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    Summary
    EudraCT Number:2015-001775-41
    Sponsor's Protocol Code Number:UX023-CL304
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-12-13
    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 ConcernedFrance - ANSM
    A.2EudraCT number2015-001775-41
    A.3Full title of the trial
    An Open-Label, Single-Arm, Phase 3 Study to Evaluate the Effects of KRN23 on
    Osteomalacia in Adults with X-linked Hypophosphatemia (XLH)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to examine the efficacy of KRN23 on bone quality
    A.4.1Sponsor's protocol code numberUX023-CL304
    A.5.4Other Identifiers
    Name:EMA/902676Number:Unique Product Identifier
    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
    B.5.2Functional name of contact pointChristine Leonard
    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.5.4Telephone number14154838962
    B.5.6E-mailChristyLeonard@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/3/14/1351
    D.3 Description of the IMP
    D.3.1Product nameRecombinant human IgG1 monoclonal antibody to fibroblast growth factor 23 [FGF23]
    D.3.2Product code KRN23
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBunesumab
    D.3.9.1CAS number 1610833-03-8
    D.3.9.2Current sponsor codeKRN23
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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 typeFully Human Monoclonal Antibody
    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
    XLH is a disorder of hypophosphatemia, renal phosphate wasting, and the most common inheritable form of rickets. In XLH patients, excess circulating fibroblast growth factor (FGF23) impair phosphate reabsorption in the kidney. Chronic low serum phosphorus levels lead to defective bone mineralization and, consequently, to rickets in children and osteomalacia in adults, the two major pathologic outcomes of the hypophosphatemia.
    E.1.1.1Medical condition in easily understood language
    Inheritable form of rickets
    E.1.1.2Therapeutic area Body processes [G] - Bones and nerves physological processes [G11]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10016206
    E.1.2Term Familial hypophosphataemic rickets
    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
    Establish the effect of KRN23 treatment on improvement in XLH-associated osteomalacia as determined by the following histomorphometric indices
    · Osteoid Thickness (O.Th)
    · Osteoid surface/Bone surface (OS/BS)
    · Osteoid volume/Bone volume (OV/BV)
    · Mineralization lag time (MLt)

    E.2.2Secondary objectives of the trial
    The key secondary efficacy objective is to establish the effect of KRN23 treatment on
    increasing serum phosphorus levels in adults with XLH. Other secondary efficacy objectives are to establish the effect of KRN23 treatment in adults with XLH on:
    · Changes from baseline in parameters of bone mineralization including mineral apposition rate (MAR), mineralizing surface (MS/BS), bone formation rate (BFR),
    and others
    · Additional PD markers reflecting the status of phosphorus homeostasis and renal
    function
    · Bone remodeling as assessed by bone turnover markers
    · PROs assessing skeletal pain and fatigue
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Individuals eligible to participate in this study must meet all of the following criteria:
    1) Male or female, aged 25 - 65 years, inclusive
    2) Diagnosis of XLH supported by classic clinical features of adult XLH (such as short stature or bowed legs), and at least ONE of the following at Screening:
    · Documented PHEX mutation in the patient or a directly related family
    member with appropriate X-linked inheritance
    · Serum iFGF23 level > 30 pg/mL by Kainos assay
    3) Biochemical findings consistent with XLH based on overnight fasting (min. 8 hours):
    · Serum phosphorus < 2.5 mg/dL at Screening
    · TmP/GFR < 2.5 mg/dL at Screening
    4) Presence of skeletal pain attributed to XLH/osteomalacia, as defined by a score of ≥ 4 on the Brief Pain Inventory question 3 (BPI-Q3, Worst Pain) at Screening.
    (Skeletal pain that, in the opinion of the investigator, is attributed solely to causes
    other than XLH/osteomalacia—for example, back pain or joint pain in the presence of
    severe osteoarthritis by radiograph in that anatomical location—in the absence of any
    skeletal pain likely attributed to XLH/osteomalacia should not be considered for
    eligibility.)
    5) Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min (using the Chronic Kidney
    Disease Epidemiology Collaboration [CKD-EPI] equation) or eGFR of 45-60 mL/min at Screening with confirmation that the renal insufficiency is not due to nephrocalcinosis
    6) Provide written informed consent after the nature of the study has been explained, and prior to any research-related procedures
    7) Willing to provide access to prior medical records for the collection of biochemical
    and radiographic data and disease history
    8) Females of child-bearing potential must have a negative urine pregnancy test at
    Screening and be willing to have additional pregnancy tests during the study.
    Females considered not to be of childbearing potential include those who have been
    in menopause for at least two years prior to Screening, or have had tubal ligation at
    least one year prior to Screening, or have had a total hysterectomy or bilateral
    salpingo-oophorectomy.
