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    Summary
    EudraCT Number:2021-005455-37
    Sponsor's Protocol Code Number:178-CL-207
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2022-07-14
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2021-005455-37
    A.3Full title of the trial
    A Phase 3, Open Label, Multicenter, Baseline-Controlled Sequential Dose Titration Study Followed by a Fixed Dose Observation Period to Evaluate Pharmacokinetics, Efficacy and Safety of Mirabegron Prolonged-Release Microgranula-Based Suspension in Children from 6 Months to Less Than 3 Years of Age with Neurogenic Detrusor Overactivity
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to investigate how effective and safe the study medication 'mirabegron prolonged-release microgranula based suspension' is and how long it stays in the body in children from 6 months to less than 3 years of age with symptoms of an overactive bladder with neurologic cause.
    A.4.1Sponsor's protocol code number178-CL-207
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/187/2022
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAstellas Pharma Global Development 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 supportAstellas Pharma Global Development Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstellas Pharma Europe B.V.
    B.5.2Functional name of contact pointClinical Trial Unit
    B.5.3 Address:
    B.5.3.1Street AddressSylviusweg 62
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333 BE
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031715455050
    B.5.6E-mailCTU@astellas.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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namemirabegron
    D.3.2Product code YM178
    D.3.4Pharmaceutical form Prolonged-release granules for oral suspension
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMirabegron
    D.3.9.1CAS number 223673-61-8
    D.3.9.2Current sponsor codeYM178
    D.3.9.3Other descriptive nameMirabegron
    D.3.9.4EV Substance CodeSUB32690
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number8
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 Yes
    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 No
    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
    Neurogenic detrusor overactivity (NDO)
    E.1.1.1Medical condition in easily understood language
    -not being able to control urination (incontinence)
    -strong urge to urinate
    E.1.1.2Therapeutic area Body processes [G] - Biological Phenomena [G16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10012547
    E.1.2Term Detrusor hyperreflexia
    E.1.2System Organ Class 10038359 - Renal and urinary disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.1
    E.1.2Level LLT
    E.1.2Classification code 10059617
    E.1.2Term Overactive bladder
    E.1.2System Organ Class 10038359 - Renal and urinary disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10029279
    E.1.2Term Neurogenic bladder
    E.1.2System Organ Class 10038359 - Renal and urinary disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    ● To evaluate the efficacy of mirabegron prolonged-release microgranula-based suspension after multiple dose administration in the pediatric population.
    E.2.2Secondary objectives of the trial
    ● To evaluate the additional efficacy of mirabegron prolonged-release microgranulabased suspension
    ● To evaluate the safety and tolerability of mirabegron prolonged release microgranulabased suspension after multiple-dose administration.
    ● To evaluate the PK of mirabegron prolonged-release microgranula-based suspension after multiple-dose administration
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Participant is eligible for participation in the study if all of the following apply:
    1. IRB/IEC approved written informed consent and privacy language as per national regulations (e.g., Health Insurance Portability and Accountability Act authorization for US study sites) must be obtained from the participant’s LAR prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).
    2. Participant is male or female and 6 months to less than 3 years of age.
    3. Participant’s weight is a minimum of 6 kg.
    4. Participant has a previous myelomeningocele (documented at the screening visit).
    5. Participant has a diagnosis of NDO confirmed by urodynamic investigation at baseline (day 1). The diagnosis of NDO should be confirmed by the presence of ≥ 1 involuntary detrusor contraction > 15 cm H2O from baseline detrusor pressure, and/or a decrease in
    bladder compliance leading to an increase in baseline detrusor pressure of > 20 cm H2O.
    6. Participant has a diagnosis of DSD.
    7. Participant is using CIC.
    8. Participant is suitable for a regimen of 4 to 6 CICs per day, fixed for the duration of the study in the opinion of the investigator using the 7-day baseline e-diary.
    9. Participant is able to swallow the study drug.
    10. Participant’s LAR is willing and able to comply with the study requirements (including compliant use of the e-diary) and with the concomitant medication restrictions.
    11. Participant’s LAR agree not to allow participant to participate in another interventional study while on treatment and throughout the pretreatment period.
    E.4Principal exclusion criteria
    Participant will be excluded from participation in the study if any of the following apply: Participant
    1. has a bladder capacity less than 25% of expected age-related capacity,
    confirmed by urodynamic investigation at baseline (day 1).
    2. has vesicoureteral reflux grade 3 to 5 in the opinion of the investigator.
    3. has a known genitourinary condition, other than NDO, that may cause overactive contractions and/or incontinence (e.g., bladder exstrophy, urinary tract obstruction, urethral diverticulum or fistula) or kidney/bladder stones or another persistent local pathology that may cause urinary symptoms.
    4. has had an indwelling urinary catheter within 4 weeks prior to the baseline
    visit.
    5. has undergone bladder augmentation surgery.
    6. with surgically corrected underactive sphincter.
    7. receives electrostimulation therapy, if started within 30 days before visit 1 screening or is expected to start during the study period. Participants who are on an established regimen (defined as starting more than 30 days before visit 1 screening) may remain on this for the duration of the study.
    8. has been administered intravesical botulinum toxin; except if given > 4 months prior to visit 1 screening and the participant experiences symptoms
    comparable to those existing prior to the botulinum toxin injections.
