Reduced versus standard intradetrusor OnabotulinumtoxinA injections for treatment of overactive bladder

Abstract

Background

Intradetrusor onabotulinumtoxinA injection is an effective advanced treatment for overactive bladder. While the effective dosages have been well studied, very little data exist on treatment efficacy using differing injection techniques. The objective of this study was to determine whether the efficacy of a reduced injection technique of 5 injection sites was noninferior to the standard technique of 20 injection sites of intradetrusor onabotulinumtoxinA for treatment of overactive bladder.

Methods

In this randomized noninferiority trial, men and women seeking treatment of overactive bladder with intradetrusor onabotulinumtoxinA injections were randomized to receive 100 units administered via either a reduced injection technique of 5 injection sites or a standard injection technique of 20 injection sites. Subjects completed a series of standardized questionnaires at baseline and at 4–12 weeks postprocedure to determine symptom severity and treatment efficacy. The primary outcome was treatment efficacy as determined by Overactive Bladder Questionnaire‐Short Form with a noninferiority margin of 15 points. Secondary outcomes were incidence of urinary tract infection and urinary retention requiring catheterization.

Results

Data from 77 subjects were available for analysis with 39 in the control arm (20 injections) and 38 in the study arm (5 injections). There was a significant improvement in both arms from baseline to follow‐up in Overactive Bladder Questionnaire‐Short Form and International Consultation on Incontinence Questionnaire scores (p < 0.001). Overall treatment success was 68% with no statistically significant difference between arms. A significant difference between arms was found on the Overactive Bladder Questionnaire‐Short Form quality of life survey favoring the control arm (confidence interval [CI]: 0.36–20.5, p = 0.04). However, there were no significant differences between arms in the remaining validated questionnaires. The study arm did not demonstrate noninferiority to the control arm. Subjects in the study arm were significantly more likely to express a willingness to undergo the procedure again (odds ratio = 3.8, 95% CI: 1.42–10.67, p = 0.004). Adverse events did not differ between arms.

Conclusions

A reduced injection technique for administration of intradetrusor onabotulinumtoxinA demonstrates similar efficacy to the standard injection technique but did not demonstrate noninferiority. Subjects preferred the reduced injection technique over the standard technique. A reduced injection technique is a safe and effective alternative to the standard technique.

1. INTRODUCTION

Overactive bladder (OAB) affects 17% of the general population. ¹ It not only significantly affects quality of life for the individual, but also has an estimated economic burden of over $80 billion in the United States. ² Initial treatments such as dietary modifications, pelvic floor physical therapy, and oral medications for OAB frequently fail to adequately relieve symptoms, leaving patients seeking further treatment with third‐line therapies such as intradetrusor onabotulinumtoxinA injection or sacroneuromodulation. Even if medical treatments are initially effective, patients often are with medication management due to either bothersome side effects or suboptimal results. ³ , ⁴ , ⁵

A large body of evidence has demonstrated the efficacy of intradetrusor onabotulinumtoxinA injection for treatment of OAB. Since its approval in 2013 by the Food and Drug Administration for the treatment of OAB, onabotulinumtoxinA has become a highly utilized third‐line treatment for OAB. ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² Side effects include suprapubic pain, hematuria, urinary tract infection (UTI), and urinary retention requiring temporary catheterization. ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² This treatment significantly improves urinary urgency and frequency with approximately 20%–27% of patients with urgency urinary incontinence temporarily cured following treatment. ¹¹ , ¹³

The technique described by the manufacturer's instructions for use of onabotulinumtoxinA (Botox, Allergan) recommends 20 injection sites for idiopathic OAB. ¹⁴ The rationale for injecting in multiple locations is to distribute the toxin throughout the posterior bladder wall with small volumes at each site to limit distant spread of the toxin to extravesical organs. In clinical practice, many physicians adjust this technique using varying dilutions, numbers of injection sites, and volumes of fluid injected at each site. In this study, we sought to compare the efficacy and safety of a reduced injection technique of onabotulinumtoxinA at 5 injection sites compared to the manufacturer's standard technique of 20 injection sites. We hypothesized that a reduced injection technique would be noninferior to the standard technique.

