This was a multi-institutional, randomized, double-blind, placebo controlled, institutional review board approved clinical trial done by participants in the National Institute of Child Health and Human Development sponsored Pelvic Floor Disorders Network. BoNT-A is not licensed for this indication and, therefore, an Investigational New Drug application was obtained from the Food and Drug Administration for research use in this trial. Participants were neurologically intact women at least 21 years old with refractory urge incontinence, defined as inadequate symptom control after at least 2 first line therapies, which had to include 2 anticholinergic medications and at least 1 of supervised behavioral therapy, physical therapy or biofeedback. Inclusion required at least 6 urge incontinence episodes in a standardized 3-day bladder diary and documented urodynamic DOI within the last year. The full methods of the trial have been previously published.6
Eligible participants underwent a standardized telephone interview approximately 14 days before their injection visit. The interview included the Pelvic Floor Distress Inventory,7
Pelvic Floor Impact Questionnaire,7
Sexual Function Questionnaire,8
Life Orientation test9
Participants were randomized at the time of first injection to BoNT-A or placebo in a 2:1 randomization. BoNT-A (200 U) was dissolved in 6 ml saline and provided in 2 syringes, each containing 3 ml. Two placebo syringes each contained 3 ml saline. For placebo and BoNT-A 0.1 ml indigo carmine was added to the total volume as a marker for detrusor injection sites. Syringes were prepared by study pharmacists and they appeared identical to the injecting physician. All physicians administering injections were experienced with cystoscopic injection techniques and they performed the procedure in standardized fashion, as instructed using an injection technique video.
Following the administration of local anesthesia 6 ml of masked substance were injected at approximately 15 to 20 detrusor muscle sites. Injections were spread out to cover the posterior bladder wall in 3 rows, sparing the bladder trigone and ureteral orifice. All subjects received an antibiotic before the injection and for 3 days thereafter. Subjects unable to void after injection were taught intermittent self-catheterization.
Subjects with inadequate symptom improvement (PGI-I 4 or greater) who requested a second injection were eligible to receive an open label injection of 200 U BoNT-A at least 8 weeks but no more than 52 weeks after the first injection. All subjects were to be followed for 12 months after the first injection but not less than 1 month following the second injection or to study withdrawal up to a maximum of 13 months.
Post-injection followup included telephone interviews by personnel at a single quality of life center as well as monthly research interviews by a coordinator from each clinical study site. Increased PVR was defined as a PVR volume of greater than 200 ml irrespective of symptoms. At the in person visit 4 weeks following the study procedure subjects with PVR more than 200 ml were instructed on catheterization techniques and a bladder drainage program was begun. Any subject with a clinically positive urine dipstick test was sent for urine culture and treated with antibiotics as necessary.
Subjects were followed up to 12 months unless they received any new treatment for overactive bladder symptoms. In that case they were withdrawn from study and end of study measures were performed. The primary outcome measurement was time to failure (PGI-I 4 or greater) after the first injection.
To allow sufficient time for the onset of action of BoNT-A the earliest outcome measurement was 60 days after injection. Failure was defined as a PGI-I score of 4 or greater, the commencement of any new treatment at any time after the first injection or increased intensity of previously established treatment for DOI.
Secondary outcome measures were changes in the frequency of incontinence episodes, changes in symptom and quality of life measures, including the Patient Global Impression of Symptom Control, and the occurrence and duration of voiding dysfunction requiring catheterization. Safety and adverse events were reported and monitored at 3-month intervals by an independent data safety and monitoring board.
After interval analysis data revealed a higher than anticipated rate of increased PVR in subjects who received BoNT-A injection the study was placed on clinical hold and further injections were stopped. Increased surveillance of randomized participants included weekly telephone calls until PVR was less than 200 cc. In addition, subjects with increased PVR had an additional office visit 8 weeks after injection, at which time catheterized PVR was measured, and urinalysis and culture were done.
This trial was designed to test efficacy rates of 30% for placebo and 50% for BoNT-A after approximately 6 months of followup. A dichotomous outcome (success/failure) was assumed with 2:1 randomization. A sample size of 210 subjects provided 80% power to test the hypothesis using a 2-tailed 5% level of significance. This sample size also permitted the testing of an effect size of 0.2 in the continuous measures of quality of life. No allowance was made for subjects lost to followup.
Analysis of the demographic variables was performed to evaluate the groups for similarity. The primary outcome (time to failure) was analyzed by fitting a Cox regression model. Comparisons between the continuous secondary outcomes (Pelvic Floor Distress Inventory, Pelvic Floor Impact Questionnaire, Sexual Function Questionnaire and SF-36) between groups were made with appropriate parametric and nonparametric testing.