Botulinum A Toxin/Dimethyl Sulfoxide Bladder Instillations for Women With Refractory Idiopathic Detrusor Overactivity: A Phase 1/2 Study

Abstract

We completed a phase 1/2 trial to evaluate the safety and potential efficacy of direct intravesical instillation of a botulinum type A toxin/dimethyl sulfoxide (DMSO) solution for treatment of idiopathic detrusor overactivity in women. Twenty-five women with medication-resistant, urodynamic-confirmed idiopathic detrusor overactivity were enrolled. A total of 9 patients were treated in phase 1 of the study. Three patients were given a 66% dosing of solution; 22 patients received the full 300 units of botulinum toxin and 50 mL of DMSO (50% concentration). Adverse effects, 24-hour pad weights, episodes of incontinence, postvoid residuals, and scores on the Blaivas-Groutz anti-incontinence scale, Indevus Urgency Severity Scale, Incontinence Impact Questionnaire-short form, and Urogenital Distress Inventory (6 items) questionnaire were recorded at baseline, 1 month, and 3 months after instillation. No serious adverse effects or clinically important increases in postvoid residual occurred. Among the 21 women who completed phase 2 of the study, the median number of incontinent episodes decreased from 4 at baseline to 2 at 1 month (P=.004) and increased to 4 at 3 months (P=.81). Median scores improved from baseline to 1 month on the Incontinence Impact Questionnaire (from 13 to 7; P=.007) and Urogenital Distress Inventory (from 10 to 5; P=.003). Although 11 women (52%) reported severe urgency based on the Indevus Urgency Severity Scale at baseline, only 1 (5%; P<.001) and 3 (14%; P=.004) women reported severe scores at 1 and 3 months, respectively. Direct instillation of botulinum toxin/DMSO solution is safe. Its promising clinical effect warrants further evaluation in a randomized, placebo-controlled phase 3 setting.

OnabotulinumtoxinA significantly attenuates bladder afferent nerve firing and inhibits ATP release from the urothelium

“…This could provide an explanation for the rapid onset of response seen in the present study compared with the latency of response observed in clinical studies where the toxin is injected transurothelially. Intravesical instillation has previously been suggested as an alternative method of delivery , but no study has adequately investigated whether intravesical administration in humans without injection is sufficient for the agent to cross the urothelial barrier. The data presented in the present study provide evidence that this may be possible, although further experiments are required to assess the efficacy and safety of this approach before application in humans.…”

Botulinum toxin for the lower urinary tract

“…There is a recent report of using of dimethyl sulphoxide (DMSO) for liquid BoNT bladder instillation [82]. DMSO does not maintain the natural state of the BoNT protein, and must be formulated immediately before instillation.…”

Intravesical instillation of botulinum toxin A: an in vivo murine study and pilot clinical trial

“…Only a few open-label studies have addressed the use of BoNT-A instillation in patients with IC/PBS or neurogenic bladder [30,31]. The outcomes of these open-label studies, like those of the animal studies, suggest that the BoNT-A instillation affects bladder afferent mechanisms rather than motor nerves and improves LUTS without significantly affecting detrusor contractility.…”