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    Summary
    EudraCT Number:2013-004137-32
    Sponsor's Protocol Code Number:111-202
    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:2015-06-18
    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 ConcernedFrance - ANSM
    A.2EudraCT number2013-004137-32
    A.3Full title of the trial
    A Phase 2, Open-label, Sequential Cohort Dose-escalation Study 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 Study to Evaluate Safety, Tolerability, and Efficacy of BMN 111 in Children with Achondroplasia
    A.4.1Sponsor's protocol code number111-202
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02055157
    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 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 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 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 INNTBD
    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 typerange
    D.3.10.3Concentration number0.2 to 10
    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 18.0
    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 Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the initial 6-month phase is:
    •To evaluate the safety and tolerability of daily SC injections of BMN 111 administered for 6 months

    The primary objective of the study extension is:
    •To evaluate the safety and tolerability of daily SC injections of BMN 111 administered for up to 24 months
    E.2.2Secondary objectives of the trial
    The secondary objectives of the study are:
    •To evaluate change from baseline in annualized growth velocity following daily SC injections of BMN 111 administered for 6 months, and up to 24 months
    •To evaluate changes from baseline in growth parameters following daily SC injections of BMN 111 administered for 6 months, and up to 24 months
    •To evaluate changes from baseline in body proportions (upper arm to forearm length, upper leg to lower leg length, and upper to lower body segment ratios) following daily SC injections of BMN 111 administered for 6 months, and up to 24 months
    •To evaluate the PK profile of BMN 111 in children with ACH following daily SC injections of BMN 111
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.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 18 are willing and able to provide written assent (if required by local regulations or the IRB/EC) after the nature of the study has been explained and prior to performance of any research-related procedure.
    2.Are 5 to 14 years old, inclusive, at study entry
    3.Have ACH, documented by clinical grounds and confirmed by genetic testing
    4.Have at least a 6-month period of pretreatment growth assessment in Study 111 901 immediately before study entry, and has one documented standing height at least 6 months (+/- 10 days) prior to the screening visit for 111-202
    5.Females ≥ 10 years old must have a negative pregnancy test at the Screening Visit and be willing to have additional pregnancy tests during the study.
    6.If sexually active, willing to use a highly effective method of contraception while participating in the study
    7.Are ambulatory and able to stand without assistance
    8.Are willing and able to perform all study procedures as physically possible
    9.Parents or caregivers are willing to administer daily injections to the subjects

    Additional Inclusion Criteria for Optional, Open-label Extension Phase:
    1.Appropriate written informed consent
    E.4Principal exclusion criteria
    1.Have hypochondroplasia or short stature condition other than ACH (eg, trisomy 21, pseudoachondroplasia)
    2.Have any of the following:
    a.Hypothyroidism or hyperthyroidism
    b.Insulin-requiring diabetes mellitus
    c.Autoimmune inflammatory disease (including celiac disease, lupus (SLE), juvenile dermatomyositis, scleroderma, and others)
    d.Inflammatory bowel disease
    e.Autonomic neuropathy
    f.Recent acute illness associated with volume depletion (e.g., nausea, vomiting, diarrhea) that has not completely resolved prior to the first dose of the study drug
    3.Have an unstable condition likely to require surgical intervention during the study (including progressive cervical medullary compression)
    4.Growth plates have fused
    5.Have a history of any of the following:
    a.Renal insufficiency, defined as creatinine > 2 mg/dl
    b.Anemia
    c.Baseline systolic BP < 75 mm Hg or recurrent symptomatic hypotension (defined as episodes of low BP generally accompanied by symptoms i.e., dizziness, fainting) or recurrent symptomatic orthostatic hypotension
    d.Cardiac or vascular disease, including the following:
    i.Cardiac dysfunction (abnormal ECHO including abnormal LV mass) at Screening Visit
    ii.Hypertrophic cardiomyopathy
    iii.Pulmonary hypertension
    iv.Congenital heart disease with ongoing cardiac dysfunction
    v.Cerebrovascular disease
    vi.Aortic insufficiency
    vii.Clinically significant atrial or ventricular arrhythmias
    6.Have the following confirmed ECG findings:
    a.Right or left atrial enlargement or ventricular hypertrophy
    b.PR interval > 200 msec
    c.QRS interval > 110 msec
    d.Corrected QTc > 450 msec
    e.Second- or third-degree atrioventricular block
    7.Documented Vitamin D deficiency (i.e., concentration of 25-hydroxy-vitamin D in the blood serum occurs at 12 ng/mL or less)
    8.Require any investigational agent prior to completion of study period
    9.Have received another investigational product or investigational medical device within 30 days before the Screening visit
    10.Have used any other investigational product or investigational medical device for the treatment of ACH or short stature at any time
    11.Current chronic therapy with antihypertensive medications, ACE inhibitors, angiotensin II receptor blockers, diuretics, beta-blockers, calcium-channel blockers, cardiac glycosides, systemic anticholinergic agents, any medication that may impair or enhance compensatory tachycardia, diuretics, or other drugs known to alter renal or tubular function
    12.Have been treated with growth hormone, IGF-1, or anabolic steroids in the previous 6 months or long-term treatment (> 3 months) at any time
    13.Have had regular long-term treatment (> 1 month) with oral corticosteroids (low-dose ongoing inhaled steroid for asthma, or intranasal steroids, are acceptable)
    14.Concomitant medication that prolongs the QT/QTc interval within 14 days or 5 half lives, whichever is longer, before the Screening visit
    15.Pregnant or breastfeeding at the Screening Visit or planning to become pregnant (self or partner) at any time during the study.
    16.Have had limb-lengthening or bone-related surgery or expected to have limb-lengthening or bone-related surgery during the study period. Subjects with previous limb-lengthening or bone-related surgery may enroll if surgery occurred at least 18 months prior to the study and healing is complete without sequelae.
    17.Have had a fracture of the long bones or spine within 6 months prior to screening (except for fracture of digits or toes)
    18.Have AST or ALT at least 3x ULN or total bilirubin at least 2x ULN (except for subjects with known history of Gilbert’s disease)
    19.Evidence of severe sleep apnea requiring surgery or new initiation of CPAP (based on the screening sleep study)
    20.Have current malignancy, history of malignancy, or currently under work-up for suspected malignancy
    21.Have known hypersensitivity to BMN 111 or its excipients
    22.Has 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
    23.Concurrent disease or condition that, in the view of the Investigator, would interfere with study participation or safety evaluations, or would predispose the subject to hypotension (such as recent gastroenteritis or dehydration for any reason)

