International Journal of Urology (2015) 22, 835--841

doi: 10.1111/iju.12833

Original Article: Clinical Investigation

Botulinum toxin type A injection for refractory interstitial cystitis: A randomized comparative study and predictors of treatment response Yoshiyuki Akiyama,1,2 Akira Nomiya,3 Aya Niimi,1 Yukio Yamada,1 Tetsuya Fujimura,1 Tohru Nakagawa,1 Hiroshi Fukuhara,1 Haruki Kume,1 Yasuhiko Igawa2 and Yukio Homma1 1

Department of Urology, 2Department of Continence Medicine, Graduate School of Medicine, The University of Tokyo, and Department of Urology, Mitsui Memorial Hospital, Tokyo, Japan

3

Abbreviations & Acronyms Ach = acetylcholine AE = adverse events BCG = bacillus Calmette– Guerin BoNT-A = botulinum toxin type A DMSO = dimethyl sulfoxide FVC = frequency volume chart GRA = global response assessment HB-EGF = heparin-binding epidermal growth factor-like growth factor HD = hydrodistension IC = interstitial cystitis IPSS = International Prostate Symptom Score NSAIDs = non-steroidal anti-inflammatory drugs OABSS = Overactive Bladder Symptom Score OSSI/OSPI = O’Leary and Sant’s symptom index and problem index QOL = quality of life RCT = randomized controlled trial VAS = visual analog scale (for pain) Correspondence: Yukio Homma M.D., Ph.D., Department of Urology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 1138655, Japan. Email: homma-uro @umin.ac.jp Received 9 January 2015; accepted 5 May 2015. Online publication 2 June 2015

© 2015 The Japanese Urological Association

Objectives: To determine whether botulinum toxin type A can represent an alternative treatment option for patients with interstitial cystitis refractory to conventional therapies. Methods: This is a single-center, prospective, open labeled, randomized comparative study. Patients with refractory interstitial cystitis were randomly divided into two groups: immediate injection (group A) or 1-month delayed injection (group B) of botulinum toxin type A after allocation. The rate of treatment response (global response assessment ≥+1: slightly improved), and changes in symptom scores and frequency volume chart variables were compared between groups 1 month after allocation. Using subjects of both groups as a single cohort, predictive factors for treatment response at 1 month post-injection and the duration of response were explored. Results: A total of 34 patients (group A n = 18, group B n = 16) were allocated. The response rate was significantly higher in group A than group B (72.2% vs 25.0%, P = 0.01). All symptom measures showed significant improvement in group A than group B. When both groups were combined as a single cohort, the response rate was 73.5% at 1 month, 58.8% at 3 months, 38.2% at 6 months and 20.6% at 12 months. The mean duration of response was 5.4 months. Multivariate analysis showed that past exposure to hydrodistension more than three times correlated with better outcomes. Conclusions: Botulinum toxin type A injection could be an alternative treatment option for patients with interstitial cystitis refractory to conventional therapies, especially for those who have received repeated hydrodistensions and transurethral fulguration.

Key words: botulinum toxins type A, hydrodistension, interstitial cystitis, intravesical administration, randomized controlled trial.

Introduction IC is a chronic disease characterized by hypersensitive symptoms and/or bladder pain with detrimental effects on sufferers’ quality of life.1 Treatments for IC are empirical and symptom-centered, as the etiology and objective severity index of IC is still unknown. The effects of presently available therapeutic options; that is, oral and intravesical agents, neurostimulation, vaginal massage, and surgery, are limited. Recently, intravesical injection of BoNT-A has been introduced as a new treatment modality.2 Repeated injections of BoNT-A are known to provide better therapeutic effects and long-term success rates than a single injection.3 However, the efficacy of this treatment is still controversial, partly because of a limited number of RCT.4 Furthermore, in most of those RCT, BoNT-A was administered with HD carried out simultaneously or shortly before, with the control arm receiving intravesical therapies, such as HD or BCG.4,5 No studies have yet examined the effect of BoNT-A injection alone, not involving endoscopic or intravesical interventions. We carried out a randomized comparative study to evaluate whether BoNT-A injection could be an alternative treatment option to conventional therapies for intractable IC. Furthermore, predictive factors for favorable response have been explored. 835

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Methods The study protocol was approved by the institutional review board of The University of Tokyo (#P2010020-11X). All participants were fully informed of the study procedure and possible complications of BoNT-A administration, and were given written informed consent at enrollment.

