Efficacy and Safety of GSK1358820 in Subjects With Overactive Bladder

A Phase III Study to Evaluate the Efficacy and Safety of GSK1358820 (Botulinum Toxin Type A) in Patients With Overactive Bladder

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.

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.