Vaginal hormone-free moisturising cream is not inferior to an estriol cream for treating symptoms of vulvovaginal atrophy: Prospective, randomised study

Susana Garcia de Arriba; Lisa Grüntkemeier; Manuel Häuser; Theodor W May; Clarissa Masur; Petra Stute

doi:10.1371/journal.pone.0266633

. 2022 May 12;17(5):e0266633. doi: 10.1371/journal.pone.0266633

Vaginal hormone-free moisturising cream is not inferior to an estriol cream for treating symptoms of vulvovaginal atrophy: Prospective, randomised study

Susana Garcia de Arriba ^1,^*, Lisa Grüntkemeier ¹, Manuel Häuser ¹, Theodor W May ², Clarissa Masur ¹, Petra Stute ³

Editor: Walid Kamal Abdelbasset⁴

PMCID: PMC9098008 PMID: 35551533

Abstract

This prospective, open-label, multicentre, multinational, randomised trial investigated the non-inferiority of treatment with a vaginal hormone-free moisturising cream compared to a vaginal estriol (0.1%) cream in a panel of post-menopausal women suffering from symptoms of vulvovaginal dryness in a parallel group design. In total, 172 post-menopausal women were randomly allocated to either one of the two treatments, each administered for 43 days. The primary endpoint was the total severity score of subjective symptoms (dryness, itching, burning and pain unrelated to sexual intercourse) of the respective treatment period. Secondary endpoints were severity of single subjective symptoms (including dyspareunia if sexually active), impairment of daily life, Vaginal Health Index, as well as assessment of safety. In both groups, women treated with hormone-free moisturising cream and those treated with estriol cream, total severity score improved significantly compared to baseline by 5.0 (from 6.1 to 1.1) and by 5.4 (from 6.0 to 0.6), respectively, after 43 days of treatment (p < 0.0001). One-sided test of baseline differences (for a clinically relevant difference Δ = 1.5) confirmed the hormone-free moisturising cream to be non-inferior to the estriol cream. Severity of dyspareunia as well as impairment of daily life due to subjective symptoms, significantly improved for both treatment groups (p<0.0001). Subgroup analysis of women with mild or moderate impairment of daily life at baseline caused by “vaginal dryness” symptoms benefited from both creams, while women with severe impairment showed a significantly greater benefit from the estriol cream (p = 0.0032). Both treatments were well tolerated with no serious adverse events occurring. This study provides clinical evidence that a hormone-free vaginal moisturising cream cannot only improve vaginal dryness compared to an 0.1% estriol cream but also can relieve dyspareunia as well as improve woman’s impairment of daily life, justifying its use as a first choice for mild or moderate vulvovaginal dryness symptoms.

Introduction

With increasing life expectancy, clinical manifestations of menopausal symptoms are becoming more relevant. Changes in the genitourinary tract associated with decreased estrogenization [1] include decreased vaginal vascularization, lubrication, as well as thinning of the vaginal epithelium [2]. The collagen and water content of the vaginal skin decreases, epithelial cells die and exfoliate leading to a substantial loss of glycogen which is associated with a relevant decrease in the lactobacillus population and an increase in vaginal pH [3]. As a result, epithelium integrity is dry and disturbed [4].

Approximately 50% of postmenopausal women experience vulvovaginal atrophy (VVA) symptoms, also referred to as genitourinary syndrome of menopause (GSM) [4, 5]. The main symptom vulvovaginal dryness negatively affects both, sexual function [6] and overall quality of life [7]. From a subjective perspective, GSM symptoms include dryness, itching, burning sensation and pain (unrelated to sexual intercourse) as well as dyspareunia (pain during sexual intercourse) [2, 5].

According to the NAMS position statement [8], the primary aim of an appropriate GSM treatment is to alleviate the subjective vulvovaginal atrophy symptoms. First-line therapies comprise non-hormonal, long-acting vaginal moisturizers [8, 9]. For symptomatic GSM not responding to hormone-free approaches, low-dose vaginal estriol and vaginal estradiol products are recommended [9, 10]. This statement has been gaining strength in last 10 years even though clinical data comparing the use of hormone-free to hormonal vaginal products are missing.

Several hormone-free vaginal products are available to improve the moisture balance in the vagina as well as to reduce the vulvovaginal symptoms [11]. Many hormone-free formulations are water-based gel formulations lacking lipid components. However, since the vaginal epithelium is a multi-layered stratified squamous epithelium [12], a cream formulation containing both, water and skin-soothing lipids appears to be a promising treatment option [5, 6] to maintain hydration and suppleness [13]. The efficacy of this oil-in-water hormone-free vaginal moisturising cream under investigation, improving subjective vulvovaginal atrophy symptoms and its tolerability have been previously confirmed in pre- and postmenopausal women [14] as well as in breast cancer patients [15].

The aim of this study was to provide evidence regarding efficacy of a vaginal hormone-free moisturising cream compared to a cream with 0.1% estriol.

Methods

Study design

This prospective, open-label, randomized, controlled trial (RCT) to show non-inferiority with two parallel groups (hormone-free moisturising cream vs. estriol cream) was conducted at 8 centres in Germany and Switzerland from 07 November 2016 (first enrolment) to 19 June 2017 (last patient finished), according to the Declaration of Helsinki and the GCP guidelines. The study was approved by the Independent Ethics Committee of Schleswig-Holstein (Code121/16II) in Germany and by Kantonale Ethikkommission Bern (Code 2016–01464) in Switzerland, respectively. All women gave written informed consent before starting the study. This clinical trial was registered at EudraCT (2016-002199-28) and at ClinicalTrials.gov (NCT03044652). The study is compliant with CONSORT guidelines for non-inferiority and equivalence randomized trials [16] and with the FDA guideline for non-inferiority clinical trials [17].

