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    The EU Clinical Trials Register currently displays   42567   clinical trials with a EudraCT protocol, of which   7008   are clinical trials conducted with subjects less than 18 years old.
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    Summary
    EudraCT Number:2018-004364-66
    Sponsor's Protocol Code Number:BMR111-208
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2019-09-11
    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 ConcernedUK - MHRA
    A.2EudraCT number2018-004364-66
    A.3Full title of the trial
    A Phase 2 Open-Label Long-Term Extension Study to Evaluate the Safety
    and Efficacy of BMN 111 in Children with Achondroplasia
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 2 open-label long-term study of BMN 111 in children with Achondroplasia
    A.4.1Sponsor's protocol code numberBMR111-208
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/379/2017
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorBioMarin 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 supportBioMarin Pharmaceutical Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBioMarin Pharmaceutical Inc.
    B.5.2Functional name of contact pointClinical Trials Information
    B.5.3 Address:
    B.5.3.1Street Address105 Digitial Drive
    B.5.3.2Town/ cityNovato
    B.5.3.3Post code94949
    B.5.3.4CountryUnited States
    B.5.6E-mailclinicaltrials@bmrn.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/3/12/1094
    D.3 Description of the IMP
    D.3.1Product nameModified recombinant human c-type
    D.3.2Product code Natriuretic peptide
    D.3.4Pharmaceutical form Lyophilisate for solution for injection
    D.3.4.1Specific paediatric formulation Yes
    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 INNVosoritide
    D.3.9.1CAS number 1480721-61-5
    D.3.9.2Current sponsor codeBMN 111
    D.3.9.3Other descriptive nameMODIFIED RHCNP
    D.3.9.4EV Substance CodeSUB120857
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.8
    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 Yes
    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.IMP: 2
    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/3/12/1094
    D.3 Description of the IMP
    D.3.1Product nameModified recombinant human c-type
    D.3.2Product code Natriuretic peptide
    D.3.4Pharmaceutical form Lyophilisate for solution for injection
    D.3.4.1Specific paediatric formulation Yes
    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 INNVosoritide
    D.3.9.1CAS number 1480721-61-5
    D.3.9.2Current sponsor codeBMN 111
    D.3.9.3Other descriptive nameMODIFIED RHCNP
    D.3.9.4EV Substance CodeSUB120857
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.0
    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 Yes
    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
    Achondroplasia
    E.1.1.1Medical condition in easily understood language
    Dwarfism
    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 10000452
    E.1.2Term Achondroplasia
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Evaluate the long-term safety, tolerability of BMN 111
    Evaluate change in height/length z-score in children with ACH treated
    with BMN 111
    E.2.2Secondary objectives of the trial
    Evaluate the effect of BMN 111 on AGV
    • Evaluate the pharmacokinetics of BMN 111
    • Evaluate the effect of BMN 111 on body proportions and ratios of the
    extremities
    • Evaluate the effect of BMN 111 on bone morphology/quality by X-ray
    and dual X-ray absorptiometry (DXA)
    • Evaluate the long-term effect of BMN 111 on health-related quality of
    life, developmental status and functional independence , using agespecific
    QoL and functional independence questionnaires
    • Evaluate bone metabolism and pharmacodynamic biomarkers
    • Evaluate immunogenicity of BMN 111 and assess impact on safety, PK,
    and efficacy measures
    • Describe the incidence of surgical and medical interventions related to
    achondroplasia
    • Assess effect on sleep disordered breathing by polysomnography in
    patients up to 5 years old.
    • Evaluate the effect of BMN 111 on skull and brain morphology,
    including foramen magnum, ventricular and brain parenchymal
    dimensions by MRI in patients up to 3 years old.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Must have completed Study 111-206 (eligible to enroll in 111-208 within 3 months after completing 111-206 at the discretion of the principal investigator and medical monitor).
    2.Parent(s) or guardian(s) are willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to performance of any research-related procedure. Also, subjects under the age of majority are willing and able to provide written assent (if required by local regulations or the IRB/IEC) after the nature of the study has been explained and prior to performance of any research-related procedure. Subjects who reach the age of majority in their country while the study is ongoing will be asked to provide their own written consent again upon reaching the legal age of majority.
