defense against illness. This is done with
a blood test called AAV8 DetectCDx, that is being developed for use with
DTX301.
Study objective
This study has been transitioned to CTIS with ID 2024-514337-38-00 check the CTIS register for the current data.
Primary
To evaluate the efficacy of DTX301 on the improvement of OTC function by
maintaining safe plasma ammonia levels
Secondary
To evaluate the efficacy of DTX301 in 3 response categories
To evaluate the effect of DTX301 on OTC deficiency patient health outcomes
To evaluate the effect of DTX301 on occurrence of HACs
To evaluate the effect of DTX301 on plasma ammonia over time
To evaluate the safety of DTX301
To characterize the immune response to OTC protein (anti-OTC antibodies)
Tertiary
To evaluate the effect of DTX301 on executive and verbal function (Cogstate
Cognitive Assessment)
To evaluate the effect of DTX301 on ureagenesis
To evaluate the effect of DTX301 on total body nitrogen (serum ammonia plus
glutamine)
To evaluate the effect of DTX301 on citrulline
To evaluate the effect of DTX301 on patient health outcomes and disease care
burden
Study design
Study Design:
This study includes the following sequential stages (see Figure 1):
• Screening (Day -60 to -10): After providing signed informed consent/assent
(as applicable), patients will complete all screening assessments outlined in
Table 3. At the start of screening, patients (or caregivers, as appropriate)
will be given access to an app that is configured with patient-reported outcome
(PRO) instruments (Hyperammonemia Indicator Questionnaire [HI Q], OTC
Deficiency Impact Questionnaire [OTC D IQ], Patient Global Impression of
Disease Frequency [PGIF], and Patient Global Impression of Disease Change
[PGIC]) and an electronic diary (eDiary) for recording dietary intake, ammonia
scavenger therapies, and OTC deficiency-related symptoms.
• Randomization (approximately Day -10): Patients must be randomized at least
10 days before the scheduled investigational product (IP) infusion to allow
time for IP and the prophylactic oral prednisolone/placebo kit to be delivered
to the site.
• Baseline (Day 0): On the day before IP administration, patients will be
admitted to the hospital or research facility for baseline assessments.
• Day 1 IP Administration: On Day 1, patients randomized to the DTX301 arm will
receive a single, blinded, peripheral intravenous (IV) infusion of DTX301.
Patients randomized to the Placebo arm will receive a single, blinded,
peripheral IV infusion of normal saline.
After completion of the baseline Ureagenesis Rate Test (URT) and 24-hour plasma
ammonia assessment and prior to IP administration, patients in the DTX301 arm
will start a prophylactic oral corticosteroid regimen (ie, prednisolone) to
minimize or prevent potential vector-induced hepatic effects. Patients in the
Placebo arm will receive a matching oral placebo regimen at the same time to
maintain the study blind.
• The Primary Efficacy Analysis Period (PEAP) (Day 1 to Week 64): The PEAP is
the time from Day 1 postdose through the completion of the Week 64 predose
assessments. The primary analysis will be conducted when all patients have
completed the Week 64 Visit or discontinued the study.
• Week 64 IP Administration: At Week 64, patients will receive a second blinded
infusion of IP. Patients in the DTX301 arm will receive Placebo at Week 64,
while patients in the Placebo arm will receive a single, blinded, peripheral IV
infusion of DTX301 at Week 64 after confirmation that the patient is still
eligible for IP infusion.
Before the first patient reaches the Week 64 time point, an independent,
unblinded statistician will review preliminary primary efficacy results and
will confirm with Data Monitoring Committee (DMC) members that it is
appropriate for patients in the Placebo arm to receive DTX301 (crossover
treatment).
Patients will begin a prophylactic oral corticosteroid taper regimen
(prednisolone or matching oral placebo) before the Week 64 IP administration
(after completion of the Week 64 URT and 24-hour plasma ammonia assessment).
• The Follow-up Period (Week 64 postdose through Week 260 for the DTX301 arm,
or Week 128 postdose through Week 324 for patients in the Placebo/DTX301 arm):
Study assessments during the Follow-up Period will further characterize
clinically meaningful ammonia control after DTX301 administration and will
provide extended safety information (through 5 years from the time of DTX301
administration) to inform the overall risk-benefit profile.
