E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Symptoms and general pathology [C23] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10021635 |
E.1.2 | Term | Incomplete bladder emptying |
E.1.2 | System Organ Class | 100000004857 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060695 |
E.1.2 | Term | Residual urine |
E.1.2 | System Organ Class | 100000004857 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10005071 |
E.1.2 | Term | Bladder retention |
E.1.2 | System Organ Class | 100000004857 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10012549 |
E.1.2 | Term | Detrusor muscle weakness |
E.1.2 | System Organ Class | 100000004857 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10047863 |
E.1.2 | Term | Weakness detrusor muscle |
E.1.2 | System Organ Class | 100000004857 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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)
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full 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. |
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E.3 | Principal 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 (including breastfeeding partner(s)) 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. If the male subject has not had a vasectomy or is not sterile as defined below, his female partner(s) is utilizing 1 form of highly effective birth control*starting at screening and will continue throughout study treatment and for 90 days after the male subject receives 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 partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy 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.
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E.4 | Principal 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. Clinical signs and symptoms of UTI, which is combined with a result of urine test (e.g., positive 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.
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy Primary: •Change from baseline to visit 4 in PVR after standardized bladder filling measured by catheterization (PVRC2).
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Change from baseline visit 2 to visit 4. |
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E.5.2 | Secondary 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.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Change from baseline visit 2 (absolute) to visits 3, 4 and/or EoT. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 23 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If 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 |
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E.8.7 | Trial 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
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The end of the study is defined as the last visit or follow-up contact of the last subject in the study. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |