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    Summary
    EudraCT Number:2018-000202-37
    Sponsor's Protocol Code Number:BUR02
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-06-17
    Trial results View 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 ConcernedItaly - Italian Medicines Agency
    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)
    Studio di fase 3b, in aperto sull'anticorpo anti-FGF23, Burosumab (KRN23), in adulti con ipofosfatemia legata al cromosoma X (X Linked Hypophosphatemia, XLH)
    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)
    Studio di fase 3b, in aperto sull'anticorpo anti-FGF23, Burosumab (KRN23), in adulti con ipofosfatemia legata al cromosoma X (X Linked Hypophosphatemia, XLH)
    A.3.2Name or abbreviated title of the trial where available
    NA
    NA
    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 Limited
    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.5.5Fax 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-EU/1/17/1262/001-002-003
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameBurosumab
    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 INNBurosumab
    D.3.9.2Current sponsor codeKRN23
    D.3.9.3Other descriptive namerecombinant human igG1 monoclonal antibody to fibrolblast growth facttor23 (FGF-23)
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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)
    La XLH è un raro disordine genetico grave, cronicamente debilitante e rappresenta una necessità medica non soddisfatta. Si stima che questa deficienza genetica si verifichi in un rapporto di circa 1:20,000 nati vivi (Burnett et al. 1964), (Imel et al. 2005). La XLH è la forma di rachitismo ereditario più comune e il difetto ereditario più comune nel trasporto del fosfato attraverso il tubulo renale. La XLH viene trasmessa sotto forma di disordine dominante X-collegato (Dixon et al. 1998).
    E.1.1.1Medical condition in easily understood language
    Inheritable form of rickets
    Forma di rachitismo ereditario
    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.
    Continuare a valutare l'efficacia e la sicurezza a lungo termine di burosumab come trattamento per pazienti adulti affetti da XLH e fornire un trattamento continuo ai soggetti arruolati in precedenza nelle sperimentazioni cliniche UX023-CL303 e 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.
    Gli obiettivi sono valutare l’efficacia e la sicurezza di burosumab somministrato mediante iniezioni sottocutanee (SC) ogni 4 settimane e consentire ai soggetti di continuare ad accedere a burosumab fino a dicembre 2019 o fino a che sia disponibile in commercio, senza alcuna spesa a carico del paziente, in ogni singolo Paese.
    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) Subject who successfully completed Study UX023-CL303 or UX023CL304. 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 UX023CL304.
    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) I soggetti devono essere in grado di fornire il consenso informato scritto, dopo che è stata loro illustrata la natura dello studio e prima dell'esecuzione di qualsiasi procedura correlata alla ricerca.
    2) Soggetti che hanno completato correttamente lo studio UX023-CL303 o UX023-CL304. I soggetti devono aver completato lo studio fino alla visita finale dello studio compresa. I soggetti che hanno interrotto lo studio anticipatamente a causa di eventi avversi, per decisione dello Sponsor o dello Sperimentatore, non saranno arruolati in questo studio. L’arruolamento dei soggetti non dipende da alcuna risposta agli endpoint primari o secondari degli studi UX023-CL303 o UX023-CL304.
    3) I soggetti devono essere disposti a fornire l'accesso alle cartelle cliniche precedenti per la raccolta di dati anamnesici su crescita, analisi biochimiche e radiografie, nonché per l'anamnesi patologica.
    4) I soggetti devono, secondo il parere dello Sperimentatore, essere disposti e in grado di completare tutti gli aspetti dello studio, aderire al calendario visite dello studio ed essere
    conformi alle valutazioni dello studio.
    5) Per le donne in età fertile, il test di gravidanza su urine deve risultare negativo allo Screening e devono essere disposte a sottoporsi a ulteriori test di gravidanza durante lo studio. Per "donne non in età fertile" si intendono le donne in menopausa da almeno due anni prima dello Screening o che si siano sottoposte alla legatura delle tube almeno un anno prima dello Screening o che abbiano subito un'isterectomia totale o una salpingo-ovariectomia bilaterale. Se sono sessualmente attivi, i soggetti di sesso maschile e femminile devono, per la durata dello studio, essere disposti a utilizzare un metodo contraccettivo altamente efficace.
