A Randomized, Double-blind, Placebo-controlled, Multicenter, Phase 2a, Proof-of-Concept Study of ASP8302 in Subjects with Underactive Bladder

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.

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.
9. Prohibited medications or subject is using restricted medications under
conditions different to those specified in the concomitant medication section.
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.
20 Current or history of alcohol and/or drug abuse within the last 24 months
prior to screening.
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.
24. Employee of the Astellas Group, third parties associated with the study, or
the clinical study site team.
25. To have any condition, which in the opinion of the investigator makes the
subject unsuitable for study participation., 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.