Patient inclusion and exclusion criteria Between September 2010 and February 2012, we recruited 40 IC patients who had received HD at least once and medical treatment of one or more oral drugs or intravesical agents, yet remained to be symptomatic; six points or higher for OSSI/OSPI, and four points or higher for VAS (0–10) for pain. Diagnosis of IC was made according to clinical guidelines for interstitial cystitis and hypersensitive bladder syndrome.1 All patients fulfilled the National

Institute of Diabetes and Digestive and Kidney Diseases criteria.6 Patients were excluded from the present study when they had urinary tract infection, bladder cancer, neurogenic disorder, urinary calculi, voiding difficulty with post-voided residual ≥100 mL, past treatment with BoNT-A, anticholinergic agents within 1 month before treatment, systemic diseases of neuromuscular junction, severe respiratory dysfunction and allergy to BoNT-A.

Study design (Fig. 1) Randomized comparative study a month after allocation Patients were randomly divided into either immediate injection of BoNT-A 100 U (group A) or 1-month delayed injection of BoNT-A 100 U after maintaining the present therapies (oral

Assessed for eligibility (n = 40)

Enrollment

Excluded (n = 6) • Not meeting inclusion criteria (n = 1) • Declined to participate (n = 5) Randomized (n = 34)

Allocation Group B Maintaining the present therapies for one month

Group A Immediate injection of BoNT-A 100 U Allocated to intervention (n = 18) • Received allocated intervention (n = 18)

Allocated to intervention (n = 16) • Received allocated intervention (n = 16)

Follow-Up after allocation for randomized comparative study

Analysis 1 month after allocation Analysed (n = 18) at 1 month • Excluded from analysis (n = 0)

Analysed (n = 16) at 1 month • Excluded from analysis (n = 0)

Delayed injection of BoNT-A 100 U • Received allocated intervention (n = 16) Follow-Up As a single cohort of BoNT-A injection (Received intervention (n = 34)) • Follow-up every month until 1 year

Fig. 1 Study protocol of the present study (CONSORT diagram).

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© 2015 The Japanese Urological Association

Botulinum toxin for refractory interstitial cystitis

Table 1 Participants’ demographics and characteristics at enrollment All participants (Group A + Group B) n (male/female) Mean age (years) Age at onset of IC (years) Duration of IC (years) No. Hunner/non-Hunner type HD Times on average Bladder volume at the last HD (mL) Term from the last HD (months) Instillation (no. patients) Heparin + lidocaine instillation DMSO instillation Medicine (no. patients) Anticholinergic agent NSAIDs Antihistaminic agent + steroid Suplatast tosilate Tricyclic antidepressant Others Measured parameters at baseline OSSI OSPI VAS OABSS IPSS QOL index Daytime frequency (times) Nocturia (times) Average voided volume (mL) Maximum voided volume (mL) Post-void residual (mL)

Group A (immediate injection)

Group B (delayed injection)

P-value

34 (8/26) 64.9  13.7 [34–82] 58.3  14.3 [24–78] 6.6  4.4 [1–21] 24/10

18 (4/14) 64.3  13.2 [34–81] 57.8  15.9 [24–78] 6.2  3.9 [1–16] 14/4

16 (4/12) 65.6  14.6 [37–82] 58.9  12.8 [33–77] 7.1  4.9 [2–21] 10/6

1 0.76 0.81 0.54 0.46

2.7 [1–8] 509  254 [100–1200] 17.1  12.7 [3–53]

