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Efficacy and Safety Study of GSK1358820 in Japanese Patients With Urinary Incontinence Due to Neurogenic Detrusor Overactivity

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02849418
Recruitment Status : Completed
First Posted : July 29, 2016
Results First Posted : July 10, 2019
Last Update Posted : July 10, 2019
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief 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.


Condition or disease Intervention/treatment Phase
Urinary Bladder, Overactive Drug: GSK1358820 Drug: Placebo Phase 3

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 21 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Phase III Study to Evaluate the Efficacy and Safety of GSK1358820 (Botulinum Toxin Type A) in Patients With Urinary Incontinence Due to Neurogenic Detrusor Overactivity
Actual Study Start Date : October 11, 2016
Actual Primary Completion Date : March 2, 2018
Actual Study Completion Date : December 20, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: GSK1358820 Injection 200 U
Subjects will receive a single treatment with 200 U GSK1358820 injection (30 mL of study drug will be administered as 30 injections, each of 1.0 mL) in the detrusor of bladder, using cystoscopy and under local anesthesia. General anesthesia may be used excluding neuromuscular blocking agents. If the criteria for re-treatment between 12 to 36 weeks after first treatment are met, subjects will receive a second treatment with GSK1358820. Following this, subjects could receive another re-treatment up to 36 weeks after the first treatment, upon meeting the criteria, provided a minimum of 12 weeks elapse since previous treatment.
Drug: GSK1358820
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 Comparator: Placebo Injection
Subjects will receive a single treatment with placebo (30 injections, each of 1 mL) in the detrusor of bladder, using cystoscopy and under local anesthesia. General anesthesia may be used excluding neuromuscular blocking agents. If the criteria for re-treatment between 12 to 36 weeks after first treatment are met, subjects will receive treatment with GSK1358820. Following this, subjects could receive another re-treatment up to 36 weeks after the first treatment, upon meeting the criteria, provided a minimum of 12 weeks elapse since previous treatment
Drug: Placebo
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




Primary Outcome Measures :
  1. Change From Baseline in the Daily Average Number of Urinary Incontinence Episodes at Week 6 [ Time Frame: Baseline and Week 6 in treatment phase 1 ]
    Participants were instructed to enter data on the bladder diary over 3 consecutive days. For Baseline and post-treatment visits, analysis was based on the diary data collected during a 3-day interval for each visit. Each 3-day interval consistsed of 3 consecutive 24-hour periods, with the first period starting from the time of the first urinary episode on the first of the 3 days. A valid diary day was defined as any of the three 24-hour periods with 2 or more any type of urinary incontinence episodes. Data collected from a 24-hour period with less than 2 urinary incontinence episodes (i.e., an invalid diary day) were set to missing. Baseline was defined was the latest pre-dose 3-day diary which had at least one valid diary day. Change from Baseline was calculated as the post-dose visit value minus the Baseline value.


Secondary Outcome Measures :
  1. Changes From Baseline in Maximum Cystometric Capacity (MCC) by Urodynamic Assessment at Week 6 [ Time Frame: Baseline and Week 6 in treatment phase 1 ]
    MCC was calculated by urodynamic assessment according to International Continence Society (ICS) standard guidelines. Baseline was the latest pre-dose assessment with a non-missing value. Change from Baseline was calculated as the post-dose visit value minus the Baseline value.

  2. Changes From Baseline in Maximum Detrusor Pressure During the First Involuntary Detrusor Contraction (IDC) (PmaxIDC) by Urodynamic Assessment at Week 6 [ Time Frame: Baseline and Week 6 in treatment phase 1 ]
    PmaxIDC was calculated by urodynamic assessment according to ICS standard guidelines. Baseline was the latest pre-dose assessment with a non-missing value. Change from Baseline was calculated as the post-dose visit value minus the Baseline value.

  3. Changes From Baseline in Volume at First IDC (VPmaxIDC) by Urodynamic Assessment at Week 6 [ Time Frame: Baseline and Week 6 in treatment phase 1 ]
    VPmaxIDC was calculated by urodynamic assessment according to ICS standard guidelines. Baseline was the latest pre-dose assessment with a non-missing value. Change from Baseline was calculated as the post-dose visit value minus the Baseline value.

