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    Summary
    EudraCT Number:2020-005266-34
    Sponsor's Protocol Code Number:UX701-CL301
    National Competent Authority:Portugal - INFARMED
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-11-22
    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 ConcernedPortugal - INFARMED
    A.2EudraCT number2020-005266-34
    A.3Full title of the trial
    A Randomized, Double-blind, Placebo-controlled, Multicenter, Seamless, Adaptive, Safety, Dose-finding, and Phase 3 Clinical Study of UX701 AAV-mediated Gene Transfer for the Treatment of Wilson Disease
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to understand the safety and the effects of a virus that transfers a modified protein responsible for copper metabolism (copper-transporting P-type adenosine triphosphatase, ATP7B) in adults with Wilson disease.
    A.4.1Sponsor's protocol code numberUX701-CL301
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04884815
    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 pointDirector, Regulatory Affairs
    B.5.3 Address:
    B.5.3.1Street Address19 Presidential Way
    B.5.3.2Town/ cityWoburn, MA
    B.5.3.3Post code01801
    B.5.3.4CountryUnited States
    B.5.4Telephone number0016177140696
    B.5.6E-mailMGollwitzer@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/3/20/2378
    D.3 Description of the IMP
    D.3.1Product nameUX701
    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 INNUX701
    D.3.9.3Other descriptive nameAdeno-associated viral vector serotype 9 encoding human ATP7B
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number11000000000000
    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 numberThe EMA/CAT considers that product UX701, falls within the definition of gene therapy medicinal product as provided in Article 2 of Regulation (EC) No 1394/2007. EMA/545854/2020.
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution 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
    Wilson disease
    E.1.1.1Medical condition in easily understood language
    Inherited disorder of copper metabolism
    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 10047988
    E.1.2Term Wilson's disease
    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
    Stage 1 (Phase 1/2) Primary
    • To evaluate the safety of single IV doses of UX701 in patients with Wilson disease
    • To select the UX701 dose with the best benefit/risk profile based on the totality of safety and efficacy data at Week 52

    Stage 2 (Phase 3) Primary
    • To evaluate the effect of UX701 on copper regulation based on 24-hour urinary copper concentration and percent reduction in SOC medication at Week 52
    E.2.2Secondary objectives of the trial
    Stage 2 (Phase 3) Secondary
    • To evaluate the effect of UX701 on biomarkers of copper metabolism and regulation
    • To evaluate the effect of UX701 on patient- and clinician-reported outcomes
    • To evaluate the effect of UX701 on the need for continued SOC medication to maintain copper regulation
    • To evaluate the effect of UX701 on liver function and overall health
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Optional liver biopsy substudy:
    Gene transfer with UX701 has the potential to restore ATP7B function, establish normal copper metabolism, reduce elevated copper in the liver, and improve liver health. An optional liver biopsy substudy will assess the tissue level effects of UX701. Subjects who consent to participate in the substudy will undergo a liver biopsy during the Screening Period and at Week 52. The substudy aims to enroll up to 20 subjects in Stage 2. Subjects in Stage 1 may participate in the substudy if interested. Data from subjects in Stage 1 will provide supportive evidence for the respective dose cohort.
    E.3Principal inclusion criteria
    1. Patients ≥ 18 years of age at the time informed consent is provided.
    2. Confirmed diagnosis of Wilson disease based on genetic confirmation of heterozygous or homozygous biallelic ATP7B mutation.
    3. Ongoing copper chelator (ie, penicillamine, trientine) and/or zinc therapy for at least 12 months at Screening, with no medication or dose changes for at least 6 months at Screening.
    4. Stable Wilson disease as evidenced by stable 24-hour urinary copper concentration during the Screening Period (defined as 2 values within 30% at 2 time points approximately 4 weeks apart).
    5. Ongoing restriction of high copper containing foods for at least 12 months at Screening, continued through study participation.
