Long-Term Adherence in a Randomized Controlled Clinical Trial Suggests Feasibility of a Novel Therapeutic Ultrasound Device to Treat Vulvovaginal Atrophy

doi:10.21203/rs.3.rs-3992029/v1

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Research Article

Long-Term Adherence in a Randomized Controlled Clinical Trial Suggests Feasibility of a Novel Therapeutic Ultrasound Device to Treat Vulvovaginal Atrophy

https://doi.org/10.21203/rs.3.rs-3992029/v1

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Background

A randomized (1:1), double-blind, sham-controlled study assessed effectiveness of home-use therapeutic ultrasound for vulvovaginal atrophy (VVA) in post-menopausal women. The objective of the present secondary analyses was to assess participant-reported compared to objectively-tracked adherence to the home-use therapy, and the association between treatment adherence and VVA improvement.

Methods

Participants applied ultrasound 8 min/day to the vaginal introitus for 12 weeks followed by open-label ultrasound treatment to week 48. In 42 post-menopausal women (ages 48–70) with self-assessed vaginal dryness and clinician-diagnosed VVA, self-reported treatment adherence was collected by daily electronic diary. Objective adherence was obtained from a device log recording date, time, and use duration. Clinicians scored vaginal tissue health using the Vaginal Health Index (VHI).

Results

At week 12, self-reported and device-log adherence rates (mean ± SD; Paired t-test) in the modified intent-to-treat population were high among those who remained in the study and were similar in both active treatment (n = 14) and sham (n = 15) groups. Active treatment self-reported adherence was 85.44% ± 20.07% and device-log adherence was 80.66% ± 26.89% (P = 0.6). Sham self-reported adherence was 89.82% ± 8.01% and device-log adherence was 82.53% ± 20.31% (P = 0.2). There was a significant, positive association between ultrasound treatment dose and improved VHI from baseline to week 12 (r = 0.510, P = 0.04; Pearson’s correlation). Thereafter, among participants who remained enrolled in the study, adherence (by device log) was not significantly different at week 24 or week 48 compared to the first 12 weeks (P = 0.5, ANOVA). Compared to baseline (Paired t-test), improvement in VHI was seen at week 24 (P = 0.03) and week 48 (P = 0.06). There were no differences in treatment-emergent adverse events (AEs) between ultrasound treatment versus sham. Participants liked that the ultrasound therapy was non-invasive (37%); easy to use (26%); less messy than typical treatments (16%); able to make the participant feel healthier (10%); and was able to generate tissue moisture (11%).

Conclusions

Participant-reported adherence was not statistically different than objectively tracked adherence. Both measures of adherence were high among those who remained in the study, and such adherence to daily, at-home ultrasound therapy proved efficacious in improving VVA.

Trial registration

Clinicaltrials.gov NCT03931213. 24/04/2019, https://clinicaltrials.gov/study/NCT03931213?id=NCT03931213&rank=1&tab=history&a=2

Genitourinary syndrome of menopause

therapeutic ultrasound

adherence

Genitourinary Syndrome of Menopause (GSM) results from the decrease of estrogen, whether from natural, surgical, or chemically induced menopause (e.g., chemotherapy). This decrease results in reduced blood flow to vaginal and urinary tract tissues, and decreased vaginal tissue elasticity and lubrication.^1,2 The main vaginal symptoms (dryness, irritation, and dyspareunia)³ and associated tissue changes were previously described as vulvovaginal atrophy (VVA), which is now considered a component of GSM.⁴ VVA is a major quality of life concern for millions of women worldwide. VVA prevalence ranges from 23.4% of pre-menopausal women to 47% of late post-menopausal women with no history of breast cancer and 61.5% of post-menopausal breast cancer survivors.⁵

To properly manage VVA, daily or at least twice per week participant adherence to a treatment regimen is essential.⁶ Therapies for women with VVA include nonhormonal, over-the-counter (OTC) lubricants with sexual activity and regular use of long-acting vaginal moisturizers. For women with moderate-to-severe VVA and those who do not respond to lubricants and moisturizers, several other options are available including low-dose vaginal estrogen therapy (ET), vaginal dehydroepiandrosterone (DHEA), ospemifene, and systemic ET (when vasomotor symptoms are also present).³

