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    Summary
    EudraCT Number:2017-003693-13
    Sponsor's Protocol Code Number:8302-CL-0201
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-08-09
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2017-003693-13
    A.3Full title of the trial
    A Randomized, Double-blind, Placebo-controlled, Multicenter, Phase 2a, Proof-of-Concept Study of ASP8302 in Subjects with Underactive Bladder
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to investigate the effect and safety of ASP8302 in the treatment of subjects with an underactive bladder
    A.4.1Sponsor's protocol code number8302-CL-0201
    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 SponsorAstellas Pharma Europe B.V.
    B.1.3.4CountryNetherlands
    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 Europe B.V.
    B.4.2CountryNetherlands
    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 pointService Desk - Global Clinical Dev.
    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 number+31 (0)71 545 5050
    B.5.5Fax number+31 (0)71 545 5840
    B.5.6E-mailcontact@nl.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.3.2Product code ASP8302
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    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 INNto be confirmed
    D.3.9.1CAS number 1839583-68-4
    D.3.9.2Current sponsor codeASP8302
    D.3.9.3Other descriptive nameASP8302
    D.3.9.4EV Substance CodeSUB192042
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 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 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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Underactive Bladder
    E.1.1.1Medical condition in easily understood language
    Underactive Bladder
    E.1.1.2Therapeutic area Diseases [C] - Symptoms and general pathology [C23]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10021635
    E.1.2Term Incomplete bladder emptying
    E.1.2System Organ Class 100000004857
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10060695
    E.1.2Term Residual urine
    E.1.2System Organ Class 100000004857
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10005071
    E.1.2Term Bladder retention
    E.1.2System Organ Class 100000004857
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10012549
    E.1.2Term Detrusor muscle weakness
    E.1.2System Organ Class 100000004857
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10047863
    E.1.2Term Weakness detrusor muscle
    E.1.2System Organ Class 100000004857
    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 ASP8302 compared with placebo in subjects with UAB
    •To investigate the safety and tolerability of ASP8302 compared with placebo in subjects with UAB
    •To investigate the pharmacokinetics of ASP8302 in subjects with UAB
    •To support the development of the UAB - Patient Reported Outcome (PRO)
    E.2.2Secondary objectives of the trial
    Not applicable.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    In approx 7 selected sites (in Europe and Japan), a urodynamic pressure flow sub-study will be performed.
    Pharmacogenomics sub-study may be conducted in the future with acquired blood samples.
    E.3Principal inclusion criteria
    At Study Entry – Screening (visit 1):
    1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved written informed consent and privacy language as per national regulations must be obtained from the subject prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).
    2. Subject is considered an adult according to local regulation at the time of signing the informed consent form (ICF).
    3. Subject is diagnosed with UAB, defined as a bothersome chronic incomplete bladder emptying:
    • clinical condition is present for ≥ 6 months before screening, and
    • subject has a PVR ≥ 75 mL (measured by ultrasound after uroflowmetry; V1_PVRUS1).
    4. Subject on CIC should have been on CIC for at least 1 month and should be able to void spontaneously and not be completely dependent on CIC.
    5. Female subject must either:
    •Be of non-childbearing potential:
    -Post-menopausal (defined as at least 1 year without any menses for which there is no other obvious pathological or physiological cause) prior to screening, or
    -Documented surgically sterile (e.g., hysterectomy, bilateral salpingectomy, bilateral oophorectomy).
    •Or, if of childbearing potential:
    -Agrees not to try to become pregnant during the study and for 28 days after the final study drug administration
    -Agrees to have a serum pregnancy test on all visits
    -And have a negative serum pregnancy test at the screening visit
    -And agrees to consistently use 1 form of highly effective birth control* starting at screening and throughout the study period and for 28 days after the final study drug administration.
    6. Female subject must agree not to breastfeed starting at screening and throughout the study period, and for 28 days after the final study drug administration.
    7. Female subject must not donate ova starting at screening and throughout the study period, and for 28 days after the final study drug administration.
    8. A sexually active male subject with female partner(s) of childbearing potential is eligible if he agrees to use a male condom starting at screening and continue throughout study treatment and for 90 days after the final study drug administration.
    9. Male subject must not donate sperm starting at screening and throughout the study period and for 90 days after the final study drug administration.
    10. Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy or time partner is breastfeeding throughout the study period and for 28 days after the final study drug administration.
    *Highly effective forms of birth control include:
    • Consistent and correct usage of established hormonal contraceptives that inhibit ovulation
    • Established intrauterine device or intrauterine system
    • Bilateral tubal occlusion
    • Vasectomy (a vasectomy is a highly effective contraception method provided the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used)
    • Male is sterile due to a bilateral orchiectomy
    • Sexual Abstinence is considered a highly effective method only if defined as refraining from heterosexual activity during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant.