  4. Changes From Baseline in Maximum Detrusor Pressure During the Storage Phase (PdetMax) by Urodynamic Assessment at Week 6 [ Time Frame: Baseline and Week 6 in treatment phase 1 ]
    PdetMax was calculated by urodynamic assessment according to ICS standard guidelines. Baseline was the latest pre-dose assessment with a non-missing value. Change from Baseline was calulcated as the post-dose visit value minus the Baseline value.

  5. Change From Baseline in the Daily Average Number of Urinary Incontinence Episodes [ Time Frame: Baseline and Week 2, Week 6 , Week 12, Week 18, Week 24, Week 36 and Week 48 ]
    Participants were instructed to enter data on the bladder diary over 3 consecutive days. For Baseline and post-treatment visits, analysis was based on the diary data collected during a 3-day interval for each visit. Each 3-day interval consistsed of 3 consecutive 24-hour periods, with the first period starting from the time of the first urinary episode on the first of the 3 days. A valid diary day was defined as any of the three 24-hour periods with 2 or more any type of urinary incontinence episodes. Data collected from a 24-hour period with less than 2 urinary incontinence episodes (i.e., an invalid diary day) were set to missing. Baseline was defined was the latest pre-dose 3-day diary which had at least one valid diary day. Change from Baseline was calulcated as the post-dose visit value minus the Baseline value. The current results are presented up to week 24 for Interim Analysis and the data for remaining time points will be provided at the time of final data reporting.

  6. Percent Change From Baseline in the Daily Average Number of Urinary Incontinence Episodes [ Time Frame: Baseline and Week 2, Week 6 , Week 12, Week 18, Week 24, Week 36 and Week 48 ]
    Participants were instructed to enter data on the bladder diary over 3 consecutive days. For Baseline and post-treatment visits, analysis was based on the diary data collected during a 3-day interval for each visit. Each 3-day interval consistsed of 3 consecutive 24-hour periods, with the first period starting from the time of the first urinary episode on the first of the 3 days. A valid diary day was defined as any of the three 24-hour periods with 2 or more any type of urinary incontinence episodes. Data collected from a 24-hour period with less than 2 urinary incontinence episodes (i.e., an invalid diary day) were set to missing. Baseline was defined was the latest pre-dose 3-day diary which had at least one valid diary day. Change from Baseline was calculated as the post-dose visit value minus the Baseline value. The current results are presented up to week 24 for Interim Analysis and the data for remaining time points will be provided at the time of final data reporting.

  7. Change From Baseline in the Daily Average Number of Voids [ Time Frame: Baseline and Week 2, Week 6 , Week 12, Week 18, Week 24, Week 36 and Week 48 ]
    Participants were instructed to enter data on the bladder diary over 3 consecutive days. For Baseline and post-treatment visits, analysis was based on the diary data collected during a 3-day interval for each visit. Each 3-day interval consistsed of 3 consecutive 24-hour periods, with the first period starting from the time of the first urinary episode on the first of the 3 days. A valid diary day was defined as any of the three 24-hour periods with 2 or more any type of void episodes. Data collected from a 24-hour period with less than 2 void episodes (i.e., an invalid diary day) were set to missing. Baseline was defined was the latest pre-dose 3-day diary which had at least one valid diary day assessment. Change from Baseline was calculated as the post-dose visit value minus the Baseline value. The current results are presented up to week 24 for Interim Analysis and the data for remaining time points will be provided at the time of final data reporting.