Many breast cancer survivors are fearful of local/vaginal hormone therapy to treat their VVA, yet their compliance with nonhormonal OTC products is low, likely due to minimal efficacy.^7,8 Forty percent of women find OTC treatment strategies “completely unsatisfactory” due to difficulty of use and lack of desired treatment outcome.⁷

In 2003, the World Health Organization found that “adherence to long-term therapy for chronic illnesses in developed countries averaged 50%.”⁹ This low statistic highlights the importance of developing therapies that can be used properly. Adherence is a complex issue influenced by a wide variety of participant-related, therapy-related, and condition-related factors. The current literature notes that these factors include, but are not limited to, level of participant education, duration participants have lived with the condition, participant expectations regarding treatment outcome, therapy side effects, ease of use, and method of adherence data gathering (i.e., paper diaries vs electronic diaries/self-reporting apps).^9–11

An at-home, nonhormonal, non-invasive therapeutic ultrasound device (Madorra Inc., Portland, OR) is in development with the potential to increase treatment adherence and help women successfully manage VVA. The ultrasound device was shown to significantly improve the patient-reported vaginal symptoms of VVA (dryness, soreness, irritation, dyspareunia) (P = 0.05) and clinician-scored Vaginal Health Index (VHI) (P = 0.03) compared to sham in a 12-week, multicenter, double-blind, randomized, controlled trial (RCT) (Clinicaltrials.gov NCT03931213, 24/04/2019).¹² Therapeutic ultrasound was used to treat post-menopausal vaginal dryness by increasing vaginal blood flow via ultrasonic diathermy,¹² which is expected to increase transudation of extravascular fluid from the blood vessels to the vaginal epithelium.²

For evaluating the effectiveness of therapeutic ultrasound, the study aimed to optimize participant adherence by tracking self-reported participant data electronically and by sending daily text reminders.¹² Targeting multiple influencing factors at once to increase adherence is in accordance with the WHO recommendations, which state that unidimensional interventions, especially those focused solely on participant-related factors, are largely ineffective.⁹ Since devices that are more convenient for participants tend to have higher adherence rates,⁹ the therapeutic ultrasound device was designed to be a simple, non-invasive, completely external, at-home treatment regimen. The study also reported no serious AEs that could have decreased participant adherence.¹² In addition, as it is well known that using electronic participant diaries instead of paper diaries leads to higher adherence rates,^13–18 all study participants self-reported their adherence data using a diary app on their smart phones [Research Electronic Data Capture (REDCap), Seattle, WA] for the first 24 weeks of the trial. To collect objective adherence data that did not require voluntary participant reporting, software was installed in the device that logged the date, time, and duration of use.

Here we report secondary analyses of the study assessing participant-reported compared to device-log adherence, as well as the association between objective treatment adherence and improvement in participant VVA.

Study Design

This 12-week, double-blind, RCT was a superiority design to evaluate effectiveness of therapeutic ultrasound for treatment of VVA.¹² This study was conducted between October 4, 2019, and February 3, 2021, at 5 research centers in Australia. Women were randomized (1:1) to one of two parallel groups by a centralized, remote online IVRS/IWRS in blocks of 4, stratified by site, to either active treatment or sham and instructed by their clinician on how to appropriately use their device by placing it against their introitus for 8 minutes daily at home. All participants, clinicians, and study staff were blinded to randomized treatment allocation. Further study design details have been previously reported.¹²

The study protocol and the patient informed consent form were approved by the ethics committees of Monash Health, Family Planning NSW, and Bellberry Ltd in Australia. The Therapeutic Goods Administration (TGA) was notified of the clinical study prior to initiation, per the TGA’s Clinical Trial Notification Scheme. The study was conducted in accordance with the International Conference on Harmonization Guideline for Good Clinical Practice and the ethical principles in the Declaration of Helsinki.

