In phase 3 trials, onabotulinumtoxinA (onabotA) 100U, administered as 20 evenly spaced intradetrusor injections avoiding the trigone (standard injection paradigm), significantly reduced urinary incontinence (UI) and improved quality of life (QoL) in patients with overactive bladder (OAB). The reported rate of clean intermittent catheterization (CIC) use was 6.5%. This phase 4 study tested the hypothesis that an alternative injection pattern for onabotulinumtoxinA of 10 injections into the trigone and peri-trigonal region could be effective and have a lower incidence of CIC use compared with the standard injection paradigm. Here we report final double blind and open label results.

This was a multicenter, randomized, double-blind trial (Clinicaltrials.gov identifier, NCT03052764) which included adults with OAB and UI that was inadequately managed with an anticholinergic. Eligibility criteria were identical to prior phase 3 and 4 studies. The study was performed in compliance with Good Clinical Practice regulations and was approved by an instituitional review board prior to study initiation. All patients provided written informed consent prior to enrollment. Patients were randomized 2:1 to onabotA 100U or placebo, administered as 2 trigonal and 8 peri-trigonal injections (Figure 1). Patients eligible for retreatment received onabotA 100U in the open label extension.

120 patients (115 female; 5 male) were randomized to onabotA (n=80) or placebo (n=40). At week 12 following treatment 1, the least squares mean (LSM) reduction in UI (episodes/day) from baseline was significantly greater for onabotA versus placebo (-2.90 versus -0.16; p<.0001). The proportion of patients achieving ≥75% reduction in UI episodes from baseline was 37.5% versus 8.1%. There was a significant improvement from baseline in LSM incontinence (I)-QoL total score for onabotA versus placebo (20.7 versus -3.5; p=.0012). In the first 12 weeks after treatment 1, CIC was used by 2/78 (2.6%) patients in the onabotA group and 0 in the placebo group. Both were male with a history of risk factors for CIC. Incidence of urinary tract infection (UTI) was higher for onabotA versus placebo (overall: 30.8% versus 17.9%; symptomatic: 17.9% vs 7.7%). 91 patients (90 female; 1 male) received onabotA open label retreatment (onabotA/onabotA, n=58; placebo/onabotA, n=33). At week 12 following treatment cycle 2, the mean change from the open label baseline in UI was -1.76 in the onabotA/onabotA group and -3.44 in placebo/onabotA group. 43.4% and 29.0% patients in the onabotA/onabotA and placebo/onabotA groups, respectively achieved ≥75% reduction in UI episodes from baseline, and the mean change from baseline in I-QoL was 9.1 and 23.4. In the first 12 weeks after treatment 2, CIC was used by 3/91 patients (3.3%, all female). Incidences of overall and symptomatic UTIs were 30.8% and 14.3%, respectively.

Although not a direct comparison, the results of this study suggests that the alternative onabotA injection paradigm reduces the need for CIC versus the standard paradigm (2.6% versus 6.5%).There was no CIC use in the female population following the first study treatment. Efficacy with the alternative onabotA paradigm was similar to that of the standard paradigm, but the UTI rate appears to be higher (30.8% versus 19.4%). Outcomes for patients who received a second alternative onabotA injection in the open label period of the trial were similar to those observed after the first treatment in the double blind period of the trial.

The efficacy of the alternative onabotA injection paradigm utilizing fewer, more targeted injections was similar to the standard injection paradigm; CIC use was lower, but UTI rates were higher. The efficacy and safety of the alternative injection paradigm in patients receiving onabotA after treatment 2 was similar to that observed after treatment 1, and the QoL improvement was also maintained through the entirety of this study.