Cheryl Guttman Krader, BS, Pharm

Cheryl Guttman Krader is a contributor to Dermatology Times, Ophthalmology Times, and Urology Times.

A nonimplanted, intravaginal neuromodulation device (FemPulse) for treating overactive bladder (OAB) symptoms demonstrated favorable results in a feasibility study assessing wearability, safety, and clinical utility, reported Suzette E. Sutherland, MD, MS, FPMRS, at the 2020 American Urological Association Virtual Experience.

“This device aims to provide a simple, convenient, and affordable form of continuous neuromodulation to ameliorate bothersome symptoms of OAB. The collective findings of the feasibility study justify its further investigation,” said Sutherland, the primary study investigator and director of Female Urology at the University of Washington School of Medicine in Seattle.

Sutherland’s coinvestigators were Steven W. Siegel, MD, FPMRS, Minnesota Urology in St. Paul, Minnesota, and Michael J. Kennelly, MD, FACS, FPMRS, McKay Urology, in Charlotte, North Carolina.

The FemPulse device is a pessary-like ring that is placed against the cervix for delivering electrical stimulation to the inferior hypogastric plexus, known as the pelvic plexus. The final iteration of the device will be a self-contained unit. However, the device investigated in this feasibility study was an initial prototype that was connected via wires exiting the vagina to an FDA-cleared transcutaneous electrical nerve stimulator (TENS).

The multicenter feasibility study randomized 21 women 2:1 to treatment versus sham groups. The treatment subjects received a conductive connector and stimulation at around 70% of the subject’s sensation threshold. The system used for sham patients had a nonconductive connector, but all other aspects of the set-up were identical. At the initial study visit, patients completed pretherapy (or sham) quality-of-life (QOL) questionnaires; underwent a vaginal exam; were assessed for device fit, comfort, and self-maneuverability; and underwent preliminary stimulation testing and mapping, after which the device was removed. The participants then completed a 3-day bladder diary and returned the following week for randomization, device placement, and configuration. They completed another 3-day bladder diary and then returned for a final visit on the following day to undergo device removal, a final vaginal examination, and complete posttherapy (or sham) QOL questionnaires.

In an intent-to-treat (ITT) cohort that included all 19 women who completed the study, the device was fit easily and was reported to be comfortable. In addition, it exhibited good self-maneuverability, as 86% of subjects could place and orient the device and 79% were able to remove it without assistance.

“A few patients had difficulty reaching the device to remove it either because of the length of their vaginal canal or their body habitus. A future iteration of the device will include a feature for assisting with self-placement and removal,” Sutherland said.

Safety of the device was demonstrated, as there were no clinically important direct or reflexive effects on heart rate, rhythm, or blood pressure during stimulation, nor any untoward issues in the vagina due to the device. One woman reported mild lower abdominal ache or cramping that resolved when the device was removed. She also noted scant pink-tinged blood on the device following final removal.

“This patient had no sense of discomfort or irritation on [the] vaginal exam that was attributable to the device. It was concluded that the blood was related to postmenopausal atrophic tissues,” Sutherland said.

Clinical utility was evaluated by analyses of changes in voids per 24 hours, urgent voids per 24 hours, changes in urinary urge, and incontinence-related QOL questions from 3 validated questionnaires. In the ITT cohort, similar improvements in these parameters were seen in both the treatment and control groups. However, signals of treatment benefit were observed in an efficacy-analysis (EA) subgroup comprised of 11 women (7 treatment subjects, 4 controls).

“The EA subgroup excluded 6 treatment subjects and 2 controls who reported feeling the stimulation, and who were therefore thought to be biased,” said Sutherland.

“It was in this EA subgroup that a trend toward OAB improvement in the stimulation group compared to controls was seen, which in turn provides the justification to pursue larger-scale investigations into the efficacy of the FemPulse device for the treatment of OAB.

Disclosure: FemPulse provided funding for the study. Dr Sutherland is a study investigator and consultant for FemPulse and other companies that market or are developing treatments for OAB.

1. Sutherland SE, Kennelly MJ, Siegel SW. Evaluation of a non-implanted, transvaginal, electrical stimulation continence device for overactive bladder: EVANESCE-OAB. Paper presented at: 2020 American Urological Association Virtual Experience; June 27-28, 2020. Abstract PD27-09

Articles

Feasibility study results indicate the nonimplanted, intravaginal device is safe and comfortable.

