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    Summary
    EudraCT Number:2015-003836-11
    Sponsor's Protocol Code Number:111-301
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-10-20
    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 number2015-003836-11
    A.3Full title of the trial
    A Phase 3 Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety 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 Study to Evaluate the Safety and Efficacy of BMN 111 in Children with Achondroplasia
    A.4.1Sponsor's protocol code number111-301
    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 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 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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboLyophilisate and solvent for solution for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    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 Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Evaluate change from baseline in annualized growth velocity at 52 weeks in subjects treated with BMN 111 compared with control subjects in the placebo group.
    E.2.2Secondary objectives of the trial
    • Evaluate change from baseline in height Z-score in subjects treated with BMN 111 compared with control subjects in the placebo group at 52 weeks
    • Evaluate change from baseline in upper:lower segment body ratio in subjects treated with BMN 111 compared with control subjects in the placebo group at 52 weeks
    • Evaluate safety and tolerability of BMN 111 in children with ACH
    • Evaluate the pharmacokinetics 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. Subjects who reach the age of 18 years while the study is ongoing will be asked to provide their own written consent.
    2. 5 to < 18 years old 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 assessments, including standing height, and are currently active participants in 111-901.
    5. Females ≥ 10 years old or who have begun menses 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. Caregivers are willing to administer daily injections to the subjects and complete the required training
    E.4Principal exclusion criteria
    1. Have hypochondroplasia or short stature condition other than ACH (e.g., trisomy 21, pseudoachondroplasia)
    2. Have any of the following: Hypothyroidism or hyperthyroidism; Insulin-requiring diabetes mellitus; Autoimmune inflammatory disease (including celiac disease, lupus (SLE), juvenile dermatomyositis, scleroderma, and others); Inflammatory bowel disease; Autonomic neuropathy
    3. Have a history of any of the following: Renal insufficiency defined as serum creatinine > 2 mg/dl; Chronic anemia; Baseline systolic blood pressure (BP) < 70 millimeters of mercury (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; Cardiac or vascular disease (including Cardiac dysfunction (abnormal echocardiogram) at Screening Visit; Hypertrophic cardiomyopathy; Pulmonary hypertension; Congenital heart disease; Cerebrovascular disease; Aortic insufficiency or other clinically significant valvular dysfunction; Clinically significant atrial or ventricular arrhythmias)
    4. Have a clinically significant finding or arrhythmia on screening electrocardiogram (ECG) that indicates abnormal cardiac function or conduction or QTc-F > 450 msec
    5. Have an unstable condition likely to require surgical intervention during the study (including progressive cervical medullary compression or severe untreated sleep apnea)
    6. Evidence of growth plate closure (proximal tibia, distal femur) based on bilateral lower extremity X-rays (including both anterior-posterior [AP] and lateral views) obtained at the Screening visit
    7. Documented Vitamin D deficiency (concentration of blood 25-hydroxy-vitamin D <12 ng/mL or <30 nmol/L)
    8. Require any investigational agent prior to completion of study period9. Have received another investigational product or investigational medical device within 6 months before the Screening Visit
    10. Have used any investigational product or investigational medical device for the treatment of ACH or short stature at any time, including BMN 111
    11. 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)
    12. Have been treated with growth hormone, insulin-like growth factor 1 (IGF-1), or anabolic steroids in the previous 6 months or treatment greater than 6 months at any time
    13. Have had > 1 month treatment with oral corticosteroids (low-dose ongoing inhaled steroid for asthma, or intranasal steroids, are acceptable) in the previous 12 months
    14. Planned or expected to have limb-lengthening surgery during the study period. Subjects with previous limb-lengthening surgery may enroll if surgery occurred at least 18 months prior to the study and healing is complete without sequelae.
    15. Planned or expected bone-related surgery (ie. surgery involving disruption of bone cortex), during the study period. Subjects with previous bone-related surgery may enroll if surgery occurred at least 12 months prior to the study and healing is complete without sequelae.
    16. Have had a fracture of the long bones or spine within 6 months prior to screening
    17. Pregnant or breastfeeding at the Screening Visit or planning to become pregnant (self or partner) at any time during the study
    18. Have aspartate aminotransferase (AST) or alanine aminotransferase (ALT) at least 3x upper limit of normal (ULN) or total bilirubin at least 2x ULN (except for subjects with known history of Gilbert’s disease)
    19. History of severe untreated sleep apnea
    20. Have had new initiation of sleep apnea treatment (e.g. CPAP or sleep apnea-mitigating surgery) in the previous 2 months prior to screening
    21. Have current malignancy, history of malignancy, or currently under work-up for suspected malignancy
    22. Have known hypersensitivity to BMN 111 or its excipients
    23. Have a history of hip surgery or hip dysplasia atypical for achondroplasia subjects
    24. Have clinically significant hip injury in the 30 days prior to screening
    25. History of slipped capital femoral epiphysis or avascular necrosis of the femoral head
    26. Are unable to lie flat when in prone position (needed for hip exam)
    27. Have abnormal findings on baseline clinical hip exam or imaging assessments that are determined to be clinically significant as determined by the investigator
    28. Concurrent disease or condition that, in the view of the investigator, would interfere with study participation or safety evaluations, for any reason
    29. 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) at Week 52 (12- month).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Anthropometric measurements: Screen, Day 1, Week 13, Week 26, Week 39, Week 52
    E.5.2Secondary end point(s)
    The secondary efficacy endpoints include the change from baseline in height Z-score and the change from baseline in upper:lower body segment ratio.

    Safety will be evaluated by assessment of AEs, SAEs, laboratory test results (urinalysis, chemistry, hematology), changes in vital signs, physical examination, ECG, X-rays/DXA, clinical hip assessment, and anti-BMN 111 immunogenicity assessments.

    PK sampling will be carried out over the 12-month study period in subjects randomized to BMN 111 or placebo.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Anthropometric measurements: Screen, Day 1, Week 13, Week 26, Week 39, Week 52

    Clinical labs (urinalysis, chemistry, hematology): Screen, Day 1, Day 10, Week 6, Week 13, Week 26, Week 39, Week 52, Week 54

    Vital signs and AEs: Screen, Day 1, Day 2, Day 3, Day 10, Week 6, Week 26, Week 39, Week 52, Week 54 (follow-up)

    Physical exam: Screen, Day 1, Day 10, Week 6, Week 13, Week 26, Week 39, Week 52, Week 54 (follow-up)

    ECG: Screen, Day 1, Day 10, Week 13, Week 26, Week 39, Week 52, Week 54 (follow-up)

    X-Ray/DXA: Screen, Week 26, Week 52

    Clinical hip assessment: Screen, Week 26, Week 52

    Anti-BMN 111 immunogenicity: Day 1, Week 13, Week 26, Week 39, Week 52, Week 54 (follow-up)

    PK: Day 1 (full), Week 13 (partial), Week 26 (full), Week 39 (partial), Week 52 (full)
    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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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 Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 EEA13
    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
    Germany
    Italy
    Japan
    Spain
    Turkey
    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 years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    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 Yes
    F.1.1Number of subjects for this age range: 110
    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: 88
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 20
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 2
    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 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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Subjects are children and adolescents 5 to less than 18 years of age at the time of consent.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 110
    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)
    Following completion of 52 weeks subjects in both treatment groups may be eligible to receive BMN 111 in an open-label extension study, to assess safety and efficacy of BMN 111 over a longer term.
    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 Decision2016-12-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-01-20
    P. End of Trial
    P.End of Trial StatusOngoing
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