Intravesical Botulinum Toxin A Injections in Treatment of Interstitial Cystitis Refractory to Conventional Treatment

This study has been completed.

Sponsor:

Information provided by (Responsible Party):

Hann-Chorng Kuo, Buddhist Tzu Chi General Hospital

ClinicalTrials.gov Identifier:

NCT01969773

First received: October 22, 2013

Last updated: February 16, 2017

Last verified: February 2017

History of Changes

Purpose

This study was designed in a multicenter, randomized, double-blind, placebo controlled trial to test the actual therapeutic effects of intravesical BoNTA injection. The results of this study might provide clinical evidence for a better therapeutic regimen in the treatment of IC/PBS.

Condition	Intervention	Phase
Interstitial Cystitis	Drug: Botulinum toxin A Drug: Normal saline instillation	Phase 2


Study Type:	Interventional
Study Design:	Allocation: Randomized Intervention Model: Single Group Assignment Intervention Model Description: The patients were allocated to the treatment or control group by permuted block randomization code in a 2:1 ratio Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) Masking Description: The attending doctors, patients, and study nurses did not know which solution was injected to their bladders, to keep the study in a double-blind condition. Primary Purpose: Treatment
Official Title:	Intravesical Botulinum Toxin A Injection in Treatment of Interstitial Cystitis Refractory to Conventional Treatment - A Prospective, Multicenter, Randomized, Double-blind, Placebo-controlled Clinical Trial

Resource links provided by NLM:

MedlinePlus related topics: Botox Interstitial Cystitis

Drug Information available for: OnabotulinumtoxinA

U.S. FDA Resources

Further study details as provided by Hann-Chorng Kuo, Buddhist Tzu Chi General Hospital:

Primary Outcome Measures:

Net change of Patient Perception of Visual Analogue Scale (VAS) [ Time Frame: Baseline and 8 weeks ]
Efficacy:

The primary end-point of this study is the reduction of bladder pain at 8-week follow-up. If patient has a reduction of VAS pain score of 2 or more, they will be considered as successfully treated at baseline and 8 weeks after BoNT-A injection within and between the treatment group and control groups.

Safety:

Systemic adverse events

Secondary Outcome Measures:

Net change of Patient Perception of global response assessment (GRA) [ Time Frame: Baseline and 8 weeks ]
Efficacy:

The treatment outcome will be assessed by the global response assessment (GRA) to evaluate the overall perception of treatment resultant at baseline and 8 weeks after BoNT-A injection within and between the treatment group and control groups.

Safety:

Systemic adverse events
Net change of O'Leary-Sant symptom and problem indexes [ Time Frame: Baseline and 8 weeks ]
Efficacy:

The IC symptoms will be assessed by the O'Leary-Sant symptom and problem indexes at baseline and 8 weeks after BoNT-A injection within and between the treatment group and control groups.

Safety:

Systemic adverse events
Net change of the functional bladder capacity (FBC) [ Time Frame: Baseline and 8 weeks ]
Efficacy:

Patients will be requested to keep a 3-day voiding diary prior to treatment to record the functional bladder capacity (FBC). Then the patients will be followed up at out-patient clinic at 8 weeks.

Safety:

Systemic adverse events
Net change of the number of urinary frequency [ Time Frame: Baseline and 8 weeks ]
Efficacy:

Patients will be requested to keep a 3-day voiding diary prior to treatment to record the number of urinary frequency at baseline and 8 weeks after BoNT-A injection within and between the treatment group and control groups.

Safety:

Systemic adverse events
Net change of the number of nocturnal [ Time Frame: Baseline and 8 weeks ]
Efficacy:

Patients will be requested to keep a 3-day voiding diary prior to treatment to record the number of nocturnal at baseline and 8 weeks after BoNT-A injection within and between the treatment group and control groups.

Safety:

Systemic adverse events
Net change of the Quality of Life (QoL) [ Time Frame: Baseline and 8 weeks ]
Efficacy:

Efficacy measured the net change of the Quality of Life (QoL) at baseline and 8 weeks after BoNT-A injection within and between the treatment group and control groups.

Safety:

Systemic adverse events
Net change of the maximal flow rate (Qmax) [ Time Frame: Baseline and 8 weeks ]
Efficacy:

Efficacy measured the net change of the maximal flow rate (Qmax) at baseline and 8 weeks after BoNT-A injection within and between the treatment group and control groups.

Safety:

Systemic adverse events
Net change of the voided volume [ Time Frame: Baseline and 8 weeks ]
Efficacy:

Efficacy measured the net change of the voided volume at baseline and 8 weeks after BoNT-A injection within and between the treatment group and control groups.