  8. Percent Change From Baseline in the Daily Average Number of Voids [ Time Frame: Baseline and Week 2, Week 6 , Week 12, Week 18, Week 24, Week 36 and Week 48 ]
    Participants were instructed to enter data on the bladder diary over 3 consecutive days. For Baseline and post-treatment visits, analysis was based on the diary data collected during a 3-day interval for each visit. Each 3-day interval consistsed of 3 consecutive 24-hour periods, with the first period starting from the time of the first urinary episode on the first of the 3 days. A valid diary day was defined as any of the three 24-hour periods with 2 or more any type of void episodes. Data collected from a 24-hour period with less than 2 void episodes (i.e., an invalid diary day) were set to missing. Baseline was defined was the latest pre-dose 3-day diary which had at least one valid diary day assessment. Change from Baseline was calculated as the post-dose visit value minus the Baseline value. The current results are presented up to week 24 for Interim Analysis and the data for remaining time points will be provided at the time of final data reporting.

  9. Change From Baseline in Average Volume Voided Per Micturition [ Time Frame: Baseline and Week 2, Week 6 , Week 12, Week 18, Week 24, Week 36 and Week 48 ]
    The total volume voided was measured and recorded by participants over one 24-hour period during the 3-day bladder diary collection period. To perform this measurement, urine collection containers provided by the sponsor were used. The volume voided per void was determined by the sponsor from the total urine volume measured by the participants divided by the number of voids (excluding urinary incontinence episode). Baseline was defined was the latest pre-dose 3-day diary which had at least one valid diary day assessment. Change from Baseline was calculated as the post-dose visit value minus the Baseline value. The current results are presented up to week 24 for Interim Analysis and the data for remaining time points will be provided at the time of final data reporting.

  10. Percent Change From Baseline in Average Volume Voided Per Micturition [ Time Frame: Baseline and Week 2, Week 6 , Week 12, Week 18, Week 24, Week 36 and Week 48 ]
    The total volume voided was measured and recorded by participants over one 24-hour period during the 3-day bladder diary collection period. To perform this measurement, urine collection containers provided by the sponsor were used. The volume voided per void was determined by the sponsor from the total urine volume measured by the participants divided by the number of voids (excluding urinary incontinence episode). Baseline was defined was the latest pre-dose 3-day diary which had at least one valid diary day assessment. Change from Baseline was calculated as the post-dose visit value minus the Baseline value. The current results are presented up to week 24 for Interim Analysis and the data for remaining time points will be provided at the time of final data reporting.

  11. Percentage of Participants Attaining 100%, >=75% and >=50% Reduction From Baseline in the Daily Average of Urinary Incontinence Episodes [ Time Frame: Baseline and Week 2, Week 6 , Week 12, Week 18, Week 24, Week 36 and Week 48 ]
    Participants were instructed to enter data on the bladder diary over 3 consecutive days. For Baseline and post-treatment visits, analysis was based on the diary data collected during a 3-day interval for each visit. Each 3-day interval consisted of 3 consecutive 24-hour periods, with the first period starting from the time of the first urinary episode on the first of the 3 days. A valid diary day was defined as any of the three 24-hour periods with 2 or more any type of urinary incontinence episodes. Data collected from a 24-hour period with less than 2 urinary incontinence episodes (i.e., an invalid diary day) were set to missing. Percentage of participants attaining 100%, >=75% and >=50% reduction from Baseline in the daily average of urinary incontinence episodes up to Week 24 of Treatment Cycle 1 have been presented. The current results are presented up to week 24 for Interim Analysis and the data for remaining time points will be provided at the time of final data reporting.

  12. Time to Qualification for Retreatment After First Treatment [ Time Frame: Up to 24 weeks in treatment phase 1 ]
    Participants can be considered for re-treatment beginning at the week 12 visit following the initial treatment or the week 12 visit following any re-treatment. Qualification criteria was; participants must have initiated request for re-treatment, participants experienced at least 4 episodes of urinary incontinence, with no more than one urinary-free day, post-void residual (PVR) urine volume must have been <200 mL for participants who micturated or had a mixed catheterization/spontaneous micturition pattern, Body weight >=40 kilogram; investigator deemed re-treatment appropriate. Time to the participant's first qualification for 2nd treatment from the day of 1st treatment was calculated as the earliest date when participants given "Yes" response to the question of participants qualification for retreatment minus the day of first treatment plus 1.

