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    Summary
    EudraCT Number:2021-006597-23
    Sponsor's Protocol Code Number:UX143-CL301
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2023-02-08
    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 ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2021-006597-23
    A.3Full title of the trial
    An Operationally Seamless, Randomized Phase 2/3 Study Consisting of a Phase 2 Single Blind, Dose-Evaluation Phase and a Phase 3 Double-Blind, Placebo-controlled Phase to Assess the Efficacy and Safety of Setrusumab in Subjects with Osteogenesis Imperfecta
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to test product setrusumab in subjects with brittle bone syndrome.
    A.4.1Sponsor's protocol code numberUX143-CL301
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT05125809
    A.5.4Other Identifiers
    Name:INDNumber:113385
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/536/2022
    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 pointUX143-CL301 Global Operations
    B.5.3 Address:
    B.5.3.1Street Address60 Leveroni Court
    B.5.3.2Town/ cityNovato
    B.5.3.3Post codeCA 94949
    B.5.3.4CountryUnited States
    B.5.6E-mailUX143-CL301@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/3/16/1686
    D.3 Description of the IMP
    D.3.1Product nameSetrusumab
    D.3.2Product code BPS804, UX143
    D.3.4Pharmaceutical form Lyophilisate 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 INNSETRUSUMAB
    D.3.9.1CAS number 1847394-95-9
    D.3.9.3Other descriptive nameUX143, BPS804
    D.3.9.4EV Substance CodeSUB193275
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number160
    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) Yes
    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 Yes
    D.3.11.13.1Other medicinal product typeMonoclonal antibody
    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
    Osteogenesis imperfecta (OI)
    E.1.1.1Medical condition in easily understood language
    Brittle bone syndrome
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10031243
    E.1.2Term Osteogenesis imperfecta
    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
    Phase II: Identify a setrusumab dosing strategy in subjects with OI
    Phase III: Evaluate the effect of setrusumab vs placebo on reduction in fracture rate, excluding morphometric vertebral fractures and fractures
    of the fingers, toes, face, and skull
    E.2.2Secondary objectives of the trial
    Phase II:
    - Evaluate the pharmacokinetics (PK) of setrusumab doses in subjects with OI
    - Determine the pharmacodynamic (PD) effects of setrusumab on bone formation and turnover markers
    - Evaluate the effect of setrusumab on lumbar spine bone mineral density (BMD)
    - Evaluate the safety profile of setrusumab for the treatment of subjects with OI
    - Evaluate the immunogenicity of setrusumab for the treatment of subjects with OI