The use of a participant diary app, along with a device log (participants were informed about this feature), allowed for the validation of self-reported adherence data as well as the assessment of the feasibility of long-term, daily participant use of the ultrasound therapy. The objective device-log adherence data enabled assessment of the association of dose-response with a clinician-scored effectiveness outcome, the VHI. A participant satisfaction survey was administered at study end to understand what factors aided or interfered with treatment adherence.

The study was split into 3 phases. Phase One (weeks 0–12) was conducted as an RCT, where participants received either active treatment or sham. During Phases Two (weeks 12–24) and Three (weeks 24–48), all participants received an open-label, active treatment device but were still blinded as to which device they had received for Phase One. During Phases One and Two only, participants tracked their own adherence with the daily reminder diary app (consisting of short, two-question surveys to assess self-reported adherence). During Phase Three, participants stopped recording diary app entries. A device logger recorded the date, time, and duration the device was used throughout all 3 phases.

Participants received clear instructions on adherence with therapy at the initial screening visit. During the study, the only data which site personnel could access were each participant’s diary of daily adherence to therapy. The Investigator or designated site staff were responsible for providing additional instructions to re-educate any participant who was not compliant with treatment or with completing the diary, as required. The CONSORT checklist was used when writing this report.¹⁹

Study Participants

Post-menopausal women (defined by natural or treatment-induced amenorrhea or oophorectomy at least 12 months prior to screening) 22–70 years of age were eligible to participate in this study if they had menopausal onset of subjective vaginal dryness (with a score of at least 1 on a 4-point scale; where 0 = none, 1 = mild, 2 = moderate, and 3 = severe) and an entry pelvic exam documenting VVA. Women who used systemic or local therapies containing estrogens, progestins, androgens, or selective estrogen receptor modulators in the past 6 months or planned to use these types of therapies during the study were excluded from participation. Additionally, study participants were not allowed to use any other treatment for symptomatic VVA during the study period, including, but not limited to, radiofrequency and laser, and vaginal moisturizers and lubricants (lubricants were allowed for sexual activity but not for 24 hours prior to their study-visit pelvic exams). Women were also ineligible if they had active malignancies or any severe medical condition related to urogenital disease that may have confounded the study. Other exclusion criteria are reported in the primary report of this study.¹²

Materials

Each participant was provided with either an active treatment device or a sham device for the first 12-week randomized, double-blind phase of the study, along with single-use contact pads for device-to-skin coupling. The active treatment device is described in the primary report of this study.¹²

Other than ultrasound emission, the sham device was identical to the operating device. The contact pads were proprietary hydrogels (Madorra Inc., Portland, OR). The contact pads magnetically attached to the ultrasound-emitting face of the device (or mock ultrasound-emitting face in the case of sham treatment) to provide sufficient coupling for the ultrasound waves to properly transmit to the participant in the active treatment group, and to prevent unblinding in the sham group.

Data Collection

Therapy adherence data were collected via 2 methods. The first method was the self-report electronic diary, which each participant was prompted to use via daily text messages and weekly emails through week 24. The daily diary survey asked each participant if she had used her device for that day, and if yes, for how many minutes. The second method of adherence data collection was through the device log, which was downloaded for analysis at the end of the study. The device recorded the date, time, and duration for every treatment session after randomization through study end date.

Improvement in VVA was quantified as a positive change from baseline in clinician-assessed VHI, which has a total score (5–25) as the sum of five domains, each rated 1–5 (1 = none, 2 = poor, 3 = fair, 4 = good, 5 = excellent): vaginal elasticity, fluid volume, pH, epithelial integrity, and moisture.²⁰ VHI was scored at baseline and weeks 12, 24, and 48 by a clinician who was blinded to treatment arm.

Statistical Analysis

A sample size of 21 participants per treatment arm was calculated using data from the literature to achieve 80% power in detecting a difference in change from baseline score of 0.6 between

active treatment and sham with an assumed pooled standard deviation of 0.70 for the primary

effectiveness endpoint (change from baseline in Vaginal Assessment Scale composite score) (0.025 one-tailed significance level), as described previously.¹² The intent-to-treat (ITT) study population comprised all participants randomized and was used for the safety analysis reported previously.¹² The participants in the ITT population who remained in the study comprised the modified-intent-to-treat (mITT) population and were included in the effectiveness analyses reported previously.¹² Given the large amount of data lost to clinic closures during the COVID-19 quarantine, no data imputation was performed and analyses were conducted for all participants with baseline and follow-up clinical evaluation for whom full self-reported and objective adherence data were available for the length of the participant’s enrollment in the study. Participants were excluded from data analysis if they had any protocol deviations. (Protocol deviations were prespecified before the data analysis was initiated.) Data comparisons were considered statistically significant at an alpha of 0.05. Analysis was performed using Minitab.

