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The European Union Clinical Trials Register allows you to search for protocol and results information on:
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    The EU Clinical Trials Register currently displays   42567   clinical trials with a EudraCT protocol, of which   7008   are clinical trials conducted with subjects less than 18 years old.
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    Summary
    EudraCT Number:2016-001057-40
    Sponsor's Protocol Code Number:301OTC01
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2016-12-15
    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 ConcernedUK - MHRA
    A.2EudraCT number2016-001057-40
    A.3Full title of the trial
    A Phase 1/2, Open-Label Safety and Dose-Finding Study of Adeno-Associated Virus (AAV) Serotype 8 (AAV8)-Mediated Gene Transfer of Human Ornithine Transcarbamylase (OTC) in Adults with Late-Onset OTC Deficiency
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An early-phase clinical study of a virus transferring the gene for human Ornithine Transcarbamylase (OTC) in adults with late-onset OTC deficiency
    A.4.1Sponsor's protocol code number301OTC01
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02991144
    A.5.4Other Identifiers
    Name:IND NumberNumber:17190
    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 Address840 Memorial Drive
    B.5.3.2Town/ cityCambridge
    B.5.3.3Post codeMA 02139
    B.5.3.4CountryUnited States
    B.5.4Telephone number+16177140705
    B.5.6E-mailJRae@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 INNNot yet assigned
    D.3.9.3Other descriptive nameDTX301
    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 number5000000000000
    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.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Ornithine transcarbamylase 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 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the safety of single intravenous (IV) doses of DTX301 in adults with late-onset OTC deficiency.
    E.2.2Secondary objectives of the trial
    To establish a dose of DTX301 that has a clinically meaningful increase in the rate of ureagenesis to allow further clinical development.
    To evaluate the efficacy of single IV doses of DTX301 in adults with late-onset OTC deficiency, in the setting of tapering or discontinuing ammonia scavenger medications.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Willing and able to provide written informed consent.
    2. Males and females ≥18 years of age with documented diagnosis of late-onset (defined as first manifestation of signs and symptoms at ≥30 days of age) OTC deficiency, confirmed via enzymatic, biochemical, or molecular testing. This may include identification of a pathogenic mutation, pedigree analysis, liver OTC activity that is <20% of normal activity, or elevated urinary orotate (>20 μmol/mmol creatinine) after an allopurinol challenge test.
    3. Documented history of ≥1 symptomatic hyperammonemia event with ammonia ≥100 μmol/L.
    4. Subject’s OTC deficiency is stable as evidenced by either a) no clinical symptoms of hyperammonemia OR b) plasma ammonia level <100 μmol/L within the 4 week period preceding the Screening visit.
    5. Subject's plasma ammonia level on Day 1 (predose) is <100 μmol/L, for patients who historically maintain normal ammonia levels, and the subject is clinically stable OR subject's plasma ammonia level on Day 1 (predose) is < 200 μmol/L, for patients who historically are not able to fully control ammonia levels with baseline management, and the subject is clinically stable. If the Day 1 (predose) ammonia level is inconsistent with the subject's clinical status, the ammonia level may be repeated to
    ensure accurate results.
    6. On ongoing daily stable dose of ammonia scavenger therapy for ≥4 weeks.
    7. Willing to taper or discontinue ammonia scavengers during the study if deemed safe by the investigator.
    8. No known allergic reaction to any component of DTX301.
    9. Willing and able to comply with study procedures and requirements, including periodic inpatient hospitalizations, frequent blood draws, and urine collections over a 24-hour period.
    10. Hematology and coagulation panel results are within the normal range or, if outside the normal range, deemed not clinically significant in the opinion of the investigator.
