Efficacy and safety of intracavernosal incobotulinumtoxinA (Xeomin) as add-on therapy to sildenafil for the treatment of erectile dysfunction insufficiently responsive to phosphodiesterase type 5 inhibitors.

Background: Studies suggest intracavernosal botulinum toxin A (BTX/A) could improve difficult-to-treat erectile dysfunction (ED) ie with an insufficient response to phosphodiesterase type 5 inhibitors (PDE5-Is).

Aim: To investigate efficacy and safety of intracavernosal injection (ICI) of BTX/A combined with sildenafil 100 mg on demand in patients with ED and insufficient response to PDE5-Is.

Methods: Double-blind, placebo-controlled, multicenter, randomized phase 2 trial to investigate the efficacy and safety of bilateral 0.5 ml ICIs of incobotulinumtoxinA 50 U or placebo, both combined with sildenafil 100 mg on demand in men with ED and insufficient response to sildenafil 100 mg on demand. The inclusion criteria were International Index of Erectile Function-Erectile Function (IIEF-EF) domain score < 17 and >50% of attempts at sexual intercourse unsuccessful during a 4-week open-label run-in phase with sildenafil 100 mg on demand.

Outcomes: Mean change in IIEF-EF score and the proportion of "Yes" responses to Sexual Encounter Profile (SEP)-Q2 (ability to penetrate) and SEP-Q3 (ability to maintain an erection for successful intercourse) at 3 months.

Results: Out of 226 patients screened, 165 patients were randomized (mean age: 60.1 years, mean IIEF-EF on sildenafil 100 mg: 11.1). Intention-to-treat (ITT) analysis showed no significant improvement in IIEF-EF score with incobotulinumtoxinA 100 U combined with sildenafil 100 mg at 3 months. IncobotulinumtoxinA 100 U improved penetration (SEP-Q2) and erection maintenance (SEP-Q3), but not significantly. These results were confirmed by the complete-case and per-protocol analyses. Adjusted analysis for 100% adherence to sildenafil 100 mg showed a significant interaction effect (P = .032), suggesting greater IIEF-EF improvement in fully compliant patients. The safety profile was positive.

Clinical implications: IncobotulinumtoxinA 100 U combined with sildenafil 100 mg on demand is safe; however, there is yet no robust evidence to support its use to treat ED.

Strengths and limitations: Main strengths include the double-blind, placebo-controlled design, which was preceded by an open-label run-in phase, a 3-month follow-up, the use of ITT analysis and meaningful outcome measures. Limitations include no adherence to sildenafil (28%), inconsistent clamping at the penile crus post-incobotulinumtoxinA injection, and an underpowered sample size due to an overestimated treatment effect.

Conclusion: Despite negative ITT effectiveness results, this study demonstrated the safety of intracavernosal BTX/A. The results raise hypotheses regarding its potential role in combination with PDE5-Is, warranting further investigation. Future trials should refine patient selection and injection technique, assess dose-response effects, and improve protocol adherence to yield more reliable results for ED resistant to PDE5-Is.