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Clinical Study of UX701 AAV-Mediated Gene Transfer for the Treatment of Wilson Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04884815
Recruitment Status : Recruiting
First Posted : May 13, 2021
Last Update Posted : April 28, 2022
Sponsor:
Information provided by (Responsible Party):
Ultragenyx Pharmaceutical Inc

Brief Summary:
The primary objectives of this study are 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 and to evaluate the effect of UX701 on copper regulation.

Condition or disease Intervention/treatment Phase
Wilson Disease Genetic: UX701 Other: Placebo Drug: oral corticosteroids Drug: Placebo for oral corticosteroids Phase 1 Phase 2

Detailed Description:

This study is a randomized, double-blind, placebo-controlled, seamless, adaptive Phase 1/2/3 clinical study of UX701 in patients with Wilson disease.

Stage 1 (Phase 1/2) is designed to evaluate the safety and efficacy of 3 dose levels of UX701 to establish initial safety of UX701 and select a safe and efficacious dose for further evaluation. Stage 2 (Phase 3) is designed to evaluate the safety and efficacy of UX701 using the dose selected in Stage 1. Stage 3 (long-term follow-up) is designed to evaluate the long-term safety, efficacy, and clinical benefit of UX701. All participants will be followed for at least 5 years from the time of UX701 administration.

Participants who receive UX701 will receive prophylactic oral corticosteroids. Participants who receive placebo will receive placebo oral corticosteroids to maintain the study blind.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : September 27, 2021
Estimated Primary Completion Date : January 2026
Estimated Study Completion Date : January 2031

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Stage 1: UX701 Dose Level 1
Participants randomized to receive a single, peripheral intravenous (IV) infusion of UX701 at dose level 1 plus prophylactic oral corticosteroids.
Genetic: UX701
nonreplicating, recombinant gene transfer vector

Drug: oral corticosteroids
Participants who receive UX701 (at Baseline or during Stage 3) will receive prophylactic oral corticosteroids.
Other Name: prednisolone

Placebo Comparator: Stage 1: Placebo for Dose Level 1
Participants randomized to receive a single, peripheral IV infusion of matching placebo plus placebo oral corticosteroids.
Other: Placebo
normal saline

Drug: Placebo for oral corticosteroids
Participants who receive placebo investigational product (IP) will receive placebo oral corticosteroids to maintain the study blind.

Experimental: Stage 1: UX701 Dose Level 2
Participants randomized to receive a single, peripheral IV infusion of UX701 at dose level 2 plus prophylactic oral corticosteroids.
Genetic: UX701
nonreplicating, recombinant gene transfer vector

Drug: oral corticosteroids
Participants who receive UX701 (at Baseline or during Stage 3) will receive prophylactic oral corticosteroids.
Other Name: prednisolone

Placebo Comparator: Stage 1: Placebo Dose Level 2
Participants randomized to receive a single, peripheral IV infusion of matching placebo plus placebo oral corticosteroids.
Other: Placebo
normal saline

Drug: Placebo for oral corticosteroids
Participants who receive placebo investigational product (IP) will receive placebo oral corticosteroids to maintain the study blind.

Experimental: Stage 1: UX701 Dose Level 3
Participants randomized to receive a single, peripheral IV infusion of UX701 at dose level 3 plus prophylactic oral corticosteroids.
Genetic: UX701
nonreplicating, recombinant gene transfer vector

Drug: oral corticosteroids
Participants who receive UX701 (at Baseline or during Stage 3) will receive prophylactic oral corticosteroids.
Other Name: prednisolone

Placebo Comparator: Stage 1: Placebo Dose Level 3
Participants randomized to receive a single, peripheral IV infusion of matching placebo plus placebo oral corticosteroids.
Other: Placebo
normal saline

Drug: Placebo for oral corticosteroids
Participants who receive placebo investigational product (IP) will receive placebo oral corticosteroids to maintain the study blind.

