Efficacy and Safety of GSK1358820 in Subjects With Overactive Bladder
Condition: Urinary Bladder, Overactive
MeSH terms: Urinary Bladder, Overactive
Intervention: GSK1358820; Placebo; Antibiotic therapy; Bladder diary; King's Health Questionnaire (KHQ); Overactive Bladder Symptom Score (OABSS); Treatment Benefit Scale (TBS)
Intervention description: GSK1358820 injection contains botulinum toxin type A (100 U), sodium chloride (0.9 milligrams [mg]), and human serum albumin (0.5 mg). 10 mL of the drug will be injected at 20 sites (0.5 mL at each site) in the detrusor muscle, spaced approximately 1 centimeter (cm) apart. The injection will be administered under local anesthesia, via cystoscopy. Permitted anesthesia options for cystoscopy are intraurethral lidocaine (or similar) gel, and for treatment administration, installation of 1-2% lidocaine (or similar anesthetic) into the bladder.; Placebo injection is made up of sodium chloride (0.9 mg). 10 mL of the injection will be injected at 20 sites (0.5 mL at each site) in the detrusor muscle, spaced approximately 1 cm apart. The injection will be administered under local anesthesia, via cystoscopy. Permitted anesthesia options for cystoscopy are intraurethral lidocaine (or similar) gel, and for treatment administration, installation of 1-2% lidocaine (or similar anesthetic) into the bladder.; Subjects will use prophylactic antibiotic therapy approved for the indication of UTIs, at the discretion of the investigator, with the exception of those in the class of aminoglycosides. The therapy will begin 1 to 3 days prior to the administration of study treatment, and continue for 1 to 3 days following the treatment.; The bladder diary is a self-reporting tool to record subject's data on micturition. Subjects will enter data in the diary over 3 consecutive days. During Screening, data will be collected within 28 days prior to first treatment. During treatment periods, data will be collected within a week prior to each scheduled visit. The bladder diary will capture the following information: 1) Date and time of urinary episode, 2) episodes of micturition, 3) episodes of urinary incontinence, 4) episodes of urgency, 5) intensity of urgency, 6) episodes of nocturia, 7) use of CIC, and 8) urine volume. Diary data will not be collected when a subject experiences symptoms of a UTI.; The KHQ will assess the impact of urinary incontinence on QOL. It is a questionnaire with 21 items and the following 9 domains: 1) General health, 2) Incontinence impact, 3) Role limitations, 4) Physical limitations, 5) Social limitations, 6) Personal relationships, 7) Emotion, 8) Sleep/energy, 9) Severity measure. The items are answered by subjects themselves, and scores are summated using a defined algorithm.; The OABSS will comprehensively assess symptoms of OAB, such as frequency of micturition, nocturia, urinary urgency, and urge incontinence. It consists of 4 questions which will be responded by subjects themselves, by selecting the most appropriate answer for each question.; The TBS consists of one question ("My condition has"), to which the subject will answer by selecting one of the following responses: greatly improved, improved, not changed, worsened. The TBS will assess treatment benefit of GSK1358820.
Intervention MeSH terms: Anti-Bacterial Agents
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 250.0
Sex: All
Minimum age: 20 Years
Healthy volunteers: No
Keywords: Overactive bladder; Botulinum toxin type A; Urinary incontinence

Summary:

      GSK1358820 is a botulinum neurotoxin A complex that has been approved for the treatment of
      overactive bladder (OAB) in several countries, however, it has not been approved for OAB
      treatment in Japan. This study has been planned to evaluate the efficacy and safety of
      GSK1358820 in Japanese OAB patients with urinary incontinence whose symptoms have not been
      adequately managed with other medications for OAB.

      The primary objective of this study is to evaluate the superiority of a single dose treatment
      of GSK1358820 100 units (U) compared with placebo.

      The study comprises a screening phase up to 28 days, followed by a double-blind treatment
      phase of 12 to 48 weeks wherein subjects will receive a single treatment of either GSK1358820
      100 U injection or Placebo injection, in a ratio of 1:1, with further stratification within
      the treatment arms according to the number of urinary urge incontinence episodes during
      screening. Subjects meeting the criteria for re-treatment will receive a second and third
      treatment. Each re-treatment will be with open-label GSK1358820 100 U injection, and will be
      spaced at least 12 weeks from the previous treatment.

