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    Summary
    EudraCT Number:2018-000202-37
    Sponsor's Protocol Code Number:BUR02
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-08-31
    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 number2018-000202-37
    A.3Full title of the trial
    A Phase 3b Open-label Study of the Anti-FGF23 Antibody,
    Burosumab (KRN23) in Adult Patients with X-linked
    Hypophosphatemia (XLH)
    Étude de phase IIIb en ouvert sur l'anticorps anti-FGF23, le burosumab
    (KRN23), chez des adultes atteints d'hypophosphatémie liée à l'X (ou XLH
    pour X-linked Hypophosphatemia)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3b Open-label Study of the Anti-FGF23 Antibody,
    Burosumab (KRN23) in Adult Patients with X-linked
    Hypophosphatemia (XLH)
    Étude de phase IIIb en ouvert sur l'anticorps anti-FGF23, le burosumab
    (KRN23), chez des adultes atteints d'hypophosphatémie liée à l'X (ou XLH
    pour X-linked Hypophosphatemia)
    A.4.1Sponsor's protocol code numberBUR02
    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 SponsorKyowa Kirin Pharmaceutical Development Ltd
    B.1.3.4CountryUnited Kingdom
    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 supportKyowa Kirin Pharmaceutical Development Ltd
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIcon Clinical Research Ltd
    B.5.2Functional name of contact pointRegulatory Affairs
    B.5.3 Address:
    B.5.3.1Street Address100 Milton Park Ave
    B.5.3.2Town/ cityAbingdon
    B.5.3.3Post codeOX14 4RY
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number4407931653684
    B.5.6E-mailmarkas.marriott@iconplc.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 Yes
    D.2.1.1.1Trade name CRYSVITA
    D.2.1.1.2Name of the Marketing Authorisation holderKyowa Kirin Ltd
    D.2.1.2Country which granted the Marketing AuthorisationIreland
    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 fibrolblast growth facttor23 (FGF-23)
    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
    Intravascular use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBUROSUMAB
    D.3.9.2Current sponsor codeKRN23
    D.3.9.4EV Substance CodeSUB184986
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number10 to 30
    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 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
    XLH is a rare, genetic disorder that is serious, chronically debilitating and represents an
    unmet medical need. This genetic deficiency is estimated to occur in about 1:20,000 live
    births (Burnett et al. 1964), (Imel et al. 2005). XLH is the most common inherited form of
    rickets and the most common inherited defect in renal tubular phosphate transport. XLH is
    transmitted as an X-linked dominant disorder (Dixon et al. 1998).
    XLH est un trouble génétique rare, et grave, chronique débilitante et
    représente un besoin médical non satisfait. L'incidence de cette anomalie
    génétique est estimée à environ 1/20 000 naissances (Burnett et al.,
    1964), (Imel et al., 2005). XLH est la forme la plus commune de
    rachitisme héréditaire et le plus courant défaut héréditaire dans le
    transport de phosphate tubulaire rénale. XLH est transmis comme un
    trouble dominant lié à le X (Dixon et al., 1998).
    E.1.1.1Medical condition in easily understood language
    Inheritable form of rickets
    forme de rachitisme héréditaire
    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 20.0
    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
    To continue to evaluate the long-term efficacy and safety of burosumab as a treatment for adult
    patients with XLH and to provide continued treatment for subjects previously enrolled in
    UX023-CL303 and UX023-CL304 clinical trials.
    Continuer d'évaluer l'efficacité et l'innocuité à long terme du burosumab dans le traitement de patients adultes atteints de XLH et fournir un
    traitement continu aux patients précédemment inclus dans les études cliniques UX023-CL303 et UX023-CL304
    E.2.2Secondary objectives of the trial
    The objectives are to assess the efficacy and safety of burosumab administered via subcutaneous (SC) injections every 4 weeks and to allow
    subjects continued access to burosumab up until December 2019 or until commercially available, with no cost to the patient, in each individual country.
    Les objectifs sont d'évaluer l'efficacité et l'innocuité du burosumab
    administré par des injections sous-cutanées (SC) toutes les 4 semaines
    et de permettre aux patients l'accès continu au burosumab jusqu'en
    décembre 2019 ou jusqu'à ce que commercialement disponible, sans
    frais pour le patient, en chaque pays
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Subjects who provide written informed consent after the nature of the study has been
    explained, and prior to any research-related procedures.