2.6 [1–8] 516  216 [250–1000] 17.3  14.9 [3–53]

2.8 [1–6] 500  301 [100–1200] 17.0  10.1 [6–49]

0.63 0.85 0.34

11 4

6 1

5 3

5 22 13 15 11 17

3 11 7 4 4 8

2 11 6 11 7 9

13.5 11.4 6.8 8.0 21.9 5.6 20.4 4.6 106.8 174.7 38.4

          

3.9 [6–20] 2.9 [6–16] 2.2 [4–19] 3.6 [1–15] 6.7 [3–32] 0.8 [3–6] 10.6 [7–52] 3.9 [0–21] 61.1 [20–330] 107.7 [50–500] 30.9 [0–95]

14.2 12.1 7.3 8.5 22.6 5.8 18.6 4.2 127.5 201.9 43.2

          

3.6 [7–19] 2.5 [7–16] 1.7 [4–10] 4.0 [1–15] 6.0 [13–32] 0.4 [5–6] 8.0 [7–40] 3.1 [0–10] 73.1 [40–330] 131.6 [50–500] 39.3 [0–95]

12.6 10.6 6.3 7.5 21.1 5.3 22.6 5.1 86.7 145.3 32.4

          

4.3 [6–20] 3.2 [6–16] 2.5 [4–10] 3.4 [2–12] 7.6 [3–33] 1.1 [3–6] 13.1 [10–52] 4.8 [2–21] 39.7 [20–165] 73.3 [50–300] 16.2 [16–92]

0.31 0.20 0.20 0.65 0.72 0.10 0.52 0.78 0.13 0.28 0.80

Values are expressed as mean  SD [range].

medicines shown in Table 1) for a month (group B). Randomization was carried out through central registration using an allocation table. The primary end-point was the response rate between the two groups, evaluated by GRA a month after allocation. Patients who rated the efficacy as better than +1 in GRA in the seven-point scale, meaning “slightly improved,” “improved” or “remarkably improved,” were considered as responders in treatment. For the secondary end-points, symptom changes from baseline were compared a month after allocation by OSSI/OSPI, VAS for pain, scale of QOL (1–6), based on the QOL index of the IPSS, OABSS and FVC variables.7,8

From 1 month onward after allocation as a single cohort A month after allocation, group B patients received BoNT-A injection in the same manner as group A. Thereafter, the participants of both groups were categorized as a single cohort. The outcomes were evaluated every month until 1 year. The duration of response and predictive factors for treatment response were explored.

Therapeutic protocol Under general anesthesia and cystoscopic control, BoNT-A (onabotulinumtoxin-A, Allergan, Irvine, CA, USA) 100 U, © 2015 The Japanese Urological Association

diluted in 15 mL normal saline, was injected suburothelially at 30 sites by 0.5 mL each in the trigonal area of the bladder through a 25-G needle (Olympus, Tokyo, Japan). Instilled saline volume was minimized to avoid hydrodistension. The first- or second-generation cephem antibiotic was administered perioperatively. AE were closely monitored by urinalysis and interviews, beginning 2 weeks after injection, and every month thereafter throughout the study period.

Statistical analysis To detect the difference in the rate of treatment response between the two groups with a significance level of 5% and a power 80%, 15 patients in each group were required. Accounting for the 20% withdrawal rate, at least 19 patients in each group were required to evaluate the primary end-point. Intergroup comparisons were made using the v2-test and Fisher’s correct test for categorical variables, and Student’s unpaired t-test and Wilcoxon rank-sum test for continuous variables. For a single-case cohort, symptomatic variables were compared between baseline and 1 month post-injection using Wilcoxon signed-rank test. To explore predictive factors for treatment response at 1 month post-injection, logistic regression analysis was used with all the variables catego837

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rized into two groups by either greater or less than the median value. The duration of response was evaluated using the Kaplan–Meier method. The log–rank test was used to compare the duration of response between Hunner and non-Hunner types, and between sex differences. A P-value