Intravesical Botulinum Toxin A Injections in Treatment of Interstitial Cystitis Refractory to Conventional Treatment
Condition: Interstitial Cystitis
MeSH terms: Cystitis; Cystitis, Interstitial
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Botulinum toxin A; Normal saline instillation
Intervention type(s): Drug; Drug
Intervention description(s): Patients will be randomly assigned to receive intravesical injection of 100U of BoNT-A (BOTOX, Allergan, Irvine, CA, USA); Patients will be randomly assigned to receive intravesical injection of injection with normal saline.
Other intervention name(s): BoNT-A; BOTOX; N/S
Intervention MeSH terms: Botulinum Toxins; Botulinum Toxins, Type A; abobotulinumtoxinA
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)
Primary purpose: Treatment
Keywords: Botulinum Toxin A (BoNT-A); Interstitial Cystitis