Intervention
We will treat the patient once with the study drug. It will be given as a
one-time infusion through the vein. The infusion will take approximately 30
minutes. The infusion cannot be reversed or undone. We cannot remove the vector
or OTC gene from the body once we have given it to the patient.
For this study, we will have 2 groups:
• Group 1. The people in this group will get DTX301.
• Group 2. The people in this group will get placebo.
A draw will decide which treatment (DTX301 or placebo) the patient is given.
There is a 50% chance that he/she will receive DTX301. The patient and the
investigator do not know which group he/she in. But if it is important for
his/her health, we can look this up.
If the patients joins the study, he/she will also receive medication to
suppress inflammation (steroids or a placebo. This is intended to help the
liver cells to stay normal.
Study burden and risks
DTX301
DTX301 may cause side effects. It is important that you tell your study doctor
of all changes in your health after you receive DTX301 even if you think that
some of the changes are not important or not caused by DTX301. Any experimental
drug carries potential serious adverse complications, including a risk of
death. You will be observed in the hospital after receiving the infusion of the
gene transfer product to monitor for any side effects or discomforts. Several
hundred people have been given AAV-based gene transfer, and no life threatening
or irreversible side effects been reported in the immediate period after
infusion.
: Potential risks related to use of DTX301, an AAV gene therapy vector
delivered in the bloodstream (IV), may include but are not limited to the
following:
• Liver damage
• Liver effects induced by the vector (transporter of the gene therapy) Immune
response
• Allergic reaction
• Development of cancer
• Vector shedding
The medicinal product can also have side effects that we do not know about at
the moment.
You can read more about this in appendix E of the ICF.
Sodium Acetate (used with the URT)
When you drink this mixture, you may experience a temporary unpleasant salty or
acidic taste, nausea or increased belly sounds or flatulence.
Medication to suppress inflammation (steroids)
The follow side effects are common:
• Fluid retention
• Change in glucose
• High blood pressure
• Behaviour and mood changes
• Increased appetite and weight gain
• Increase of ammonia level
• Blurred vision
• Acne
These side effects are usually temporary and reverse when you stop taking the
medication to suppress inflammation. You can read more about this in appendix E
of the ICF.
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Age
Inclusion criteria
Eligible individuals must meet all of the following criteria:
1. Male or female patient 12 years of age or older at the time of signed
informed consent.
2. Provide informed consent after the nature of the study has been
explained, and prior to any research-related procedures. If a minor,
willing and able (if possible) to provide assent and have a legally
authorized representative provide informed consent after the nature of
the study has been explained, and prior to any research-related
procedures.
3. Confirmed clinical diagnosis of late-onset OTC deficiency with
historical documentation by enzymatic (ie, liver biopsy), biochemical (ie,
hyperammonemia in the presence of elevated plasma glutamine, low
citrulline, and elevated spot urine orotic acid), or molecular testing (ie,
OTC analysis).
4. Documented history of >= 1 symptomatic hyperammonemia episode
with ammonia level >= 100 µmol/L for confirmation of clinical disease.
5. Patient is currently receiving ammonia scavenger therapy and/or
protein-restricted diet, is free from symptomatic hyperammonemia and
has not required emergent active intervention for hyperammonemia
within 4 weeks before screening/baseline.
6. Plasma 24-hour ammonia (AUC0-24) is <= 4800 µmol*h/L at
screening. If the ammonia AUC0-24 is inconsistent with the patient's
clinical status, the assessment may be repeated to ensure accurate
results.
7. If on ongoing daily ammonia scavenger therapy, must be at stable
daily dose(s) for >= 4 weeks prior to screening.
8. If on a protein-restricted diet, must be on a stable protein-restricted
diet as evidenced by a stable amount of total protein intake (ie, daily
protein intake in grams per day does not vary more than 20%) for >= 4
weeks prior to screening.
9. Willing and able to comply with study procedures and requirements,
including periodic inpatient hospitalizations, frequent blood and urine
collections, blood collections over a 24-hour period, questionnaires,
cognitive assessments, and patient/caregiver reported outcome
assessments. If a minor, must have a caregiver(s) willing and able to
assist in all applicable study requirements.