As adherence to the study protocol was a prespecified secondary analysis to the primary effectiveness endpoints,¹² no formal power calculations were performed. Adherence for any given day was defined as the use of the device at any point in a 24-hour period, for the 8-minute duration of the therapy session. Percent adherence was measured as the total number of therapy sessions, divided by the number of days the participant was in the study, multiplied by 100. A participant was considered nonadherent for a particular day if she skipped her therapy that day or used the device less than the full 8-minutes. A participant could outline reasons for nonadherence in her daily diaries.

To assess participant adherence to the device treatment regimen, the participant’s self-reported diary was compared to her objective device-log data during Phases One and Two by Paired t-test. Comparison of adherence between active therapy and sham groups in Phase One was performed by Unpaired t-test. Adherence between Phases One, Two, and Three was compared using Analysis of Variance (ANOVA). Pearson’s correlation was used to calculate correlations between device-log adherence and diary adherence and between device-log adherence and VHI during Phase One. Analysis of Covariance (ANCOVA) was performed to compare change in VHI score between active treatment and sham groups during Phase One. A Paired t-test was used to compare change in VHI score from baseline to the end of Phase Two and the end of Phase Three.

Participant Disposition and Demographics

Fifty-nine women were screened for the study, and 42 women were enrolled and randomized to active treatment (n = 21) or sham (n = 21) (the ITT safety population).¹² Thirty women remained in the study at week 12, 27 remained at week 24, and 19 remained at week 48 (Fig. 1). Reasons for discontinuation were participant withdrawal of consent (19.0% active; 28.6% sham); AEs unrelated to the therapeutic ultrasound (23.8% active; 33.3% sham); or lost to follow-up (4.8% sham).¹² Demographics and baseline characteristics of the mITT population (the 30 participants who remained in the study at week 12) were not significantly different between the active (n = 15) and sham (n = 15) randomized groups (Table 1). At baseline, participants had, on average, a moderate severity score (approx. 2.0) for vaginal dryness and a poor severity score (< 15.0) for VHI.

Table 1

Participant baseline characteristics (mITT population)
Characteristic	Active (n = 15)	Sham (n = 15)
Age, mean (SD), y	59.3 (5.57)	57.6 (5.99)
Years Menopause, mean (SD), y	11.9 (9.23)	9.9 (6.92)
History of Cancer, n (%)	4 (36)	7 (64)
BMI, mean (SD), kg/m²	27.2 (4.67)	27.6 (4.09)
Vaginal Dryness Average Score (0–3), mean (SD)	2.20 (0.77)	2.29 (0.61)
VHI Total Score (5–25), mean (SD)	12.3 (3.02)	12.7 (3.22) ^a
mITT, modified intent-to-treat; SD, standard deviation; y, years; n, number; %, percent; BMI, body mass index; kg, kilogram; m, meter; VHI, vaginal health index; ^a = n of 14.

Adherence Rates and VHI

A summary of adherence rates is shown in Table 2 and are described for each phase of the study below.

Table 2

Participant adherence^a rates (percent^b, mean ± SD) Phase One, Two, and Three
Phase	Collection Method	Treatment	Adherence %, Mean ± SD
One (Weeks 0–12)	Self-report diary	Active (n = 14)	85.44 ± 20.07
	Self-report diary	Sham (n = 15)	89.82 ± 8.01
	Device Log	Active (n = 14)	80.66 ± 26.89
	Device Log	Sham (n = 15)	82.53 ± 20.31
Two (Weeks 12–24)	Self-report diary	Active (n = 25)	79.29 ± 22.91
Two (Weeks 12–24)	Device Log	Active (n = 25)	75.81 ± 24.07
Three (Weeks 24–48)	Device log	Active (n = 16)	73.64 ± 23.83
^aAdherence for any given day was defined as the use of the device for the full 8 minutes at any point in a 24-hour period. ^bPercent adherence was measured as the total number of therapy sessions, divided by the number of days the participant was in the study, multiplied by 100. SD, standard deviation; %, percent.