2. MATERIALS AND METHODS

This study was approved by the Walter Reed National Military Medical Center (WRNMMC) Institutional Review Board (WRNMMC‐2019‐0232) and was registered on clinicaltrials.gov (NCT04020510). All patients provided written informed consent before randomization and participation in the study. From July 2019 through July 2021, all patients who presented to the Urogynecology or Urology clinics at WRNMMC for advanced therapy for treatment of idiopathic OAB with intradetrusor onabotulinumtoxinA injection were evaluated for eligibility in the study. All patients, both male and female, age 18 or older with primary symptoms of urinary urgency, frequency, or urgency urinary incontinence who had failed prior behavioral therapies and either failed or declined oral medication treatments were eligible for enrollment. Additionally, all patients had to be willing to perform self‐catheterization if urinary retention occurred. Patients were excluded from participation for the following: a diagnosis of neurogenic OAB, concurrent use of OAB medications, baseline postvoid residual (PVR) greater than 200 ml, untreated symptomatic prolapse POP‐Q (Pelvic Organ Prolapse Quantification) stage 2 or greater, evidence of active UTI, prior intradetrusor botulinum toxin (onabotulinumtoxinA or abobotulinumtoxinA) treatment in the previous 6 months, greater than 400 units of botulinum toxin treatment in the preceding 3 months cumulatively in other areas of the body, injections requiring sedation in the operating room, diagnosis of interstitial cystitis/bladder pain syndrome, pregnancy or planned pregnancy, pre‐existing neuromuscular disorders, such as myasthenia gravis or amyotrophic lateral sclerosis, that might put patients at increased risk of exposure to botulinum toxin, known allergy to botulinum toxin, inability to follow‐up, or communication barriers.

Patients meeting inclusion criteria were approached before the procedure regarding interest in study participation. Consenting patients were enrolled and asked to provide demographic information as well as complete validated questionnaires including the Overactive Bladder Questionnaire Short Form (OAB‐q SF), International Consultation on Incontinence Questionnaire‐Short Form (ICIQ‐SF), ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ and Patient Global Impression of Improvement (PGI‐I). ²⁰ The OAB‐q SF is separated into a symptom bother score (OAB‐q SB) and quality of life score (OAB‐q QOL), each ranging from 0 to 100. Higher scores on the OAB‐q SB indicates greater symptom bother, whereas higher scores on the OAB‐q QOL indicate better quality of life. The ICIQ‐SF is a three‐item questionnaire with scores ranging from 0 to 21 with higher scores indicating greater symptom severity. These two surveys are recommended with highest level evidence by the International Continence Society for use in research on OAB ²¹ and both have a minimally important difference that has been established which correlates with clinical symptoms. ¹⁵ , ²² Additional surveys were used to capture a global impression on both symptom severity before treatment and efficacy of treatment. The PGI‐I is a single item survey assessing patient impression of symptom improvement following treatment with 7 options ranging from “very much better” (1) to “very much worse” (7). These validated surveys provide an assessment of the patient perception of symptom severity and treatment effect, with scores correlating with objective findings on voiding diaries and pad weights. ²⁰

All subjects provided a urine sample for assessment of infection before the procedure. If an active UTI was diagnosed, the procedure was rescheduled following adequate treatment. All injections were performed in the office setting with either flexible or rigid cystoscopy without sedation. Subjects received peri‐procedural antibiotic prophylaxis and local anesthetic consisting of 2% lidocaine gel applied to the urethra before the procedure. All subjects were offered an oral anxiolytic if desired. A preprocedural pelvic pain score was reported using an 11‐point visual pain scale ranging from 0 to 10 (0 = being no pain and 10 = being severe pain) immediately before the procedure.