  13. Time to Request for Retreatment After First Treatment [ Time Frame: Up to 24 weeks in treatment phase 1 ]
    The time taken by the participants to request re-treatment was reported. Time to the participant's first request for 2nd treatment from the day of 1st treatment was calculated as the earliest date when participants provided "Yes" response to the question of participants request for retreatment minus the day of first treatment plus 1.

  14. Change From Baseline in King's Health Questionnaire (KHQ) Domain Score [ Time Frame: Baseline and Week 2, Week 6 , Week 12, Week 18, Week 24, Week 36 and Week 48 ]
    KHQ is a 21 item questionnaire, consisting of 9 domains: General health (GH) (1[Very good] to 5[Very poor]), Incontinence impact (Int Imp) (1[Not at all] to 4[A lot]), Role Limitations (RL) (1[Not at all] to 4[A lot]), Physical limitations (PL) (1[Not at all] to 4[A lot]), Social limitations (SL) (0[not applicable] to 4[A lot]), Personal relationships (PR) (0[Not applicable] to 4[A lot]), Emotions (1[Not at all] to 4[Very much]), Sleep or energy (S or E) (1[Never] to 4[All the time]) and Severity or Coping (S or C) (1[Never] to 4[All the time]). Domain score for GH was calculated as score of one item minus 1/4x100; Int Imp: score of one item minus 1/3x100; RL, PL, PR, S or E: summed scores of 2 items minus 2/6x100; SL, Emotions: summed scores of 3 items minus 3/9x100; S or C: summed scores of 5 items minus 5/15x100. Baseline is the latest pre-dose assessment with a non-missing value,including those from unscheduled visits. Change from Baseline was any visit value minus Baseline value.

  15. Percentage of Participants With Positive Response on Treatment Benefit Scale (TBS) [ Time Frame: Baseline and Week 2, Week 6 , Week 12, Week 18, Week 24, Week 36 and Week 48 ]
    TBS consisted of 4 answers to 1 questions, to which participants had to answer considering their current condition (urinary problems, urinary incontinence) compared to their condition before receiving any study treatment the trial. Responses for questions were coded as 1 to 4 where 1 - Greatly improved, 2 - Improved, 3 - Not changed and 4 - Worsened. The answers of 1 - Greatly improved or 2 - Improved were regarded as positive response. Other answers including missing data were regarded as NO positive response. The current results are presented up to week 24 for Interim Analysis and the data for remaining time points will be provided at the time of final data reporting.

  16. Number of Participants With Serious Adverse Events (SAEs) and Non -SAE [ Time Frame: Up to Week 48 ]
    AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant. Safety for double blind phase (SPDB) comprised of all participants who received at least one dose of study treatment. This population was based on the treatment the participant actually received. The current results are presented up to week 24 for Interim Analysis and the data for remaining time points will be provided at the time of final data reporting.

  17. Change From Baseline in Vital Sign Parameters Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) [ Time Frame: Baseline and Week 2, Week 6 , Week 12, Week 18, Week 24, Week 36 and Week 48 ]
    Vital sign parameter SBP and DBP were measured in seated position after 5 minutes rest. Baseline was defined as latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value. NA indicates standard deviation was not calculated due to insufficient number of participants. The current results are presented up to week 24 for Interim Analysis and the data for remaining time points will be provided at the time of final data reporting.

  18. Change From Baseline in Vital Sign Parameter Heart Rate [ Time Frame: Baseline and Week 2, Week 6 , Week 12, Week 18, Week 24, Week 36 and Week 48 ]
    Vital sign parameter heart rate was measured in seated position after 5 minutes rest. Baseline was defined as latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value. NA indicates standard deviation was not calculated due to insufficient number of participants. The current results are presented up to week 24 for Interim Analysis and the data for remaining time points will be provided at the time of final data reporting.

  19. Change From Baseline in Vital Sign Parameter Temperature [ Time Frame: Baseline and Week 2, Week 6 , Week 12, Week 18, Week 24, Week 36 and Week 48 ]
    Vital sign parameter temperature was measured in seated position after 5 minutes rest. Baseline was defined as latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value. NA indicates standard deviation was not calculated due to insufficient number of participants. The current results are presented up to week 24 for Interim Analysis and the data for remaining time points will be provided at the time of final data reporting.