10. From the time written informed consent is provided through Week
128, females of childbearing potential and fertile males must consent to
use highly effective contraception as defined by the United States Food
and Drug Administration (FDA) and Clinical Trial Facilitation
Coordination Group (CTFG) Recommendations Related to Contraception
and Pregnancy in Clinical Trials. If female, agree not to become
pregnant. If male, agree to not father a child or donate sperm.
Exclusion criteria
Individuals who meet any of Exclusion Criteria 1 to 16 will not be eligible
to participate in the study. Individuals who meet Exclusion Criteria 17
will not be eligible to undergo the URT:
1. Liver transplant, including hepatocyte cell therapy/transplant.
2. History of liver disease as evidenced by any of the following: portal
hypertension, ascites, splenomegaly, esophageal varices, hepatic
encephalopathy, or a liver biopsy with evidence of stage 3 fibrosis.
3. Significant hepatic inflammation or cirrhosis as evidenced by imaging
or any of the following laboratory abnormalities: alanine
aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 ×
ULN, total bilirubin > 1.5 × ULN (except if patient has a diagnosis of
Gilbert's syndrome), alkaline phosphatase > 2.5 × ULN. NOTE: Any of the
LFTs may be retested.
4. Estimated glomerular filtration rate < 60 mL/min/1.73 m2 at
screening by the CKD-EPI 2021 creatinine-based formula (Inker et al.,
2021) for patients >= 18 years of age or the Schwartz bedside formula
(Schwartz and Work, 2009) for patients < 18 years of age.
5. Evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV)
infection, documented by current use of antiviral therapy for HBV or HCV
or by hepatitis B surface antigen (HBsAg) or HCV RNA positivity. NOTE:
Patients with a history of HCV infection must have documentation of 2
negative viral assays by polymerase chain reaction (PCR), collected at
least 6 months apart, to be considered negative for HCV. Patients with a
history of HCV infection who test positive for HCV RNA at screening can
be rescreened once, after they have been treated and have
documentation of at least 2 negative samples collected at least 6 months
apart.
6. History of human immunodeficiency virus (HIV) infection AND any of
the following: CD4+ cell count < 350 cells/mm3, change in antiretroviral
therapy regimen within 6 months prior to Baseline (Day 0), or plasma
viral load > 200 copies/mL, documented on 2 separate occasions, as
measured by PCR.
7. Active infection (viral or bacterial).
8. Detectable pre-existing antibodies to the AAV8 capsid.
9. History of a malignancy for which the patient has received treatment
in the past 2 years except for prostate cancer treated with watchful
waiting or surgically removed nonmelanoma skin cancer.
10. Any of the following that, in the judgment of the Investigator, places
the patient at increased risk for adverse effects:
• Known hypersensitivity to DTX301, its excipients, or its placebo
• Known hypersensitivity to prednisolone, its excipients, or its placebo
11. Chronic use of inhibitors of urea synthesis (eg, valproic acid) or
drugs that significantly affect renal clearance (eg, probenecid).
12. Presence or history of any condition that, in the view of the
Investigator, would interfere with participation, pose undue risk, or
confound interpretation of results, including but not limited to:
• Underlying conditions that may require systemic corticosteroids if the
condition worsens (eg, autoimmune disorders)
• Patient in a catabolic state (eg, due to current infection), or in whom a
catabolic state may be reasonably foreseeable (eg, due to planned
procedures)
• Patient is considered vulnerable by local regulations (eg, imprisoned or
institutionalized)
13. Marked neurological deficit or compromise that, in the Investigator's
opinion, would interfere with the patient's safety or ability to participate
in the study.
14. Pregnant or breastfeeding or planning to become pregnant within 64
weeks after receiving DTX301 (ie, through Week 128 of this study).
15. Participation (current or previous) in another gene transfer study.
16. Use of any investigational product within 3 months prior to
screening, or during the study.
17. Patient who meet any of the following criteria are not eligible to
undergo the URT:
• Unable to fast safely for 12 hours
• History of hyperammonemic crisis (HAC) triggered by minimal
vomiting
• Age < 18 years at screening
Note: Any patient < 18 years of age at screening will not undergo
ureagenesis rate testing for the duration of study.
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 | CTIS2024-514337-38-00 |
| EudraCT | EUCTR2020-003384-25-NL |
| CCMO | NL78036.000.21 |