Efficacy and Safety Study of GSK1358820 in Japanese Patients With Urinary Incontinence Due to Neurogenic Detrusor Overactivity
Efficacy and Safety Study of GSK1358820 in Japanese Patients With Urinary Incontinence Due to Neurogenic Detrusor Overactivity
This study will evaluate the efficacy and safety of GSK1358820 in Japanese patients with
 neurogenic detrusor overactivity (NDO) with urinary incontinence, whose symptoms have not
 been adequately managed with medications for urinary incontinence due to NDO.

 This study consists of a screening phase up to 28 days followed by a double-blind Treatment
 phase 1 of 12 to 48 weeks wherein subjects will receive a single treatment of either
 GSK1358820 200 Units (U) injection or placebo injection. After the first treatment, subjects
 who meet the re-treatment criteria between 12 to 36 weeks can enter an open-label Treatment
 phase 2 to receive a second treatment with GSK1358820 200 U. Subjects will be permitted to
 receive re-treatment up to 2 times, and there should be a gap of minimum of 12 weeks since
 the previous treatment. The duration of overall treatment phases is 48 weeks. The total
 duration of participation for any subject will not exceed 52 weeks, including screening.
Inclusion Criteria:

 -  Aged >=20 years at the time of signing the informed consent

 -  Subject has urinary incontinence as a result of neurogenic detrusor overactivity for a
 period of at least 3 months prior to screening as a result of spinal cord injury or
 multiple sclerosis, determined by documented subject history. In addition:

 1. Spinal cord injury subjects must have a stable neurological injury level C5 or
 below occurring >=6 months prior to screening.

 2. Multiple sclerosis subjects must be clinically stable in the investigator's
 opinion, for >=3 months prior to screening and have an Expanded Disability Status
 Scale score <=6.5

 -  Subject has NDO for a period of at least 3 months prior to screening, determined by
 documented subject history. The presence of an involuntary detrusor contractions (IDC)
 must also be demonstrated during the urodynamic assessment during the screening period
 or Day 1 (prior to randomization).

 -  Subject has not been adequately managed with one or more medications (i.e.,
 anticholinergics or beta-3 adrenergic receptor agonist) for treatment of urinary
 incontinence due to NDO . Not adequately managed is defined as:

 An inadequate response after at least a 4-week period of medication(s) for urinary
 incontinence due to NDO on an optimized dose(s), i.e., subject is still incontinent despite
 medication(s) for urinary incontinence due to NDO, or Limiting side effects (i.e.,
 condition that subject reduced dosage or discontinued the medication due to side effect)
 after at least a 2-week period of medication(s) for urinary incontinence due to NDO on an
 optimized dose(s)

 -  Subject has >=6 episodes of urinary incontinence, with no more than one urgency
 incontinence-free day in the 3-day subject bladder diary completed during the
 screening phase

 -  Subject currently uses or is willing to use clean intermittent catheterization (CIC)
 to empty the bladder (indwelling catheter is not permitted). Subjects currently on CIC
 should be willing to maintain a CIC schedule of at least 3 times per day throughout
 the study. Caregiver may perform CIC.

 -  Body weight >=40 kilogram (kg) at screening

 -  Males or females：

 1. Male subjects with female partners of child bearing potential must comply with
 the following contraception requirements from the time of first dose of study
 medication until the study exit:

 -  Vasectomy with documentation of azoospermia.

 -  Male condom plus partner use of one of following the contraceptive
 options:Intrauterine device or intrauterine system that meets the standard
 operating procedure (SOP) effectiveness criteria including a <1% rate of
 failure per year, as stated in the product label; or oral contraceptive,
 either combined or progestogen alone These allowed methods of contraception
 are only effective when used consistently, correctly and in accordance with
 the product label. The investigator is responsible for ensuring that
 subjects understand how to properly use these methods of contraception

 2. Female subject is eligible to participate if she is not pregnant (as confirmed by
 a negative urine or serum human chorionic gonadotrophin [hCG] test), not
 lactating, and at least one of the following conditions applies:

 • Non-reproductive potential defined as: Pre-menopausal females with one of the
 following: Documented tubal ligation, Documented hysteroscopic tubal occlusion
 procedure with follow-up confirmation of bilateral tubal occlusion, Hysterectomy,
 Documented Bilateral Oophorectomy.