  20. Number of Participants With Shift From Baseline in Hematology Parameters [ Time Frame: Up to Week 48 ]
    Blood samples were collected from participants for analysis of following hematology parameters; Basophils, Eosinophils, Hemoglobin, Hematocrit, Lymphocytes, Monocytes, Neutrophil, Total Neutrophils, Platelet count, Red Blood Cell (RBC) count, and White Blood Cell count (WBC). Participants were counted in the worst case category that their value changes to (Low, Normal or High), unless there is no change in their category. Participants whose value category was unchanged (e.g. High to High) or whose value became normal, were recorded in the 'To Normal or No Change' category. Participants were counted twice if the participant had values that changed 'To Low' and 'To High', so the percentages may not add to 100 percent. Baseline is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Shift from Baseline was calculated as any visit value minus Baseline value.

  21. Number of Participants With Shift From Baseline in Clinical Chemistry Parameters [ Time Frame: Up to Week 48 ]
    Blood samples were collected for analysis of following clinical chemistry parameters; Albumin, Alkaline Phosphatase (Alk Phosp), Alanine Amino Transferase (ALT), Aspartate Amino Transferase (AST), Direct Bilirubin (Bil), Total Bil, Calcium, Chloride, Creatinine, Glucose, Potassium, Sodium, Total Protein, Urea/blood urea nitrogen (BUN) and Uric acid. Participants were counted in the worst case category that their value changes to (Low, Normal or High), unless there is no change in their category. Participants whose value category was unchanged (e.g. High to High) or whose value became normal, are recorded in the 'To Normal or No Change' category. Participants were counted twice if the participant had values that changed 'To Low' and 'To High', so the percentages may not add to 100 percent. Baseline is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Shift from Baseline was calculated as any visit value minus Baseline value.

  22. Number of Participants With Worst-case Urinalysis Results Post-Baseline Relative to Baseline by Dipstick Analysis [ Time Frame: Up to Week 48 ]
    Urinalysis parameters assessed were urine occult blood, urine protein. In this dipstick test, the level of ketones, glucose, occult blood and protein in urine samples was recorded as negative trace, 1+, 2+, and 3+ and 4+ (the plus sign increases with a higher level of glucose, ketones, or proteins in the urine: 1+=slightly positive, 2+=positive, 3+=high positive etc.). Number of participants with worst-case urinalysis results post-Baseline relative to Baseline by dipstick analysis have been presented. The current results are presented up to week 24 for Interim Analysis and the data for remaining time points will be provided at the time of final data reporting.

  23. Number of Participants With UTI [ Time Frame: Up to Week 48 ]
    A urine culture and sensitivity test were performed when urinalysis results with a urine reagent strip were suggestive of a urinary tract infection (UTI) (positive nitrites or leukocyte esterase). UTI was recorded as an AE, irrespective of symptoms when the result of urine culture was positive (with the presence of bacteriuria with >=10^5 Colony Forming Unit per milliliter (CFU/mL) and leukocyturia with >5 per high power field was noted. Number of participants with UTI undergoing urine culture and sensitivity analysis have been presented. The current results are presented up to week 24 for Interim Analysis and the data for remaining time points will be provided at the time of final data reporting.

  24. Change From Baseline in Post Void Residual (PVR) Urine Volume [ Time Frame: Baseline and Week 2, Week 6 , Week 12, Week 18, Week 24, Week 36 and Week 48 ]
    PVR was measured in non-catheterizing participants, or those with mixed patterns (ie, they do both CIC and spontaneous voiding). PVR urine volume was assessed by ultrasound, bladder scan or catheterization after participants performed a voluntary void according to the study schedule. PVR urine volume could be assessed at any other time depending on clinical need. In case PVR urine volume indicated a clinically meaningful elevation, were asked to void once again (allowing the participants sufficient time to void) and the PVR urine volume was then reassessed. For participants who had a PVR urine volume measurement repeated, only the repeat value was recorded. NA indicates standard deviation was not calculated due to insufficient number of participants. The current results are presented up to week 24 for Interim Analysis and the data for remaining time points will be provided at the time of final data reporting.

