Repeat botulinum injections found safe, efficacious

July 23, 2013

Repeat injections of onabotulinumtoxinA (Botox) continue to be a safe and effective treatment for urinary incontinence due to neurogenic detrusor overactivity, according to interim results from a long-term extension study of phase III pivotal trials.

San Diego-Repeat injections of onabotulinumtoxinA (Botox) continue to be a safe and effective treatment for urinary incontinence due to neurogenic detrusor overactivity (NDO), according to interim results from a long-term extension study of phase III pivotal trials.

A total of 387 patients who entered the extension study and received at least one botulinum injection (200 U or 300 U) were analyzed; 283, 195, 108, 59, and 40 patients received 2, 3, 4, 5, 6, and 7 treatment cycles, respectively. Outcomes analyses showed the repeat treatments had consistent benefit for decreasing urinary incontinence episodes and increasing volume voided. In addition, analyses considering only patients who had received two or three injections (since relatively small numbers of patients had received ≥4 injections) showed the longevity of the treatment effect remained durable, averaging about 9.5 months. Furthermore, no new safety signals emerged as patients continued on botulinum.

“Intradetrusor injection of onabotulinumtoxinA has been shown to be well tolerated and provide effective treatment in patients with urinary incontinence due to

Dr. KennellyNDO who failed or were intolerant of antimuscarinic therapy. However, most reports on repeated injections are from a single center or small patient series. The purpose of this extension study is to give long-term experience for a large cohort of patients,” said first author Michael Kennelly, MD, director of Charlotte Continence Center and co-director of the Women’s Center for Pelvic Health, Carolinas Rehabilitation, Charlotte, NC.

“The efficacy and safety results are encouraging. However, this is an interim analysis. The cohort will finish the trial at the end of August 2013, and we hope that the outcomes based on the whole dataset will substantiate the findings presented today,” Dr. Kennelly said during a presentation of the findings at the AUA annual meeting in San Diego.

The phase III pivotal trial program evaluating botulinum for urinary incontinence due to NDO was comprised of two 1-year, multicenter, double-blind, placebo-controlled trials enrolling patients with multiple sclerosis or spinal cord injury who were randomized into three groups to receive placebo or botulinum, 200 U or 300 U. Patients who chose to could enter the extension study, which began in 2009, at the end of their participation in the double-blind trial; placebo patients received botulinum, while patients in the botulinum groups continued with their original dose. However, as a result of a protocol change in March 2011, all botulinum injections are now given with the currently approved 200-U dose.

Criteria for retreatment eligibility were specified in the protocol and required that patients request retreatment, be at least 12 weeks out from their previous injection, and demonstrate at least one urinary incontinence episode on a 3-day voiding diary.

Voided volume increases by 150 mL

At baseline, patients were experiencing an average of 4.5 incontinence episodes/day and had an average voided volume of ~150 mL. When evaluated 6 weeks after the initial injection and all repeat injections, patients benefited with a decrease of ~3 to >4 incontinence episodes/day, regardless of the botulinum dose, and voided volume increased by about 150 mL.

At the time of the interim analysis, 263 patients were still ongoing in the trial. Of the 119 patients who had discontinued, only 10 (2.8%) withdrew because of an adverse event and only six (1.6%) due to lack of efficacy.

“Those figures are pretty phenomenal,” said Dr. Kennelly.

Adverse events that occurred at a rate >5% included urinary tract infection (defined as positive urine culture with bacteriuria >105 CFU/mL and >5 white blood cells/high power field), urinary retention, and pyrexia. However, the rate for each of those events decreased with ensuing injections.

On study entry, about 45% of patients were not performing clean intermittent catheterization (CIC). The incidence of de novo CIC for patients receiving botulinum, 200 U was 30.2% after the first treatment and <5% after the second and third treatment cycles. Among patients who were not already performing CIC after three botulinum injections, none needed to initiate CIC after subsequent injections.

Dr. Kennelly is a consultant/adviser and investigator for Allergan. One of his co-authors is a consultant/adviser, investigator, and meeting participant/lecturer for Allergan, and two co-authors are employees of Allergan.UT

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