Study population

Only postmenopausal women (amenorrhea > 12 months or bilateral oophorectomy with or without hysterectomy > 3 months) exhibiting subjective vulvovaginal dryness symptoms with a total severity sum score (TSS) ≥ 3, a visual analogue scale (VAS) value “Overall impairment of daily life due to the condition vulvovaginal dryness” > 0, a Papanicolaou test (Pap test) class I or class II and a body mass index (BMI) between 19 kg/m² and 35 kg/m² were included in this study.

Women with known allergies to any of the cream ingredients or had used systemic/local hormonal therapies within 3 months before first visit as well as women who used moisturizers (vagina/vulva), systemic corticosteroids, antibiotics or antimycotics 14 days before first visit and/or during the trial were excluded. No violations of the exclusion criteria were detected in the trial.

Patients admitted to the trial were randomized either to receive the estriol cream or to receive the hormone-free moisturising cream in a 1:1 ratio. Separate randomization lists (using randomly permuted blocks with a fixed block size of four) were provided for each centre. Randomization codes were generated centrally by utilizing the software SAS^® for Windows version 9.4. Randomization was performed by a statistician who was not directly involved in the analysis of the trial. Upon randomization, each patient received a unique randomization number. The medication and the randomization numbers were allocated to the trial centres according to the randomization lists (S1 File).

Product application

The reference product (Ovestin^® 1 mg creme, Aspen Bad Oldesloe GmbH, Germany), hereafter referred to as “estriol cream” contains 1 mg estriol in 1 g cream and is approved as medicinal product. The investigational product (Vagisan^® Moisturising Cream, Dr. August Wolff GmbH & Co. KG Arzneimittel, Germany), is a hormone-free oil-in-water emulsion (cream) and certified as class IIb medical device for intra- and extra-vaginal use (CE 0483). It has a lipid content of 23%, a pH adjusted to 4.5 with lactic acid and an osmolality of 374 mOsm/kg, which is in accordance with the WHO’s recommendation of < 380 mOsm/kg for personal lubricants [18, 19].

Both vaginal creams were applied by the patients themselves according to the respective package leaflet. Hormone-free moisturising cream was applied intravaginally, using the provided applicator (approximately 2.5 g) once daily at night, and in the outer genital area (a cream ribbon of approx. 0.5 cm) several times per day, as needed. Once symptoms had improved, the frequency of cream application could be reduced, as needed. The estriol cream (0.5 g) was applied intravaginally once daily for the first 3 weeks with the provided applicator and twice-weekly thereafter, according to package leaflet.

Study endpoints

The primary objective of this trial was to confirm the non-inferiority of the treatment with hormone-free moisturising cream compared to an estriol cream (0.1%). The comparison was based on the subjective assessment of the symptoms of vulvovaginal dryness (dryness, itching, burning and pain unrelated to sexual intercourse). Symptoms were assessed on Visits 1, 2 and 3 as well as once weekly at home in a patient diary, rating their severity on a five-point scale (0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe). total severity score was defined as the sum of the single score dryness, itching, burning and pain unrelated to sexual intercourse. In total, the total severity score scale ranges from 0 = no complaints to 16 = very severe complaints. Differences to Baseline (Visit 1) of the total severity score assessed after 43 days of treatment (Visit 3) served as primary endpoint for the test of non-inferiority.

Secondary endpoints included the participants’ assessment of (1) the severity score of single subjective symptoms; (2) the severity scoring of dyspareunia (by sexually active participants only) according to a five-point scale (0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe), (3) the impairment of daily life due to single subjective symptoms and the impairment of daily life due to dyspareunia assessed by using a VAS ranging from 0 (no impairment) to 10 (very pronounced impairment); (4) the overall impairment of daily life score due to “vaginal dryness”, assessed on an VAS which was categorized as follows: 0.1 to 3.3 = mild, 3.4 to 6.6 = moderate, 6.7 to 10 = severe; (5) the Vaginal Health Index (VHI) and the vaginal status of Lactobacillus flora as objective assessment of vaginal findings at each visit by the investigator’s clinical evaluation [20]. The Vaginal Health Index is the sum of the scores of the criteria overall elasticity, fluid secretion type and consistency, vaginal pH, epithelial mucosa and moisture which are graded from 1 (worst) to 5 (best). Safety was assessed by evaluating the occurrence of adverse events (AEs).

The severity five-point scale used in this study has already been successfully used in other gynaecological studies [14, 15], while the Vaginal Health Index is a standardized index to assess the health status of the vagina [20]. According to the protocol, patients were asked to report concomitant therapies and adverse events (AEs) on all visits.

Statistical analysis

172 women, who received at least one application of the test products, regardless of the number of further assessments, were included into the safety population (SP) and 169 of these women with at least one post-baseline assessment were included into the intention to treat population (ITT). 151 women (per protocol population, PP) finished the study in accordance with the trial protocol without major protocol deviations (Fig 1). Study endpoints were analysed primarily for the PP population and repeated, for sensitivity reasons, for the ITT population [16].

Fig 1 — Disposition of patients. SP, Safety Population; ITT, Intention-To-Treat Population; PP, Per Protocol Population.

According to the study protocol, a one-sided test on differences to baseline of total severity score (Day 43) was carried out in the PP population to determine whether the reduction of this value in the hormone-free moisturising cream group was not clinically inferior compared to the estriol cream group. Delta (Δ) value of 1.5 was defined as the limit for a clinically relevant difference.

