Abstract
Objective: To assess the safety and tolerability of ultra-low dose estradiol and dydrogesterone (E0.5 mg/D2.5 mg) among postmenopausal women. Methods: This pooled analysis of data from three clinical studies assessed the effects of continuous combined ultra-low-dose estradiol and dydrogesterone among postmenopausal women. Participants received E0.5 mg/D2.5 mg or placebo for 13 weeks (double-blind, randomized, European study), E0.5 mg/D2.5 mg or placebo for 12 weeks (double-blind, randomized, Chinese study), or E0.5 mg/D2.5 mg for 52 weeks (open-label, European study). Safety outcomes included treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), treatment discontinuation due to a TEAE, and adverse events of special interest (AESIs). Results: Overall, 1027 women were included in the pooled analysis (E0.5 mg/D2.5 mg, n = 736; placebo, n = 291). Mean treatment exposure was 288.9 days in the E0.5 mg/D2.5 mg group and 86.6 days in the placebo group. The proportion of women experiencing ≥1 TEAE was similar in the E0.5 mg/D2.5 mg and placebo groups (50.1% vs 49.5%, respectively). TESAEs occurred in 12 (1.6%) women receiving E0.5 mg/D2.5 mg and 9 (3.1%) women receiving placebo. Discontinuation of study treatment was infrequent in both groups (E0.5 mg/D2.5 mg: 1.5%; placebo: 2.4%). The occurrence of breast pain was more common in the E0.5 mg/D2.5 mg group than in the placebo group (2.0% vs 0.3%) as was uterine hemorrhage (6.5% vs 2.4%). The incidence of acne, hypertrichoses and weight increased was similar between groups. Conclusions: Across three studies, ultra-low-dose estradiol plus dydrogesterone was well tolerated among postmenopausal women, with no increase in TEAEs or TESAEs compared with placebo.
Introduction
Menopausal symptoms are associated with a substantial quality of life burden for women, underpinning the need for effective management [Citation1–3]. Vasomotor symptoms are a key driver of the impaired quality of life reported among menopausal women [Citation3,Citation4] and are most effectively treated with menopausal hormone therapy (MHT) [Citation5]. Existing guidelines recommend individualized MHT according to women’s symptoms and circumstances using the most appropriate dose of estrogen and selecting the most suitable route of estrogen administration [Citation5–13]. To increase endometrial safety, non-hysterectomized women require estrogen combined with progestogen that can be given in continuous or sequential form [Citation5–10]. Sequential MHT has been associated with an increased risk of endometrial hyperplasia, with continuous administration being associated with endometrium protection [Citation14].
Ultra-low dose estradiol plus dydrogesterone consists of 0.5 mg 17β-estradiol continuously combined with 2.5 mg dydrogesterone (Femoston-Mini® 0.5 mg/2.5 mg; a trade name that may vary by country) and has been shown in clinical studies to reduce vasomotor symptoms in postmenopausal women compared with placebo [Citation15–18]. To date, ultra-low dose estradiol plus dydrogesterone has been reported to be well tolerated in several studies [Citation15–20]. Nonetheless, further information can reinforce the consistency of its safety profile and support decisions about the treatment of menopause symptoms. We therefore performed a pooled data analysis from three clinical trials to assess the safety and tolerability of ultra-low dose estradiol and dydrogesterone among postmenopausal women.
