Efficacy and Safety Study of GSK1358820 in Japanese Patients With Urinary Incontinence Due to Neurogenic Detrusor Overactivity
Condition: Urinary Bladder, Overactive
MeSH terms: Urinary Incontinence; Enuresis; Urinary Bladder, Overactive
Intervention: GSK1358820; Placebo
Intervention description: GSK1358820 injection contains botulinum toxin type A (100 U), sodium chloride (0.9 milligrams [mg]), and human serum albumin (0.5 mg). The 30 mL of study drug will be administered as 30 injections each of 1.0 mL, evenly distributed at 30 sites in the detrusor muscle, spaced approximately 1 centimeter (cm) apart. The injection will be administered using cystoscopy and under local anesthesia. General anesthesia may be used excluding neuromuscular blocking agents.; Placebo injection contains sodium chloride (0.9 milligrams [mg]); 30 mL of the injection will be injected at 30 sites in the detrusor muscle, spaced approximately 1 centimeter (cm) apart. The injection will be administered using cystoscopy and under local anesthesia. General anesthesia may be used excluding neuromuscular blocking agents
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 21.0
Sex: All
Minimum age: 20 Years
Healthy volunteers: No
Keywords: Botulinum toxin type A; Urinary Incontinence; Neurogenic Detrusor Overactivity

Summary:

      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.
    

Eligibility criteria:

        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.