Phase One: Weeks 0–12

At the end of Phase One, there were 30 participants in the study (the mITT population). The primary reason that led to study withdrawal was vulvovaginal discomfort, due to irritation from the antimicrobial agent used in the formulation of the contact pad, in both the active (n = 4) and sham (n = 5) groups. Other participants (n = 3) withdrew for personal reasons unrelated to the study treatment. One participant's (active) device log failed to record usage during Phase One, so her data were not included in the analyses. Thus, the Phase One analyses included 29 participants (14 active and 15 sham).

The active group had diary self-reported adherence (mean ± SD) of 85.44% ± 20.07% and mean device-log, objectively tracked adherence of 80.66% ± 26.89% (P = 0.6). The sham group had diary adherence of 89.82% ± 8.01% and device-log adherence of 82.53% ± 20.31% (P = 0.2). Additionally, active versus sham diary self-reported adherence was not significantly different (P = 0.5) nor was active versus sham device-log adherence (P = 0.8). Therefore, data from both groups were combined, yielding a total diary self-reported adherence of 87.71% ± 14.97% and a total device-log adherence of 81.63% ± 23.30%, which were not significantly different (P = 0.2). For the combined active and sham groups, there was a significant positive correlation (r = 0.759, P < 0.0001) between total diary self-reported adherence and total device log adherence (Fig. 2).

Week 12 VHI data were only available for 17 of 29 participants (9 active and 8 sham) without protocol deviations, primarily due to clinic closures resultant from the COVID-19 quarantine and loss of follow-up data. This group of 17 participants is defined as the per protocol (PP) group. The active group compared to the sham group had a significantly greater improvement in VHI score (mean ± SEM) of 2.32 ± 0.58 vs. 0.02 ± 0.62 (P = 0.03)¹² improving their tissue health on average approximately 19% from poor to fair (≥ 15).

To evaluate the presence or absence of a dose-response relationship between the objective measure of treatment adherence (device log) and clinician-scored change in vaginal tissue health (VHI) from baseline to week 12, the active and sham groups of the PP population were then combined. For this analysis, adherence for each participant in the sham group was recorded as 0%, since these participants received no actual ultrasound therapy from the device. One participant’s (active) device log failed to record usage during Phase One, thus her data were excluded from this analysis, resulting in 8 participants in the active group. There was a statistically significant, positive dose-dependent response found between adherence and improvement in vaginal tissue health (r = 0.510, P = 0.04) (Fig. 3).

Phase Two: Weeks 12–24

At the start of Phase Two, all 30 mITT participants received open-label, active treatment devices. During this phase, three participants discontinued for personal reasons unrelated to study treatment or due to an AE unrelated to the therapeutic ultrasound, one participant did not use her device after week 12, and another participant stopped filling out her diary around week 15; all five of these participants’ data were excluded from analysis. Data from the 25 participants who remained in the study were included in Phase Two adherence analysis.

Diary and device-log adherence (means ± SD) for all participants on open-label active treatment were combined. Overall, the diary self-reported adherence was high at 79.29% ± 22.91%. Device-log adherence was also high at 75.81% ± 24.07%. There were no significant differences between the diary and device-log adherence rates (P = 0.6). Additionally, there was a significant, strong, positive linear correlation between the diary and device-log adherence for Phase Two (r = 0.949, P < 0.0001).

Week 24 VHI data were collected from 16 of the 25 participants still enrolled at the end of Phase Two (data were lost for 9 participants due to clinic closures from the COVID-19 pandemic). One of the 16 participants had used a prohibited gel (a protocol deviation) and thus was excluded from this analysis. The 15 remaining participants showed an average improvement (mean ± SD) from their baseline VHI score of 3.07 ± 5.32 (P = 0.03),¹² improving their tissue health on average approximately 25%.

