Feasibility and acceptability of the menstrual cup for non-surgical management of vesicovaginal fistula among women at a health facility in Ghana

Objective To assess the feasibility of the menstrual cup for short-term management of urinary leakage among women with vesicovaginal fistula (VVF) Methods A repeated measures design compared volume of leakage with and without the cup via a 2-hr pad test among women with VVF seeking surgical repair at a health facility in Ghana. Subsequently a gynecological exam was administered to assess safety outcomes, followed by a questionnaire to assess acceptability and perceived efficacy. A paired t-test was used to analyze reduction of leakage in ml, and percent reduction was reported. Study limitations include observer bias while evaluating adverse outcomes and the possibility of social desirability bias during questionnaire administration that might overestimate the effect of the cup and women’s acceptability. Results Of the 32 patients screened, 11 were eligible (100% consent rate). At baseline, mean (±SD) leakage in ml was 63.2 (±49.2) (95% CI: 30.2–96.3) over two hours, while the mean leakage over two hours of use of the cup was 16.8 (±16.5) (95% CI: 5.7–27.9). The mean difference of 46.4 (±52.1) ml with use of the cup (95% CI: 11.4–81.4) was statistically significant (p = 0.02). With the cup, women experienced an average 61.0% (±37.4) (95% CI: 35.9–86.2) leakage reduction, a difference 10/11 users (91.0%) perceived in reduced leakage. One participant, reporting four previous surgical attempts, experienced a 78.7% leakage reduction. Acceptability was high—women could easily insert (8/11), remove (8/11), and comfortably wear (11/11) the cup and most (10/11) would recommend it. No adverse effects attributable to the intervention were observed on exam, although some women perceived difficulties with insertion and removal. Data collection tools were appropriate with slight modification advised. Conclusion A larger trial is warranted for a more robust evaluation of the menstrual cup for management of urinary leakage due to VVF among women who have not yet accessed surgery or for whom surgery was not successful.


INTRODUCTION
Obstetric fistula, a debilitating birthing injury, leads to urinary incontinence and subsequent psychosocial and economic consequences for as many as two million women predominantly in Sub-Saharan Africa. Surgical repair is possible; however, most women either do not access surgery or successful repair is not guaranteed, leaving them few or no options to control chronic urinary leakage. The menstrual cup is a medical device inserted into the vagina to collect menstrual flow, which could also be used to control urine leakage for women with vesicovaginal fistula (VVF). While surgical management of VVF would remain the gold standard in treatment, the menstrual cup could be an alternative for women who do not have access to surgery or are poor surgical candidates. Therefore, this study will assess the feasibility of the menstrual cup for short-term management of fistula among women with VVF in a health facility in Ghana. A repeated measures design will be used to compare leakage pre and post 2-hr use of the device among 11 women. For limited-efficacy testing [2], the cup's effect will be determined by estimating the change in volume of urine leaked before and while using the cup, which will be measured via a 2-hour pad test. [1] Post-use safety outcomes will be assessed objectively by gynecological examination (erythema, edema/induration, erosion, and bleeding) and subjectively by questionnaire responses (itch, vaginal pain, lower abdominal pain, vaginal bleeding, new odor, other).
After use, participants will be read a structured questionnaire on demographics, clinical characteristics, perceived usual severity of leakage [4], perceived efficacy, and acceptability. Using a Likert scale with values ranging from 1-5, acceptability will be reported based on ease of insertion, removal, and cleaning; comfort while wearing; useful for fistula management; interference with activities. Responses will be dichotomized where 0 will equal disagreement, while 1 will equal agreement with the respective aspect of acceptability (the exception is interference with activities which is reverse coded). A summarizing acceptability scale will not be reported.
Additional feasibility factors will be assessed throughout to inform the necessary steps of a future study, including rates of enrollment and consent and appropriateness of data collection. Appropriateness of the data collection tools will be determined by whether tools can be interpreted in local dialects and whether participants understand questions.

ANALYSIS SETS/ POPULATIONS/SUBGROUPS
This single-arm, unblinded clinical feasibility trial will be conducted at Mercy Women's Catholic Hospital in Mankessim in the Central Region of Ghana. Participants seeking care for obstetric fistula will be included. Both women who have not yet accessed surgery and those who have previously attempted repair will be included in the sample, and their outcomes will be compared.

Intervention
The menstrual cup (DivaCup, Diva International Inc., 222 McIntyre Drive, Kitchener, Ontario, Canada N2R 1E8) is approved by the United States Food and Drug Administration for the collection of menstrual blood. Made of 100% silicone and holding up to 30ml, it is available as model one for nulliparous women under 30 years old and model two for multiparous women and/or women age 30 or older. All study participants will likely use model two, although this will be informed by expert clinical opinion decided upon during initial gynecological exam.