Subjects were randomized to either the control arm (20 injections) or the study arm (5 injections) immediately before the procedure. Subjects in the control arm received the standard injection technique as described in the onabotulinumtoxinA (Botox®, Allergan) instructions (100 units of onabotulinumtoxinA diluted in 10 ml of preservative‐free injectable saline in 20 injection sites with 0.5 ml per injection spread throughout the posterior bladder wall sparing the trigone, Figure 1A). Subjects in the study arm received the same dilution injected at 5 sites with 2 ml per injection site (Figure 1B). Five injection sites were chosen as the study number as that number is easily divisible by the control number of 20 and allowed us to keep the dilution consistent between groups. Following the procedure, subjects were asked to report a postprocedure pelvic pain score (0–10) and to rate their willingness to repeat the procedure based on their experience using the same 11‐point visual pain scale. They were also asked to rate their willingness to repeat the procedure based on their experience again using the 11 point scale with a score of 0 indicating complete unwillingness and a score of 10 indicating complete willingness to repeat the procedure.

Figure 1.

(A) OnabotulinumtoxinA control arm injection technique. The control injection paradigm consisted of 20 injection sites containing 0.5 ml in each site. (B) OnabotulinumtoxinA study arm injection technique. The study injection paradigm consisted of 5 injection sites containing 2 ml in each site

Subjects were block randomized with blocks of 20 in a 1:1 ratio using a simple randomization technique. Allocation concealment was maintained with the use of sequentially numbered opaque sealed envelopes. The numbered envelopes were placed in each study packet and the envelope was opened immediately before the procedure to reveal the arm to which each subject was randomized.

Subjects were followed‐up 4–12 weeks following the procedure. This follow‐up range was chosen because efficacy of intradetrusor onabotulinumtoxinA has taken effect by 4 weeks and is sustained through 12 weeks. ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² At that visit, they completed the OAB‐q SF, ICIQ‐SF, PGI‐S, and PGI‐I as well as a PVR measurement. If patients had any UTI symptoms or a suboptimal response to the treatment, they underwent straight catheterization to obtain a urine sample with the PVR to evaluate for possible infection. If they denied symptoms of UTI and reported satisfactory response to the treatment, they underwent a bladder scan to obtain the PVR. Subjects with a PVR greater than 200 ml with symptoms of incomplete bladder emptying or PVR greater than 400 ml regardless of symptoms were recommended and instructed to perform clean intermittent catheterization. Subjects with a UTI diagnosed at the time of the initial follow‐up were treated with antibiotics and then asked to repeat the study questionnaires following treatment. Any UTIs diagnosed within 12 weeks of the procedure were tracked and included in the analysis for secondary outcomes.

The primary outcome was treatment efficacy at 4–12 weeks following intradetrusor onabotulinumtoxinA injection based on scores from the OAB‐q QOL. Secondary outcomes were efficacy based on the other validated questionnaires, assessment of subject experience with technique, comparison of postprocedure pain, UTI, and urinary retention between the two techniques. A noninferiority design was used to compare the two injection techniques and we hypothesized that the study technique of 5 injections would be noninferior to the standard technique of 20 injections. Assuming a standard deviation of 26 points on the OAB‐q QOL, ¹³ and a noninferiority margin of 15 points on the OAB‐q SF, a total of 76 subjects with 38 subjects in each group was needed for analysis to achieve a power of 80%. We chose a margin of 15 points instead of 10, which is the minimally important difference for the questionnaire, to ensure a change that was clinically meaningful as for some questionnaire subscales a change of greater than 10 points may be needed to reflect clinical improvement. ²²

Baseline demographics were summarized using means and confidence intervals for continuous data and counts, and percentages with appropriate binomial or multinomial confidence intervals for categorical data. Outcome variables were evaluated using t‐tests for OAB‐q SF and ICIQ SF scores, the Wilcoxon test for comparison of pain scores, and the Fisher's exact test for assessment of treatment efficacy on the PGI‐I and comparison of willingness to repeat the procedure. Secondary outcomes incidence of UTI and urinary retention were analyzed using the Chi‐square or Fisher's exact tests. All data were analyzed using R (R Core Team, Vienna, Austria). Alpha was set at 0.05.