Phase Three: Weeks 24–48

By design, during Phase Three of the study, participants no longer self-reported their adherence. Therefore, only device-log adherence data were available for analysis. Six participants withdrew during weeks 24–48 due to personal reasons linked to the ongoing COVID-19 pandemic or a non-serious AE unrelated to the therapeutic ultrasound, leaving 19 participants enrolled at the end of the study. Due to protocol deviations, 3 participants were excluded from analysis. One participant was not included due to initiation of a prohibited estrogen therapy at week 36, and 2 were not included because they stopped participating in the study at the beginning of Phase Three. Device-log adherence (mean ± SD) for the remaining 16 participants was 73.64% ± 23.83%. There was no significant difference in device-log adherence rates (mean ± SEM) between Phases One (n = 29, 81.63% ± 4.33%), Two (n = 25, 75.81% ± 4.81%), or Three (n = 16, 73.64% ± 5.96%) (P = 0.5) (Fig. 4).

Week 48 VHI data were collected from 13 of the 19 participants still enrolled at the end of Phase Three (data were lost for 6 participants due to clinic closures from the COVID-19 pandemic). Two participants did not have adherence data for Phase Three (protocol deviations for stopping therapy, described above), and 1 participant used a prohibited gel (protocol deviation, described above). The 10 participants remaining showed an average improvement (mean ± SD) from their baseline VHI score of 3.20 ± 4.66 (P = 0.06),¹² improving their tissue health approximately 26%.

Using a survey at study end, 53% of 19 participants reported wanting to continue using the ultrasound therapy device and 47% reported they would purchase the device. Participants liked that the ultrasound therapy was non-invasive (37%); easy to use (26%); less messy than typical VVA treatments (16%); able to make the participant feel healthier (10%); and was able to generate tissue moisture (11%). When given a choice of treatments for VVA, 41% of participants reported they would choose the ultrasound therapy device, 23% would use moisturizers/lubricants, 12% would choose vaginal hormone therapy, 6% would choose herbs, and 18% said “other/unknown.” Participants reported the factors that interfered with their treatment adherence included the requirement of daily use (42%), length of time of daily use (16%), and insufficient effectiveness (16%).

Therapeutic ultrasound was found to prospectively improve vaginal tissue health in post-menopausal women with vaginal dryness in a double-blind, RCT.¹² In the present analysis, the clinician-scored VHI correlated with an objective measure of adherence stored in the device log. To our knowledge, this is the first study to objectively measure adherence to VVA therapy over time. This study uniquely objectively assessed participant adherence and therefore validated the use of electronic self-reported diaries. Adherence rates were similar between participant self-reported data and objectively tracked device-log data, indicating that study participants overall accurately reported their daily therapy compliance. Correlation analysis between diary and device-log adherence yielded significant positive linear correlations, indicating a close predictive relationship between each participant’s self-reported and objectively tracked adherence rates. Also, adherence rates were high among those who remained in the study, irrespective of either method of collection, indicating that women were motivated to use the therapy. Additionally, there was no difference in adherence rates between active and sham groups, highlighting perhaps the strength of the study blinding and may also be a further testament to overall high motivation for this therapy. Overall, the findings support existing literature highlighting the benefits of electronic participant diaries as an easy, less burdensome, and reliable method of measuring participant self-reported adherence.^15,17

Adherence to therapy remained high among participants who were enrolled throughout the duration of the 1-year study, as there was no significant difference in adherence rates over time. Mean device-log adherence rate peaked at 81.63% during Phase One (week 12) and dropped only to 73.64% during Phase Three (week 48). When compared with the average adherence to treatment for chronic illnesses of 50%,⁹ the adherence rates in the present study are remarkably higher. Adherence to medical therapies and in daily-use medical device clinical studies is also generally not high.^21,22 A review of adherence research over a 30-year period concluded that between 30% and 50% of all study participants complied poorly with their therapy, irrespective of disease, prognosis, and setting.²¹ Some examples include a study of regular self-administration of eye drops for glaucoma therapy to prevent blindness that showed non-adherence for 33% of participants.²² In another example, in a one-year RCT of vibrational device daily therapy for menopausal osteoporosis, only 37% of participants were at least 80% compliant while 72% of participants were at least 60% compliant.²³ Relevant benefit of treatment was only observed in those in the highest quartile of adherence (86% compliant).²³ In an orthodontic appliance adherence study, a thermal sensor objectively measured wear time up to a year.²⁴ Although all participants were informed that their adherence was being monitored by the sensors, as in the present study, mean adherence at one year was still low (62.5%), compared to the present study (73.6%).

