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    Summary
    EudraCT Number:2017-002404-28
    Sponsor's Protocol Code Number:111-302
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-12-13
    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 ConcernedGermany - BfArM
    A.2EudraCT number2017-002404-28
    A.3Full title of the trial
    A Phase 3, 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 3 Long-Term Extension Study to Evaluate the Safety and Efficacy of BMN 111 in Children with Achondroplasia
    A.4.1Sponsor's protocol code number111-302
    A.5.4Other Identifiers
    Name:INDNumber:111299
    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 Digital 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 Yes
    D.2.1.1.1Trade name Voxzogo
    D.2.1.1.2Name of the Marketing Authorisation holderBioMarin International Limited
    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/3/12/1094
    D.3 Description of the IMP
    D.3.1Product namemodified recombinant human C-type natriuretic peptide
    D.3.2Product code BMN 111
    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 1480724-61-5
    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 Yes
    D.2.1.1.1Trade name Voxzogo
    D.2.1.1.2Name of the Marketing Authorisation holderBioMarin International Limited
    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/3/12/1094
    D.3 Description of the IMP
    D.3.1Product namemodified recombinant human C-type natriuretic peptide
    D.3.2Product code BMN 111
    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 1480724-61-5
    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
    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 25.0
    E.1.2Level LLT
    E.1.2Classification code 10000452
    E.1.2Term Achondroplasia
    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
    The primary objective of this extension study is to:
    - Evaluate the long-term safety, tolerability, and efficacy for growth in children with ACH treated with BMN 111
    E.2.2Secondary objectives of the trial
    The secondary objectives of the study are to:
    •Evaluate the pharmacokinetics of BMN 111
    •Evaluate immunogenicity of BMN 111 and assess impact on safety, PK, and efficacy measures
    •Evaluate body proportion ratios of the extremities
    •Evaluate effect of BMN 111 on bone morphology/quality by X-ray and DXA
    •Evaluate changes in health-related quality of life as measured the Quality of Life in Short Stature Youth (QoLISSY) and the PedsQL questionnaires
    •Evaluate changes in functional independence as measured by the Wee FIM clinician-reported outcome
    •Evaluate change from baseline in bone metabolism biomarkers
    •To evaluate the effect of BMN 111 on final adult height
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Must have completed Study 111-301
    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. Females ≥ 10 years old or who have begun menses must have a
    negative pregnancy test at the Baseline Visit and be willing to have additional pregnancy tests during the study
    4. If sexually active, are willing to use contraception as specified in section 9.3.3 of the protocol,
    5. Are willing and able to perform all study procedures
    E.4Principal exclusion criteria
    1. Permanently discontinued BMN 111 or placebo prior to completion of Study 111-301
    2. Have a clinically significant finding or arrhythmia on Baseline electrocardiogram (ECG) that indicates abnormal cardiac function or conduction or QTc-F > 450 msec
    3. Evidence of decreased growth velocity (AGV < 1.5 cm/year) as assessed over a period of at least 6 months or of growth plate closure (proximal tibia, distal femur) through bilateral lower extremity X-rays including both AP and lateral views
    4. Require any investigational agent prior to completion of study period
    5. Current therapy with antihypertensive medications, angiotensin-
    converting 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 9.3.2.1)
    6. Planned or expected to have limb-lengthening surgery during the
    study period
    7. Pregnant or breastfeeding at the Baseline Visit or planning to become
    pregnant (self or partner) at any time during the study
    8. Concurrent disease or condition that, in the view of the investigator,
    would interfere with study participation or safety evaluations, for any
    reason
    9. Have a condition or circumstance that, in the view of the investigator,
    places the subject at high risk for poor treatment compliance or for not
    completing the study
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is the change from baseline in annualized growth velocity (AGV).