3. RESULTS

A total of 84 subjects were enrolled and randomized and 77 subjects were available for primary outcome analysis, with 38 in the study group and 39 in the control group (Figure 2). Subject demographics in the study and control groups were similar with regard to age, gender, diabetes status, prior treatment with intradetrusor onabotulinumtoxinA, and for female subjects’ menopausal status and vaginal estrogen use (Table 1). Rigid cystoscopy was used for the vast majority of procedures.

Figure 2.

CONSORT diagram flow diagram for subjects screened and enrolled in the study

Table 1.

Subject demographics

Baseline characteristic	Control (N = 42)	Study (N = 41)	All (N = 83)
Age (SD)	61.0 (15.2)	58.5 (13.6)	59.8 (14.4)
Gender
Female	41 (97.6%)	40 (97.6%)	81 (97.6%)
Male	1 (2.4%)	1 (2.4%)	2 (2.4%)
Diabetes
No	37 (88.1%)	38 (92.7%)	75 (90.4%)
Yes	3 (7.1%)	3 (7.3%)	6 (7.2%)
Missing	2 (4.8%)	0 (0%)	2 (2.4%)
Prior bladder Botox
No	29 (69.0%)	23 (56.1%)	52 (62.7%)
Yes	12 (28.6%)	17 (41.5%)	29 (34.9%)
Missing	1 (2.4%)	1 (2.4%)	2 (2.4%)
Postmenopausal (females only)
No	12 (29.2%)	9 (22.5%)	21 (25.9%)
Yes	28 (68.3%)	31 (77.5%)	59 (72.8%)
Missing	1 (2.4%)	0 (0%)	1 (1.2%)
Vaginal estrogen use (females only)
No	30 (73.2%)	32 (80.0%)	62 (76.5%)
Yes	11 (26.8%)	8 (20.0%)	19 (23.5%)

Note: Data are presented as mean ± standard deviation (SD) or number (percentage).

For the primary outcome, a statistically significant difference in scores on the OAB‐q QOL was found between groups, with a greater improvement seen in the control group (mean change of 21.3 points in the study group vs. 31.8 in the control group, confidence interval [CI]: 0.36–20.5, p = 0.04, Figure 3B). However, there were no statistically significant differences on the OAB‐q SB and ICIQ‐SF scores between the groups (Figure 3D and 3F). The mean change in symptom score from baseline to 4–12 weeks on the OAB‐q SB was −34.2 in the study group and −44.7 in the control group (CI: −22.2–1.19, p = 0.08). The mean score differences on the ICIQ‐SF were −4.89 in the study group and −5.39 in the control group (CI: −2.82–1.82, p = 0.66). While the difference between the means of 10.5 points for both the OAB‐q SB and OAB‐q QOL is within the prespecified noninferiority margin of 15 points, the confidence intervals for both cross that margin. Therefore, these data do not support noninferiority of the reduced injection technique to the control technique (Figure 4).

Figure 3.

Subject questionnaire scores. (A) Change in OABq‐SF quality of life scores in the study (5 injection, blue) and control (20 injection, red) groups from baseline to 4–12 weeks postprocedure. (B) Difference in the mean change in OABq‐SF quality of life scores between the study and control groups. (C) Change in OABq‐SF symptom bother scores in the study and control groups from baseline to 4–12 weeks postprocedure. (D) Difference in the mean change in OABq‐SF symptom bother scores between the study and control groups. (E) Change in ICIQ SF scores in the study and control groups from baseline to 4–12 weeks postprocedure. (F) Difference in the mean change in ICIQ SF scores between the study and control groups

Figure 4.