    6. Willing and able to comply with all study procedures and requirements, including frequent blood collection, total urine collection over a 24-hour period, patient-reported outcome assessments, and long-term follow-up.
    E.4Principal exclusion criteria
    1. Detectable pre-existing antibodies to the AAV9 capsid (AAV9 DetectCDx)
    2. Stage 1 only: History of copper chelator or zinc therapy noncompliance, in the Investigator’s judgment, within 12 months prior to Screening
    3. History of liver transplant
    4. Decompensated hepatic cirrhosis or presence of advanced liver disease as evidenced by portal hypertension, ascites, splenomegaly, esophageal varices, or hepatic encephalopathy.
    5. Significant hepatic inflammation as evidenced by any of the following laboratory abnormalities:
    • Stage 1 only: ALT or AST > 2.5 ULN
    • Stage 2 only: ALT or AST > 3.0 × ULN
    • Total bilirubin > 2.0 × ULN
    • Alkaline phosphatase > 2.5 × ULN
    6. Model for End-Stage Liver Disease (MELD) score > 13
    7. Wilson Index score > 11
    8. Hemoglobin < 9 g/dL
    9. History of prolonged QT syndrome (QT interval > 450 msec on electrocardiogram [ECG])
    10. Presence of Stage 3 or higher chronic kidney disease based on estimated glomerular filtration rate < 60 mL/min/1.73 m^2.
    11. History of active or latent tuberculosis, history of positive purified protein derivative (PPD) or tine test, positive QuantiFERON-TB Gold tuberculosis test, or positive T-SPOT.TB test if QuantiFERON-TB Gold tuberculosis test is not available.
    12. Moderate to severe depression, recent or active suicidal ideation with intent or suicidal behavior, psychosis, or unstable psychiatric illness meeting any of the following criteria:
    • Moderate to severe depression defined as a Beck Depression Inventory-II (BDI-II) score > 20 at Screening
    • History of suicide attempt (including actual, interrupted, or aborted attempt) within 5 years prior to Screening, or history of suicidal ideation with intent within 6 months prior to Screening
    − Patients with a history of suicide attempt more than 5 years prior to Screening should be evaluated by a mental healthcare professional before enrolling into the study
    • Columbia Suicide Severity Rating Scale (C-SSRS) assessment with a Yes response to Question 4 or Question 5 at Screening
    • Moderate to severe psychosis at Screening, defined as a total Brief Psychiatric Rating Scale (BPRS) score > 10 for the following questions: Question 3 Emotional Withdrawal, Question 11 Suspiciousness, Question 12 Hallucination, Question 15 Unusual Thought Content, and Question 16 Blunt Affect
    • History of psychiatric inpatient hospitalization within 1 year prior to Screening or psychiatric medication changes within 8 weeks prior to Screening
    13. History or presence of hepatitis C virus infection as defined by the laboratory assessment criteria.
    14. Presence of hepatitis B virus infection (documented by positive hepatitis B surface antigen, hepatitis B surface antibody, or hepatitis B core antibody [immunoglobulin G]), hepatitis C virus infection (documented by positive hepatitis C antibody or hepatitis C virus RNA titer), or both.
    15. History of human immunodeficiency virus infection
    16. Presence or history of any condition that, in the Investigator’s opinion, would interfere with participation, pose undue risk, or confound interpretation of study results. This includes any intercurrent febrile or non-febrile illness during Screening, including common viral infections, influenza, and COVID-19 until full clinical recovery
    17. Pregnant or breastfeeding or planning to become pregnant (self or partner) at any time during the study
    18. Female subject of childbearing potential who has a positive serum pregnancy test at Screening or a positive urine pregnancy test at Baseline, or who is unwilling to have additional pregnancy tests during the study. Female subjects are considered not of childbearing potential if they have not experienced menarche, are postmenopausal (defined as having no menses for at least 12 months without an alternative medical cause), or are permanently sterile due to total hysterectomy, bilateral salpingectomy, or bilateral oophorectomy
    19. Known hypersensitivity to UX701 or its excipients, copper chelators (ie, penicillamine, trientine), zinc, or oral corticosteroids that, in the Investigator’s judgment, places the subject at increased risk for adverse effects
    20. Participation in another gene transfer study or use of another gene transfer product before or during study participation
    21. History of illicit drug use within 60 days prior to Screening or positive results from a urine drug screen during the Screening Period, not including medications prescribed for a diagnosed medical condition or use of cannabinoids for recreational or medicinal purposes.