Experimental: Stage 2: UX701
Participants randomized to receive a single, peripheral IV infusion of UX701 at a dose selected in Stage 1 plus prophylactic oral corticosteroids.
Genetic: UX701
nonreplicating, recombinant gene transfer vector

Drug: oral corticosteroids
Participants who receive UX701 (at Baseline or during Stage 3) will receive prophylactic oral corticosteroids.
Other Name: prednisolone

Placebo Comparator: Stage 2: Placebo
Participants randomized to receive a single, peripheral IV infusion of matching placebo plus placebo oral corticosteroids.
Other: Placebo
normal saline

Drug: Placebo for oral corticosteroids
Participants who receive placebo investigational product (IP) will receive placebo oral corticosteroids to maintain the study blind.

Experimental: Stage 3: UX701
Participants originally randomized in Stage 1 or Stage 2 to placebo will be eligible for a single, peripheral IV infusion of UX701 at the selected dose plus prophylactic oral corticosteroids.
Genetic: UX701
nonreplicating, recombinant gene transfer vector

Drug: oral corticosteroids
Participants who receive UX701 (at Baseline or during Stage 3) will receive prophylactic oral corticosteroids.
Other Name: prednisolone

Placebo Comparator: Stage 3: Placebo
Participants originally randomized in Stage 2 to UX701 will receive a single, peripheral IV infusion of matching placebo plus placebo oral corticosteroids.
Other: Placebo
normal saline

Drug: Placebo for oral corticosteroids
Participants who receive placebo investigational product (IP) will receive placebo oral corticosteroids to maintain the study blind.




Primary Outcome Measures :
  1. Incidence of Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs), Treatment-Related TEAEs, and Treatment-Related TESAEs [ Time Frame: Up to Week 52 ]
  2. Stage 1: Change in 24-hour Urinary Copper Concentration from Baseline at Week 52 [ Time Frame: Baseline, Week 52 ]
  3. Stage 1: Change in Total Copper from Baseline at Week 52 [ Time Frame: Baseline, Week 52 ]
  4. Stage 1: Change in Total Ceruloplasmin from Baseline at Week 52 [ Time Frame: Baseline, Week 52 ]
  5. Stage 1: Change in Total Non-Ceruloplasmin-bound Copper (NCC) from Baseline at Week 52 [ Time Frame: Baseline, Week 52 ]
  6. Stage 1: Change in Total Free Copper from Baseline at Week 52 [ Time Frame: Baseline, Week 52 ]
  7. Stage 1: Change in Total Ceruloplasmin Activity from Baseline at Week 52 [ Time Frame: Baseline, Week 52 ]
  8. Stage 1: Percent Reduction in Standard of Care (SOC) Medication by Week 52 [ Time Frame: Week 52 ]
  9. Stage 1: Number of Subjects Who Discontinue SOC Medication by Week 52 [ Time Frame: Week 52 ]
  10. Stage 1: Number of Consecutive Weeks off SOC Medication at Week 52 [ Time Frame: Week 52 ]
  11. Stage 2: Change in 24-hour Urinary Copper Concentration from Baseline at Week 52, evaluated for superiority [ Time Frame: Baseline, Week 52 ]
  12. Stage 2: Percent Reduction in SOC Medication by Week 52, Evaluated for Superiority [ Time Frame: Week 52 ]

Secondary Outcome Measures :
  1. Stage 2: Change in Ceruloplasmin Activity Levels from Baseline at Week 52, Evaluated for Superiority [ Time Frame: Baseline, Week 52 ]
  2. Stage 2: Change in Wilson Disease Functional Rating Scale (WDFRS) Patient Scores from Baseline at Week 52, Evaluated for Superiority [ Time Frame: Baseline, Week 52 ]
  3. Stage 2: Number of Subjects who Discontinue SOC Medication by Week 52 [ Time Frame: Week 52 ]
  4. Stage 2: Change in WDFRS Clinician Scores from Baseline at Week 52 [ Time Frame: Baseline, Week 52 ]
  5. Stage 2: Change in Liver Copper Concentration Assessed by Liver Biopsy from Baseline at Week 52 [ Time Frame: Baseline, Week 52 ]