Noninferiority testing for the overactive bladder questionnaire short form scores graphical representation of the noninferiority testing between the study and control groups for both the quality of life (QOL) and symptom bother (bother) scores. The vertical lines represent zero difference and the noninferiority margin of 15 points. Higher values on the X‐axis represent greater benefit of control versus treatment

Of all trial subjects, 68% responded positively to the treatment based on PGI‐I scores at 4–12 weeks of “very much better” or “much better,” with 65.8% in the standard 20 injection control group and 70.2% in the reduced 5 injection study group and reporting improvement (odds ratio [OR] = 1.06, 95% CI: 0.46–3.25, p = 0.81). Subjects in both groups also demonstrated improvement in both symptom bother and quality of life following treatment. In the OAB‐q QOL, subjects in both groups demonstrated significant improvement following treatment (both groups p < 0.0001, Figure 3A). Likewise, the OAB‐q SB (both groups p < 0.0001, Figure 3C) and ICIQ‐SF (both groups p < 0.0001, Figure 3E) both demonstrated improvement in symptoms from baseline to 4–12 weeks.

When evaluating the patient experience with each injection technique, both groups had evidence of pain following the procedure (p < 0.0001), but the change in pre‐ and postprocedure pain was not significantly different between groups (p = 0.94). When subjects were asked immediately postprocedure how willing they were to repeat the procedure based on their experience, more patients expressed complete willingness in the reduced injection study group (OR = 3.8, 95% CI: 1.42–10.67, p = 0.004) (Figure 5).

Figure 5.

Subject Willingness to repeat procedure proportion of subjects in the control (20 injection) and study (5 injection) groups that expressed complete willingness to repeat the procedure with a score of 10 on the 11‐point visual scale assessed immediately postprocedure

Two subjects required catheterization postprocedure, both in the study group. An additional subject in the control group experienced symptoms of likely urinary retention but was unable to follow‐up in the office due to the COVID‐19 pandemic. Her symptoms ultimately resolved. UTIs occurred in 27 subjects (22%), 6 in the study group and 11 in the control group (p = 0.28). One subject in the control group experienced a serious adverse event of gross hematuria on postprocedure day 4 requiring readmission for continuous bladder irrigation. Of note, it was discovered at the time of admission that the subject was taking Ibrutinib, a chemotherapy agent which has antiplatelet properties, at the time of the procedure.

4. DISCUSSION

A reduced injection technique for intradetrusor onabotulinumtoxinA for treatment of idiopathic OAB is both safe and effective but did not demonstrate non‐inferiority to the standard technique. Both groups met the minimally important difference for the OAB‐q SB and OAB‐q QOL of 10 points, with greater changes in scores correlating with greater improvements in symptoms. ²² While both techniques provide significant symptom relief, the control technique conferred superior improvement in quality of life.

Subjects in both the study and control groups experienced significant improvement in their OAB symptoms on all study questionnaires and there was no difference in the percentage of subjects reporting improvement based on PGI‐I scores of “very much better” or “much better.” While the reduced injection technique did not affect postprocedure pain scores, subjects in the study group expressed a greater willingness to undergo the procedure again in the future.

Several placebo‐controlled trials have established the efficacy of intradetrusor onabotulinumtoxinA injections for the treatment of OAB. ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹³ Each of these studies utilized the standard injection technique of 20 injection sites with 0.5 ml per site. In our study, 68% of subjects reported successful management of their OAB symptoms with this treatment, which is consistent with reported success rates with both 100 and 200 units in the literature. ¹¹ , ¹³

Very few adverse events occurred in this trial, which further supports the safety of this treatment for OAB. There were no differences in incidence of UTI or need for catheterization between the study and control groups. The incidence of UTI of 22% found in our study is consistent with the 15.5%–36% reported in the literature. ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ The incidence of urinary retention requiring catheterization of 2.6% in our study is lower than the 5%–16% reported in the literature. ⁶ , ⁷ , ⁸ , ⁹ , ¹¹ , ¹³ This may be due to liberal definitions of urinary retention and criteria for recommending catheterization that were used in this study compared to others. ¹¹ , ¹³ The isolated adverse event of gross hematuria requiring admission for continuous bladder irrigation highlights the importance of stopping anticoagulants before this procedure as similar events have been reported in the literature. ²³