Wearable neuromodulation device shows promise for overactive bladder

 study evaluating the ablative effects of lasers for endocorporeal lithotripsy indicate that a super-pulsed thulium fiber laser (TFL) has greater efficiency than a holmium:YAG (Ho:YAG) laser, even when using the TFL with a smaller core-diameter fiber (CDF), reported Frédéric Panthier, MD, at the 2020 European Association of Urology Virtual Congress.

The study compared a 50 W TFL (IPG Photonics) and a 30W MH1 Ho:YAG laser (Rocamed) for ablating hard and soft stone phantoms. Ablation rates (mm3/min) for the TFL were determined for its fine dusting (0.15 J/100 Hz), dusting (0.5 J/30 Hz), and fragmentation (1 J/15 Hz) modes and using both a 150 μm and 272 μm CDF (Sureflex). The Ho:YAG laser was equipped with a 272 μm CDF (Sureflex) and tested in dusting (0.5 J/30 Hz) and fragmentation (1 J/15 Hz) modes. Average power was 15 watts for all settings.

“Our results showed that with equal settings and laser fibers, 

 ablation rates were twofold higher with the TFL than the Ho:YAG laser in fragmentation mode and fourfold higher for dusting,” said Panthier, department of Urology, Hôpital Tenon, Sorbonne Université, Paris, France.

“Most interesting, the ablation rate was still at least 50% higher using the TFL with the 150 μm CDF compared to the Ho:YAG laser with the 272 μm CDF.”

The experiments were done using immerged cubes of calcium oxalate monohydrate for the hard stones and uric acid for the soft stones. The setup included a spiral trajectory jointly controlled in contact mode with the stones and a laser activation time of 30 seconds. After drying of the stones, ablation volume was measured using three-dimensional scanning and segmentation.

In experiments with the hard stones where both lasers were equipped with a 272 μm CDF, the ablation rate was fourfold higher using the TFL compared with the Ho:YAG laser in dusting mode and twofold higher with the TFL compared with the Ho:YAG laser in fragmentation mode.For soft stones and with use of the 272 μm CDFs, the ablation volume was threefold higher for the TFL in dusting mode and twofold higher in fragmentation mode when compared with the Ho:YAG laser. All of the differences favoring the TFL were statistically significant.

Comparisons of the performance of the TFL using the 150 μm and 272 μm CDFs showed that across all 3 of its modes and for both stone types, the 272 μm CDF was associated with a significantly higher ablation rate than the 150 μm CDF except in fine dusting against soft stones (

The TFL with the 150 μm CDF was associated with a significantly higher ablation rate than the Ho:YAG laser with the 272 μm CDF for dusting of hard and soft stones and fragmentation of hard stones, but not for fragmentation of soft stones (

= .12). Compared to the Ho:YAG laser with the 272 μm CDF in dusting mode, the TFL in fine dusting mode was associated with a twofold higher ablation rate using the 150 μm CDF and a threefold higher ablation rate using the 272 μm CDF.

Panthier has no potential conflict of interest to report.

1. Panthier F , Doizi S, Berthe L, et al. In vitro comparison of ablation rates between superpulsed thulium fiber laser and ho:YAG laser for endocorporeal lithotripsy. 2020 European Association of Urology Virtual Congress. July 17-26, 2020. Abstract PT131.

<<<More from the 2020 EAU Annual Congress

Super-pulsed thulium fiber laser (TFL) has greater efficiency than a holmium:YAG laser, even when using the TFL with a smaller core-diameter fiber, according to preclinical findings. 

Thulium fiber laser shows efficiency advantage in experimental setting

A machine learning algorithm (MLA) incorporating readily available clinical information demonstrated promising performance for predicting quality of life in kidney stone patients.

The research was presented at the 2020 European Association of Urology Virtual Congress by David-Dan Nguyen, on behalf of the Wisconsin Quality of Life research group.1

The MLA was built using data collected for the development and validation of the Wisconsin Stone Quality of Life Questionnaire (WISQOL). In its first version, the MLA adequately estimated health-related quality of life of kidney stone patients and outperformed linear models. Assessment of its ability to classify patients into quintiles by quality of life scores showed that the MLA did best at identifying the highest and lowest quintiles, reported Nguyen, medical student, McGill University, Montreal, Quebec, Canada.

