Intravesical Instillation of Liposome Encapsulated Botulinum Toxin A (Lipotoxin) in Treatment of Interstitial Cystitis

Study Overview
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Brief Summary
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To evaluate the efficacy and safety of intravesical instillation of Lipotoxin for the treatment of IC/BPS

Detailed Description
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Liposome has been proven able to carry botulinum toxin protein across the cell membrane and effect on urothelial receptors in human overactive bladder. However, the therapeutic duration is limited to 1 month. Intravesical BOTOX injection in patients with interstitial cystitis (IC) can effectively decrease pain, improve bladder capacity and decrease frequency. However, the need of cystoscopic injection limits its wide application. A total of 100 eligible women with non-ulcer IC will be enrolled to receive intravesical instillation of Lipotoxin containing 80mg liposomes and 200U BOTOX (treatment group), 200U BOTOX in normal saline (N/S) (active control group) or normal saline (placebo control group) single treatment. At least 90 evaluable patients will be included for the final analysis. All patients should have IC symptoms for at least 6 months, and proven to have grade 2 diffused glomerulations after cystoscopic hydrodistention (HD) within recent 1 year without Hunner's lesion. Patients should not have UTI in recent 12 months, no urinary tract stone. Patients should have been proven free of detrusor overactivity or bladder outlet obstruction. Patients should not receive intravesical hyaluronic acid treatment in recent 6 months, or intravesical Botox injection in recent 12 months. Intravesical instillation of Lipotoxin at OPD and the patient should hold the solution for 2 hours to allow bladder distention. Retreatment with Lipotoxin at 3 months if patient reports ineffective. Primary end-point is the change of the O'Leary-Sant symptom score (including ICSI and ICPI) from baseline to 1 month after treatment. Secondary endpoints include VAS, daily frequency, nocturia and FBC as record in 3-day voiding diary, Qmax, voided volume, PVR and global response assessment (GRA). Four visits are required at baseline screening (before first treatment), treatment (V1), 2 weeks (V2), 4 weeks (V3, primary end-point) and 12 weeks (V4).

Official Title
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Intravesical Instillation of Liposome Encapsulated Botulinum Toxin A (Lipotoxin) in Treatment of Interstitial Cystitis - a Randomized, Double-blind, Placebo-controlled, Prospective Study

Conditions
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Interstitial Cystitis

Intervention / Treatment
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* Drug: Liposome encapsulated BoNT-A
* Drug: BOTOX 200U in normal saline
* Drug: Normal saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults with age of 20 years old or above Patients with symptoms of frequency, urgency, nocturia, and/or bladder pain. Proven to have glomerulations (at least grade 2) by cystoscopic hydrodistention under anesthesia in recent 1 year Free of active urinary tract infection Free of bladder outlet obstruction on enrollment Free of overt neurogenic bladder dysfunction and limitation of ambulation Patient or his/her legally acceptable representative has signed the written informed consent form Exclusion Criteria: Hunner's lesion proven by cystoscopy 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 >250ml Patients with uncontrolled confirmed diagnosis of acute urinary tract infection Patients have laboratory abnormalities at screening including: ALT> 3 x upper limit of normal range, 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 in the condition to enter the trial Patient had received intravesical treatment for IC within recent 1 month Patients participated investigational drug trial within 1 month before entering this study

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a double-blind, randomized, placebo-controlled physician initiated study enrolled patients with refractory IC/BPS. Patients were assigned to intravesical instillation of lipotoxin (onabotulinumtoxinA 200 U with 80mg sphingomyelin), onabotulinumtoxinA 200 U in normal saline, or normal saline.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A: Liposome encapsulated BoNT-A<br>Liposome encapsulated BoNT-A ( mixed BOTOX 200U/10ml in Liposome 80mg/40ml) in single intravesical instillation | Drug: Liposome encapsulated BoNT-A<br>* Liposome encapsulated BoNT-A ( mixed BOTOX 200U/10ml in Liposome 80mg/40ml) in single intravesical instillation<br>* Other names: onabotulinumtoxinA 200U;|
| Experimental: Group B: BoNT-A 200 U in Normal saline<br>BOTOX 200U in normal saline (BoNT-A/NS) 50ml in single intravesical instillation | Drug: BOTOX 200U in normal saline<br>* BOTOX 200U in normal saline (BoNT-A/NS) 50ml in single intravesical instillation<br>* Other names: onabotulinumtoxinA 200U;|
| Placebo Comparator: Group C: Normal saline<br>Normal saline (N/S) 50ml in single intravesical instillation | Drug: Normal saline<br>* Normal saline (N/S) 50ml in single intravesical instillation<br>* Other names: Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of the O'Leary-Sant symptom score | Change of the O'Leary-Sant symptom score from baseline to 1 month after the treatment day | Baseline and 1 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Net changes of the Visual Analog Scale (VAS) | Net changes of the Visual Analog Scale from baseline to 1 month after the treatment day Safety (1) Local adverse event incidences (hematuria, miction pain, UTI, urinary retention). | Baseline and 1 month | 
| Net changes of the functional bladder capacity (FBC) | Net changes of the functional bladder capacity from baseline to 1 month after the treatment day Safety (1) Local adverse event incidences (hematuria, miction pain, UTI, urinary retention). | Baseline and 1 month | 
| Net changes of the voiding frequency at daytime as recorded in 3-day voiding diary | Net changes of the voiding frequency at daytime from baseline to 1 month after the treatment day Safety (1) Local adverse event incidences (hematuria, miction pain, UTI, urinary retention). | Baseline and 1 month | 
| Net changes of the voiding frequency at night time as recorded in 3-day voiding diary | Net changes of the voiding night time from baseline to 1 month after the treatment day Safety (1) Local adverse event incidences (hematuria, miction pain, UTI, urinary retention). | Baseline and 1 month | 
| Net Change of the Global response assessment (GRA) | Global response assessment (GRA) of therapeutic result by the patient (categorized from -3 to +3, indicating markedly worse to markedly improved) at 3 months after the treatment day. Safety (1) Local adverse event incidences (hematuria, miction pain, UTI, urinary retention). | Baseline and 1 month | 
| Net Change of the maximum flow rate | Net changes of the maximum flow rate from baseline to 1 month after the treatment day. Safety (1) Local adverse event incidences (hematuria, miction pain, UTI, urinary retention). | Baseline and 1 month | 
| Net Change of the voided volume | Net changes of the voided volume from baseline to 1 month after the treatment day. Safety (1) Local adverse event incidences (hematuria, miction pain, UTI, urinary retention). | Baseline and 1 month | 
| Net Change of the PVR | Net changes of the PVR from baseline to 1 month after the treatment day. Safety (1) Local adverse event incidences (hematuria, miction pain, UTI, urinary retention). | Baseline and 1 month | 
| Net Change of the urinary nerve growth factor | Changes of urinary nerve growth factor from baseline to 1 month after treatment day. Safety (1) Local adverse event incidences (hematuria, miction pain, UTI, urinary retention). | Baseline and 1 month | 
| Net Change of the cytokines level | Changes of cytokines level from baseline to 1 month after treatment day. Safety (1) Local adverse event incidences (hematuria, miction pain, UTI, urinary retention). | Baseline and 1 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IC/PBS, VAS, Botulinum Toxin A, Lipotoxin