    Safety will be evaluated by the incidence of AEs, SAEs, and clinically significant changes in vital signs, physical examination, Tanner stage, ECG, echocardiogram, bone morphology/quality assessed by X-rays/DXA, and laboratory test results (urinalysis, chemistry, hematology). Additionally, imaging, hip monitoring, immunogenicity, salivary cortisol, serum prolactin, and FSH/LH levels (FSH/LH will be monitored for all subjects >8 years of age, and for subjects at Tanner stage 2, whichever is earlier); and anxiety, motor and cognitive assessment with the Childhood Behavioral Checklist (CBCL) and WeeFIM will be utilized for safety-related reviews and analysis. Additional assessments will be conducted to evaluate changes from baseline in bone metabolism and BMN 111 activity biomarkers.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Anthropometric measurements: 111-301 Week52/302 BL, Weeks 13, 26,39, 52, 65, 78, 91, 104, every 26 weeks up to 260

    Clinical labs; Vital signs/AEs; Physical exam; ECG; Anti-BMN 111 immunogenicity; bone metabolism biomarkers: 111-301 Week 52/302 BL, Day 1, Weeks 13, 26, 39, 52, 65, 78, 91, 104, every 26 weeks up to 260

    ECG, X-Ray/DXA: 111-301 Week 52/302 BL, Weeks 52, 104, 156, 208, 260

    Clinical hip assessment:111-301 Week 52/302 BL, Weeks 26, 52, 78, 104, every 26 weeks up to 260

    Salivary cortisol; serum prolactin; FSH/LH: 111-301 Week 52/302 BL, 26, 52, 78, 26 weeks up to week 260

    CBCL and WeeFIM:111-301 Week 52/302 BL, 26, 52, 78, 104, every 26 weeks up to 260

    BMN 111 activity biomarkers:111-301 Week 52/302 BL, Day1, Weeks 26, 52, 78, 104, every 26 weeks up to 260
    E.5.2Secondary end point(s)
    1)The secondary efficacy endpoints include the change from baseline in height [Z-score], height, final adult height, a and the change from baseline in upper:lower body segment ratio.

    2)PK sampling will be carried out over the study period.

    3)Health-related Quality of Life (HRQoL) and ADL questionnaires will be administered to assess quality of life and daily activities performance of
    study subjects.

    4) Evaluate immunogenicity of BMN 111 and assess impact on safety,PK and efficacy measures

    5) Evaluate change from baseline in body proportion ratios of the extremities

    6) Evaluate effect of BMN 111 on bone morphology/quality by X-ray and DXA
    E.5.2.1Timepoint(s) of evaluation of this end point
    Anthropometric measurements: 111-301 Week 52/302 BL, Weeks 13, 26, 39, 52, 65, 78, 91, 104, every 26 weeks up to Week 260

    PK: 301 Week 52/302 BL, Day 1, Week 26, Week 52, Week 78, Week 104, every 26 weeks up to Week 260

    Health-related Quality of Life (PedsQL, QoLISSY), Functional Independence Assessment (Wee FIM), and CBCL: 111-301 Week 52/302
    BL, Week 26, Week 52, Week 78, Week 104, every 26 weeks up to Week 260

    DXA (BMD and BMC of whole body less head, spine): Week 52/302 BL, Week 52, Week 104, Week 156, Week 208, Week 260

    Anti-BMN 111 immunogenicity: Week 52/302 BL, Day 1. Week 13, Week 26, Week 39, Week 52, Week 65, Week 78, Week 91, Week 104, every 26
    week up to Week 260
    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) 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) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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 EEA7
    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
    Turkey
    United Kingdom
    United States
    Germany
    Spain
    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
    LPLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years11
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years13
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days19
    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: 119
    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: 69
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 50
    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
    Paediatric subjects who are below age of majority will sign assents and have parents or guardians sign consents
    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 39
    F.4.2.2In the whole clinical trial 119
    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)
    X-rays (lower extremity, lumber, left hand and wrist) will be performedevery 2 years until subject reaches near final adult height. Once subjecthas reach near final adult height, X-rays (lumbar only) will be performed every 5 years until end of study.
    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 Decision2019-01-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-03-07
    P. End of Trial
    P.End of Trial StatusOngoing
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