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    Summary
    EudraCT Number:2020-003384-25
    Sponsor's Protocol Code Number:DTX301-CL301
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-12-17
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - PEI
    A.2EudraCT number2020-003384-25
    A.3Full title of the trial
    A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study of Adeno-Associated Virus Serotype 8 (AAV8)-Mediated Gene Transfer of Human Ornithine Transcarbamylase (OTC) in Patients with Late-Onset OTC Deficiency
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study of a virus transferring the gene for human Ornithine Transcarbamylase (OTC) in patients older than 12 years old with late-onset OTC deficiency
    A.4.1Sponsor's protocol code numberDTX301-CL301
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT05345171
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUltragenyx Pharmaceutical Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportUltragenyx Pharmaceutical, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUltragenyx Pharmaceutical, Inc.
    B.5.2Functional name of contact pointGene Therapy Regulatory Affairs
    B.5.3 Address:
    B.5.3.1Street Address60 Leveroni CT
    B.5.3.2Town/ cityNovato, CA
    B.5.3.3Post code94949
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1617538 5277
    B.5.6E-mailKPackard@ultragenyx.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/16/1623
    D.3 Description of the IMP
    D.3.1Product nameDTX301
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNavalotcagene ontaparvovec
    D.3.9.1CAS number 2227000-30-6
    D.3.9.2Current sponsor codeDTX301
    D.3.9.4EV Substance CodeSUB184280
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number1.5 x 10^13 GC/mL
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Yes
    D.3.11.3.5.1CAT classification and reference numberClassified as gene therapy medicinal product, EMA/CAT/803478/2015
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms Yes
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product name(1-13C) Sodium Acetate
    D.3.4Pharmaceutical form Powder for oral solution
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSodium Ethanoate (1- 13 C)
    D.3.9.1CAS number 23424-28-4
    D.3.9.3Other descriptive nameSodium acetate (1-13C)
    D.3.9.4EV Substance CodeSUB236073
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number27.35
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboConcentrate for solution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Late-onset Ornithine transcarbamylase (OTC) deficiency
    E.1.1.1Medical condition in easily understood language
    Inherited disorder causing accumulation of ammonia
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10071107
    E.1.2Term Ornithine transcarbamylase deficiency
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of DTX301 on the improvement of OTC function by maintaining safe plasma ammonia levels
    E.2.2Secondary objectives of the trial
    - 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 charakterize the immune response to OTC protein (anti-OTC antibodies)
    E.2.3Trial contains a sub-study No
    E.3Principal 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.
    E.4Principal 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 18 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 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 subject 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.
    E.5 End points
    E.5.1Primary end point(s)
    • Percentage of patients at Week 64 who have achieved complete response (Modified Intention-to-Treat [mITT], DTX301 vs Placebo, test for superiority)
    • Plasma ammonia as measured by 24-hour ammonia (AUC0-24) at Week 64 for all subjects as assessed by the geometric mean ratio (ITT, DTX301 vs Placebo, test for non-inferiority)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 64
    E.5.2Secondary end point(s)
    • Percentage of patients at Week 64 who have achieved complete response, response, or no response (mITT, DTX301 vs Placebo, test for superiority)
    • 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
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 64
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA12
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Brazil
    Canada
    Japan
    United Kingdom
    United States
    Croatia
    France
    Germany
    Italy
    Netherlands
    Portugal
    Spain
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LPLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 12
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 12
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 38
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 28
    F.4.2.2In the whole clinical trial 50
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Standard of care
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-07-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-08-02
    P. End of Trial
    P.End of Trial StatusOngoing
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