    2) Subjects who successfully completed Study UX023-CL303 or UX023-CL304. Subjects
    should have completed the study up to and including the final study visit. Subjects who were
    prematurely discontinued due to adverse events, Sponsor’s decision or Investigator’s decision
    will not be enrolled in this study. Subjects’ enrolment is not dependent on any response to
    Primary or Secondary endpoints in studies UX023-CL303 or UX023-CL304.
    3) Willing to provide access to prior medical records for the collection of historical growth,
    biochemical and radiographic data, and disease history.
    4) 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.
    5) 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
    child-bearing 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. If sexually active, male and female subjects
    must be willing to use one highly effective method of contraception for the duration of the
    study.
    1) Les patients devront donner leur consentement éclairé écrit après explication de la nature de l'étude et avant la réalisation de toute
    procédure de l'étude.
    2) Les patients devront être parvenus au terme de l'étude UX023-CL303 ou UX023-CL304. Les patients devront être restés dans l’étude jusqu’à la fin, c’est-à-dire jusqu’à la visite d’étude finale. Les patients sortis prématurément de l’étude en raison d’événements indésirables ou sur décision du promoteur ou de l’investigateur ne pourront pas être inclus dans cette étude. L’inclusion ne dépendra pas de la réponse des patients aux critères d’évaluation principal ou secondaires de l’étude UX023-CL303 ou UX023-CL304.
    3) Les patients devront autoriser l'accès à leur dossier médical antérieur pour le recueil de leurs données de croissance antérieures, de
    données biochimiques et radiographiques, et de l'historique de leur maladie.
    4) Les patients devront, de l'avis de l'investigateur, être disposés et aptes à accomplir tous les aspects de l'étude, à se conformer au
    calendrier des visites d'étude et à effectuer les évaluations.
    5) Les femmes en capacité de procréer devront obtenir un résultat négatif au test de grossesse urinaire pratiqué lors de la sélection et
    accepter d'effectuer d'autres tests de grossesse pendant l'étude. Les femmes qui ne sont pas considérées comme étant en capacité de
    procréer comprennent les femmes ménopausées depuis au moins deux ans avant la sélection, celles qui ont subi une ligature des trompes un an
    au moins avant la sélection et celles qui ont subi une hystérectomie totale ou une salpingo-ovariectomie bilatérale. S'ils sont actifs sexuellement, les patients (hommes et femmes) devront accepter d'utiliser une méthode de contraception hautement efficace pendant la durée de l'étude.
    E.4Principal exclusion criteria
    1) Hypocalcemia or hypercalcemia, defined as serum calcium levels outside the age-adjusted
    normal limits and deemed as clinically significant in the opinion of the investigator.
    2) Presence of a concurrent disease or condition that would interfere with study participation
    or affect safety in the opinion of the investigator or Sponsor.
    3) Use of any investigational product other than burosumab or investigational medical device
    within 30 days prior to Screening, or requirement for any investigational agent prior to
    completion of all scheduled study assessments.
    4) Subjects with major protocol deviations in Study UX023-CL303 or UX023-CL304 which
    in the view of the investigator places the subject at high risk of poor treatment compliance or
    of not completing the study.
    1) Hypocalcémie ou hypercalcémie, définies comme un taux sérique de calcium en dehors des limites de la normale ajustées selon l'âge et
    considéré cliniquement significatif de l'avis de l'investigateur.
    2) Présence d'une maladie ou affection concomitante qui perturberait la participation à l'étude ou compromettrait la sécurité du patient de l'avis
    de l'investigateur ou du promoteur.
    3) Utilisation d'un produit expérimental autre que le burosumab ou d'un dispositif médical expérimental au cours des 30 jours précédant la
    sélection, ou nécessité d'utiliser un agent expérimental avant l'achèvement de toutes les évaluations prévues de l'étude.
    4) Patients ayant présenté des déviations majeures au protocole lors de l'étude UX023-CL303 ou UX023-CL304 qui, de l'avis de l'investigateur,
    indiquent une forte probabilité de non-observance du traitement ou de non-achèvement de l'étude par le patient
    E.5 End points
    E.5.1Primary end point(s)
    Primary efficacy objective: Establish the effect of burosumab treatment on maintaining serum
    phosphorous levels to within normal range in adults with XLH.