A one-sided t-test for independent samples or Mann-Whitney-Wilcoxon test (depending on the result of the Shapiro-Wilk test for normality) was performed. In addition, it was checked whether a two-sided test for Δ = 1.5 and a one-sided test for a ("sharper") Δ = 1.0 also confirmed the non-inferiority of hormone-free moisturising cream.

The sample size was calculated with the Software “N” (IDV, Gauting, Munich) and verified by SAS Sample Size 3.1. A sample size of 138 (69 for each arm) for a one-sided t-test for non-Inferiority (α = 0.05) sufficed to assure a statistical power of 90% to reject the null hypothesis. To account for an assumed drop-out rate of 20% a total of n = 172 patients was randomized.

All secondary endpoints were evaluated descriptively and interpreted in the context of an explorative data analysis. The endpoint Area Under the Curve (AUC) over the course of the study was used for the statistical evaluation of the comparison of the two treatments for all secondary endpoints given above and using the t-test or the Mann-Whitney-Wilcoxon test (depending on the Shapiro-Wilk tests for normality).

All results are expressed as the mean and standard deviation (SD) or Standard Error of the Mean (SEM). A p value < 0.05 was considered as statistically significant.

Results

Study population

In total, 172 women were included in the study, 87 were randomized to the hormone-free moisturising cream group and 85 women to the estriol cream group (Fig 1). 98.8% of women met all eligibility criteria. 21 women were excluded from analysis due to major protocol violations such as antibiotic intake (n = 1) and premature trial termination. Premature termination (n = 10, 5.8%) occurred more than twice as much in the estriol cream group (n = 7, 8.2%) as compared to the hormone-free moisturising cream group (n = 3, 3.4%) (Fig 1). Four of the premature terminations in estriol group were due to AEs such as lower abdominal pain, candida vulvitis, palpitations with rising blood pressure and one broken artificial tooth with surgery. None of the premature termination in the hormone-free moisturising group was related to AEs. Demographic and baseline characteristics are summarized in Table 1.

Table 1. Demographic and baseline characteristics.

Characteristics	Values per treatment group
Characteristics	Hormone-free cream	Estriol cream
Number of Women PP (ITT)	80 (86)	71 (83)
Age (years)	59.5 ± 7.3	61.7 ± 6.9
BMI (kg/m²)	25.8 ± 3.8	25.9 ± 3.7
Sexually active (n)	64	42
Severity Scoring of individual symptoms at baseline*
Dryness	2.3 ± 0.8	2.3 ± 0.9
Itching	1.4 ± 0.1	1.4 ± 0.1
Burning	1.4 ± 0.1	1.5 ± 0.1
Pain unrelated to sexual intercourse	1.1 ± 0.9	1.1 ± 1.0
Dyspareunia (if sexually active)	2.6 ± 0.1	2.7 ± 0.2

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Data are given as Mean ± standard desviation.

*Severity scale of individual subjective symptoms were assessed using a five-point scale 0 = none; 1 = mild; 2 = moderate; 3 = severe; 4 = very severe.

Non-inferiority of hormone-free moisturising cream efficacy

The total severity score for both treatments decreased over time (Fig 2). From Day 1 to Day 43, the total severity score for hormone-free moisturising cream decreased from 6.1 ± 0.3 to 1.1 ± 0.2 and for estriol cream group from 6.0 ± 0.3 to 0.6 ± 0.1.

Accordingly, the total severity score decreased by 5.0 (95% confidence interval (CI): 4.6, 5.4) for hormone-free moisturising cream and by 5.4 (95% CI: 4.9, 5.8) for estriol cream group. Analysis of the differences to baseline of the TSS on Day 43 showed that the assumption of the t-test did not hold (normality rejected by Shapiro-Wilk test). Wilcoxon-Mann-Whitney Wilcoxon was used instead. The result was significant (p = 0.0002) supporting the non-inferiority of hormone-free in comparison to estriol. Therefore, the analysis of the differences to baseline of the total severity score on Day 43 (one-sided test; Δ = 1.5) confirmed hormone-free moisturising cream to be noninferior as compared to the estriol cream (PP: p < 0.001; ITT: p < 0.001). Non-inferiority could also be verified with two-sided testing (Δ = 1.5) and even with a "sharper" one-sided testing (Δ = 1.0).

After 1 week of treatment (Day 7), total severity score decreased 49% and 48% by hormone-free moisturising cream and estriol cream, respectively (Fig 2). Symptom relief improved over time in a similar manner for both vaginal creams. Thus, the relief of symptoms was achieved in a similar time frame for both creams (Fig 2).

Efficacy assessment of subjective symptoms

The mean severity score for each individual subjective symptom significantly decreased over time in both treatment groups (data not shown). At baseline, most of the women suffered from at least mild vulvovaginal subjective symptoms in both treatment groups (Fig 3).

Fig 3 — Percentage of patients suffering from at least mild subjective symptoms or free of symptoms. Number of patients (PP): Hormone-free moisturizing cream n = 80; Estriol cream n = 71.

Dryness was the symptom that affected more than 96% of the women in both treatment groups. The percentage of symptom-free women increased progressively with the duration of the treatment in both studies (Fig 3). At the end of the hormone-free moisturising cream treatment, 63.8% of the women reported to be symptom-free with respect to dryness, 78.8% with respect to itching and 77.5% to burning as well as 87.5% to pain unrelated to sexual intercourse (for estriol cream 76.1%, 80.3%, 91.5%, and 94.4%, respectively). None of the women in any treatment group evaluated their symptoms as severe or very severe on Day 43. An improvement of the symptom dryness until Day 43 was reported by 91.3% of women in the hormone-free moisturising cream group and by 95.8% of women in the estriol cream group, respectively (Fig 4). An improvement of the symptoms itching and burning was reported by 75.0% and 73.8% of the women in of the hormone-free moisturising cream group and by 80.3% and 85.9% in the estriol cream group, respectively (Fig 4).