“Urolithiasis is a disease with complex symptoms that poses a significant burden on the quality of life of those affected by it. As such, an overarching goal of the management of urolithiasis is to improve quality of life. Patient-reported outcomes play an important goal in guiding the management of a disease, and there has been increasing efforts, including the development of certain tools, to specifically measure the quality of life of kidney stone patients,” he said.

“In the future with more data, hopefully our model can be improved to be used in more refined clinical settings.”

The WISQOL questionnaire is a disease-specific, validated health-related quality of life instrument capturing the unique symptoms of patients with urolithiasis and functional impact of their stone disease. It was developed by a team led by Kristina L. Penniston, PhD, and Stephen Y. Nakada, MD, both of the University of Wisconsin School of Medicine and Public Health, Madison.

Using the WISQOL score as the gold standard, 3 MLA candidate models were built to predict quality of life score from demographic, symptomatic, and clinical data. Nguyen reported that using Pearson’s correlation testing to evaluate regression performance, the gradient boosting model outperformed the deep learning and multivariable lasso regression models (out-of-sample r values for correlation between quality of life estimates and the WISQOL total score = 0.622, 0.592, and 0.438, respectively).

Classification performance of the MLAs was analyzed with area under the receiver operating characteristics curve (AUC). For the gradient boosting model, the out-of-sample AUC for quintile stratification was 0.70, and it performed best distinguishing between lowest and highest quintiles (AUC = 0.79 and 0.83, respectively).

“Our model underperformed in classifying patients in the middle quintile of quality of life,” Nguyen said.

“Future endeavors include scaling the tool as an aid to urologists that do not have the resources to collect precise quality of life scores via questionnaire and retrospectively generating quality of life scores in existing cohorts,” the investigators wrote.

1. Nguyen D-D, Luo JW, Lim JRZ, et al. Wisconsin quality of life machine learning algorithm for predicting quality of life in kidney stone patients. 2020 European Association of Urology Virtual Congress. July 17-26, 2020. Abstract 785

The machine learning algorithm incorporates readily available clinical information.

Algorithm may predict health-related quality of life in patients with urolithiasis

HERO, the phase 3 clinical trial investigating relugolix for the treatment of advanced prostate cancer, met its primary end point showing that the oral gonadotropin-releasing hormone (GnRH) antagonist provided sustained testosterone suppression to castrate levels through 48 weeks of follow-up.

The FDA recently granted a priority review designation to a new drug application for relugolix for the treatment of patients with advanced prostate cancer, according to Myovant Sciences, the manufacturer of the oral GnRH receptor antagonist.

Additional findings from the randomized, controlled study (NCT04352946) showed that men treated with relugolix achieved faster and more sustained testosterone suppression than the control group treated with subcutaneous leuprolide and had a markedly lower risk of having a major adverse cardiovascular event (MACE), said Neal D. Shore, MD.

Shore presented data from HERO as a late-breaking abstract for the 2020 American Urological Association virtual meeting. He is the lead author of an article reporting the study’s findings that was published online in the 

“Prostate cancer is the most common cancer diagnosis in the United States, and cardiovascular mortality is the leading cause of death among patients with prostate cancer. Luteinizing hormone-releasing hormone receptor agonists, such as leuprolide, that are used for androgen deprivation therapy [ADT] in advanced prostate cancer have several drawbacks. They are associated with an early testosterone surge, do not fully suppress follicle-stimulating hormone [FSH], which may be a mitogen for cancer cells, and since 2011 have carried an FDA mandated label warning about an increased risk of myocardial infarction, sudden cardiac death, and stroke,” said Shore, the medical director at Carolina Urologic Research Center in Myrtle Beach, South Carolina.

“Through a direct inhibitory effect on pituitary GnRH receptors, relugolix more completely suppresses both luteinizing hormone and FSH compared with leuprolide, and relugolix avoids an early testosterone surge. Based on the results of HERO, relugolix has the potential to become a new standard for ADT in men with advanced prostate cancer.”