    Objectif d'efficacité principal : déterminer l'effet du traitement par burosumab sur le maintien du taux sérique de phosphore à des valeurs
    normales chez des adultes atteints de XLH.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Until December 2019 or reimbursed commercially available product is supplied
    jusqu'à décembre 2019 ou jusqu'à ce qu'il soit commercialisé et remboursé.
    E.5.2Secondary end point(s)
    Key secondary objectives: Evaluate the effect of burosumab treatment in adults with XLH on:
    o Pre-existing (identified during UX023-CL303 or UX023-CL304) pseudofracture
    healing and enthesopathy
    o Patient impression of their improvement (compared to baseline in this study and
    previous UGX023 study)
    o Walking ability as measured by Six Minute Walk Test (6MWT)
    o Mobility as measured by Timed Up and Go (TUG) test completion time
    o Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Brief
    Pain Inventory (BPI) and Brief Fatigue Inventory (BFI)
    o Pharmacodynamic:
     Serum phosphorus
     Serum 1,25-dihydroxyvitamin D (1,25(OH) 2 D)
     Urinary phosphorus
    Phosphate reabsorption: ratio of renal tubular maximum reabsorption rate of
    phosphate to glomerular filtration rate (TmP/GFR).
     Carboxy-terminal cross-linked telopeptide of type I collagen (CTx), procollagen
    type 1 N-propeptide (P1NP), bone alkaline phosphatase and alkaline phosphatase
    Safety Objectives:
     Establish the long-term safety and tolerability profile of burosumab in the treatment of
    adults with XLH including adverse events (AEs), ectopic mineralization risk,
    cardiovascular effects and immunogenicity profile.
     Assess impact of burosumab on pre- and post-prandial serum concentrations of
    phosphorus and calcium in a subset of study subjects.
    Principaux objectifs secondaires : évaluer l'effet du traitement par burosumab sur les aspects suivants chez des adultes atteints de XLH :
    o Consolidation de pseudo-fractures et enthésopathie préexistantes (identifiées lors de l'étude UX023-CL303 ou UX023-CL304)
    o Impression d'amélioration du patient (par rapport à l'inclusion dans cette étude et à l'étude UGX023 antérieure)
    o Capacité de marche mesurée par le test de marche de 6 minutes (ou 6MWT pour 6 Minutes Walk Test)
    o Mobilité mesurée par le test lever-marcher chronométré (ou TUG pour Timed Up and Go)
    o Indice d'évaluation de l'arthrose des universités Western Ontario et McMaster (WOMAC), questionnaire d'évaluation de la douleur (ou BPI
    pour Brief Pain Inventory) et questionnaire d'évaluation de la fatigue (ou BFI pour Brief Fatigue Inventory)
    o Pharmacodynamie :
    • Taux sérique de phosphore
    • Taux sérique de 1,25-dihydroxyvitamine D (1,25(OH)2D)
    • Taux urinaire de phosphore
    • Réabsorption du phosphate : taux maximal de réabsorption tubulaire rénale du phosphate en fonction du débit de filtration glomérulaire
    (TmP/DFG)
    • Télopeptide carboxy-terminal réticulé du collagène de type 1 (CTx), propeptide N-terminal du procollagène de type 1 (P1NP), phosphatase
    alcaline osseuse et phosphatase alcaline.
    Objectifs concernant l'innocuité :
    • Évaluer le profil d'innocuité et de tolérance à long terme du burosumab dans le traitement d'adultes atteints de XLH, notamment les
    événements indésirables (EI), le risque de minéralisation ectopique, les effets cardiovasculaires et le profil d'immunogénicité.
    • Évaluer l'impact du burosumab sur les taux sériques préprandiaux et postprandiaux de phosphore et de calcium dans un sous-ensemble de
    patients de l'étude.
    E.5.2.1Timepoint(s) of evaluation of this end point
    not applicable
    Non applicable
    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 No
    E.6.7Pharmacodynamic No
    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.8.3 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 No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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
    Dernière visite du dernier patient
    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 months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months10
    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: 40
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 No
    F.3.3.1Women of childbearing potential not using contraception Information not present in EudraCT
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    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 state24
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 40
    F.4.2.2In the whole clinical trial 40
    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)
    None
    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 Decision2018-09-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-10-09
    P. End of Trial
    P.End of Trial StatusOngoing
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