Fig 4 — Percentage of treated patients with improvement of their individual subjective symptoms at the end of the treatment (Day 43). Number of patients (PP): Hormone-free moisturizing cream n = 80; Estriol cream n = 71.

Efficacy assessment of dyspareunia severity (if sexually active)

More than 95% of the sexually active women (n = 106) were affected by dyspareunia at Day 1. From Day 1 to Day 43, the mean severity score for dyspareunia improved by 1.7 (95% CI: 2.0, 1.3) for the hormone-free moisturising cream and by 2.2 (95% CI: 2.6, 1.8) for estriol cream, respectively. Comparing the AUC of the severity score for dyspareunia among sexually active women, no statistically significant difference between both treatments was found (p = 0.398). At Day 1, 59.4% and 41.5% of sexually active women rated dyspareunia as severe or very severe in the hormone-free moisturising cream and estriol cream groups, respectively (Fig 5). On Day 43 of treatment an improvement of the symptom dyspareunia was reported by 84% of the hormone-free moisturising cream treated women and 87% of the estriol cream treated women. In the hormone-free cream group, 38.6% of the women reported to be symptom-free and 57.9% in estriol cream group, respectively.

Fig 5 — Percentage of patients for the assessment of dyspareunia severity (if sexually active). The total number of patients refers to sexually active patients at Day 1/ Day 43: Hormone-free moisturizing cream n = 64/57; Estriol cream n = 42/37. Scale severity score for dyspareunia: 0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe.

Overall impairment of daily life due to individual subjective symptoms

Both treatments improved the impairment of daily life due to each individual subjective symptom over time as compared to baseline (data not shown). Interestingly, when comparing both treatment groups, no significant difference was detected for each individual subjective symptom after 43 days of treatment (Fig 6). An improvement of the impairment of daily life (Day 43) due to individual subjective symptoms was reported by 96% of the hormone-free moisturising cream treated women and by 99% by of the estriol cream treated women.

Fig 6 — Values represent Mean ± 95% CI. Not significant (n.s.). *Due to different baseline values, an ANCOVA using the baseline value as covariate was performed. The result demonstrated no significant difference at Day 43 between treatments.

Impairment of daily life due to the condition dyspareunia (if sexually active)

The impairment of daily life due to dyspareunia for sexually active women improved in both treatment groups over time. In the hormone-free moisturising cream group, the mean score decreased from 7.03 ± 0.34 to 1.56 ± 0.32. In the estriol cream group, the mean dyspareunia score decreased from 6.60 ± 0.45 to 0.65 ± 0.27. Comparison of AUC values of both treatment groups revealed no statistically significant differences (p = 0.066) for the improvement of the impairment of daily life due to the condition dyspareunia. An improvement of the impairment of daily life due to dyspareunia until Day 43 was reported by 98.2% of the women in the hormone-free moisturising cream group and by 86.8% of the estriol-treated women.

Overall impairment of daily life due to the condition "vaginal dryness"

The overall impairment of daily life due to the condition "vaginal dryness" for both treatments was statistically significantly different in favour of the estriol cream group (p < 0.01). A subgroup analysis stratified by the severity of the impairment of daily life due to the condition "vaginal dryness" showed that the difference between both groups was only significant for women who started the study with a severe overall impairment (p < 0.01) but not for those with mild (p = 0.298) or moderate (p = 0.086) impairment (Fig 7).

Fig 7 — Number of patients (PP) with mild/moderate/severe “vaginal dryness” in each treatment group: Hormone-free moisturizing cream n = 20/24/32; Estriol cream n = 19/30/21. Mean ± 95% CI of the AUC value. Not significant, p > 0.05.

Objective assessment of vaginal findings (VHI)

On Day 1, the overall elasticity was evaluated as poor for up to 40% of the women in both treatment groups. The mean difference to baseline on Day 43 was 1.0 ± 0.1 for the hormone-free moisturising cream-treatment group and 1.8 ± 0.1 for the estriol-treatment group. An improvement of the overall elasticity until Day 43 was reported by 67.5% of the hormone-free moisturising cream-treated women and 84.5% of the estriol treated women.

On Day 1, the fluid secretion was evaluated as scant and thin yellow for up to one-third of the women in both treatment groups. The mean difference to baseline on Day 43 was 1.2 ± 0.1 for the hormone-free moisturising cream-treatment group and 1.9 ± 0.1 for the estriol-treatment group. An improvement of the fluid secretion until Day 43 was reported by 73.8% of the hormone-free moisturising cream-treated women and 85.9% of the estriol-treated women.

On Day 1, the vaginal pH was evaluated as greater or equal to 6.1 for more than one-third of the women in both treatment groups. The mean difference to baseline on Day 43 was 0.3 ± 0.2 for the hormone-free moisturising cream-treatment group and 1.9 ± 0.2 for the estriol-treatment group. An improvement of the vaginal pH until Day 43 was reported by 41.3% of the treated women and 73.2% of the estriol-treated women.

On Day 1, petechiae noted before contact was documented for none of the women of the hormone-free moisturising cream-treatment group and for 4.2% of women of the estriol-treatment group (n = 3). The mean difference to baseline on Day 43 was 0.4 ± 0.1 for the group treated with hormone-free moisturising cream and 1.0 ± 0.1 for the estriol-treatment group, respectively. An improvement of the epithelial mucosa until Day 43 was reported by 36.3% of the hormone-free moisturising cream-treated women and 81.7% of the estriol-treated women.