    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) Ipocalcemia o ipercalcemia, definiti come livelli sierici di calcio al di fuori dei limiti normali corretti per l'età e, secondo il parere dello Sperimentatore, considerati clinicamente
    significativi.
    2) Presenza di una malattia o condizione concomitante che, secondo il parere dello Sperimentatore e dello Sponsor, interferirebbe con la partecipazione allo studio o comprometterebbe la sicurezza.
    3) Utilizzo, nelle 30 settimane prima dello Screening, di un qualunque prodotto sperimentale diverso da burosumab o di un qualunque dispositivo medico sperimentale o necessità di utilizzare un agente sperimentale diverso prima del completamento di tutte le valutazioni previste dallo studio.
    4) Soggetti con deviazioni importanti dal protocollo nell'ambito dello studio UX023-CL303 o UX023-CL304 che, secondo il parere dello Sperimentatore, pongono il soggetto ad alto
    rischio di scarsa compliance al trattamento o di non completare lo studio.
    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.
    Obiettivo di efficacia primario: stabilire l’effetto del trattamento con burosumab sul mantenimento dei livelli di fosforo nel siero entro l’intervallo normale in adulti affetti da XLH.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Until December 2019 or reimbursed commercially available product is supplied
    Fino a dicembre 2019 o fino a quanto viene fornito il prodotto commerciale rimborsato
    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
    o 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:
    o 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.
    o Assess impact of burosumab on pre- and post-prandial serum concentrations of phosphorus and calcium in a subset of study subjects.
    Obiettivi secondari chiave: valutare l’effetto del trattamento con burosumab in adulti affetti da XLH su:
    o guarigione di pseudofratture ed entesopatia preesistenti (identificate durante lo studio UX023-CL303 o UX023-CL304)
    o impressione dei pazienti sul loro miglioramento (rispetto al basale di questo studio e dello studio precedente UGX023)
    o Capacità deambulatoria misurata mediante il Six Minute Walk Test (6MWT)
    o Mobilità misurata mediante il tempo di completamento del test Timed Up and Go (TUG)
    o Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Brief Pain Inventory (BPI) e Brief Fatigue Inventory (BFI)
    o Farmacodinamica:
    - Fosforo nel siero
    - Livello di 1,25-diidrossivitamina D (1,25(OH) 2 D) nel siero
    - Fosforo urinario
    o Riassorbimento del fosfato: rapporto della velocità di riassorbimento massimo nel tubulo renale di fosfato rispetto alla velocità di filtrazione glomerulare (TmP/GFR).
    - Telopeptide reticolato C-terminale del collagene di tipo I (CTx), propeptide N-terminale del procollagene di tipo 1 (P1NP), fosfatasi alcalina ossea e fosfatasi alcalina

    Obiettivi di sicurezza:
    o Stabilire il profilo di sicurezza e tollerabilità a lungo termine di burosumab nel trattamento di adulti affetti da XLH incluso eventi avversi (EA), rischio di mineralizzazione ectopica, effetti cardiovascolari e profilo di immunogenicità.
    o Valutare l’impatto di burosumab sulle concentrazioni di fosforo e calcio nel siero pre- e postprandiale in un sottogruppo di soggetti dello studio.
    E.5.2.1Timepoint(s) of evaluation of this end point
    NA
    NA
    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 No
    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 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 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 Information not present in EudraCT
    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
    LVLS
    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 No
    F.3.3.2Women of child-bearing potential using contraception No
    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 50
    F.4.2.2In the whole clinical trial 50
    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
    Nessuno
    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 Decision2018-10-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-11-13
    P. End of Trial
    P.End of Trial StatusOngoing
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