    Additional Exclusion Criteria for Optional, Open-label Extension Phase:
    1.Use of proscribed therapies during the initial 6 months of the study
    2.Permanently discontinued BMN 111 during the initial 6 months of the study
    E.5 End points
    E.5.1Primary end point(s)
    Safety will be evaluated by the incidence of AEs, SAEs, and clinically significant changes in vital signs, ECG results, imaging, echocardiographic results, physical examination, anti-BMN 111 immunogenicity assessments, and laboratory test results (urinalysis, chemistry, hematology). Additionally, imaging, biomarker, and physical measurement data, including a flexion-extension measure of elbow joint range of motion measured with goniometer, will be utilized for safety-related reviews and analysis.
    E.5.1.1Timepoint(s) of evaluation of this end point
    AEs,SAEs,vital signs,phys exam-Screening,D1,2,3,4,10,15,22,29,43,85,127,183,208,Early Term,M8,10,12,15,18,21,24,25,Dose Escalation,Early Term
    ECG-Screening,D10,29,85,183,208,Early Term,M8,10,12,15,18,21,24,Dose Esc,Early Term
    ECHO-Screening,D183,M12,18,24,Early Term
    Anti-BMN 111 immuno-D1,10,29,85,183,208,Early Term,M8,10,12,15,18,21,24,25,Dose Esc,Early Term
    Lab tests-Screening,D1,4,10,15,29,43,85,127,183,208,Early Term,M8,10,12,15,18,21,24,25,Dose Esc,Early Term
    Imaging:
    X-ray (PA of hand and wrist)-Screening,D183,Early Term,M12,18,24,Early Term; AP lower extremity radiograph-Screening,D183,Early Term,M12,24,Early Term
    E.5.2Secondary end point(s)
    Efficacy will be assessed by change from baseline in height growth velocity (annualized to cm/year), absolute growth, subject growth compared with ACH and non-ACH standardized pediatric growth curves, and change in body proportions. These changes will be assessed by anthropometric measurements and measurement ratios.
    E.5.2.1Timepoint(s) of evaluation of this end point
    6-month initial phase:
    Screening, Days 43, 85, 127, 183, and Early Term

    Extension phase:
    Months 8, 10, 12, 15, 18, 21, 24, 25, and Early Term

    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 Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    tolerability
    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 Yes
    E.8.1.7.1Other trial design description
    sequential cohort dose-escalation
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA2
    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
    France
    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
    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 months25
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months25
    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: 24
    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: 23
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 1
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 10
    F.4.2.2In the whole clinical trial 24
    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)
    This protocol includes an optional 18-month extension phase of the study.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Medical Research Network Ltd.
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-09-12
    N.Ethics Committee Opinion of the trial application
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-10-02
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