    11. Subject agrees not to participate in another interventional study while participating in this study.
    At Randomization (visit 2):
    12. Subject has a PVR ≥ 100 mL (measured by catheterization, i.e., PVRC2).
    13. Subject has a VVST ≥ 50 mL and a BVE (V2_BVE) ≥ 10%. The VVST and V2_PVRC2 will be used to calculate V2_BVE = [VVST/(V2_PVRC2 + VVST)] *100.
    Waivers to the inclusion criteria will NOT be allowed.
    E.4Principal exclusion criteria
    At Study Entry – Screening (visit 1):
    Related to lower urinary tract:
    1. Subject has significant BOO:
    •Clinically significant urethral stricture in the opinion of the investigator.
    •Female subject has uterine prolapse ≥ Grade 2 Shaw’s system (down to or outside the introitus), moderate or severe cystocele (reaches or protrudes outside the introitus).
    •Male subject has a bladder outlet obstruction index (BOOI) ≥ 40 on PFS (either performed on screening or within 12 months of the screening visit), or –if PFS is not available–a PV of > 40 mL (Europe) > 30 mL (Japan) on ultrasound (either performed on screening or within 6 months of the screening visit). Note: if PFS is available and PV is above the cut-off level, the subject is not to be excluded if BOOI is < 40.
    • Other condition that in the opinion of the investigator constitutes significant BOO.
    2. Urgency urinary incontinence clinically significant in the opinion of the investigator.
    3. 1 or more bladder diverticuli clinically significant in the opinion of the investigator.
    4.Vesico-ureteral/renal reflux clinically significant in the opinion of the investigator.
    5. Urinary catheter in situ.
    6. 1 of the following conditions as a primary cause for their UAB, or a condition that could potentially influence treatment outcome:
    •Neurological lesion or condition, including cerebrovascular accident, spinal lumbar disc hernia, spinal cord injury, multiple sclerosis, Parkinson’s disease, Guillain–Barré syndrome, pudendal, hypogastric or pelvic nerve lesion. Diabetes mellitus is allowed if controlled with or without medical treatment.
    •Increased pelvic floor muscle activity during voiding (e.g., dyssynergic striated sphincteric activity/striated sphincteric activity during voiding, Fowler syndrome and pelvic floor muscle spasm).
    •Previous bladder surgery. Prior Benign Prostatic Obstruction surgery is allowed if performed more than 6 months prior to screening.
    •Previous implant surgery for incontinence still in situ.
    •Significant active urological pain syndrome
    •Previous pelvic radiation therapy
    7. Dependence on use of a manual assistance method intended to improve bladder emptying.
    Related to (previous or current) treatment and/or study drug:
    8. 1 or more of the following non-medication therapies:
    •Electrostimulation therapy.
    •Intravesical or injection based treatment.
    •An ongoing bladder training program and/or pelvic floor muscle exercises, which started within 6 weeks prior to visit 1.
    •Muscle-derived stem cell injection in the bladder or urethra or bladder transplantation at any time prior to screening.
    10. Known or suspected hypersensitivity to ASP8302 or any of the inactive ingredients.
    11. Inflammatory bowel disease or clinically significant diarrhea.
    12. Subject is known to be immunocompromised due to conditions such as human immunodeficiency virus/acquired immune deficiency syndrome or hepatitis C.
    13. Diagnosed with clinically significant cardiovascular or cerebrovascular diseases within 6 months prior to visit 1.
    14.Diagnosed with clinically significant asthma, chronic bronchitis and/or chronic obstructive pulmonary disease.
    15. Mean Fridericia corrected QT interval (QTcF) > 430 ms for males or > 450 ms for females, a pre-existing long QT syndrome or hypokalemia.
    16. Clinically significant abnormal 12-lead ECG.
    17. Current or previous malignant disease of the pelvis. Subjects with a history of (non-pelvic) cancer are considered eligible if the subject has undergone therapy and the subject has been considered disease free for at least 5 years. Subject with completely excised basal cell carcinoma or squamous cell carcinoma of the skin and completely excised cervical cancer in situ are also considered eligible.
    18. Moderate to severe hepatic impairment.
    19. Severe renal impairment defined as estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2.
    21. Evidence of a UTI confirmed by a urine culture containing > 100,000 cfu/mL in midstream urine. If a UTI is confirmed in the visit 1 sample, the run-in period should be stopped. After successful treatment of the UTI, the subject can be rescreened and if eligible enroll in the study.