The high adherence rates among those who remained in the present study over an extended period (24–48 weeks) also support the feasibility of the long-term, daily use of the therapeutic ultrasound device.

There were several limitations of this study. First, participants were told of the presence of the device logger. Other studies have found that informing participants of adherence tracking leads to improvements (or, in some cases, no change) in adherence rates.^24–26 However, the present study did not contain a control group that was uninformed about objective adherence tracking, so conclusions cannot be drawn about whether informing participants resulted in higher adherence. In addition, this study used an electronic participant diary app, and higher adherence rates have been found to be associated with the use of electronic diaries.¹⁷ Again, since this study did not have a control group that completed paper diaries, it cannot be determined whether diary app usage raised participant adherence rates. Moreover, the electronic participant diary app was accompanied by daily text reminders. This may have increased participant device and diary app usage. Again, without a comparator group that did not receive text reminders, it cannot be determined if these notifications increased participant adherence.

Further, intrinsic biases and experimental conditions also may have affected the data analysis. For instance, although the Investigators were blinded to participant treatment arm when scoring the VHI, they knew the patient and the sequence of follow-up. However, the blinding survey showed that only 53% of Investigators correctly guessed the participants’ treatment assignment after Phase One, emphasizing the robustness of the investigator blinding in this study.¹² Another limitation of this study is that excluding participants who withdrew from the study from the analyses could have contributed to a discontinuation bias, even though they did not cite therapy-related reasons for withdrawing. The participants who remained enrolled throughout the full duration of the study had high adherence with therapy. Also, the participants were mainly Caucasian with an average BMI of 27 kg/m², and thus do not represent the broader population of post-menopausal women with VVA. Additionally, participant discontinuations due to contact pad irritation and COVID-19 closures resulting in loss of follow-up data reduced analysis group sample sizes and decreased the power of the significance tests performed. The contact pad has subsequently been reformulated and clinically tested in a second double-blind, sham-controlled trial (Clinicaltrials.gov NCT04887701, 24/04/2019).

The high, long-term adherence rates among those who remained in the study suggest that the therapeutic ultrasound device could be an effective treatment option for women with VVA who find current OTC or hormone-based treatment strategies insufficient, unsatisfactory, or unsuccessful. When the 12-week randomized, double-blind data are considered, the results indicate a potential benefit of treatment strongly dependent on dose adherence, as using the therapeutic ultrasound device for 8 minutes daily was associated with a greater improvement in vaginal tissue health.¹² Additionally, the high adherence among those who remained in the study over the 1-year follow up, along with improvement in tissue health as compared to baseline, suggests sustained effectiveness with consistent use of the therapy. However, participants reported that the requirement of daily use was the factor that most interfered with their adherence. Further studies may be warranted to assess if fewer days per week of therapy, e.g. as a maintenance dose, or other changes would result in effective therapy and even higher adherence.

More generally, the data gathered during this study align with existing literature on electronic diary usage in clinical trials as an accurate measure of true participant adherence to a treatment regimen.¹⁷ Women in the study reported liking the device primarily because it was non-invasive, easy to use, and improved symptoms. These reasons may have contributed to the high adherence seen among those who remained in the study. Also, there were no serious AEs related to the 1-year use of ultrasound for treatment of VVA.¹²

In this study, a home-use, therapeutic ultrasound device provided women with a safe,¹² effective, non-invasive, and easy-to-use alternative treatment option for VVA. Participants who remained in the study had high adherence to the daily treatment regimen over one year and accurately self-reported their adherence. A dose-response relationship between treatment and improvement in VVA was observed, emphasizing the importance of sustained adherence for effective therapy outcome. The therapeutic ultrasound device has the potential to offer postmenopausal women with VVA a satisfactory, long-term treatment option.

