Overactive Bladder
Conditions
Keywords
Overactive bladder, Detrusor overactivity, Liposome, Botulinum toxin A
Brief summary
Overactive bladder (OAB) is a bothered symptom syndrome. Traditional medication for OAB is antimuscarinic agent. However, adverse events such as dry mouth, constipation, blurred vision, and dizziness may prohibit patient to take this drug for OAB. Intravesical botulinum toxin A (BoNT-A) is a novel treatment however, BoNT-A can cause acute urinary retention and large postvoid residual. In this grant we will evaluate liquid liposome delivery of BoNT-A (Liposome encapsulated BoNT-A) into the bladder without the need for cystoscopic-guided needle injection for refractory OAB.
Detailed description
Overactive bladder (OAB) is a symptom syndrome characterized by urgency frequency with or without urgency incontinence, usually no metabolic or anatomical disorders can be found and it may have great impact on quality of life. Traditional medication for OAB is antimuscarinic agent which targets at the muscarinic receptors. There are several adverse events such as dry mouth, constipation, blurred vision, and dizziness related to antimuscarinics, therefore, some patients cannot tolerated this treatment. Intravesical botulinum toxin A (BoNT-A) has recently emerged as novel treatment for OAB refractory to antimuscarinics, however, BoNT-A injection can cause acute urinary retention and large postvoid residual. Urinary tract infection usually occurred following large postvoid residual and urinary retention. If we can deliver BoNT-A through the urothelium to the suburothelial space, but not into the detrusor layer, we might have therapeutic effects on the urothelial sensory nerves without compromising the detrusor contractility. This treatment will enable us to prevent the undesired detrusor underactivity after BoNT-A injection, especially in the elderly patients who had impaired detrusor contractility and OAB. Liposomes are vesicles, composed of concentric phospholipid bilayers separated by aqueous compartments. Because liposomes adsorb to cell surfaces and fuse with cells, they are being used as vehicles for drug delivery and gene therapy. In this grant we will evaluate liquid liposome delivery of BoNT-A (Liposome encapsulated BoNT-A) into the bladder without the need for cystoscopic-guided needle injection for refractory OAB, and study the mechanism of action of intravesical liposomal drug delivery. If successful, we will leverage our technology transfer expertise and bring the science from the bench top to the bed side to apply for a physician sponsored Investigational New Drug (IND) trial using liposome-BoNT in patients with OAB or DO.
Interventions
DRUGLiposome encapsulated botulinum toxin A
Liposome encapsulated BoNT-A ( mixed BOTOX 200 U/10 mL water in Liposome 80 mg/40 mL water) in single intravesical instillation, one time treatment at the treatment day
Normal saline (BoNT-A/NS) 50 mL in single intravesical instillation
Sponsors
Buddhist Tzu Chi General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Adults with age of 20 years old or above 2. Patients with symptoms of urgency frequency and/or urge incontinence and a urgency severity scale (USS) of at least 2, with or without urodynamically proven detrusor overactivity (DO) (defined by the International Continence Society (ICS) recommendation as: spontaneous detrusor contraction occurring during bladder filling phase or occurring before uninhibited detrusor contraction voiding at bladder capacity in the urodynamic study) 3. Free of active urinary tract infection 4. Free of bladder outlet obstruction on enrollment 5. Free of overt neurogenic bladder dysfunction 6. Having been treated with antimuscarinic agents for at least 4 weeks without effect or with intolerable adverse effects 7. Patient has not been treated with bladder surgery for OAB, such as enterocystoplasty, that might affect the therapeutic effect of test drug 8. Patient can record voiding diary for the urinary frequency and urgency 9. Patient or his/her legally acceptable representative has signed the written informed consent form
Exclusion criteria
1. Use of antimuscarinic agent and effective in treatment of lower urinary tract symptoms 2. Patients with severe cardiopulmonary disease and such as congestive heart failure, arrhythmia, poorly controlled hypertension, not able to receive regular follow-up 3. Patients with bladder outlet obstruction on enrollment 4. Patients with postvoid residual \>150 mL 5. Patients with uncontrolled confirmed diagnosis of acute urinary tract infection 6. Patients have laboratory abnormalities at screening including: Alanine aminotransferase (ALT) \>3 x upper limit of normal range Aspartate aminotransferase (AST) \>3 x upper limit of normal range Patients have abnormal serum creatinine level \>2 x upper limit of normal range 7. Patients with any contraindication to be urethral catheterization during treatment 8. Female patients who is pregnant, lactating, or with child-bearing potential without contraception. 9. Myasthenia gravis, Eaton Lambert syndrome. 10. Patients with any other serious disease considered by the investigator not suitable for general anesthesia or in the condition to enter the trial 11. Patients participated investigational drug trial within 1 month before entering this study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change of the Total Frequency Per 3 Days | Baseline to 4 weeks after initial treatment | Efficacy: Mean change of the total frequency per 3 days from baseline to 4 weeks after the treatment day based on the 3-day voiding diary. Change = Week 4 minus Baseline value |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change of the Urgency Urinary Incontinence (UUI) Per 3 Days | Baseline to 4 weeks after initial treatment | Efficacy: Mean change of the urgency urinary incontinence (UUI) per 3 days from baseline to 4 weeks after the treatment day based on the 3-day voiding diary. Change = Week 4 minus Baseline value |
| Net Change of the Overactive Bladder Symptom Score (OABSS) | Baseline to 4 weeks after initial treatment | Efficacy:(measured the net change of variables from baseline to 1 month) Overactive bladder symptom score (OABSS) The OABSS is a 4-item questionnaire developed to evaluate OAB symptoms. The maximal scores are 2, 3, 5 and 5 for daytime frequency, nighttime frequency, urgency and urgency in continence, respectively. The OABSS range = 0 to 15 ((asymptomatic to very symptomatic). Change = Week 4 minus Baseline value |
| Net Change of the Functional Bladder Capacity (FBC) | Baseline to 4 weeks after initial treatment | Efficacy:(measured the net change of variables from baseline and 1 month) Functional bladder capacity (FBC) Change = Week 4 minus Baseline value |
| Mean Change of the Urgency Episodes Per 3 Days | Baseline to 4 weeks after initial treatment | Efficacy: Mean change of the Urgency episodes per 3 days from baseline to 4 weeks after the treatment day based on the 3-day voiding diary. Change = Week 4 minus Baseline value |
| Net Change of the Postvoid Residual Volume (PVR) | Baseline and 1 month after initial treatment | Efficacy:(measured the net change of variables from baseline and 1 month) Postvoid residual volume (PVR) Change = Week 4 minus Baseline value |
| Net Change of the Urgency Severity Score (USS) Within 3 Days | Baseline to 4 weeks after initial treatment | Efficacy:(measured the net change of variables from baseline and 1 month) Urgency severity score (USS) within 3 days. The USS have 1-point scale ranging from 0 to 4. The USS grades urgency per toilet void as none, mild, moderate or severe. |
| Net Change of the Global Response Assessment (GRA) | Baseline to 4 weeks after initial treatment | Efficacy:(measured the net change of variables from baseline and 1 month) The Global response assessment (GRA) have seven point scale is centered at zero (no change): markedly worse; moderately worse; slightly worse; no change; slightly improved; moderately improved; and markedly improved. |
| Net Change of the Maximum Flow Rate (Qmax) | Baseline to 4 weeks after initial treatment | Efficacy:(measured the net change of variables from baseline and 1 month) Maximum flow rate (Qmax) Change = Week 4 minus Baseline value |
Countries
Taiwan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Experimental Arm Liposome encapsulated BoNT-A (mixed BOTOX 200 U/10 mL in Liposome 80mg/40ml) in single intravesical instillation
Liposome encapsulated botulinum toxin A: Liposome encapsulated BoNT-A (mixed BOTOX 200 U/10 mL water in Liposome 80 mg/40 mL water) in single intravesical instillation, one time treatment at the treatment day | 31 |
| Control Arm Normal saline 50 mL in single intravesical instillation
Normal saline instillation: Normal saline (BoNT-A/NS) 50ml in single intravesical instillation | 31 |
| Total | 62 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 2 |
| Overall Study | Withdrew consent | 1 | 1 |
Baseline characteristics
| Characteristic | Experimental Arm | Control Arm | Total |
|---|---|---|---|
| Age, Continuous | 64.43 years STANDARD_DEVIATION 12.49 | 65.81 years STANDARD_DEVIATION 14.48 | 65.12 years STANDARD_DEVIATION 13.49 |
| Associated medical conditions Diabetes Mellitus | 3 participants | 9 participants | 12 participants |
| Associated medical conditions Hypertension | 5 participants | 12 participants | 17 participants |
| Associated medical conditions Non disease | 22 participants | 8 participants | 30 participants |
| Associated medical conditions Other disease | 1 participants | 1 participants | 2 participants |
| Associated medical conditions Pelvic surgery | 0 participants | 1 participants | 1 participants |
| Background or Prior disease Any prior disease | 31 participants | 31 participants | 62 participants |
| Background or Prior disease None | 0 participants | 0 participants | 0 participants |
| Prior therapy None | 2 participants | 2 participants | 4 participants |
| Prior therapy Prior therapy taken | 29 participants | 29 participants | 58 participants |
| Region of Enrollment Taiwan | 31 participants | 31 participants | 62 participants |
| Sex: Female, Male Female | 18 Participants | 15 Participants | 33 Participants |
| Sex: Female, Male Male | 13 Participants | 16 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 31 | 16 / 31 |
| serious Total, serious adverse events | 1 / 31 | 2 / 31 |
Outcome results
Primary
Mean Change of the Total Frequency Per 3 Days
Efficacy: Mean change of the total frequency per 3 days from baseline to 4 weeks after the treatment day based on the 3-day voiding diary. Change = Week 4 minus Baseline value
Time frame: Baseline to 4 weeks after initial treatment
Population: Control arm: subject number S025 was removed from analysis for not meeting the requirement for analysis, thus control arm 27 subjects
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Experimental Arm | Mean Change of the Total Frequency Per 3 Days | -4.64 Frequency per 3 days |
| Control Arm | Mean Change of the Total Frequency Per 3 Days | -0.19 Frequency per 3 days |
Secondary
Mean Change of the Urgency Episodes Per 3 Days
Efficacy: Mean change of the Urgency episodes per 3 days from baseline to 4 weeks after the treatment day based on the 3-day voiding diary. Change = Week 4 minus Baseline value
Time frame: Baseline to 4 weeks after initial treatment
Population: Control arm: subject number S025 was removed from analysis for not meeting the requirement for analysis, thus control arm 27 subjects
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental Arm | Mean Change of the Urgency Episodes Per 3 Days | -7.43 Frequency per 3 days |
| Control Arm | Mean Change of the Urgency Episodes Per 3 Days | -3.43 Frequency per 3 days |
Secondary
Mean Change of the Urgency Urinary Incontinence (UUI) Per 3 Days
Efficacy: Mean change of the urgency urinary incontinence (UUI) per 3 days from baseline to 4 weeks after the treatment day based on the 3-day voiding diary. Change = Week 4 minus Baseline value
Time frame: Baseline to 4 weeks after initial treatment
Population: Control arm: subject number S025 was removed from analysis for not meeting the requirement for analysis, thus control arm 27 subjects
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental Arm | Mean Change of the Urgency Urinary Incontinence (UUI) Per 3 Days | 0.43 Frequency per 3 days |
| Control Arm | Mean Change of the Urgency Urinary Incontinence (UUI) Per 3 Days | 0.56 Frequency per 3 days |
Secondary
Net Change of the Functional Bladder Capacity (FBC)
Efficacy:(measured the net change of variables from baseline and 1 month) Functional bladder capacity (FBC) Change = Week 4 minus Baseline value
Time frame: Baseline to 4 weeks after initial treatment
Population: Control arm: subject number S025 was removed from analysis for not meeting the requirement for analysis, thus control arm 27 subjects
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental Arm | Net Change of the Functional Bladder Capacity (FBC) | -12.86 mL |
| Control Arm | Net Change of the Functional Bladder Capacity (FBC) | 18.15 mL |
Secondary
Net Change of the Global Response Assessment (GRA)
Efficacy:(measured the net change of variables from baseline and 1 month) The Global response assessment (GRA) have seven point scale is centered at zero (no change): markedly worse; moderately worse; slightly worse; no change; slightly improved; moderately improved; and markedly improved.
Time frame: Baseline to 4 weeks after initial treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Experimental Arm | Net Change of the Global Response Assessment (GRA) | Improved | 21 participants |
| Experimental Arm | Net Change of the Global Response Assessment (GRA) | No change | 7 participants |
| Control Arm | Net Change of the Global Response Assessment (GRA) | Improved | 19 participants |
| Control Arm | Net Change of the Global Response Assessment (GRA) | No change | 9 participants |
Secondary
Net Change of the Maximum Flow Rate (Qmax)
Efficacy:(measured the net change of variables from baseline and 1 month) Maximum flow rate (Qmax) Change = Week 4 minus Baseline value
Time frame: Baseline to 4 weeks after initial treatment
Population: Control arm: subject number S025 was removed from analysis for not meeting the requirement for analysis, thus control arm 27 subjects
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental Arm | Net Change of the Maximum Flow Rate (Qmax) | 0.11 mL/s |
| Control Arm | Net Change of the Maximum Flow Rate (Qmax) | -0.84 mL/s |
Secondary
Net Change of the Overactive Bladder Symptom Score (OABSS)
Efficacy:(measured the net change of variables from baseline to 1 month) Overactive bladder symptom score (OABSS) The OABSS is a 4-item questionnaire developed to evaluate OAB symptoms. The maximal scores are 2, 3, 5 and 5 for daytime frequency, nighttime frequency, urgency and urgency in continence, respectively. The OABSS range = 0 to 15 ((asymptomatic to very symptomatic). Change = Week 4 minus Baseline value
Time frame: Baseline to 4 weeks after initial treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental Arm | Net Change of the Overactive Bladder Symptom Score (OABSS) | -1.86 units on a scale |
| Control Arm | Net Change of the Overactive Bladder Symptom Score (OABSS) | -0.75 units on a scale |
Secondary
Net Change of the Postvoid Residual Volume (PVR)
Efficacy:(measured the net change of variables from baseline and 1 month) Postvoid residual volume (PVR) Change = Week 4 minus Baseline value
Time frame: Baseline and 1 month after initial treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental Arm | Net Change of the Postvoid Residual Volume (PVR) | -2.65 mL |
| Control Arm | Net Change of the Postvoid Residual Volume (PVR) | -2.31 mL |
Secondary
Net Change of the Urgency Severity Score (USS) Within 3 Days
Efficacy:(measured the net change of variables from baseline and 1 month) Urgency severity score (USS) within 3 days. The USS have 1-point scale ranging from 0 to 4. The USS grades urgency per toilet void as none, mild, moderate or severe.
Time frame: Baseline to 4 weeks after initial treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Experimental Arm | Net Change of the Urgency Severity Score (USS) Within 3 Days | Improved | 11 participants |
| Experimental Arm | Net Change of the Urgency Severity Score (USS) Within 3 Days | No change | 16 participants |
| Experimental Arm | Net Change of the Urgency Severity Score (USS) Within 3 Days | Worsen | 1 participants |
| Control Arm | Net Change of the Urgency Severity Score (USS) Within 3 Days | Improved | 4 participants |
| Control Arm | Net Change of the Urgency Severity Score (USS) Within 3 Days | No change | 20 participants |
| Control Arm | Net Change of the Urgency Severity Score (USS) Within 3 Days | Worsen | 4 participants |