      The total duration of participation for any subject will not exceed 52 weeks, including
      screening and the 48-week treatment period.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Aged >=20 years at the time of signing the informed consent.

          -  Subject has symptoms of OAB (frequency and urgency) with urinary incontinence for a
             period of at least 6 months immediately prior to screening, determined by documented
             subject history.

          -  Subject has not been adequately managed with one or more medications (that is,
             anticholinergics or beta-3 adrenergic receptor agonist) for treatment of their OAB
             symptom. 'Not adequately managed' is defined as: An inadequate response after at least
             a 4-week period of OAB medication(s) on an approved optimized dose(s), that is,
             subject is still incontinent despite medication(s) for OAB; or limiting side effects
             (that is, condition that subject reduced dosage or discontinued the medication due to
             side effect after at least a 2-week period of OAB medication(s) on an approved
             optimized dose(s)).

          -  Subject who experiences all of the following, in the 3-day subject bladder diary
             completed during the screening phase:

               1. >= 3 episodes of urinary urgency incontinence, with no more than one urgency
                  incontinence-free day

               2. urinary frequency (defined as an average of >= 8 micturitions [toilet voids] per
                  day, that is, a total of >= 24 micturitions)

          -  Subject is willing to use clean intermittent catheterization (CIC) to drain urine if
             it is determined to be necessary by the investigator (or subinvestigator).

          -  Body weight >=40 kilograms (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 the contraceptive options below:
                       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 (example, using the
             toilet without assistance, 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 symptoms of OAB due to any known neurological reason (example, spinal cord
             injury, multiple sclerosis, cerebrovascular accident, Alzheimer's disease, Parkinson's
             disease, etc.)

          -  Subject has a predominance of stress incontinence determined by subject history.

          -  Subject has a history or evidence of any diseases, functional abnormalities or bladder
             surgery, other than OAB, 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 prohibited within 7 days prior to the start of the
                  screening phase

               4. History of interstitial cystitis, in the opinion of the investigator (or
                  subinvestigator)

               5. 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).

               6. 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.

               7. An active genital infection, other than genital warts, either concurrently or
                  within 4 weeks prior to Screening

               8. Male with previous or current diagnosis of prostate cancer or a prostate specific
                  antigen (PSA) level of >10 nanograms (ng)/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.

               9. Evidence of urethral and/or bladder outlet obstruction, in the opinion of the
                  investigator (or subinvestigator)

          -  Subject has a history of 2 or more urinary tract infections (UTIs) within 6 months of
             initiation of Treatment phase 1 (Week 0) or current administration of prophylactic
             antibiotics to prevent chronic UTIs

          -  Subject has a positive urine dipstick reagent strip test at initiation of Treatment
             phase 1 (Week 0) for nitrites or leukocyte esterase, or who are considered by the
             investigator (or subinvestigator) to have UTI.

          -  Subject has a serum creatinine level >2 times the upper limit of normal (ULN) at
             screening.

          -  Alanine aminotransferase (ALT) > 2xULN; and bilirubin > 1.5xULN (isolated bilirubin >
             1.5xULN 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, hypoalbuminemia, esophageal 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

          -  QT corrected (QTc) > 450 milliseconds (msec) or QTc > 480 msec in subjects with Bundle
             Branch Block from the result of electrocardiogram (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 received anticholinergic, beta-3 adrenergic receptor agonist or any other
             medications or therapies to treat symptoms of OAB, including nocturia, within 7 days
             prior to the start of the screening phase.

          -  Subject has been treated with any intravesical pharmacologic agent (example,
             capsaicin, resiniferatoxin) for OAB symptoms 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 has not initiated appropriate antibiotic medication 1 to 3 days prior to the
             initiation of Treatment phase 1 (Week 0).

          -  Subject uses CIC or indwelling catheter to manage their urinary incontinence.

          -  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 PVR urine volume of >100 mL at screening phase. The PVR measurement can
             be repeated once; the subject is to be excluded if the repeated measure is above 100
             mL.

          -  Subject has had urinary retention or an elevated PVR urine volume within 6 months of
             screening that has been treated with an intervention (such as catheterization).
             Voiding difficulties as a result of surgical procedures that resolved within 24 hours
             are not exclusionary.

          -  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
             subinvestigator'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.