Both study treatments significantly improved the mean Vaginal Health Index score compared to baseline (p < 0.001). Comparison between the treatments (AUC values) revealed a statistically significant difference (p < 0.001) for all criteria of the Vaginal Health Index (elasticity, fluid secretion, vaginal pH, moisture, and epithelia mucosa) in favour of the estriol cream (Fig 8). Nearly 80% of the hormone-free moisturising cream treated women and more than 95% of the estriol cream treated women showed improvement of Vaginal Health Index over time. An increase of the percentage of women with a Lactobacillus status within the normal range was, as expected, only observed in the estriol cream group (47.9%).

Fig 8 — Improvement of all Vaginal Health Index criteria (objective assessment of vaginal findings) and significant differences in favor of the estriol cream. Number of patients (PP): Hormone-free moisturizing cream n = 74; Estriol cream n = 69. Mean AUC values ± 95% CI. Mann-Whitney-Wilcoxon tests were applied to evaluate any differences in the effect of the treatments (statistically significant, p < 0.001).

Global judgement of efficacy and tolerability

The efficacy was judged good or very good by more than 80% of the women treated with the hormone-free moisturising cream and by more than 90% of the estriol-treated women. Tolerability of both creams was judged good or very good by 94% and 95% of the physicians, respectively.

Safety assessment

A total of 192 non-serious adverse events was reported in this study by 79 women: 33 (37.9%) out of 87 women in the hormone-free moisturising cream group and 46 (54.1%) out of 85 women in the estriol cream group. Most of adverse events were mild (71.9%) or moderate (26.0%). Only 4 (2.1%) severe adverse events occurred: 2 unrelated to treatment, 1 probably (headache) and 1 certainly (local burning) related to the estriol cream. adverse events considered serious did not occurred in this trial. The low number of non-serious adverse events related to the hormone-free moisturising cream gave no indication for safety concerns in this study. Overall, more adverse events with a certain, probable or possible relation to the treatment occurred in the estriol group.

Discussion

The total severity score, as primary endpoint confirmed the non-inferiority of the hormone-free moisturising cream as compared to an estriol cream regarding the relief of subjective symptoms (dryness, itching, burning and pain unrelated to sexual intercourse) in postmenopausal women. Accordingly, the efficacy difference between both treatments was not clinically relevant. Importantly, feeling of dryness, the most frequent symptom at baseline improved in more than 90% of women in both treatment groups. Dyspareunia was also significantly reduced during the study without showing significant differences between both treatments. The relief of the subjective symptoms and dyspareunia over time correlates with an improvement of women’s impairment of daily life for both vaginal treatments.

A significant difference between hormone-free moisturising cream treatment and estriol cream treatment in favour of the group receiving the estriol cream was detected only in a subgroup of women who started the study with severe overall impairment of daily life due to the condition "vaginal dryness". Accordingly, these women would be advised to use a vaginal estriol cream from the beginning, if they wish. On the other hand, the results confirm that women with mild to moderate impairment of daily life due to the condition “vaginal dryness” benefit from both creams. In addition, the hormone-free moisturising cream significantly improved objective signs assessed by measurement of the Vaginal Health Index as compared to baseline. However, this improvement was significantly more pronounced after treatment with the estriol cream. Nearly 80% of the hormone-free moisturising cream-treated women and more than 95% of the estriol-treated women showed an improvement of the Vaginal Health Index over time.

The therapeutic effects of this oil-in water cream are related to the properties of the formulation, primarily the high-water content and the lipids supplied with the cream. The use of this moisturising cream is a purely symptomatic therapy where the skin of the vagina and on the vulva is provided with both, moisture and soothing lipids, similarly as for emollients used in the treatment of atopic dermatitis.

This is the first time that this hormone-free moisturising cream has been compared with an estriol cream with regard to improvement of both, subjective symptoms and objective signs of vulvovaginal atrophy over a total study duration of 6 weeks. In a previous study, this oil-in-water hormone-free vaginal moisturising cream showed clinical superiority in reducing subjective vulvovaginal dryness symptoms compared to a hormone-free moisturising gel containing hyaluronic acid in pre- and post-menopausal women [14].

The clinically relevant efficacy of vaginal estriol regarding the relief of subjective symptoms and objective findings compared to placebo or other vaginal estrogen preparations, has been sustained in several studies [21–23], reviews [24, 25] and meta-analyses [26]. In addition, the reference estriol product chosen in this study has been approved for the therapy of vulvovaginal atrophy symptoms due to estrogen deficiency for more than 25 years in Germany.

Consequently, the choice of an estriol cream (0.1%) as a reference product for clinically effective treatment of vulvovaginal atrophy symptoms corroborates the efficacy of the hormone-free vaginal cream under investigation which has been shown in this study to be non-inferior with regard to the improvement of subjective symptoms of vulvovaginal atrophy. These results provide convincing evidence to recommend the use of this hormone-free moisturising vaginal cream as first-line therapy to relieve vulvovaginal atrophy-related symptoms, as recommended by NAMS (2020) [8].

This new information expands knowledge about the benefits of using this hormone-free moisturising cream and supports the recommendation that non-hormonal treatment options are relevant for all women who wish to reduce or avoid local hormone treatment, if medically advised.

Limitations

The hormone-free moisturising cream under investigation does not contain any pharmacologically active moieties. Due to the kind of packaging of the test products (different size of tube and applicator) and the different frequency of application (dosage) a blinded study design was not feasible. Furthermore, more sexually active women were randomized to the hormone-free cream group (n = 64) as compared to the estriol cream group (n = 42). The parameter “sexually active” was not part of the inclusion criteria. After randomisation, differences in the number of “sexually active” participants between the groups were detected but did not affect the primary outcome of the study. The delay in publication of this study was caused by internal reasons.

