SUI: Phase III data offer lessons for trials evaluating cell therapy

Results of one of the first randomized controlled trials evaluating cell therapy for women with stress urinary incontinence (SUI) has helped to identify clinically meaningful efficacy endpoints to refine patient selection criteria for current and future studies, according to investigator Melissa R. Kaufman, MD, PhD.

The phase III findings, described in a presentation at the International Continence Society annual meeting in Florence, Italy, involve the use of autologous muscle-derived cells (AMDCs) that are administered as an intrasphincteric injection designed to augment sphincter function.

The randomized trial had a composite endpoint of ≥50% reduction in incontinence episode frequency (IEF) or ≥50% reduction in either 24-hour or in-office pad tests 12 months post-treatment. When investigators found that response rates for this endpoint exceeded 80% for both treatment and placebo arms, they halted the trial after 150 of a planned 246 women had been enrolled.

Now underway is a phase III trial that will look at IEF reduction endpoints that are more clinically meaningful, according to Dr. Kaufman, of Vanderbilt University Medical Center, Nashville, TN.

“The primary lesson is that complex clinical trials are an iterative process,” Dr. Kaufman said in an interview with Urology Times. “We must remain open to understanding the nuances of our design when embarking on trials for novel technologies, especially when data is not historically available to benchmark.”

The AMDCs under study are developed from muscle tissue obtained from the patient. After enzymatic and mechanical disruption, muscle cells are serially plated until adult cells exhibiting qualities believed to lead to regenerative potential are purified and expanded in quantity, according to Dr. Kaufman. After testing for safety, muscle-cell identity, and potency, the cells are packaged and returned to the clinical site for injection.

Previously published phase I/II data suggest that using AMDCs for urinary sphincter repair is safe, with adverse events that are transient, self-limited, and attributable to biopsy or injection, rather than the cells themselves (J Urol 2014; 192:469-75). Efficacy data, while early and preliminary, included a statistically significant improvement in patient-reported outcome scores at 12-month follow-up compared to baseline.

This information drove construction of the current phase III trial design, which included the composite endpoint that proved to provide “excessive inclusivity and resulted in capture of many placebo patients,” said Dr. Kaufman, who added that unreliability of pad testing in this population further confounded the results.

Next: Identifying alternate endpoints

To identify alternate endpoints, Dr. Kaufman and colleagues looked at the correlation of IEF reduction and scores on Incontinence Quality of Life (IQOL) questionnaires. They found that patients who had a ≥50% IEF reduction had greater IQOL score improvement versus patients with <50% IEF reduction. Patients with ≥75% IEF reduction displayed even greater IQOL improvement.

Moreover, a potential treatment effect was detected for the entire patient cohort using IEF endpoints, and this was pronounced for a subgroup of 17 patients (11 AMDC, six placebo) who had recurrent or persistent SUI after incontinence surgery, according to investigators.

Based on this experience, investigators have revised clinical endpoints for current and future trials to encompass ≥50% or ≥75% diary-reported incontinence episodes or less than one stress leak during the 3-day diary period.

Also see: Practice ‘report card’ tracks performance

Perhaps most critically, the experience to date helped investigators determine which patients might be optimal candidates for cellular therapy.

“In the primary phase III trial, urethral hypermobility was not assessed, so many patients without primary sphincter dysfunction were likely included,” Dr. Kaufman explained. “Initial data review suggests that patients who have previously undergone urethral stabilization may be ideal candidates for sphincter augmentation.”

Using the refined information from the initial trial, investigators are currently completing a randomized, double-blind, placebo-controlled trial assessing the safety and efficacy of AMDC urinary sphincter repair for treatment of SUI in women in the United States and Europe, and are planning a second study with two treatment injections.

Dr. Kaufman and colleagues reported funding from Cook MyoSite, Inc.

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