Safety:

Systemic adverse events
Net change of the residual urine volume (PVR) [ Time Frame: Baseline and 8 weeks ]
Efficacy:

Efficacy measured the net change of the residual urine volume (PVR) at baseline and 8 weeks after BoNT-A injection within and between the treatment group and control groups.

Safety:

Systemic adverse events


Enrollment:	60
Actual Study Start Date:	December 2012
Study Completion Date:	December 2014
Primary Completion Date:	December 2014 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Botulinum toxin A Patients will be randomly assigned to receive intravesical injection of 100U of BoNT-A (BOTOX, Allergan, Irvine, CA, USA)	Drug: Botulinum toxin A Patients will be randomly assigned to receive intravesical injection of 100U of BoNT-A (BOTOX, Allergan, Irvine, CA, USA) Other Names: BoNT-A BOTOX
Placebo Comparator: Control arm-Normal saline instillation Patients will be randomly assigned to receive intravesical injection of injection with normal saline.	Drug: Normal saline instillation Patients will be randomly assigned to receive intravesical injection of injection with normal saline. Other Name: N/S

Show Detailed Description

Eligibility


Ages Eligible for Study:	20 Years to 85 Years (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Patients with IC/PBS who have failed conventional treatments for at least 6 months will be enrolled.
A diagnosis of IC/PBS has been established based on characteristic symptoms and cystoscopic findings of glomerulations, petechia, or mucosal fissures after hydrodistention.
All patients have been treated with at least two types of treatment modalities including non-steroid anti-inflammatory drugs, oral pentosan polysulfate sodium (PPS), intravesical instillation of heparin, hyaluronic acid, or tricyclic antidepressant for at least 6 months but the symptoms remained unchanged or relapsed.

Exclusion Criteria:

Exclusion criteria proposed by NIDDK
Automatic exclusions:
1. Age <18 years old
2. Benign or malignant bladder tumors
3. Radiation cystitis Tuberculous cystitis
4. Bacterial cystitis
5. Vaginitis
6. Cyclophosphamide cystitis
7. Symptomatic urethral diverticulum
8. Uterine, cervical, vaginal, or urethral cancer
9. Active herpes
10. Bladder or lower ureteral calculi
11. Waking frequency <5 times in 12 hours
12. Nocturia <2 times
13. Symptoms relieved by antibiotics, urinary antiseptics, urinary analgesics (for example phenazopyridine hydrochloride)
14. Duration < 12 months
15. Involuntary bladder contractions (urodynamics)
16. Capacity > 400ml, absence of sensory urgency
Automatic inclusions:

1.Hunner's ulcer
Positive factors: (two positive factors are necessary for inclusion)
1. Pain on bladder filling relieved by emptying
2. Pain (suprapubic, pelvic, urethral, vaginal or peripheral)
3. Glomerulations on endoscopy
4. Decreased compliance on cystometrogram
5. Bladder distention is defined arbitrarily as 80 cm water pressure for 1 minute
Use of Anticholinergic drugs, for the treatment of lower urinary tract symptoms who have an effect.
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 urinary retention, PVR≥150 ml.
Patients with uncontrolled confirmed diagnosis of acute urinary tract infection.
Patients have laboratory abnormalities at screening including:
1. Alanine aminotransferase (ALT) > 3 x upper limit of normal range
2. Aspartate aminotransferase (AST) > 3 x upper limit of normal range.
3. Patients have abnormal serum creatinine level > 2 x upper limit of normal range.
Can not be used in the treatment of patients with transurethral catheter treatment.
Pregnant and lactating women or women who intend to become pregnant during the study or have myasthenia gravis, Eaton Lambert syndrome.
Patients with any other serious disease or condition considered by the investigator not suitable for entry into the trial.
Patients participated investigational drug trial within 1 month before entering this study.
Written informed consent has been obtained.
Patient who did not complete the 3-day micturition diary according to the instruction.
Intestinal bladder augmentation patients receive angioplasty for the treatment of overactive bladder.

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01969773

Locations


Taiwan
Buddhist Tzu Chi General Hospital
Hualien, Taiwan, 970

Sponsors and Collaborators

Buddhist Tzu Chi General Hospital

Investigators


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

More Information

Publications:

Hanno PM, Sant GR. Clinical highlights of the National Institute of Diabetes and Digestive and Kidney Diseases/Interstitial Cystitis Association scientific conference on interstitial cystitis. Urology. 2001 Jun;57(6 Suppl 1):2-6.