Differing numbers of injection sites were investigated in two small prior studies. Liao et al, ²⁴ performed a randomized control trial including 67 subjects that were randomized to 10, 20, or 40 injection sites and found no difference in efficacy or adverse events among the groups. The second was a prospective cohort trial by Avallone, et al, that included 45 subjects receiving anywhere from 1 to 3 injection sites depending on dosage of onabotulinumtoxinA being used and showed significant improvement in symptoms from baseline. ²⁵ Additionally, no adverse systemic effects were seen with injections of higher volumes. ²⁴ , ²⁵ Our study investigated a smaller number of injection sites than previously studied in a randomized trial. Additionally, we evaluated the patient experience with the treatment in conjunction with treatment efficacy, which has a significant impact on long‐term compliance with treatment.

We demonstrated significant improvement in OAB symptoms from baseline in both the study and control groups, indicating that a reduced injection technique is reasonable to use in clinical practice. Subjects significantly preferred fewer injections and expressed more willingness to repeat the procedure in the study group. This finding is notable because long term management of OAB symptoms with intradetrusor onabotulinumtoxinA injections relies on patient willingness to undergo subsequent treatment over time. Patients unwilling to undergo repeat procedures renders the treatment ineffective. Therefore, a slight decrease in efficacy may be acceptable to patients and physicians alike if a reduced injection technique allows patients to tolerate this treatment long term. Additionally, a reduced injection technique may allow a subset of patients, such as those with significant anxiety, to tolerate this treatment in the office instead of requiring sedation in an operating room setting. Any shift to increasing office‐based procedures also has a significant impact on procedure cost and safety.

Strengths of this study include the randomized design and use of patient centered outcomes. The dilution of onabotulinumtoxinA was the same for both groups, eliminating the potential for a difference in dilution to account for differences in efficacy. We also had a low drop‐out rate of 7.2%. We used validated questionnaires as our primary metric because they have been shown in prior studies to provide an adequate measure of treatment efficacy correlating with objective voiding diary findings. ¹⁵ , ²⁰ This increased external validity since the patient's impression of success or failure is what truly drives treatment continuation and compliance. Enrollment of patients in both a urogynecology and urology population also increased generalizability.

A limitation of this study is the inability to blind subjects to their treatment group. Subjects who had previous treatments with intradetrusor onabotulinumtoxinA treatment may have introduced bias to their survey results based on either a perceived decrease in efficacy due to knowledge of fewer injections used or due to an increase in perceived efficacy due to a more pleasant experience during the procedure with fewer injections. Similarly, subjects who were naive to intradetrusor onabotulinumtoxinA treatment may have introduced bias based on their knowledge of the number of injections received and their previous experience with the procedure.

With treatment efficacy of the standard 20 injection technique being reported to last approximately 6–12 months, ¹¹ , ¹³ further research is needed to determine the length of benefit with the reduced injection technique given its improved overall patient satisfaction. The use of a reduced injection technique for treatment of other patient populations, such as neurogenic OAB, should also be explored. Future studies should also investigate whether a reduced injection technique confers a lower risk of UTI given the nearly double rate of UTIs seen in the control group (28.2% vs. 15.8%).

5. CONCLUSION

A reduced 5 injection technique of intradetrusor onabotulinumtoxinA for treatment of idiopathic OAB did not demonstrate non‐inferiority to the standard technique. However, it is safe and effective, and is preferred by patients over the standard 20 injection technique.

CONFLICTS OF INTEREST

D.D.G. is a speaker for Allergan, Irvine, CA. C.M.V is on the medical advisory board for the Patty Brisben Foundation. The remaining authors report now conflicts of interest.

DiCarlo‐Meacham AM, Dengler KL, Welch EK, et al. Reduced versus standard intradetrusor OnabotulinumtoxinA injections for treatment of overactive bladder. Neurourol Urodyn. 2023;42:366‐374. 10.1002/nau.25107

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.