    9. has a current symptomatic UTI confirmed by urinalysis (urine culture containing > 100,000 cfu/mL) at baseline. If at screening and start of washout a UTI is present, the participant will be eligible for enrollment if the UTI has been treatedsuccessfully prior to baseline. If a symptomatic UTI is present at baseline, all baseline assessments should be postponed for a maximum of 7 days until the UTI is successfully treated. Successful treatment is defined as a symptom free patient with a white blood cell count in the urine < 100/microliter and urine culture below 100,000 cfu/mL.
    10. is using prohibited medications listed in [Section 10.5 Appendix 5: List of Excluded Concomitant Medications].
    11. has a diagnosis of central or congenital nephrogenic diabetes insipidus.
    12. with severe gastrointestinal (GI) condition (including toxic megacolon) or any of the following GI conditions: partial or complete obstruction, decreased motility like paralytic ileus or at risk for gastric retention.
    13. suffers from malnutrition or is severely overweight, in the opinion of the investigator. See [Section 10.8.1 CDC Weight for Age Growth Charts].
    14. has an average QTcB > 440 ms (based on the QTcB mean from the screening and baseline ECG triplicates), history of QTc prolongation or risk of QT prolongation (e.g., hypokalemia, LQTS, or family history of LQTS, exercise induced syncope).
    15. Participant has severe renal impairment (eGFR < 30 mL/min per 1.73 m2 for participants 1 year of age and older; serum creatinine ≥ 97.5th percentile for participants 6 to < 12 months of age [Table 9; Boer et al, 2010]).
    16. Participant's AST or ALT is ≥ 2 × ULN or TBL greater than or eq ).
    16. Participant’s AST or ALT is ≥ 2 × ULN or TBL greater than or equal to 1.5 × ULN.
    17. has a current or previous history of epilepsy.
    18. has a history or presence of any malignancy prior to visit 1 screening.
    19. has any other clinically significant out of range results of urinalysis, biochemistry or hematology as per the investigator’s interpretation.
    20. has an established hypertension and systolic or diastolic blood pressure greater than the 99th percentile of their normal range determined by gender, body size and age, plus 5 mmHg (reference for normal blood pressure for children < 1 year old is [Report of the second task force on blood pressure control in children, 1987] and for children ≥ 1 years old is [Flynn et al, 2017].
    21. Participant has a (median) resting heart rate > 99th percentile [Section 10.7.3 Centiles of Heart Rate for Normal Children from Birth to 18 Years of Age].
    22. has any clinically significant or unstable medical condition or disorder which, in the opinion of the investigator, precludes the participant from participating in the study.
    23. has known or suspected hypersensitivity to mirabegron, any of the excipients used in the current formulation or previous severe hypersensitivity to any drug.
    24. has participated in another clinical trial and/or has taken an investigational drug within 30 days (or 5 half-lives of the drug, or the limit set by national law, whichever is longer) prior to visit 1 screening.
    25. is being breast-fed by a woman taking any prohibited medication or fed with a milk product in which the presence of prohibited medication ingredients cannot be excluded.
    E.5 End points
    E.5.1Primary end point(s)
    ● Change from baseline in MCC after 24 weeks of treatment (based on filling urodynamics)
    E.5.1.1Timepoint(s) of evaluation of this end point
    after 24 weeks
    E.5.2Secondary end point(s)
    ● Change from baseline in urodynamic measures:
    o Bladder compliance (ΔV/ΔP) at weeks 4 and 24
    o Filling volume until first detrusor contraction (> 15 cm H2O) at weeks 4 and 24
    o Number of uninhibited detrusor contractions until leakage or until maximum 135% of age-related bladder capacity
    ● Change from baseline in e-diary measures:
    o Maximum and average catheterized daytime volume
    o Average morning catheterized volume (based on first catheterization after participant woke up)
    o Number of leakage episodes (per 24 h)
    o Number of dry (leakage-free) days per 7 days
    ● Acceptability by P-OMAQ-C at weeks 4, 24, and 52

    ● AEs
    ● Vital signs, on site and SBPM; SBPM from baseline to EOS
    ● Clinical laboratory tests (hematology, biochemistry, eGFR, urinalysis)
    ● 12-lead ECG
    ● Upper urinary tract ultrasound

    ● AUC24, Ctrough, CL/F, and VZ/F, Cmax and Tmax
    ● Additional PK parameters may be calculated based on the model used
    E.5.2.1Timepoint(s) of evaluation of this end point
    throughout and at the end of the study
    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 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) 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 Yes
    E.8.1.7.1Other trial design description
    sequential dose titration
    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.8.2.4Number of treatment arms in the trial1
    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 EEA6
    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
    Philippines
    Turkey
    United States
    Belgium
    Denmark
    Germany
    Poland
    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
    The end of the study is defined as the last visit or scheduled procedure shown in the schedule of assessments for the last participant in the study.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months9
    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: 10
    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: 4
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 6
    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 No
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state1
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 5
    F.4.2.2In the whole clinical trial 10
    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)
    Mirabegron will not be made available after conclusion of the study to participants who are still receiving and benefitting from study treatment in countries where the product does not have marketing approval and is not commercially available.
    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 Decision2022-08-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-08-01
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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