    3.Are willing and able to perform all study procedures as physically possible
    E.4Principal exclusion criteria
    1. Permanently discontinued BMN 111 or placebo prior to completion of
    Study 111-206
    2. Have a clinically significant finding or arrhythmia on ECG that
    indicates abnormal cardiac function or conduction or QTc-F > 450 msec
    3. Require any investigational agent (except BMN 111) prior to
    completion of study period
    4. Current therapy with antihypertensive medications, angiotensinconverting
    enzyme (ACE) inhibitors, angiotensin II receptor blockers,
    diuretics, beta-blockers, calcium-channel blockers, cardiac glycosides,
    systemic anticholinergic agents, GnRH agonists, any medication that
    may impair or enhance compensatory tachycardia, diuretics, or other
    drugs known to alter renal or tubular function (Table 9.3.4.1)
    5. Pregnant or planning to become pregnant (self or partner) at any time
    during the study
    6. Concurrent disease or condition that, in the view of the investigator,
    would interfere with study participation or safety evaluations, for any
    reason
    7. Have a condition or circumstance that, in the view of the investigator,
    places the subject at high risk for poor treatment compliance
    E.5 End points
    E.5.1Primary end point(s)
    •Evaluate the incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: "Through study completion, an average of 5 years" ]
    Number of study participants with treatment-emergent adverse events or serious adverse events

    •Evaluate change in height/length z-score in children with ACH treated with BMN 111 [ Time Frame: "Through study completion, an average of 5 years" ]
    E.5.1.1Timepoint(s) of evaluation of this end point
    Time Frame: "Through study completion, an average of 5 years"
    E.5.2Secondary end point(s)
    •Evaluate the change from baseline of mean annualized growth velocity (AGV) [ Time Frame: "Through study completion, an average of 5 years" ]
    •Characterize maximum concentration (Cmax) of BMN 111 in plasma [ Time Frame: "Through study completion, an average of 5 years" ]
    •Characterize the area under the plasma concentration time-curve from time 0 to infinity (AUC0-∞) [ Time Frame: "Through study completion, an average of 5 years" ]
    •Characterize the elimination half-life of BMN 111 (t½) [ Time Frame: "Through study completion, an average of 5 years" ]
    •Characterize the apparent clearance of drug [ Time Frame: "Through study completion, an average of 5 years" ]
    •Characterize the apparent volume of distribution based upon the terminal phase (Vz/F) [ Time Frame: "Through study completion, an average of 5 years" ]
    •Characterize the amount of time BMN 111 is present at maximum concentration (Tmax) [ Time Frame: "Through study completion, an average of 5 years" ]
    •Evaluate the change from baseline on body proportion ratios of the extremities [ Time Frame: "Through study completion, an average of 5 years" ]
    •Effect of BMN 111 on bone morphology and quality by XRay [ Time Frame: "Through study completion, an average of 5 years" ]
    •The effect of BMN 111 on bone morphology/quality will be assessed by measuring bone mineral density via Dual X-ray Absorptiometry [ Time Frame: "Through study completion, an average of 5 years" ]
    •Potential Changes in health-related quality of life as measured by the quality of life in Short- statured youth [ Time Frame: "Through study completion, an average of 5 years" ]
    Evaluate the long-term effect of BMN 111 on health-related quality of life, developmental status and functional independence, using age-specific QoL and functional independence questionnaires (Bayley-III, WeeFIM, ITQOL, QoLISSY, PedsQL, Child Behavior Checklist 1.5-5 [CBCL 1.5-5], Child Behavior Checklist 6-18 [CBCL 6-18]).

    •BMN 111 activity will be assessed by measuring bone and collagen metabolism [ Time Frame: "Through study completion, an average of 5 years" ]
    •Describe the incidence of surgical and medical interventions related to achondroplasia [ Time Frame: "Through study completion, an average of 5 years" ]
    •Assess effect on sleep disordered breathing by polysomnography in patients up to 5 years old. [ Time Frame: "Through study completion, an average of 1 year" ]
    •Evaluate the effect of BMN 111 on skull and brain morphology, including foramen magnum, ventricular and brain parenchymal dimensions by MRI in patients up to 3 years old. [ Time Frame: "Through study completion, an average of 1 year" ]
    E.5.2.1Timepoint(s) of evaluation of this end point
    Time Frame: "Through study completion, an average of 5 years"
    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 Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 concerned2
    E.8.5The trial involves multiple Member States No
    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
    Australia
    Japan
    United Kingdom
    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
    Until Subject attains near final adult height
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days2
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial days4
    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: 70
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 30
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 40
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) No
    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
    Subjects in this protocol will be not be able to read or write so subjects parent/guardian will be consenting on their behalf.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 10
    F.4.2.2In the whole clinical trial 70
    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 Decision2019-10-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-10-22
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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