Conclusion

The efficacy of the hormone-free moisturising vaginal cream, which is non-inferior to that of the estriol cream, the very good tolerability, the low number of adverse events as well as the satisfaction of the treated women illustrate that the hormone-free vaginal cream is a reliable therapy option for the treatment of vulvovaginal atrophy symptoms in postmenopausal women, especially in women for whom hormone therapy is contraindicated or undesirable.

Supporting information

S1 File. Clinical trial protocol–Synopsis.

(PDF)

Click here for additional data file.^{(410.8KB, pdf)}

S1 Checklist. CONSORT 2010 checklist of information to include when reporting a randomised trial*.

(PDF)

Click here for additional data file.^{(250.7KB, pdf)}

Acknowledgments

The authors are grateful for the support of the coordinating investigator and the participating centers. We thank proDERM (Hamburg, Germany) for their participation in data collection, analysis, and interpretation of data.

Abbreviations

AE: Adverse Event
ANCOVA: Analysis of Covariance
AUC: Area Under the Curve
BMI: Body Mass Index
CI: Confidence Interval
Δ: delta
ITT: the Intention To Treat Population
NAMS: The North American Menopause Society
n.s.: Not Significant
PP: Per Protocol Population
SD: Standard Deviation
SEM: Standard Error of the Mean
SP: Safety Population
TSS: total severity score
VHI: Vaginal Health Index
VVD: Vulvovaginal Dryness
VVA: Vulvovaginal Atrophy
GSM: Genitourinary Syndrome of the Menopause

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

The funder Dr. August Wolff GmbH & Co. KG Arzneimittel (Bielefeld, Germany) provided support in the form of salaries for authors [SGdA, LG, MH, and CM] and played an additional role in the study design, decision to publish, and preparation of the manuscript. However, the funder had no role in data collection and analysis. The scientific supervisor of the study [PS] was also sponsored by Dr. August Wolff GmbH & Co. KG Arzneimittel. The specific roles of these authors are articulated in the ‘author contributions’ section. There was no additional external funding received for this study.

References

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PLoS One. 2022 May 12;17(5):e0266633. doi: 10.1371/journal.pone.0266633.r001

Author response to previous submission

14 Jan 2022

Attachment

Submitted filename: CONSORT 2010 Checklist.pdf

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PLoS One. doi: 10.1371/journal.pone.0266633.r002

Decision Letter 0

Walid Kamal Abdelbasset

11 Feb 2022

PONE-D-21-39841Vaginal hormone-free moisturising cream is not inferior to an estriol cream for treating symptoms of vulvovaginal atrophy: prospective, randomised studyPLOS ONE

Dear Dr. Garcia de Arriba,

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Reviewer #1: This is a noninferiority study of a vaginal cream with an ordinal outcome collected longitudinally. My main concerns are:

1. "TSS was defined as the sum of the single score for all subjective symptoms at each time point." It is not clear what this statement means, but I THINK it means that each 4-point score was evaluated at 4 time points, and they were added? That makes no sense to me. A longitudinal analysis would look at the rate of change of the scores. Alternatively, a primary outcome assessed in a non-longitudinal way could look at the change from baseline at end of study. In any event, I don't know what summing scores over time points means. Or maybe I am interpreting your sentence incorrectly.

2. Sample size is based on a t-test, and there is no indication that your 4-point scores are normally distributed, even when added. I think this calls for sample size determined for the Wilcoxon test. Whether there is software for SS in noninferiority for nonparametric tests I am not sure, but the statistician should be able to figure it out by assuming a proversion parameter.

3. The conclusions should clearly state whether the assumptions underlying the sample size computation were realized in the clinical trial.

Minor point: Please give the block size when using permuted block. Is there any concern about selection bias with a fixed block size?

Reviewer #2: Dear authors,

Did you have performed a sample size calculation? you need to mention that as it was a clinical trial and prospective.

did you evaluate and collect the primary and secondary endpoints of the study during the treatment period? or did you assess the clinical improvements after the treatment period and if yes, how long was it after the treatment?

I think it is quite relevant to make this point clear enough. Also, the time scale of the improvement was not clear. was the estriol associated with longer term improvement than the emulsion?

Moreover, the pattern of application of the emulsion versus the estriol was very different: the emulsion was applied externally several times as needed, while the estriol cream was applied intravaginally once daily for the first 3 weeks and twice-weekly thereafter.

did the frequent application of the emulsion give a false perception of improvement? It might have contributed (bias) to the final results.

can you please elaborate enough and make these essential issues clear?

Reviewer #3: The research has been written in an acceptable manner.

Please just add full names for all abbreviations then proceeded on .

All the sections were recorded in a suitable way. No need for further assessments

**********

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Reviewer #2: Yes: Naser Al-Husban

Reviewer #3: No

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PLoS One. 2022 May 12;17(5):e0266633. doi: 10.1371/journal.pone.0266633.r003

Author response to Decision Letter 0

11 Mar 2022

Point-to-Point-Reply

We are grateful to the Reviewers and the Editor for their careful revision and the overall positive feedback we received. Accordingly, we took into account the suggestions of the Reviewers as follows:

In reply to Reviewer 1

1.1 "TSS was defined as the sum of the single score for all subjective symptoms at each time point." It is not clear what this statement means, but I THINK it means that each 4-point score was evaluated at 4 time points, and they were added? That makes no sense to me. A longitudinal analysis would look at the rate of change of the scores. Alternatively, a primary outcome assessed in a non-longitudinal way could look at the change from baseline at end of study. In any event, I don't know what summing scores over time points means. Or maybe I am interpreting your sentence incorrectly.