Methods
Study design
This pooled analysis included data from three clinical studies that assessed the efficacy and safety of continuous combined oral low and ultra-low-dose estradiol and dydrogesterone in postmenopausal women. Study 1 was a phase 3, double-blind, randomized, placebo-controlled study conducted in France, Poland, Romania and Russia (European study) [Citation17]. Study 2 was a phase 3, double-blind, randomized, placebo-controlled study conducted in China (Chinese study) [Citation18], and Study 3 was an open-label study conducted in Romania, Poland and Ukraine (open-label study) [Citation19]. Full details of these studies have been reported previously [Citation17,Citation18,Citation20]. In brief, women enrolled in the European study were randomized 2:1:2 to receive Femoston Mini® - oral continuous combined 0.5 mg 17β-estradiol/2.5 mg dydrogesterone (referred to hereafter as E0.5 mg/D2.5 mg), Femoston Conti® - continuous combined 1 mg 17β-estradiol/5 mg dydrogesterone (E1mg/D5mg) or placebo for 13 weeks [Citation17]. Femoston® is the only single fixed dose MHT containing dydrogesterone. Dydrogesterone, like the micronized progesterone, comes from a natural source (e.g. yam and soy) [Citation21,Citation22]. Its unique molecular features are obtained through a photochemical process [Citation23], creating a bent molecular conformation, conferring a high selectivity for progesterone receptors [Citation24,Citation25], with better oral bioavailability compared with oral micronized progesterone [Citation25–27]. Dydrogesterone presents a biological progestogenic, anti-estrogenic, anti-androgenic and anti-mineralocorticoid activity with no anti-gonadotrophic, estrogenic, androgenic, or glucocorticoid actions [Citation25]. Unlike other progestogens, dydrogesterone is non-thermogenetic, non-sedative, does not inhibit gonadotropin release or ovulation [Citation22], does not influence central nervous system function and psyche, and does not antagonize various central effects of estrogens [Citation28]. Patients who received E1mg/D5mg were not included in the present analysis. Women enrolled in the Chinese study were randomized 1:1 to receive continuous combined E0.5 mg/D2.5 mg or placebo once daily for 12 weeks [Citation18]. Women enrolled in the open-label study received continuous combined E0.5 mg/D2.5 mg for 52 weeks [Citation20]. This pooled analysis includes data from postmenopausal women who received either E0.5 mg/D2.5 mg or placebo and were included in the safety analysis samples of the individual studies.
The studies were conducted in accordance with the International Conference on Harmonization Guideline for Good Clinical Practice, applicable national/regional regulations and the Declaration of Helsinki and were approved by local ethics committees. All participants provided written informed consent.
Study participants
All three studies enrolled non-hysterectomized, postmenopausal women who had been amenorrheic for ≥12 months and who were aged 45–65 years (European study), 45–60 years (Chinese study) or ≥45 years (open-label study). The European study enrolled women with serum estradiol <35 pg/mL and follicle-stimulating hormone levels >40 IU/L who had experienced ≥50 moderate-to-severe hot flushes the week before the study treatment started. The Chinese study enrolled women with serum estradiol and follicle-stimulating hormone levels of <35 pg/mL and >40 IU/L, respectively, who had experienced ≥50 hot flushes over seven consecutive days during the two-week screening period. The open-label study enrolled women with symptoms of estrogen deficiency who had serum estradiol and follicle-stimulating hormone levels of 10–50 ng/L and 36–157 U/L, respectively. Full eligibility criteria have been published previously [Citation17,Citation18,Citation20].
Assessments
Primary and secondary endpoints for the three studies have been described previously [Citation17,Citation18,Citation20]. In this pooled safety analysis, the following safety outcomes were analyzed: treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), women discontinuing study treatment due to a TEAE, and in addition adverse events of special interest (AESIs) were selected: breast cancer, endometrial hyperplasia, acne, hypertrichoses and weight increased. Acne, hypertrichoses and weight gain were selected as AESIs as these changes can be concerns for patients taking hormonal therapy which may impact treatment decisions, adherence and persistence [Citation29,Citation30]. Other AESIs included reproductive and breast disorders, cardiac disorders, metabolism and nutrition disorders and neoplasms, benign, malignant and unspecified.
Statistical analyses
Statistical methods for the original study endpoints have been previously described [Citation17,Citation18,Citation20]. In this pooled analysis, all safety outcomes were analyzed descriptively. The chi2-test was used to test for differences between groups. TEAEs, TESAEs, women discontinuing study treatment due to a TEAE, and deaths were also reported according to body mass index (BMI). For BMI analysis, women were divided into two groups: BMI <25 kg/m2 and BMI ≥25 kg/m2.