 Postmenopausal defined as 12 months of spontaneous amenorrhea. Females on hormone
 replacement therapy (HRT) and whose menopausal status is in doubt will be
 required to use one of the highly effective contraception methods if they wish to
 continue their HRT during the study. Otherwise, they must discontinue HRT to
 allow confirmation of post-menopausal status prior to study enrollment.

 • Reproductive potential and agrees to follow one of the options listed below in
 the GlaxoSmithKline (GSK) Modified List of Highly Effective Methods for Avoiding
 Pregnancy in Females of Reproductive Potential (FRP) requirements from 30 days
 prior to the first dose of study medication and until the study exit. This list
 of highly effective methods (approved in Japan) is provided below, and it does
 not apply to FRP with same sex partners, when this is their preferred and usual
 lifestyle or for subjects who are and will continue to be abstinent from
 penile-vaginal intercourse on a long term and persistent basis: Intrauterine
 device or intrauterine system that meets the SOP effectiveness criteria including
 a <1% rate of failure per year, as stated in the product label; Oral
 Contraceptive, either combined or progestogen alone; Male partner sterilization
 with documentation of azoospermia prior to the female subject's entry into the
 study, and this male is the sole partner for that subject.

 These allowed methods of contraception are only effective when used consistently,
 correctly and in accordance with the product label. The investigator is
 responsible for ensuring that subjects understand how to properly use these
 methods of contraception.

 -  Subject has given signed informed consent, including compliance with the requirements
 and restrictions listed in the consent form and in this protocol (e.g., complete
 bladder diaries and questionnaires, is able to collect volume voided per micturition
 measurements over a 24-hour period, and attend all study visits in the opinion of the
 investigator(or subinvestigator).

 Exclusion Criteria:

 -  Subject has a history or evidence of any diseases, functional abnormalities or bladder
 surgery, other than NDO, that may have affected bladder function including but not
 limited to:

 1. Bladder stones (including bladder stone surgery) within 6 months prior to
 screening or confirmed occurrence of bladder stones at the screening phase

 2. Surgery (including minimally invasive surgery) within 1 year of screening for
 stress incontinence or pelvic organ prolapse

 3. Current use of an electrostimulation/neuromodulation device for treatment of
 urinary incontinence. Note: Use of any implantable device is prohibited within 4
 weeks prior to initiation of Screening phase and throughout the study period. Use
 of any external device is discontinued at least 7 days prior to the start of the
 screening phase

 4. Current use of a baclofen pump

 5. History of interstitial cystitis, in the opinion of the investigator (or
 subinvestigator)

 6. Past or current evidence of hematuria due to urological/renal pathology or
 uninvestigated hematuria. Subjects with investigated hematuria may enter the
 study if urological/renal pathology has been ruled out to the satisfaction by the
 investigator (or subinvestigator)

 7. Past or current history of bladder cancer or other urothelial malignancy,
 positive result of urine cytology or uninvestigated suspicious urine cytology
 results at the Screening phase. Suspicious urine cytology abnormalities require
 that bladder cancer or other urothelial malignancy has been ruled out to the
 satisfaction of the investigator according to local site practice.

 8. An active genital infection, other than genital warts, either concurrently or
 within 4 weeks prior to Screening

 9. Male with previous or current diagnosis of prostate cancer or a prostate specific
 antigen (PSA) level of >10 nanogram (ng)/milliliter (mL) at Screening. Subjects
 with a PSA level of >= 4 ng/mL but <= 10 ng/mL must have prostate cancer ruled
 out to the satisfaction of the investigator (or subinvestigator) according to
 local site practice.