  25. Number of Participants With Using Clean Intermittent Catheterization (CIC) for Urinary Retention or Elevated PVR [ Time Frame: Up to Week 48 ]
    CIC was used to drain the bladder and manage urinary incontinence in participants who were not able to spontaneously void. Participants who had used CIC at least once after the first treatment with the reason for urinary retention or elevated PVR have been presented. The current results are presented up to week 24 for Interim Analysis and the data for remaining time points will be provided at the time of final data reporting.

  26. Number of Participants With Kidney and Bladder Ultrasound Examination [ Time Frame: Up to Week 48 ]
    The kidney and bladder ultrasound study was performed according to the study schedule. In order to assess the presence of stones in the kidneys and bladder, an ultrasound of these structures (with the bladder at least half full) was performed. Participants were excluded from this study if the screening ultrasound demonstrated the presence of bladder stones. In the case of unclear findings in an ultrasound study, other diagnostic measures (e.g., x-ray) were required in order to confirm the presence of bladder stones. If a stone was detected in participants after the injection of the investigational product, the event was recorded as an adverse event. The current results are presented up to week 24 for Interim Analysis and the data for remaining time points will be provided at the time of final data reporting.

  27. Number of Participants With Abnormal Not Clinically Significant (A-NCS) and Abnormal Clinically Significant (A-CS) Electrocardiogram (ECG) Findings [ Time Frame: Up to Week 48 ]
    Single 12-lead ECGs was obtained at each timepoint during the study using an ECG machine that automatically calculated the heart rate and measures PR, QRS, and QT. The findings from ECG were classified as A-NCS and A-CS. Number of participants with A-NCS and A-CS findings have been reported. The current results are presented up to week 24 for Interim Analysis and the data for remaining time points will be provided at the time of final data reporting.



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Layout table for eligibility information
Ages Eligible for Study:   20 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02849418


Locations
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Japan
GSK Investigational Site
Aomori, Japan, 036-8563
GSK Investigational Site
Fukuoka, Japan, 820-8508
GSK Investigational Site
Hokkaido, Japan, 060-8648
GSK Investigational Site
Hyogo, Japan, 651-2181
GSK Investigational Site
Miyagi, Japan, 981-8563
GSK Investigational Site
Nagasaki, Japan, 852-8501
GSK Investigational Site
Okayama, Japan, 700-8558
GSK Investigational Site
Tochigi, Japan, 321-0293
GSK Investigational Site
Yamanashi, Japan, 409-3898
Sponsors and Collaborators
GlaxoSmithKline
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline
  Study Documents (Full-Text)

Documents provided by GlaxoSmithKline:
Study Protocol  [PDF] November 16, 2017
Statistical Analysis Plan  [PDF] July 30, 2018


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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02849418     History of Changes
Other Study ID Numbers: 204948
First Posted: July 29, 2016    Key Record Dates
Results First Posted: July 10, 2019
Last Update Posted: July 10, 2019
Last Verified: July 2019
Keywords provided by GlaxoSmithKline:
Botulinum toxin type A
Urinary Incontinence
Neurogenic Detrusor Overactivity
Additional relevant MeSH terms:
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Urinary Incontinence
Enuresis
Urinary Bladder, Overactive
Urination Disorders
Urologic Diseases
Lower Urinary Tract Symptoms
Urological Manifestations
Signs and Symptoms
Behavioral Symptoms
Elimination Disorders
Mental Disorders
Urinary Bladder Diseases
Anesthetics
Botulinum Toxins
Botulinum Toxins, Type A
abobotulinumtoxinA
Neuromuscular Blocking Agents
Central Nervous System Depressants
Physiological Effects of Drugs
Acetylcholine Release Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Cholinergic Agents
Neurotransmitter Agents
Neuromuscular Agents
Peripheral Nervous System Agents