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

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

To evaluate the efficacy and safety of intravesical instillation of Lipotoxin for the treatment of IC/BPS

Study Overview

• Status: Completed
• Conditions: Interstitial Cystitis
• Intervention / Treatment: Drug: Liposome encapsulated BoNT-A; Drug: BOTOX 200U in normal saline; Drug: Normal saline

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 90
• Phase: Phase 2

Contacts and Locations

Study Locations

• Taiwan
  • Hualien, Taiwan, 970
    • Buddhist Tzu Chi General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Adults with age of 20 years old or above
2. Patients with symptoms of frequency, urgency, nocturia, and/or bladder pain.
3. Proven to have glomerulations (at least grade 2) by cystoscopic hydrodistention under anesthesia in recent 1 year
4. Free of active urinary tract infection
5. Free of bladder outlet obstruction on enrollment
6. Free of overt neurogenic bladder dysfunction and limitation of ambulation
7. Patient or his/her legally acceptable representative has signed the written informed consent form

Exclusion Criteria:

1. Hunner's lesion proven by cystoscopy
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 >250ml
5. Patients with uncontrolled confirmed diagnosis of acute urinary tract infection
6. 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
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 in the condition to enter the trial
11. Patient had received intravesical treatment for IC within recent 1 month
12. Patients participated investigational drug trial within 1 month before entering this study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Buddhist Tzu Chi General Hospital
• Investigators: Principal Investigator: Hann-Chorng Kuo, M.D., Department of Urology, Buddihisst Tzu Chi General Hospital and Tzu Chi University

Publications and helpful links

General Publications

• Imamura M, Scott NW, Wallace SA, Ogah JA, Ford AA, Dubos YA, Brazzelli M. Interventions for treating people with symptoms of bladder pain syndrome: a network meta-analysis. Cochrane Database Syst Rev. 2020 Jul 30;7(7):CD013325. doi: 10.1002/14651858.CD013325.pub2.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2014
• Primary Completion (Actual): February 1, 2017
• Study Completion (Actual): February 1, 2017

Study Registration Dates

• First Submitted: September 15, 2014
• First Submitted That Met QC Criteria: September 23, 2014
• First Posted (Estimate): September 25, 2014

Study Record Updates

• Last Update Posted (Actual): March 9, 2017
• Last Update Submitted That Met QC Criteria: March 7, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: VAS; Botulinum Toxin A; IC/PBS; Lipotoxin
• Additional Relevant MeSH Terms: Urologic Diseases; Urinary Bladder Diseases; Cystitis; Cystitis, Interstitial; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Cholinergic Agents; Membrane Transport Modulators; Acetylcholine Release Inhibitors; Neuromuscular Agents; Botulinum Toxins, Type A; abobotulinumtoxinA
• Other Study ID Numbers: TCGHUROL011

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: IPD cannot be released unless researchers obtain the approval from the Ethics Committee of the Buddhist Tzu Chi General Hospital, Hualien, Taiwan

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No