    Phase III:
    - Evaluate the effect of setrusumab vs placebo on reduction in fracture rate
    -Evaluate the effect of setrusumab vs placebo on lumbar spine BMD
    - Evaluate the effect of setrusumab vs placebo on clinical outcome assessments including subject-/caregiver-reported assessments of physical function, pain, and health-related quality of life
    - Assess the safety profile of setrusumab
    - Evaluate the immunogenicity of setrusumab for the treatment of subjects with OI
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    UX143-CL301 BONE BIOPSY SUBSTUDY
    The primary objective of the UX143-CL301 bone biopsy safety substudy is to obtain additional data to rule out any significant adverse effects of
    setrusumab on bone quality, including impairment of normal bone mineralization. This will be accomplished by qualitative histological analysis of undecalcified sections of transiliac bone biopsies, followed by histomorphometric analysis of standardized static and dynamic parameters. These analyses will provide insight into the effects of setrusumab on bone mineralization and formation at the tissue level, and is required
    to characterize the safety of setrusumab in this population.
    E.3Principal inclusion criteria
    1. Males and females 5 to < 26 years of age at time of informed consent
    2. Diagnosis of OI Type I, III, or IV as confirmed by identification of pathogenic or likely pathogenic genetic variants in COL1A1 or COL1A2. If
    a variant of uncertain significance is identified, then clinical presence of expected phenotype can be used to confirm the diagnosis.
    3. ≥ 1 fracture in the past 12 months, ≥ 2 fractures in the past 24 months, or ≥ 1 tibia, femur, or humerus fracture in the past 24 months
    4. Serum 25-hydroxyvitamin D ≥ 20 ng/mL at the Screening Visit. If 25hydroxyvitamin D levels are below 20 ng/mL, 25-hydroxyvitamin D testing can be repeated after a minimum of 14 days of vitamin D supplementation as directed by the treating physician
    5. Willing to not receive bisphosphonate therapy during the study
    6. From the period following informed consent to 60 days after the last dose of study drug, females of childbearing potential and fertile males must consent to use highly effective contraception. If female, agree not to become pregnant. If male, agree not to father a child or donate sperm
    7. Willing and able to provide informed consent for subjects ≥ 18 years of age, or provide assent (if possible) 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
    8. Willing to provide access to medical records for the collection of radiographic data, fracture data, growth data, and disease history
    9. Must, in the opinion of the Investigator, be willing and able to complete all aspects of the study, adhere to the study visit schedule, and comply with the assessments
    E.4Principal exclusion criteria
    1. For Phase 2 subjects only, a history of major bone surgery within the previous 6 months prior to Screening or planned major bone surgery for the first 3 months of the study
    2. History of skeletal malignancies or bone metastases at any time
    3. History of neural foraminal stenosis (except if due to scoliosis)
    4. Clinical unstable manifestations of Chiari malformation or basilar invagination within the past 2 years. Presence of any other neurologic disease that has been clinically unstable within the past 2 years requires review by the Medical Monitor.
    5. History of or uncontrolled concomitant diseases such as hypo/hyperparathyroidism, Paget’s disease, abnormal thyroid function, thyroid disease or other endocrine disorders or conditions that could affect bone metabolism
    6. Rickets or any skeletal condition (other than OI) leading to bone deformities and/or increased risk of fractures
    7. History of stroke, myocardial infarction, TIA, or angina. Investigators should consider whether the potential benefits of treatment outweigh the potential risks in patients with other cardiovascular risk factors such as hypertension, hyperlipidemia, familial hyperlipidemia, family history of premature ischemic cardiovascular disease, smoking, diabetes mellitus, and metabolic syndrome.
    8. Hypocalcemia, defined as serum calcium levels below the age-adjusted normal limits after a ≥ 4 hour fast
    9. Estimated glomerular filtration rate < 29 mL/min/1.73 m2
    10. Prior treatment with the following:
    a. Teriparatide, growth hormone, or other bone anabolic or antiresorptive medications within 6 months of the first dose with study drug (Month
    0)
    b. Denosumab within 24 months of the first dose with study drug (Month 0)
    c. Romosozumab at any time
    11. Documented alcohol and/or drug abuse within 12 months prior to dosing or evidence of such abuse as determined by the Investigator
    12. Presence or history of any condition that, in the view of the Investigator, would interfere with participation, pose undue risk, or would confound interpretation of results
    13. Known hypersensitivity to setrusumab or its excipients that, in the judgment of the Investigator, places the subject at increased risk for adverse effects
    14. History of external radiation therapy
    15. Pregnant or breastfeeding or planning to become pregnant (self or partner) at any time during the study
    16. Use of any investigational product or investigational medical device within 4 weeks or 5 half-lives of investigational drug (whichever is longer) prior to Screening, or during the study (per discretion of the Investigator in consultation with the Medical Monitor)
    17. Concurrent participation in another clinical study without prior approval from the Investigator in consultation with the Medical Monitor
    E.5 End points
    E.5.1Primary end point(s)
    Phase II: Percent change in serum P1NP from Baseline at Month 1
    Phase III: Annualized rate of all radiographically-confirmed fractures, excluding morphometric vertebral fractures and fractures of the fingers, toes, face, and skull, during the Double Blind (DB) Treatment Period
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase II: Screening and one month
    Phase III: The timing of the primary analysis will be determined using a routine blinded information-based assessment approach. Double Blind
    Treatment Period duration for any single subject will not exceed 24 months.
    E.5.2Secondary end point(s)
    Phase II:
    1) Serum setrusumab concentration at scheduled time points
    2)
    • Baseline-corrected AUEC for serum P1NP over a 1- and 2-month timeframe
    • Percent change from Baseline in bone turnover markers (P1NP and OCN) over time
    3)
    • Change from Baseline in DXA lumbar spine BMD z-scores over time
    • Percent change from Baseline in DXA lumbar spine BMD over time
    4) Frequency, severity, and relationship to treatment of TEAEs, SAEs, and AESIs
    5) Incidence of anti-setrusumab binding and neutralizing antibodies at scheduled time points

    Phase III:
    1) • Annualized rate of all radiographically-confirmed fractures, excluding morphometric vertebral fractures, but including fractures of the fingers, toes, face and skull, during the DB Treatment Period
    • Annualized rate of all radiographically-confirmed fractures during the DB Treatment Period
    2) Change from Baseline in DXA lumbar spine BMD z-score at 12 months
    3) Change from Baseline at 12 months for:
    • POSNA-PODCI Sports/Physical Functioning and Pain/comfort subscale scores for subjects < 18 years of age at screening
    • SF-36 PF and BP Domain Scales for subjects ≥ 18 years of age at screening
    4) Frequency, severity, and relationship to treatment of TEAEs, SAEs, and AESIs
    5) Incidence of binding and neutralizing anti-setrusumab antibodies at scheduled time points
    E.5.2.1Timepoint(s) of evaluation of this end point
    Phase II: setrusumab concentration is measured at baseline, wk 2,3,4, month 1, day 45, month 2, 3, 6, 12, 18 and 24.

    Phase III: setrusumab concentration is measured at baseline, week 3, months 1, 2, 3, 6, 12, 18 and 24
    - Serum P1NP, CTX, BSAP, OCN at baseline, week 3 and months 1, 2, 3, 6, 12, 18, 24.
    - Anti-setrusumab binding and neutralizing antibodies at screening, week 3 and months 1, 2, 3, 6, 12, 18, 24.
    - DXA at 0, 3,6,12, 18 months and 24 months (final visit).
    - POSNA-PODCI Sports/Physical Functioning measured at 0, 6, 12,18 and 24 months/final visit
    - SF-36 PF and BP Domain Scales at 0, 6, 12, 18, 24 months /final visit
    - TEAEs, SAEs, and AESIs - all study visits
    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 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 Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity
    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) 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 Yes
    E.8.1.3Single blind Yes
    E.8.1.4Double blind Yes
    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 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.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA16
    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
    Canada
    United Kingdom
    United States
    Denmark
    France
    Germany
    Italy
    Netherlands
    Poland
    Portugal
    Türkiye
    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 years3
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months6
    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: 181
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 118
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 63
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Pediatric subjects incapable of giving consent.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 59
    F.4.2.2In the whole clinical trial 219
    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)
    All Subjects (Phase 2 and Phase 3) will be in the open-label Treatment Extension Period for at least 12 months and have the option to remain in the open-label period until setrusumab is commercially available in their region.
    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 Decision2023-05-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2023-02-14
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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