    9) Participants of child-bearing potential or with partners of child-bearing potential who have not undergone a bilateral salpingo-oophorectomy and are sexually active must consent to use an effective method of contraception as determined by the site
    investigator (i.e. oral hormonal contraceptives, patch hormonal contraceptives,
    vaginal ring, intrauterine device, physical double-barrier methods, surgical hysterectomy, vasectomy, tubal ligation, or true abstinence) from the period following the signing of the informed consent through 12 weeks after last dose of study drug
    10) 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
    Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study:
    1) Use of any pharmacologic vitamin D metabolite or analog (e.g. calcitriol,
    doxercalciferol, and paricalcitol) within the 2 years prior to Screening
    2) Use of oral phosphate within the 2 years prior to Screening
    3) Use of aluminum hydroxide antacids, acetazolamides, and thiazides within 7 days
    prior to Screening
    4) Use of oral bisphosphonates for 6 months or more in the 2 years prior to Screening
    5) Chronic use of systemic corticosteroids defined as more than 10 days in the 2 months prior to Screening
    6) Corrected serum calcium level ≥ 10.8 mg/dL (2.7 mmol/L) at Screening
    7) Serum iPTH ≥ 1.5 times the upper limit of normal (ULN) at Screening
    8) Use of medication to suppress PTH (cinacalcet for example) within 60 days prior to
    Screening
    9) Prothrombin time/Partial thromboplastin time (PT/PTT) outside the normal range at Screening
    10) Evidence of any disease or use of anticoagulant medication (such as warfarin,
    heparin, direct thrombin inhibitors, or xabans that, in the opinion of the investigator,
    cannot be discontinued) that may increase the risk of bleeding during the biopsy
    procedure
    11) Pregnant or breastfeeding at Screening or planning to become pregnant (self or
    partner) at any time during the study
    12) Unable or unwilling to withhold prohibited medications throughout the study
    13) Documented dependence on narcotics
    14) Use of KRN23, or any other therapeutic monoclonal antibody within 90 days prior to Screening
    15) Use of investigational product or investigational medical device within 30 days prior to Screening, or requirement for any investigational agent prior to completion of all scheduled study assessments.
    OR, in Japan, use of any investigational product or investigational medical device
    within 4 months prior to Screening, or requirement for any investigational agent prior
    to completion of all scheduled study assessments.
    16) Presence or history of any hypersensitivity, allergic or anaphylactic reactions to any monoclonal antibody or KRN23 excipients that, in the judgment of the investigator, places the subject at increased risk for adverse effects
    17) History of allergic reaction or adverse reactions to tetracycline
    18) Prior history of positive test for human immunodeficiency virus antibody, hepatitis B surface antigen, and/or hepatitis C antibody
    19) History of recurrent infection or predisposition to infection, or of known
    immunodeficiency
    20) Presence of malignant neoplasm (except basal cell carcinoma)
    21) Presence of a concurrent disease or condition that would interfere with study
    participation or affect safety
    22) Presence or history of any condition that, in the view of the investigator, places the subject at high risk of poor treatment compliance or of not completing the study
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the percent change from baseline in excess osteoid based on analysis of iliac crest bone biopsies after 48 weeks of KRN23 treatment using the following histomorphometric indices:
    · O.Th
    · OS/BS
    · OV/BV
    · MLt
    The primary analysis will be performed using the primary analysis set. Histomorphometric indices of O.Th, OS/BS, OV/BV and MLt at baseline, end of study, and their percent change from baseline at end of study will be summarized.
    E.5.1.1Timepoint(s) of evaluation of this end point
    after 48 weeks
    E.5.2Secondary end point(s)
    The key secondary efficacy endpoint is the proportion of subjects achieving mean serum phosphorus levels above the LLN (2.5 mg/dL [0.81 mmol/L]) at the mid-point of the dose interval (i.e., Weeks 2, 6, 14, and 22), as averaged across dose cycles between baseline and Week 24. The secondary efficacy endpoints will compare the effects of treatment with KRN23 on changes in:
    · MAR, MS/BS, BFR and additional measures of bone formation and remodeling
    · Additional measures to assess serum phosphorus levels between baseline and Week
    24 include:
    o Proportion of subjects achieving mean serum phosphorus levels above the
    LLN (2.5 mg/dL [0.81 mmol/L] at the end of the dosing cycle (4 weeks after
    dosing), as averaged across dose cycles
    o Mid-point of dosing cycle: mean change from baseline, and percent change
    from baseline averaged across dose cycles
    o End of dosing cycle: mean change from baseline, and percent change from
    baseline averaged across dose cycles
    o Cumulative exposure: area under the curve (AUC)
    · Change from baseline over time in serum 1,25(OH)2D, urinary phosphorus,
    TmP/GFR, and TRP
    Change and percent change from baseline over time in serum bone turnover markers,
    including P1NP, CTx-I, and BALP
    Additional analyses of serum phosphorus including observed values, change from baseline,
    percent change from baseline over time, and area under the curve will be summarized.
    Similar descriptive analyses will be performed for 1,25(OH)2D, urinary phosphorus,
    TmP/GFR, and TRP.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Bone biopsies after 48 weeks
    Serum phosphorus - Weeks 2, 6, 14, and 22

    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 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 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.8.2.4Number of treatment arms in the trial1
    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 EEA3
    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 Information not present in EudraCT
    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
    Denmark
    France
    Ireland
    Netherlands
    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 years
    E.8.9.1In the Member State concerned months12
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months12
    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: 10
    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 state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 5
    F.4.2.2In the whole clinical trial 10
    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 subject completing study UX023-CL304 will be offered to enroll into extension study UX023-CL203 entitled "Phase 2b, Open-Label, Long-Term, Extension Study to Evaluate the Safety and Pharmacodynamics of KRN23 in Adult Subjects with X-Linked Hypophosphatemia (XLH)"
    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 Decision2015-11-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-11-25
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-08-22
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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