Payne CK, Mosbaugh PG, Forrest JB, Evans RJ, Whitmore KE, Antoci JP, Perez-Marrero R, Jacoby K, Diokno AC, O'Reilly KJ, Griebling TL, Vasavada SP, Yu AS, Frumkin LR; ICOS RTX Study Group (Resiniferatoxin Treatment for Interstitial Cystitis). Intravesical resiniferatoxin for the treatment of interstitial cystitis: a randomized, double-blind, placebo controlled trial. J Urol. 2005 May;173(5):1590-4.

Nickel JC, Barkin J, Forrest J, Mosbaugh PG, Hernandez-Graulau J, Kaufman D, Lloyd K, Evans RJ, Parsons CL, Atkinson LE; Elmiron Study Group. Randomized, double-blind, dose-ranging study of pentosan polysulfate sodium for interstitial cystitis. Urology. 2005 Apr;65(4):654-8.

Sant GR, Propert KJ, Hanno PM, Burks D, Culkin D, Diokno AC, Hardy C, Landis JR, Mayer R, Madigan R, Messing EM, Peters K, Theoharides TC, Warren J, Wein AJ, Steers W, Kusek JW, Nyberg LM; Interstitial Cystitis Clinical Trials Group. A pilot clinical trial of oral pentosan polysulfate and oral hydroxyzine in patients with interstitial cystitis. J Urol. 2003 Sep;170(3):810-5.

Hanno PM, Buehler J, Wein AJ. Use of amitriptyline in the treatment of interstitial cystitis. J Urol. 1989 Apr;141(4):846-8.

Sairanen J, Forsell T, Ruutu M. Long-term outcome of patients with interstitial cystitis treated with low dose cyclosporine A. J Urol. 2004 Jun;171(6 Pt 1):2138-41.

Brady CM, Apostolidis AN, Harper M, Yiangou Y, Beckett A, Jacques TS, Freeman A, Scaravilli F, Fowler CJ, Anand P. Parallel changes in bladder suburothelial vanilloid receptor TRPV1 and pan-neuronal marker PGP9.5 immunoreactivity in patients with neurogenic detrusor overactivity after intravesical resiniferatoxin treatment. BJU Int. 2004 Apr;93(6):770-6.

Cockayne DA, Hamilton SG, Zhu QM, Dunn PM, Zhong Y, Novakovic S, Malmberg AB, Cain G, Berson A, Kassotakis L, Hedley L, Lachnit WG, Burnstock G, McMahon SB, Ford AP. Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature. 2000 Oct 26;407(6807):1011-5.

Beltinger J, McKaig BC, Makh S, Stack WA, Hawkey CJ, Mahida YR. Human colonic subepithelial myofibroblasts modulate transepithelial resistance and secretory response. Am J Physiol. 1999 Aug;277(2 Pt 1):C271-9.

Cayan S, Coşkun B, Bozlu M, Acar D, Akbay E, Ulusoy E. Botulinum toxin type A may improve bladder function in a rat chemical cystitis model. Urol Res. 2003 Feb;30(6):399-404. Epub 2003 Jan 21.

Steers WD, Tuttle JB. Mechanisms of Disease: the role of nerve growth factor in the pathophysiology of bladder disorders. Nat Clin Pract Urol. 2006 Feb;3(2):101-10. Review.

Apostolidis A, Popat R, Yiangou Y, Cockayne D, Ford AP, Davis JB, Dasgupta P, Fowler CJ, Anand P. Decreased sensory receptors P2X3 and TRPV1 in suburothelial nerve fibers following intradetrusor injections of botulinum toxin for human detrusor overactivity. J Urol. 2005 Sep;174(3):977-82; discussion 982-3.

Reitz A, Stöhrer M, Kramer G, Del Popolo G, Chartier-Kastler E, Pannek J, Burgdörfer H, Göcking K, Madersbacher H, Schumacher S, Richter R, von Tobel J, Schurch B. European experience of 200 cases treated with botulinum-A toxin injections into the detrusor muscle for urinary incontinence due to neurogenic detrusor overactivity. Eur Urol. 2004 Apr;45(4):510-5.

Smith CP, Radziszewski P, Borkowski A, Somogyi GT, Boone TB, Chancellor MB. Botulinum toxin a has antinociceptive effects in treating interstitial cystitis. Urology. 2004 Nov;64(5):871-5; discussion 875.

Kuo HC. Preliminary results of suburothelial injection of botulinum a toxin in the treatment of chronic interstitial cystitis. Urol Int. 2005;75(2):170-4.

Giannantoni A, Costantini E, Di Stasi SM, Tascini MC, Bini V, Porena M. Botulinum A toxin intravesical injections in the treatment of painful bladder syndrome: a pilot study. Eur Urol. 2006 Apr;49(4):704-9. Epub 2006 Jan 4.