We thank the Reviewer for this valuable comment. Indeed, the wording creates confusion, so we have modified the sentence to read as follows: TSS was defined as the sum of the single score dryness, itching, burning and pain unrelated to sexual intercourse (see Page 7).

1.2. Sample size is based on a t-test, and there is no indication that your 4-point scores are normally distributed, even when added. I think this calls for sample size determined for the Wilcoxon test. Whether there is software for SS in noninferiority for nonparametric tests I am not sure, but the statistician should be able to figure it out by assuming a proversion parameter.

The primary goal of a sample size calculation is to ensure that the number of subjects in a clinical trial is large enough to provide a reliable answer to the questions addressed (cp. ICH E9 Statistical principles for clinical trials). The question of our study was whether the vaginal hormone-free moisturising cream is not inferior to an estriol cream for treating symptoms of vulvovaginal atrophy. The results of the Wilcoxon-Mann-Whitney test provided enough evidence in favour of the non-inferiority of hormone-free in comparison to estriol (p=0.0002), i.e. the sample size was large enough to provide a reliable answer.

According to the statistical analysis plan (SAP), the Wilcoxon-Mann-Whitney test (and not the t-Test) was performed because the Shapiro-Wilk test rejected the hypothesis that the differences to baseline of the Total Severity Score (TSS) at 6 weeks for patients treated with the test product and the active control were normally distributed. In this context, we would like to clarify that the assumption of normal distribution was not related to the sum of the 4-point scores (TSS), but the differences to baseline of the Total Severity Score (TSS) at 6 weeks. When we planned this study, we have no reliable information on the distribution of these differences and, especially, no reliable information that these differences are not normally distributed. It should be noted that the two-sample t-Test is comparatively robust under violations of the normality distribution, particularly when the sample sizes are equal (e.g. Zimmerman DW. J Exp Educat. 1987;55(3):171-174; Heeren T, D'Agostino R. Stat Med. 1987;6(1):79-90.). Equal sample sizes were planned for the sample size calculation in this study.

We agree with the reviewer that based on the meanwhile available study data; a Wilcoxon-Mann-Whitney test would have been more appropriate for a sample size calculation. However, it should be noted that sample size calculations for the Wilcoxon-Mann-Whitney -test are by no means an easy task. There are many different proposed procedures for sample size planning for the Wilcoxon-Mann-Whitney test (e.g. Happ et al. Stat Med. Feb 10;38(3):363-375; Zhu X. Int J Clin Trials. 2021 Aug;8(3):184-195). Most methods and software for sample size calculation for the Wilcoxon-Mann-Whitney test (e.g. R package “samplesize”, GPower) assume very specific models or types of data to simplify calculations ordered categorical or metric data, location shift alternatives, etc.

In summary, sample size calculations are always based on assumptions. Whether these assumptions are actually met or not, can often only be evaluated when the study has been completed.

We have modified the sentence to read as follows: Analysis of the differences to baseline of the TSS on Day 43 showed that the assumption of the t-test did not hold (normality rejected by Shapiro-Wilk test). Wilcoxon-Mann-Whitney test was used instead. The result was significant (p=0.0002) supporting the non-inferiority of hormone-free in comparison to estriol. (Page 10-11)

1.3. The conclusions should clearly state whether the assumptions underlying the sample size computation were realized in the clinical trial.

The assumption that the underlying differences to baseline of the Total Severity Score (TSS) at 6 weeks for patients treated with the hormone-free cream and the estriol cream (active control) were normally distributed was not correct. Thus, t-test was not the appropriate test for the calculation.as the reviewer correctly mentions Wilcoxon-Mann-Whitney test was used instead. The results of the Wilcoxon-Mann-Whitney Test provided enough evidence in favour of the non-inferiority of hormone-free in comparison to estriol (p=0.0002), i.e. the sample size was large enough to provide a reliable answer. Moreover, the calculated sample size of n=172 patients included assumed a drop-out rate of 20%. However, only 10 women (5.8%) terminated early from the trial after they applied their product cream at least once.

1.4. Minor point: Please give the block size when using permuted block. Is there any concern about selection bias with a fixed block size?

As suggested by the Reviewer, we added the information concerning the block size, which was four, in the manuscript (see Page 6). We have no concerns about selection bias with a fixed block size.

In reply to Reviewer 2

2.1 Did you have performed a sample size calculation? you need to mention that as it was a clinical trial and prospective

We thank the Reviewer for this valuable comment. Yes, a sample size calculation was performed, and you can find this information on the section Statistical Analysis (see Page 8). Please notice that the study title contains also the following information “prospective, randomised study”.

2.2 Did you evaluate and collect the primary and secondary endpoints of the study during the treatment period? or did you assess the clinical improvements after the treatment period and if yes, how long was it after the treatment? I think it is quite relevant to make this point clear enough.

Indeed, primary and secondary endpoints were collected during the treatment period up to Visit 3 (Day 43). No Follow-up Visit was performed to evaluate efficacy or safety parameters after end of treatment.

2.3 Also, the time scale of the improvement was not clear.

a) was the estriol associated with longer term improvement than the emulsion?

b) Moreover, the pattern of application of the emulsion versus the estriol was very different: the emulsion was applied externally several times as needed, while the estriol cream was applied intravaginally once daily for the first 3 weeks and twice-weekly thereafter.

c) Did the frequent application of the emulsion give a false perception of improvement?

It might have contributed (bias) to the final results.

can you please elaborate enough and make these essential issues clear?