    22. History of illicit drug use within 60 days prior to Screening or positive results from a urine drug screen during the Screening Period, not including medications prescribed for a diagnosed medical condition or cannabinoids
    23. Subjects with known hypersensitivity to amide-containing local anesthetics are excluded from participating in the optional liver biopsy substudy
    E.5 End points
    E.5.1Primary end point(s)
    Stage 1 (Phase 1/2) Primary:
    Primary endpoints include the following assessments for UX701:
    • Incidence of TEAEs, TESAEs, treatment-related TEAEs, and treatment-related TESAEs
    • Change in 24-hour urinary copper concentration from Baseline at Week 52
    • Change in total copper, ceruloplasmin, NCC, free copper, and ceruloplasmin activity levels from Baseline at Week 52
    • Percent reduction in SOC medication by Week 52
    • Number of subjects who discontinue SOC medication by Week 52 (measured as complete response, partial response, or no response)
    • Number of consecutive weeks off SOC medication at Week 52

    Stage 2 (Phase 3) Primary:
    Primary endpoints include the following comparisons between UX701 and placebo:
    • Change in 24-hour urinary copper concentration from Baseline at Week 52, evaluated for superiority
    • Percent reduction in SOC medication by Week 52, evaluated for superiority
    E.5.1.1Timepoint(s) of evaluation of this end point
    Stage 1 (Phase 1/2) Primary: Day 0, Week 6, 12, 24, 36, 52
    Stage 2 (Phase 3) Primary: Day 0, Week 6, 12, 24, 36, 52
    E.5.2Secondary end point(s)
    Stage 2 (Phase 3) Secondary:
    Secondary endpoints include the following comparisons between UX701 and placebo:
    • Change in ceruloplasmin activity levels from Baseline at Week 52, evaluated for superiority
    • Change in WDFRS Patient scores from Baseline at Week 52, evaluated for superiority
    • Number of subjects who discontinue SOC medication by Week 52 (measured as complete response, partial response, or no response)a
    • Change in WDFRS Clinician scores from Baseline at Week 52
    • Change in liver copper concentration assessed by liver biopsy from Baseline at Week 52
    E.5.2.1Timepoint(s) of evaluation of this end point
    Stage 2 (Phase 3) Secondary: Day 0, Week 6, 8, 12, 14, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52
    Stage 2 (Phase 3) Safety: Day 0, Week 6, 12, 24, 36, 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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    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) 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 No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    seamless, adaptive design
    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 trial3
    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 concerned2
    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
    Brazil
    Canada
    Japan
    United States
    Austria
    France
    Poland
    Spain
    Germany
    Italy
    Portugal
    United Kingdom
    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
    The end of the Primary Analysis Follow-up Period is defined as the date of the Week 52 Visit for the last subject randomized in Stage 2.
    The end of the study is defined as the date of the last protocol-specified visit or assessment for the last subject randomized in the study.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years10
    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 years10
    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 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: 78
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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 state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 27
    F.4.2.2In the whole clinical trial 78
    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 completion of the UX701-CL301 study, subjects will be offered enrollment into a Disease Monitoring Program (DMP) that will evaluate the long-term safety and efficacy of UX701. The DMP for Wilson disease will be conducted under a separate protocol.
    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 Decision2023-01-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-04-29
    P. End of Trial
    P.End of Trial StatusOngoing
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