Other Outcome Measures:
  1. Stage 2: Development of Anti-ATP7B Antibodies [ Time Frame: Up to Week 104 ]
  2. Incidence of TEAEs, TESAEs, Treatment-Related TEAEs, and Treatment-Related TESAEs [ Time Frame: Up to Week 312 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  • Confirmed diagnosis of Wilson disease
  • 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.
  • Stable Wilson disease as evidenced by stable laboratory values during the Screening Period
  • Ongoing restriction of high copper containing foods for at least 12 months at Screening, continued through study participation.
  • 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

Key Exclusion Criteria:

  • Detectable pre-existing antibodies to the AAV9 capsid.
  • Stage 1 only: History of copper chelator or zinc therapy noncompliance, in the Investigator's judgment, within 12 months prior to Screening.
  • History of liver transplant.
  • Decompensated hepatic cirrhosis or presence of advanced liver disease as evidenced by portal hypertension, ascites, splenomegaly, esophageal varices, hepatic encephalopathy, or a liver biopsy with evidence of stage III fibrosis.
  • Significant hepatic inflammation as evidenced by imaging or any of the laboratory abnormalities.
  • Model for End-Stage Liver Disease (MELD) score > 13.
  • Wilson Index score > 11
  • Hemoglobin < 9 g/dL
  • History of prolonged QT syndrome (QT interval > 450 msec on electrocardiogram [ECG])
  • Presence of Stage 3 or higher chronic kidney disease based on estimated glomerular filtration rate < 60 mL/min/1.73 m2.
  • Marked neurological deficit or compromise that, in the Investigator's opinion, would interfere with the subject's safety or ability to participate in the study.
  • Moderate to severe depression, recent or active suicidal ideation with intent or suicidal behavior, psychosis, or unstable psychiatric illness.
  • Participation in another gene transfer study or use of another gene transfer product before or during study participation.
  • Subjects with known hypersensitivity to amide-containing local anesthetics are excluded from participating in the optional liver biopsy substudy.

Note: Other protocol defined Inclusion/ Exclusion criteria may apply


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04884815


Contacts
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Contact: Patients Contact: Trial Recruitment 1-888-756-8657 trialrecruitment@ultragenyx.com
Contact: HCPs Contact: Medical Information 1-888-756-8657 medinfo@ultragenyx.com

Locations
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United States, California
University of California Los Angeles Recruiting
Los Angeles, California, United States, 90095
Stanford University Recruiting
Redwood City, California, United States, 94063
United States, Florida
University of Miami Recruiting
Miami, Florida, United States, 33124
United States, Illinois
Northwestern University Recruiting
Chicago, Illinois, United States, 60611
United States, Indiana
Indiana University Recruiting
Indianapolis, Indiana, United States, 46202
United States, Michigan
University of Michigan Recruiting
Ann Arbor, Michigan, United States, 48109
United States, Washington
Seattle Children's Hospital Recruiting
Seattle, Washington, United States, 98105
Spain
Hospital Universitario Vall d'Hebron - PPDS Recruiting
Barcelona, Spain, 08035
Hospital Universitari i Politecnic La Fe de Valencia Recruiting
Valencia, Spain, 46026
Sponsors and Collaborators
Ultragenyx Pharmaceutical Inc
Investigators
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Study Director: Medical Director Ultragenyx Pharmaceutical Inc
Additional Information:
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Responsible Party: Ultragenyx Pharmaceutical Inc
ClinicalTrials.gov Identifier: NCT04884815    
Other Study ID Numbers: UX701-CL301
2020-005266-34 ( EudraCT Number )
First Posted: May 13, 2021    Key Record Dates
Last Update Posted: April 28, 2022
Last Verified: April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Due to the rarity of Wilson Disease, individual patient data will not be shared in order to safeguard patient privacy. The study protocol and statistical analysis plan for this study will be available with the tabulated results once posted.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Hepatolenticular Degeneration
Liver Diseases
Digestive System Diseases
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Movement Disorders
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Metabolism, Inborn Errors
Metal Metabolism, Inborn Errors
Metabolic Diseases
Prednisolone
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents