Effects and Safety of Liposome Encapsulated Botulinum Toxin A for Overactive Bladder Syndrome

Phase 2

Completed

Conditions: Overactive Bladder

Interventions: Drug: Liposome encapsulated botulinum toxin A
Drug: Normal saline instillation

Registration Number: NCT01167257

Lead Sponsor: Buddhist Tzu Chi General Hospital

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 62

Inclusion Criteria

Adults with age of 20 years old or above
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)
Free of active urinary tract infection
Free of bladder outlet obstruction on enrollment
Free of overt neurogenic bladder dysfunction
Having been treated with antimuscarinic agents for at least 4 weeks without effect or with intolerable adverse effects
Patient has not been treated with bladder surgery for OAB, such as enterocystoplasty, that might affect the therapeutic effect of test drug
Patient can record voiding diary for the urinary frequency and urgency
Patient or his/her legally acceptable representative has signed the written informed consent form

Exclusion Criteria

Use of antimuscarinic agent and effective in treatment of lower urinary tract symptoms
Patients with severe cardiopulmonary disease and such as congestive heart failure, arrhythmia, poorly controlled hypertension, not able to receive regular follow-up
Patients with bladder outlet obstruction on enrollment
Patients with postvoid residual >150 mL
Patients with uncontrolled confirmed diagnosis of acute urinary tract infection
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
Patients with any contraindication to be urethral catheterization during treatment
Female patients who is pregnant, lactating, or with child-bearing potential without contraception.
Myasthenia gravis, Eaton Lambert syndrome.
Patients with any other serious disease considered by the investigator not suitable for general anesthesia or in the condition to enter the trial
Patients participated investigational drug trial within 1 month before entering this study

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Experimental arm	Liposome encapsulated botulinum toxin A	Liposome encapsulated BoNT-A ( mixed BOTOX 200 U/10 mL in Liposome 80 mg/40 mL) in single intravesical instillation Liposome encapsulated botulinum toxin A'
Control arm	Normal saline instillation	Normal saline 50 mL in single intravesical instillation Normal saline instillation'

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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
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
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
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.