    22. Any of the following abnormal liver or kidney function parameters (as assessed in visit 1 sample):
    •ALT, AST or bilirubin increased to > 1.5 times the ULN.
    •γ-GT increased to > 3 times the ULN.
    •eGFR < 45 mL/min/1.73 m2 based on the Modification of Diet in Renal Disease formula.
    23. Received investigational therapy within 28 days or 5 half-lives, whichever is longer, prior to screening.
    At randomization (visit 2):
    26. Subject meets any of the exclusion criteria of visit 1.
    27. Severe OAB, i.e., experienced 3 or more episodes of urgency (Patient Perception of Intensity of Urgency Scale [PPIUS] Grade 3 or 4), during the 3-day micturition diary period prior to visit 2.

    E.5 End points
    E.5.1Primary end point(s)
    Efficacy
    Primary:
    •Change from baseline to visit 4 in PVR after standardized bladder filling measured by catheterization (PVRC2).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Change from baseline visit 2 to visit 4.
    E.5.2Secondary end point(s)
    Secondary*:
    •VVST at site visits
    •BVEC2 (i.e., BVE calculated with PVRC2 and VVST)
    Exploratory*:
    •PVRUS1, PVRC1, PVRUS2
    BVEUS1, BVEC1, BVEUS2
    •Uroflowmetry parameters: Voiding time, flow time, Q (max and ave), time to Qmax (absolute, % of voiding time), BC and VV.
    •Urodynamic parameters (only applicable for PFS sub-study): including uroflow measurements done during PFS, Pdet (Opening, at Qmax, mu), Pves, Pabd, bladder capacity index (BCI; males only), Watts factor (max and AUC), VCE, t20-80, BOOI (males only), Schäfer grade, position in the Maastricht-Hannover Nomogram, volume at first sensation of bladder filling, volume at first desire and volume at urgent desire.
    •3-day micturition diary parameters: number of daily micturitions (waking, nocturnal, 24-h), VV per micturition, PPIUS/total urgency and frequency score, number of urgency episodes, i.e., PPIUS Grade 3 or 4, number of incontinence episodes and pads used; for subjects on CIC: number of CICs and catheterized volume.
    •Questionnaire data: International Consultation on Incontinence Modular Questionnaire– Underactive Bladder Patient Reported Outcome (ICIQ-UAB PRO) symptom score and sub scores, symptom and bother scores as assessed by International Consultation on Incontinence Modular Questionnaire-Male/Female Lower Urinary Tract Symptoms (ICIQ-MLUTS/FLUTS), European Quality of Life 5 Dimensions Questionnaire (EQ-5D), 12 Item Short Form Health Survey (SF-12), Patient Global Impression of Change (PGI-C), Patient Global Impression of Severity (PGI-S).
    Responder analysis*:
    •PVR responders: responders will be defined as subjects with ≥ 30% reduction of PVR from baseline to EoT; a second definition of a PVR responder is a subject with ≥ 50 mL reduction from baseline to EoT.
    •PGI-C responders: responders will be defined as subjects with a response “much improved” or “very much improved” at EoT.
    •CIC responders: responders will be defined as subjects who are on CIC at baseline with at least a 50% reduction in mean number of CICs per 24 hours from baseline to EoT. A second definition of a CIC responder is at least a 50% reduction in mean catheterized volume per 24 hours from baseline to EoT. Also the percentage of subjects who were on CIC at baseline, but who have stopped using CIC at EoT will be calculated.
    *Parameter outcomes include change from baseline (absolute and %) to visits 3, 4 and/or EoT, where applicable; derivations are elucidated in the protocol and Statistical Analysis Plan (SAP).
    Safety
    •Incidence and severity of treatment-emergent adverse events (TEAEs)
    •Laboratory tests: hematology, biochemistry, urinalysis
    •Vital signs
    •ECG parameters
    •Physical examination
    Pharmacokinetics
    Plasma concentrations of ASP8302 at visits 3 and/or 4.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Change from baseline visit 2 (absolute) to visits 3, 4 and/or EoT.
    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 No
    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 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) 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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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 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 EEA15
    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
    Germany
    Japan
    Netherlands
    Poland
    Slovakia
    United Kingdom
    E.8.7Trial has a data monitoring committee No
    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 follow-up contact of the last subject 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 months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months3
    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 No
    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) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 41
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 84
    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 state21
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 75
    F.4.2.2In the whole clinical trial 125
    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 Decision2018-08-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-12-10
    P. End of Trial
    P.End of Trial StatusOngoing
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