 10. Evidence of urethral and/or bladder outlet obstruction, in the opinion of the
 investigator (or subinvestigator)

 -  Subject has a serum creatinine level >2 times the upper limit of normal (ULN) at
 screening

 -  Alanine aminotransferase (ALT) > 2×ULN; and bilirubin > 1.5×ULN (isolated bilirubin
 >1.5×ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) at
 screening

 -  Subject has current active liver or biliary disease (with the exception of Gilbert's
 syndrome or asymptomatic gallstones or otherwise stable chronic liver disease per
 investigator assessment). Notes:

 1. Stable chronic liver disease should generally be defined by the absence of
 ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric
 varices, or persistent jaundice, or cirrhosis

 2. Chronic stable hepatitis B and C (example, presence of hepatitis B surface
 antigen [HBsAg] or positive hepatitis C antibody [HCVAb] test result within 3
 months prior to first dose of study treatment) are acceptable if subject
 otherwise meets entry criteria

 -  QTc >450 milliseconds (msec) or QTc >480 msec in subjects with Bundle Branch Block
 from the result of ECG at screening. Notes:

 1. The QTc is the QT interval corrected for heart rate according to Bazett's formula
 (QTcB), Fridericia's formula (QTcF), and/or another method, machine-read or
 manually over-read

 2. The specific formula that will be used to determine eligibility and
 discontinuation for an individual subject should be determined prior to
 initiation of the study. In other words, several different formulae cannot be
 used to calculate the QTc for an individual subject and then the lowest QTc value
 used to include or discontinue the subject from the trial

 -  Subject has hemophilia or other clotting factor deficiencies or disorders that cause
 bleeding diathesis

 -  Subject changes or initiates or discontinues anticholinergic, beta-3 adrenergic
 receptor agonist or any other medications or therapies to treat urinary incontinence
 due to NDO, within 6 days prior to the start of the screening phase

 -  Subject has been treated with any intravesical pharmacologic agent (e.g., capsaicin,
 resiniferatoxin) for urinary incontinence due to NDO within 12 months prior to
 initiation of Treatment phase 1 (Week 0)

 -  Subject has previous or current use of botulinum toxin therapy of any serotype for the
 treatment of any urological condition

 -  Subject has previous use within 12 weeks prior to initiation of Treatment phase 1
 (Week 0) or current use of botulinum toxin therapy of any serotype for any
 non-urological condition or beauty care

 -  Subject has been immunized for botulinum toxin of any serotype

 -  Subject cannot withhold any antiplatelet or anticoagulant therapy or medications with
 anticoagulative effects for 3 days prior to initiation of Treatment phase 1 (Week 0).
 Some medications may need to be withheld for > 3 days, per clinical judgment of the
 investigator (or subinvestigator).

 -  Subject without a urinary tract infection (UTI) as determined from the urinalysis or
 urine culture and/or investigator opinion, has not initiated prophylactic antibiotic
 medication 1 to 3 days prior to the initiation of Treatment phase 1 (Week 0). Subject
 with a UTI as determined from the urinalysis or urine culture and/or investigator
 opinion, has not initiated antibiotic medication at least 5 days prior to the
 initiation of Treatment phase 1 (Week 0)

 -  Subject is symptomatic for UTI on day of treatment

 -  Subject has a history of sensitivity to any of the study medications, medications used
 in the study (including anesthesia), or their components or a history of drug or other
 allergy that, in the opinion of the investigator or Medical Monitor, contraindicates
 their participation

 -  Subject has any medical condition that may put them at increased risk with exposure to
 GSK1358820 including diagnosed myasthenia gravis, Eaton-Lambert syndrome, or
 amyotrophic lateral sclerosis

 -  Females who are pregnant, nursing or planning a pregnancy during the study

 -  Subject has a post void residual urine volume above 200 mL for subjects who micturate
 or have a mixed catheterization/spontaneous micturition pattern. The post void
 residual measurement can be repeated once; the subject is to be excluded if the
 repeated measure is above 200 mL.

 -  Subject has a 24-hour total volume of urine voided >3000 mL of urine collected over 24
 consecutive hours during the 3-day bladder diary collection period in the Screening
 phase

 -  Subject is currently participating in or has previously participated in another
 therapeutic study within 30 days prior to the start of the Screening phase

 -  Subject has any condition or situation which, in the investigator's (or
 sub-investigator's) opinion, puts the subject at significant risk, may confound the
 study results, or may interfere significantly with the subject's participation in the
 study.