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

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.

Background: Interstitial cystitis/painful bladder syndrome (IC/PBS) is a debilitating chronic disease of unknown etiology. Current treatments are usually unsuccessful in completely eradicating bladder pain and increasing bladder capacity. Although investigations on this topic have been enthusiastically performed, the etiology of IC/PBS remains unknown. Treatment based on single pathophysiology such as urothelial damage or neurogenic inflammation might not enough to eradicate the cascade of pathologies of IC/PBS.

Inhibition of neuroplasticity of the sensory fibers in the suburothelial space by intravesical BoNT-A injections might have good therapeutic targeting on pain and sensory urgency in patients with IC/PBS. In recent basic researches, BoNT-A has been shown to inhibit not only the release of acetylcholine and norepinephrine, but also that of nerve growth factor, adenosine triphosphate, substance P and calcitonin gene-related peptide from the nerve fibers and urothelium. This study was designed in a multicenter, randomized, double-blind, placebo controlled trial to test the actual therapeutic effects of intravesical BoNT-A injection on IC/PBS. The results of this study might provide clinical evidence for a better therapeutic regimen in the treatment of IC/PBS.

Materials and Methods: A total of 90 patients with IC/PBS who have failed conventional treatments for at least 6 months will be enrolled in this study. A diagnosis of IC/PBS has been established based on characteristic symptoms and cystoscopic findings of glomerulations, petechia, or mucosal fissures after hydrodistention. They will be investigated thoroughly on enrollment and will be excluded if not meeting the inclusion criteria of National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). However, in this study the patients with Hunner's ulcer will not be included because previous study has shown that ulcer type IC/PBS does not respond to intravesical BoNT-A injection.

A 3-day voiding diary for functional bladder capacity, urinary frequency and nocturnal, O'Leary-Sant symptom and problem indexes, visual analog score (VAS), and videourodynamic parameters and potassium chloride (KCl) sensitivity test will be used to assess the therapeutic efficacy. Patients will be informed of the possible complications associated with BoNT-A injection such as generalized muscle weakness, difficult urination, transient urinary retention, or urinary tract infections. Eligible patients will be randomly assigned to receive intravesical injection of 100U of BoNT-A (BOTOX, Allergan, Irvine, CA, USA) (the treatment group) or injection with normal saline (control group). The intravesical injection will be performed immediately followed by cystoscopic hydrodistention under intravenous general anesthesia in the operation room.

Blood (10ml) and urine samples (30ml) will be collected before intravesical injection and after bladder hydrodistention. Bladder wall biopsies will also be performed after hydrodistention. The patients will be allocated to treatment or control group by the permuted block randomization code in 2:1 ratio, which is centrally controlled by a clinical pharmacist who prepares the solution for injection. Each vial of BoNT-A will be diluted with 10 ml of normal saline, resulting in 10U BoNT-A per 1.0 ml. Patients receive 20 suburothelial injections of BoNT-A solution or normal saline, each injection site receives 5U or saline in 0.5 ml. After the BoNT-A injections, patients will be followed up in the outpatient clinic 2 weeks and 4 weeks later. Then the patients will be followed up at out-patient clinic at 2 weeks, 4 weeks and 12 weeks. The primary end-point of this study is the reduction of bladder pain at 12-week follow-up. If patient has a reduction of VAS pain score of 2 or more, they will be considered as successfully treated. The treatment outcome will also be assessed by the global response assessment (GRA) to evaluate the overall perception of treatment result. The result will be considered as excellent when patients report improvement in the GRA by \>2 or patients become free of bladder pain (VAS=0). Data will be compared between treatment and placebo groups. A p-value of less than 0.05 will be considered statistically significant.

Cystoscopy and bladder biopsy will be performed and sent for pathological examination and urological laboratory for investigations. The urine and serum biomarkers (NGF) and urothelial dysfunction markers (TUNEL for apoptosis, Ki-67 for proliferation, tryptase staining for mast cell activity, E-cadherin and zonula occludens-1 for junction protein expression) will be assessed to investigate the severity of urothelial dysfunction and chronic inflammation presented in these diseased bladders. Furthermore, the inflammatory protein assay such as TNFα, IL-6, IL-8 or TGF-beta will also be measured by protein array and western blotting. The urine and blood samples will be collected at baseline, 4 weeks, and end-point (12 weeks) in both treatment and controlled patients. The changes of urine and serum nerve growth factor (NGF) and cytokines (such as IL-1 beta, IL-6, IL-8, TNF-alpha) will be compared within group and between groups to provide laboratory evidence of decrease of bladder inflammation in IC/PBS. The changes of NGF and cytokines levels after BoNT-A injection treatments will also be compared in patients who respond and not respond to the treatment given. Urinary and serum NGF and cytokines levels were measured by the ELISA method.

Expected Results: The results of this study may demonstrate that intravesical injection of BoNT-A has a better clinical effect to provide greater pain relief and increase bladder capacity in patients with IC/PBS compared to the patients who received saline injection treatment. The clinical effect of BoNT-A on IC/PBS might be further reflected by the reduction of the serum or urinary NGF and cytokines levels.

Eligibility 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.