Rapp DE, Turk KW, Bales GT, Cook SP. Botulinum toxin type a inhibits calcitonin gene-related peptide release from isolated rat bladder. J Urol. 2006 Mar;175(3 Pt 1):1138-42.

Chuang YC, Yoshimura N, Huang CC, Chiang PH, Chancellor MB. Intravesical botulinum toxin a administration produces analgesia against acetic acid induced bladder pain responses in rats. J Urol. 2004 Oct;172(4 Pt 1):1529-32.

Giannantoni A, Di Stasi SM, Nardicchi V, Zucchi A, Macchioni L, Bini V, Goracci G, Porena M. Botulinum-A toxin injections into the detrusor muscle decrease nerve growth factor bladder tissue levels in patients with neurogenic detrusor overactivity. J Urol. 2006 Jun;175(6):2341-4.

Khera M, Somogyi GT, Kiss S, Boone TB, Smith CP. Botulinum toxin A inhibits ATP release from bladder urothelium after chronic spinal cord injury. Neurochem Int. 2004 Dec;45(7):987-93.

Kuo HC. Clinical effects of suburothelial injection of botulinum A toxin on patients with nonneurogenic detrusor overactivity refractory to anticholinergics. Urology. 2005 Jul;66(1):94-8.

Cui M, Khanijou S, Rubino J, Aoki KR. Subcutaneous administration of botulinum toxin A reduces formalin-induced pain. Pain. 2004 Jan;107(1-2):125-33.

Giannantoni A, Porena M, Costantini E, Zucchi A, Mearini L, Mearini E. Botulinum A toxin intravesical injection in patients with painful bladder syndrome: 1-year followup. J Urol. 2008 Mar;179(3):1031-4. doi: 10.1016/j.juro.2007.10.032. Epub 2008 Jan 18.

Lubeck DP, Whitmore K, Sant GR, Alvarez-Horine S, Lai C. Psychometric validation of the O'leary-Sant interstitial cystitis symptom index in a clinical trial of pentosan polysulfate sodium. Urology. 2001 Jun;57(6 Suppl 1):62-6.

Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, van Kerrebroeck P, Victor A, Wein A; Standardisation Sub-committee of the International Continence Society. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn. 2002;21(2):167-78.

Vizzard MA. Changes in urinary bladder neurotrophic factor mRNA and NGF protein following urinary bladder dysfunction. Exp Neurol. 2000 Jan;161(1):273-84.

Parsons CL, Housley T, Schmidt JD, Lebow D. Treatment of interstitial cystitis with intravesical heparin. Br J Urol. 1994 May;73(5):504-7.

Chung SD, Kuo YC, Kuo HC. Intravesical onabotulinumtoxinA injections for refractory painful bladder syndrome. Pain Physician. 2012 May-Jun;15(3):197-202.

Seki S, Erickson KA, Seki M, Nishizawa O, Igawa Y, Ogawa T, de Groat WC, Chancellor MB, Yoshimura N. Elimination of rat spinal neurons expressing neurokinin 1 receptors reduces bladder overactivity and spinal c-fos expression induced by bladder irritation. Am J Physiol Renal Physiol. 2005 Mar;288(3):F466-73.

Dell JR, Parsons CL. Multimodal therapy for interstitial cystitis. J Reprod Med. 2004 Mar;49(3 Suppl):243-52. Review.

Liu HT, Kuo HC. Intravesical botulinum toxin A injections plus hydrodistension can reduce nerve growth factor production and control bladder pain in interstitial cystitis. Urology. 2007 Sep;70(3):463-8.


Responsible Party:	Hann-Chorng Kuo, Director of Urology, Buddhist Tzu Chi General Hospital
ClinicalTrials.gov Identifier:	NCT01969773 History of Changes
Other Study ID Numbers:	TCGHUROL009
Study First Received:	October 22, 2013
Last Updated:	February 16, 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No
Plan Description:	IPD was not planned to share


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.:		Yes

Keywords provided by Hann-Chorng Kuo, Buddhist Tzu Chi General Hospital:


Botulinum Toxin A (BoNT-A) Interstitial Cystitis

Additional relevant MeSH terms:


Cystitis Cystitis, Interstitial Urinary Bladder Diseases Urologic Diseases Botulinum Toxins Botulinum Toxins, Type A abobotulinumtoxinA onabotulinumtoxinA incobotulinumtoxinA	Acetylcholine Release Inhibitors Membrane Transport Modulators Molecular Mechanisms of Pharmacological Action Cholinergic Agents Neurotransmitter Agents Physiological Effects of Drugs Neuromuscular Agents Peripheral Nervous System Agents

ClinicalTrials.gov processed this record on September 21, 2017

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