HERO is a multinational, open-label trial that randomized 934 men 2:1 to treatment with relugolix (360 mg on day 1, then 120 mg once daily) or subcutaneous leuprolide 22.5 mg (11.25 mg in Japan and Taiwan) every 3 months. Eligible men had confirmed advanced prostate cancer with a biochemical or clinical relapse, newly diagnosed metastatic disease, or advanced localized disease and were deemed as candidates for at least 1 year of ADT. Men with a history of MACE within the prior 6 months were excluded.

The relugolix and leuprolide patient groups were well-balanced at entry in their demographic and clinical characteristics. Approximately 90% of men in both arms completed the 48-week
trial, and the treatment compliance rate was 99% in both groups.

More than 90% of men in each treatment arm had at least 1 cardiovascular risk factor, and approximately 14% had a history of MACE.

“Approximately 30% of men with advanced prostate cancer would be expected to have a history of a MACE. The lower rate in HERO reflects the study’s exclusion criteria,” Shore noted.

Relugolix demonstrates noninferiority, superiority to leuprolide

The primary end point analysis showed that 96.7% of men treated with relugolix and 88.8% of the control group achieved sustained suppression of testosterone to castrate levels (< 50 ng/dL) from day 29 through week 48. In statistical analyses, relugolix demonstrated both noninferiority and superiority to leuprolide.

Relugolix also demonstrated statistically significant superiority compared with leuprolide in all key secondary end points, which included measures of onset of prostate specific antigen response and testosterone suppression, FSH reduction, and sustained castration rates (

“By day 4, 56% of men treated with relugolix achieved testosterone suppression to castrate levels. In the leuprolide arm, the testosterone level showed the expected initial surge, reaching a mean of 625 ng/mdL, and the mean did not fall to castrate levels until day 29,” he reported.

A substudy investigating testosterone recovery showed that by day 90 after treatment was stopped, serum testosterone returned to the normal range in the relugolix group (mean, 288 ng/dL), but the mean testosterone level was just 58.6 ng/dL in the leuprolide group. At day 90, 54% of relugolix-treated patients versus just 3% of leuprolide-treated ones achieved testosterone recovery, Shore reported.

In both study groups, > 90% of men experienced at least 1 adverse event (AE). The rate of a grade 3 or higher AE was 18% in the relugolix group and 20.5% in the leuprolide group. The fatal AE rate in the relugolix and leuprolide groups was 1.1% and 2.9%, respectively.

“The known consequences of ADT, including hot flashes, were the most common adverse events in both groups. The rate of diarrhea was higher in the relugolix group, but these events were mild or moderate and did not lead to treatment discontinuation,” Shore said.

The HERO protocol included a prespecified analysis of MACE, which included nonfatal myocardial infarction, nonfatal stroke, and death from any cause. At 48 weeks, MACE rates were 2.9% in the relugolix group and 6.2% in the leuprolide group. A Kaplan-Meier analysis of cumulative MACE incidence over the 48-week treatment period showed a 54% risk reduction in the relugolix group relative to the leuprolide group.

“The MACE event rate was almost 6-fold higher in the leuprolide group compared with the relugolix group among men with a history of MACE (17.8% vs 3.6%) and was 50% higher in the leuprolide group compared with the relugolix group in men without a history of MACE (4.2% vs 2.8%),” Shore said.

Disclosure: Myovant Sciences provided funding for the study. Dr Shore does research for and is a consultant to AbbVie, Ferring Pharmaceuticals, Myovant Sciences, and Tolmar.

1. Shore N, Saad F, Cookson M et al. Oral Relugolix for androgen-deprivation therapy in advanced prostate cancer. N Eng J Med 2020; 382(23):2187-2196. doi:10.1056/NEJMoa2004325

Oral GnRH receptor antagonist has “potential to become a new standard for ADT,” a study investigator says.

Author | Cheryl Guttman Krader, BS, Pharm

Articles

Wearable neuromodulation device shows promise for overactive bladder

Thulium fiber laser shows efficiency advantage in experimental setting

Algorithm may predict health-related quality of life in patients with urolithiasis

Oral gonadotropin-releasing hormone receptor antagonist shows benefits