AEs

Adverse Events

ANCOVA

Analysis of Covariance

ANOVA

Analysis of Variance

BMI

Body Mass Index

CONSORT

Consolidated Standards of Reporting Trials

COVID-19

Coronavirus Disease 2019

DHEA

Dehydroepiandrosterone

Estrogen Therapy

GSM

Genitourinary Syndrome of Menopause

ITT

Intent-to-Treat

IVRS

Interactive Voice Response System

IWRS

Interactive Web Response System

mITT

Modified-Intent-to-Treat

NSW

New South Wales

Oregon

OTC

Over-the-Counter

Per Protocol

RCT

Randomized, Controlled Trial

REDCap

Research Electronic Data Capture

Standard Deviation

SEM

Standard Error of the Mean

TGA

Therapeutic Goods Adminstration

VVA

Vulvovaginal Atrophy

Washington

WHO

World Health Organization

Ethics Approval and Consent to Participate: The study protocol and the patient informed consent form were approved by the ethics committees of Monash Health, Family Planning NSW, and Bellberry Ltd in Australia. The Therapeutic Goods Administration (TGA) was notified of the clinical study prior to initiation, per the TGA’s Clinical Trial Notification Scheme. The study was conducted in accordance with the International Conference on Harmonization Guideline for Good Clinical Practice and the ethical principles in the Declaration of Helsinki. All participants signed the patient informed consent form prior to participation in the study.

Consent for Publication: Not applicable

Availability of Data and Materials: The datasets generated and/or analyzed during the current study are not publicly available as they are proprietary, but they are available from the corresponding author on reasonable request.

Competing Interests: RB, no competing financial interests; GC has received salary from Madorra; DD, SL, and HR are employees of Madorra, Inc. and received stock options; SK received consulting fees from Madorra, Inc.

Funding: This study was funded by Madorra, Inc., Portland, OR. The sponsor participated in the design of the study. The study was conducted by the Investigators with the assistance of a contract research organization. Employees of the sponsor collaborated with an independent statistician to prepare the statistical analysis plan, and the analyses were performed by the independent statistician. The final decision on the content of the manuscript was retained by the authors.

Authors’ Contributions: Participated in data collection and review of manuscript: RB, SL; participated in data analysis and manuscript preparation: GC, DD, HR, SK.

Acknowledgements: The authors would like to thank all the women who participated in this study and the study investigators and staff at each site: Dr. Martha Hickey and Shona Darby, Royal Women’s Hospital, Melbourne, AU; Dr. John Eden and Jinzhu Liu, Women’s Health and Research Institute of Australia, Sydney, AU; Dr. Janelle Brennan and Tanya Holland, Goldfields Urology, Victoria, AU; Dr. Deborah Bateson, Dr. Clare Boerma, and Prudence Kidman, Family Planning New South Wales, Sydney, AU; and Yue Zhao, Royal North Shore Hospital, Sydney, AU. The authors would also like to acknowledge Lisa Dawes, Valerie Sars, and Richard Veerman who supported data management and Bryan Flaherty, Stephanie Kaplan, and Robert Blante for designing the therapeutic device.

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Competing interest reported. Dr. Rodney Baber, no competing financial interests; Gianna Colombo has received salary from Madorra; Dr. Darlene Dreon, Sara Lashanlo, and Holly Rockweiler are employees of Madorra, Inc. and received stock options; Dr. Sheryl Kingsberg received consulting fees from Madorra, Inc.

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Long-Term Adherence in a Randomized Controlled Clinical Trial Suggests Feasibility of a Novel Therapeutic Ultrasound Device to Treat Vulvovaginal Atrophy

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Abstract

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Background

Methods

Study Design

Study Participants

Materials

Data Collection

Statistical Analysis

Results

Participant Disposition and Demographics

Adherence Rates and VHI

Phase One: Weeks 0–12

Phase Two: Weeks 12–24

Phase Three: Weeks 24–48

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