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    Summary
    EudraCT Number:2020-001055-40
    Sponsor's Protocol Code Number:111-209
    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:2020-05-19
    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 number2020-001055-40
    A.3Full title of the trial
    A randomized, controlled, open-label clinical trial with an open-label extension to investigate the safety of BMN 111 in infants and young children with achondroplasia at risk of requiring cervicomedullary decompression surgery
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Open-label clinical trial with an open-label extension to investigate the safety of BMN 111 in infants and young children with achondroplasia
    A.4.1Sponsor's protocol code number111-209
    A.5.4Other Identifiers
    Name:INDNumber:111299
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation PlanP/060/2020
    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-mailMedInfo@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 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 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 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
    The primary objective of the study is to evaluate the safety of BMN 111 in children who are at risk of requiring cervicomedullary decompression surgery.
    E.2.2Secondary objectives of the trial
    The secondary objective of the study is to evaluate the efficacy of BMN 111 in children who are at risk of requiring cervicomedullary decompression surgery.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Individuals eligible to participate in this study must meet all of the following criteria:
    1. Parent(s) or guardian(s) willing and able to provide signed informed consent after the nature of the study has been explained and prior to performance of any research related procedure.
    2. Have ACH, documented by genetic testing.
    3. Are willing and able to perform all study procedures as physically possible.
    4. Age from 0 months to ≤12 months, at study entry (Day 1).
    5. Parent(s) or caregiver(s) are willing to administer daily injections to the subject and complete the required training.
    6. Have evidence of cervicomedullary compression (CMC) that “may” require surgical intervention defined as:
    o Baseline MRI assessment from central blinded evaluation showing at least one of the following findings:
    -Narrowing of the foramen magnum with loss of cerebrospinal fluid space surrounding the cord.
    -Narrowing of the foramen magnum with flattening of the cervical cord without T2 signal change.
    o Supported by (but not required for eligibility) the following clinical findings:
    Baseline physical examination
    -Gross or fine motor developmental milestone delay compared to expected for ACH (eg, lifting head when lying on stomach).
    • Abnormal reflex (eg, brisk reflex / abnormal clonus for age).
    • Weakness (eg, opisthotonus).
    -Baseline sleep study
    • Sleep apnea with a primary central component (eg, not secondary to obstructive sleep apnea).
    E.4Principal exclusion criteria
    Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study:
    1. Have hypochondroplasia or short-stature condition other than achondroplasia (eg, trisomy 21, pseudoachondroplasia, etc).
    2. Have CMC that either does not require surgical intervention (for example foramen magnum narrowing with preservation of the cerebrospinal fluid space) or does require immediate surgical intervention (for example narrowing of the foramen magnum with cervical cord signal change).
    3. Have any of the following:
    o Untreated congenital hypothyroidism or maternal history of hyperthyroidism.
    o Insulin-requiring neonatal diabetes mellitus.
    o Autoimmune inflammatory disease.
    o Inflammatory bowel disease.
    o Autonomic neuropathy.
    4. Have a history of any of the following:
    o Renal insufficiency.
    o Chronic anemia.
    o Baseline systolic blood pressure below age and gender specified normal range or recurrent symptomatic hypotension (defined as episodes of low blood pressure generally accompanied by symptoms eg, pallor, cyanosis, irritability, poor feeding).
    o Cardiac or vascular disease, including the following:
     Cardiac dysfunction (abnormal echocardiogram determined to be clinically significant by Investigator and Medical Monitor) at Screening.
     Hypertrophic cardiomyopathy.
     Pulmonary hypertension.
     Clinically significant structural heart disease or valvular insufficiency (associated with symptoms or requiring intervention).
     Clinically significant cerebrovascular disease.
     Clinically significant atrial or ventricular arrhythmias.
    5. Have a clinically significant finding or arrhythmia that indicates abnormal cardiac function or conduction or QTc-F ≥ 450 msec on screening ECG.
    6. Current treatment 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, drugs known to alter renal function that is expected to continue for the duration of the study.
    7. Require any other investigational product prior to completion of the study period.
    8. Have received another investigational product or investigational medical device within 30 days prior to Screening.
    9. Have used any other investigational product or investigational medical device for the treatment of achondroplasia or short stature at any time.
    10. Require current chronic therapy with antihypertensive medication or any medication that, in the Investigator’s judgment, may compromise the safety or ability of the subject to participate in this clinical study.
    11. Have been treated with growth hormone, insulin-like growth factor 1, or anabolic steroids in the 6 months prior to Screening, or long-term treatment (> 3 months) at any time.
    12. Have had regular long-term treatment ( > 1 month) with oral corticosteroids (low-dose ongoing inhaled steroid for asthma, or intranasal steroids, are acceptable) prior to Screening
    13. Have ever had prior cervicomedullary decompression surgery.
    14. Have had a fracture of the long bones or spine within 6 months prior to Screening.
    15. Have aspartate aminotransferase, alanine aminotransferase, or total bilirubin > 2 × the upper limit of normal at Screening (except for subjects with a known history of Gilbert’s syndrome or transient indirect hyperbilirubinemia).
    16. Have current malignancy, history of malignancy, or currently under work-up for suspected malignancy.
    17. Have known hypersensitivity to BMN 111 or its excipients.
    18. Have a history of hip surgery or clinically significant hip abnormality in the 30 days prior to Screening.
    19. 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.
    20. Have any concurrent disease or condition that, in the view of the Investigator, would interfere with study participation or safety evaluations, for any reason
    E.5 End points
    E.5.1Primary end point(s)
    Safety will be evaluated by the incidence of AEs, SAEs, laboratory test results (chemistry and hematology), vital signs (heart rate, blood pressure, respiratory rate, and temperature), physical examination, electrocardiogram, echocardiography, and concomitant medications. Clinical laboratory tests will be limited to the minimum necessary for evaluation of safety in order to minimize the required blood draw volume in this young pediatric population.
    E.5.1.1Timepoint(s) of evaluation of this end point
    AE, SAE recording: All visits
    Concomitant meds: All visits
    Clin lab assessments: Screen, Day 1, Weeks 6, 13, 26, 39, 52, 65, 78, 91, 104, every 26 weeks up to Week 260, Safety Follow up
    Vital Signs: Screening, Day 1, Day 2 and 3 for subjects randomized to BMN 111+ SoC only, Weeks 6, 13, 26, 39, 52, 65, 78, 91, 104, week 104 Day 2 and 3 for subjects crossing-over to BMN 111 + SoC only, every 26 weeks up to Week 260, Safety FU