    11. Males and all females of childbearing potential must be willing to use effective contraception at the time of administration of gene transfer and for the 52 weeks following administration of DTX301 to prevent the potential transmission of the AAV vector. For male subjects, appropriate contraceptive methods include the use of a condom with spermicide. For female subjects, appropriate contraceptive methods include the use of a condom with spermicide plus at least 1 of the following:
    a. Oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device;
    b. Use of a diaphragm or cervical/vault cap;
    c. Previous female sterilization (surgical bilateral oophorectomy [with or without hysterectomy] or tubal ligation) at least 6 weeks prior to DTX301 administration. In case of an oophorectomy alone, the reproductive status of the subject must have been confirmed by follow-up hormone level assessment.
    NOTE: Abstinence is an acceptable form of birth control; however, appropriate contraception must be used if the subject becomes sexually active. A condom with spermicide is required to be used by all sexually active vasectomized males in the study in order to prevent potential transmission of the vector via seminal fluid.
    NOTE: Females of childbearing potential are defined as all females physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception for the duration of the study. Females are considered post-menopausal and not of childbearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (eg, age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 6 weeks prior to enrollment. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of childbearing potential.
    E.4Principal exclusion criteria
    1. At Screening or Baseline (Day 0), plasma ammonia level =100 µmol/L for patients who historically maintain normal ammonia levels; OR plasma ammonia level = 200 µmol/L for patients who historically are not able to fully control ammonia levels with baseline management; OR signs and
    symptoms of hyperammonemia, with documented elevated ammonia level, during the 4-week period preceding Day 0. If ammonia level is inconsistent with the subject's clinical status, the ammonia level may be repeated to ensure accurate results.
    2. Liver transplant, including hepatocyte cell therapy/transplant.
    3. 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.
    4. Significant hepatic inflammation or cirrhosis as evidenced by imaging or any of the following laboratory abnormalities: alanine aminotransferase or aspartate aminotransferase >2.0 × upper limit of normal (ULN), total bilirubin >1.5 × ULN, alkaline phosphatase >2.5 × ULN.
    5. Serum creatinine >2.0 mg/dL.
    6. 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: Subjects 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. Subjects 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.
    7. 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 Day 0, or plasma viral load >200 copies/mL, documented on 2 separate occasions, as measured by PCR.
    8. Active infection (viral or bacterial).
    9. Anti-AAV8 neutralizing antibody titer >1:5.
    10. Participation (current or previous) in another gene transfer study.
    11. Participation in another investigational medicine study within 3 months of Screening.
    12. 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 non-melanoma skin cancer.
    13. 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.
    14. Has any other significant medical condition that the investigator feels would be a risk to the subject or would impede the study.
    E.5 End points
    E.5.1Primary end point(s)
    The incidence of adverse events (AEs), treatment-emergent adverse events (TEAEs), and serious adverse events (SAEs) for each dosing cohort, assessed by severity and relationship to study product.
    E.5.1.1Timepoint(s) of evaluation of this end point
    From the time the subject signs the Informed Consent Form through the end of study/early withdrawal visit.
    E.5.2Secondary end point(s)
    - The change from baseline in the rate of ureagenesis (as measured by the generation of [13C]urea over 4 hours) as determined by gas chromatography mass spectrometry over time to 52 weeks after the IV
    administration of DTX301.
    - The change from baseline (Day 0) in plasma ammonia area under the curve from time zero to 24 hours (AUC 0-24) over time to 52 weeks after IV administration of DTX301 in the setting of tapering or discontinuing ammonia scavenger medications.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Ureagenesis: at Screening, Day 1 prior to DTX301 infusion, Week 6, Week 12, Week 20, Week 24, Week 52

    Serum ammonia: Day 0, Week 6, Week 12, Week 24, Week 52
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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) Yes
    E.7.1.1First administration to humans Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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 No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA10
    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
    Canada
    Spain
    United Kingdom
    United States
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days16
    E.8.9.2In all countries concerned by the trial years2
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    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) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 17
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1
    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 state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 9
    F.4.2.2In the whole clinical trial 18
    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)
    After patients have ended their participation in the trial, they will be treated according to the normal standard of care. After completion of this study, subjects will be asked to enroll in a 4-year extension study to evaluate the long-term (a total of 5 years) safety and efficacy of DTX301.
    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 Decision2017-03-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-03-14
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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