HANDLING OF MISSING VALUES AND OTHER DATA CONVENTIONS
Data collectors will carry out quality control efforts to ensure questionnaires are complete. If any data is missing before the end of the trial, nurses will follow up with participants. In the case that there is missing data and it is missing at random, then case-wise deletion will be used. In the case that data is not missing at random, imputation will be carried out.

STATISTICAL METHODOLOGY
This clinical trial will focus primarily on feasibility of the intervention by evaluating efficacy, safety, and user acceptability. Data will be analyzed using Stata v.13. Independent and dependent variables will be examined using univariate analyses to assess central tendency, normality, and distribution. The volume leaked at baseline and with the cup inserted will be compared using a paired t-test. A 95% confidence interval will be generated for the mean difference.
Sample size calculation An a priori sample size calculation was carried out. Using Stata software and assuming a 50% reduction in leakage with use of the cup, with 90% power and an alpha of 0.05, a total of 18 subjects would be required. At the rate of about 15 fistula repairs per quarter, knowing that not all fistula patients will be eligible, the 18 subjects can be recruited in 6 months.
We originally used no estimate of variation in the original calculation that used 50% reduction for effect size and produced 18 participants needed. We later used an educated guess from a clinical expert and initial observations of effect and variance to modify the calculation using a 65% effect size and produced 11 participants needed. This calculation used alpha=0.05, power= 0.80, delta=-0.90, d0=0.00, da=-37.00, sd_d=41.00, ma1=57.00 and ma2= 20.00. As the primary objective is to investigate feasibility, not just limited-efficacy testing, the study team agreed that after 11 participants we could appropriately assess the feasibility outcomes.

Efficacy
Objective assessment An absolute and relative reduction will be assessed.
Paired t-test dmean = Sum (leakage_baseline1 -leakage_withcup1) + (leakage_baseline1 -leakage_withcup1) / number participants percent(diff) = (diff/ leakage_baseline) x 100 Let x = volume leaked without the cup and y = volume leaked with the cup. To test the null hypothesis that the true mean difference is zero, the procedure will be: 1. Calculate the difference (di = yi − xi) between the two observations on each pair. 2. Calculate the mean difference, dmean. 3. Calculate the standard deviation of the differences, sd, and use this to calculate the standard error of the mean difference, SE(dmean) = sd √ n. 4. Calculate the t-statistic, which is given by T = dmean SE(dmean) . Under the null hypothesis, this statistic follows a t-distribution with n − 1 degrees of freedom. 5. Use tables of the t-distribution to compare your value for T to the tn−1 distribution. This will provide the p-value for the paired t-test.
For this test to be valid the differences only need to be approximately normally distributed. Therefore, it would not be advisable to use a paired t-test where there were any extreme outliers. We will need to assess for outlier using the following formula [3]: where Q1 is the lower interquartile range, Q3 is the upper interquartile range, k=1.5 indicates an outlier, and k=3 indicates an extreme outlier.
To estimate a confidence interval for the true mean difference, we will use the following formula: where t* is the 2.5% point of the t-distribution on n-1 degrees of freedom.

Subjective assessment
Difference in frequency of pad change while using the cup compared to baseline.

Cup safety
Objective assessment Frequency of report of erythema, edema/induration, erosion, bleeding, change in fistula size after clinical examination

Subjective assessment
Frequency of self-report of abdominal pain, vaginal pain, itch, vaginal bleeding, new odor User acceptability Acceptability outcomes will be reported as the proportion of participants who agreed with aspects of acceptability. Likert-type responses of agreement (1-5) will be recoded to binary responses where strongly disagree, slightly disagree, and neutral will be recoded to disagree, while slightly and strongly agree will be recoded to agree (except the interference with daily activities question, which will be reverse coded).

Demographic and clinical characteristics
Demographic and clinical characteristics data will be explored using univariate analyses to describe the sample.

TABLES
For all tables, continuous variables will be reported with mean (SD) or with median (IQR) in the case there are outliers. Categorical variables will be reported with proportion (%) in each category.  Table 2. Observed and Perceived Efficacy Table 3. Acceptability 8 QC PLANS To ensure that the rights and well-being of the participants are protected, the study personnel will confirm that the participant has signed the consent of the subject prior to taking part in the trial and that the relevant personnel and test equipment are properly tested, including a calibrated scale.
To ensure the quality of the clinical data for each participant, the data manager (NR) will check whether the questionnaire is complete or whether there is an omission.