    Phys exam: Screen, Day 1, Weeks 6, 13, 26, 39, 52, 65, 78, 91, 104, every 26 weeks up to Week 260 Safety Follow up

    ECG: Screen, Day 1, Day 2 and 3 for subjects randomized to BMN 111 + SoC only, Weeks 6, 13, 26, 39, 52, 65, 78, 91, 104, week 104 Day 2 and 3 for subjects crossing-over to BMN 111 + SoC only, every 26 weeks up to Week 260, Safety Follow up

    E.5.2Secondary end point(s)
    Efficacy will be assessed by careful neurological clinical examination, MRI including the brain stem, foramen magnum, and spine, and age-specific developmental milestone acquisition (Bayley-III score). A board-certified, fellowship-trained (or equivalent) pediatric anesthesiologist will administer anesthesia during MRI measurements. Independent expert review of all MRI assessments will be performed to standardize eligibility assessment and interpretation of changes during study). Specific criteria for evaluation of signs and symptoms of foramen magnum stenosis leading to CMC include:
    • Incidence of surgical interventions for CMC including cervicomedullary decompression.
    • The effect of BMN 111 on the foramen magnum and neuroanatomy at the cervicomedullary junction.
    • The effect of BMN 111 on the anatomy of the spine including the thoracolumbar spine.
    • The effect of BMN 111 on neurological signs and symptoms of CMC.
    • The effect of BMN 111 on age-specific developmental milestones using the Bayley-III score.
    In addition, the effect of BMN 111 on sleep apnea will be evaluated and anthropometric measurements will be performed
    E.5.2.1Timepoint(s) of evaluation of this end point
    Anthropometric measurements: Day 1, Weeks 13, 26, 39, 52, 65, 78, 91, 104, every 26 weeks up to Week 260

    MRI measurements: Screening, Weeks 26, 52, 78, 104, every 52 weeks up to Week 260

    Bayley-III: Screening, Weeks 26, 52, 78, 104, every 52 weeks up to Week 260

    Neurological examination: Screening, Day 1, Weeks 6, 13, 26, 39, 52, 65, 78, 91,
    104, every 52 weeks up to Week 260, Safety Follow up
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    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 Yes
    E.8.2.3.1Comparator description
    standard of care alone
    E.8.2.4Number of treatment arms in the trial2
    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 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
    United Kingdom
    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 years5
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    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: 20
    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) Yes
    F.1.1.3.1Number of subjects for this age range: 5
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 15
    F.1.1.5Children (2-11years) No
    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 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 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 20
    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 Decision2020-07-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-07-29
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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