We thank the Reviewer for this comment.

a) This study did not investigate the duration of the treatment effects. Therefore, it could not compare the long-term effects of both vaginal creams.

b) Further, the timing (intravaginal application in the evening), frequency and dose was chosen according to the recommendations given for both marketed products as described in the respective package inserts. Thus, Hormone-free moisturising cream was applied intravaginally, using the provided applicator (approximately 2.5 g) once daily at night, and in the outer genital area (a cream ribbon of approx. 0.5 cm) several times per day, as needed. Once symptoms had improved, the frequency of cream application could be reduced, as needed. The estriol cream (0.5 g) was applied intravaginally once daily for the first 3 weeks with the provided applicator and twice-weekly thereafter, according to package leaflet.

c) After about a week of daily intravaginal application, the patient applies the Hormone-free cream much less frequently. Also, the external application of the hormone-free cream was applied just as patient´s needs and affects the external genital area. However, it has no effect on the intravaginal area which is responsible for the symptoms that were evaluated in the clinical trial.

In reply to Reviewer 3

The research has been written in an acceptable manner.

Please just add full names for all abbreviations then proceeded on.

All the sections were recorded in a suitable way. No need for further assessments

We thank the Reviewer for the positive comments. Concerns to be addressed: None, except that the Reviewer requested minor changes. As recommended, we have added full names for all abbreviations within the manuscript.

In reply to the Editor

1. We made the required changes in the manuscript in order to meet PLOS ONE's style requirements. Changes are labelled “Track Changes” in the manuscript (marked-up copy)

2. Figures have been cited as “Fig”.

3. A table with caption as well as all Figure captions have been placed in the manuscript text in read order, immediately following the paragraph where the Table/figure is first cited.

4. Text within Figures were corrected to Arial (8-12 point).

5. All Figure files format was changed to TIFF format using PACE tool. New figure files.

6. Abbreviations have been revised.

7. Updated Funding statement (see below)

8. Name of commercial company: Dr. August Wolff GmbH & Co. KG Arzneimittel (Bielefeld, Germany)

9. Amended Competing Interests Statement (see below)

10. Supporting Information S1 and S2 Files have been included

Funding Statement

Competing Interests Statement

The authors have read the journal’s policy. SGdA, LG, MH, and CM, have the following competing interest: They work for the company Dr. August Wolff GmbH & Co. KG Arzneimittel (Bielefeld, Germany) which is interested in developing products regarding treatment of vulvovaginal atrophy/ vaginal dryness symptoms. The principal investigator of the study [PS] as well as the statistical specialist [TWM] were also sponsored by Dr. August Wolff GmbH & Co. KG Arzneimittel. This does not alter the authors adherence to PLOS ONE policies on sharing data and materials.

Data Availability statement

The minimal data set underlying the results described in this manuscript are fully available. All relevant data are within the paper and its supporting information files.

Supporting information can be found in S1 File, S2 File with the following link https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-002199-28/DE

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PLoS One. doi: 10.1371/journal.pone.0266633.r004

Decision Letter 1

Walid Kamal Abdelbasset

24 Mar 2022

Vaginal hormone-free moisturising cream is not inferior to an estriol cream for treating symptoms of vulvovaginal atrophy: prospective, randomised study

PONE-D-21-39841R1

Dear Dr. Garcia de Arriba,

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PLoS One. doi: 10.1371/journal.pone.0266633.r005

Acceptance letter

Walid Kamal Abdelbasset

4 May 2022

PONE-D-21-39841R1

Vaginal hormone-free moisturising cream is not inferior to an estriol cream for treating symptoms of vulvovaginal atrophy: prospective, randomised study

Dear Dr. Garcia de Arriba:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 File. Clinical trial protocol–Synopsis.

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S1 Checklist. CONSORT 2010 checklist of information to include when reporting a randomised trial*.

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Data Availability Statement

All relevant data are within the manuscript and its Supporting Information files.

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PERMALINK

Vaginal hormone-free moisturising cream is not inferior to an estriol cream for treating symptoms of vulvovaginal atrophy: Prospective, randomised study

Susana Garcia de Arriba

Lisa Grüntkemeier

Manuel Häuser

Theodor W May

Clarissa Masur

Petra Stute

Roles

Abstract

Introduction

Methods

Study design

Study population

Product application

Study endpoints

Statistical analysis

Fig 1. CONSORT flow diagram.

Results

Study population

Table 1. Demographic and baseline characteristics.

Non-inferiority of hormone-free moisturising cream efficacy

Fig 2. Mean of Total Severity Score (TSS) over time.

Efficacy assessment of subjective symptoms

Fig 3. Vulvovaginal subjective symptoms at baseline.

Fig 4. Vulvovaginal subjective symptoms at the end of the treatment.

Efficacy assessment of dyspareunia severity (if sexually active)

Fig 5. Dyspareunia severity.

Overall impairment of daily life due to individual subjective symptoms

Fig 6. Comparison of the impairment of daily life due to each of the subjective symptoms (AUC).

Impairment of daily life due to the condition dyspareunia (if sexually active)

Overall impairment of daily life due to the condition "vaginal dryness"

Fig 7. Overall impairment of daily life due to the condition "vaginal dryness".

Objective assessment of vaginal findings (VHI)

Fig 8. Objective assessment of vaginal findings.

Global judgement of efficacy and tolerability

Safety assessment

Discussion

Limitations

Conclusion

Supporting information

Acknowledgments

Abbreviations

Data Availability

Funding Statement

References

Author response to previous submission

Decision Letter 0

Walid Kamal Abdelbasset

Roles

Author response to Decision Letter 0

Decision Letter 1

Walid Kamal Abdelbasset

Roles

Acceptance letter

Walid Kamal Abdelbasset

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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