Results
Study population
A total of 1027 women from the three studies were included in the pooled analysis. Of these, 736 had received E0.5 mg/D2.5 mg, and 291 had received placebo. Baseline demographics and characteristics are shown in . Mean age, height, weight and BMI were similar across the two treatment groups.
Table 1. Baseline demographics and clinical characteristics.
Safety and tolerability
Mean (standard deviation [SD]) treatment exposure was 288.9 (127.0) days in the E0.5 mg/D2.5 mg group and 86.6 (11.8) days in the placebo group, equating to an exposure period in the E0.5 mg/D2.5 mg group that was 2.3 times longer than for the placebo group. Around half of the women in each group experienced ≥1 TEAE (50.1% in the E0.5 mg/D2.5 mg group and 49.5% in the placebo group; ). The most common TEAEs (according to the assigned Medical Dictionary for Regulatory Activities (MedDRA) Preferred Term) were nasopharyngitis (5.3% with E0.5 mg/D2.5 mg and 7.2% with placebo), headache (5.8% with E0.5 mg/D2.5 mg and 4.1% with placebo) and uterine hemorrhage (6.5% with E0.5 mg/D2.5 mg and 2.4% with placebo; ).
Table 2. Overall safety outcomes.
Table 3. TEAEs Reported in ≥2% of women in any treatment group – preferred terms.
TEAEs by System Organ Class (SOC) are shown in Supplementary Table 1. TEAEs were most frequently reported for the SOCs infections and infestations (19.0% with E0.5 mg/D2.5 mg and 18.6% with placebo) and reproductive system and breast disorders (16.7% with E0.5 mg/D2.5 mg and 14.8% with placebo). TESAEs occurred in 12 (1.6%) women in the E0.5 mg/D2.5 mg group and 9 (3.1%) women in the placebo group (). Discontinuation of study treatment due to a TEAE was infrequent in both groups (1.5% in the E0.5 mg/D2.5 mg group and 2.4% in the placebo group; ).
There were no notable between-group differences in the selected AESIs (). AESIs that differed between subgroups were breast pain, which was more common in the E0.5 mg/D2.5 mg group than the placebo group (n = 15 [2.0%] vs. n = 1 [0.3%]), and uterine hemorrhage, which was also more common in the E0.5 mg/D2.5 mg group than the placebo group (n = 48 [6.5%] vs. n = 7 [2.4%]); Supplementary Table 2).
Table 4. Selected adverse events of special interest.
There was one death due to necrotizing pancreatitis in the E0.5 mg/D2.5 mg group, which was not considered related to treatment (). There were no notable differences in safety findings between the two BMI subgroups (data not shown).
Discussion
To our knowledge, this is the first pooled analysis of safety data from postmenopausal women treated with ultra-low-dose estradiol plus dydrogesterone. In the pooled data set, women receiving ultra-low-dose estradiol plus dydrogesterone had 2.3 times longer follow-up and treatment duration than women receiving placebo. Consistent with individual trial data, the pooled data from three clinical trials confirmed the favorable safety profile of ultra-low-dose estradiol plus dydrogesterone in postmenopausal women, with no new safety concerns. Notably, treatment discontinuation rates due to TEAEs were low.
There is a large body of evidence that consistently shows that initiation of MHT in the window of opportunity (i.e. close to the onset of menopause) leads to a reduction of all-cause mortality, including reduction in vasomotor and other menopause symptoms [Citation31], potential reductions in cancer and cardiovascular disease [Citation32], prevention of new-onset diabetes [Citation33], reduction of osteoporosis and bone fracture risk [Citation34] and improved quality of life [Citation35]. Some of the biggest concerns related to MHT include breast safety [Citation36], venous thrombotic events [Citation37], weight gain and skin changes [Citation30]. Notably, our pooled safety data analysis from 1027 postmenopausal women showed no difference in the frequency of any of these adverse events between E0.5 mg/D2.5 mg versus placebo.
The pooled analysis of two placebo-controlled, double-blinded randomized data from women recruited across Europe and China and an open-label safety study supports the safety and tolerability of E0.5 mg/D2.5 mg in postmenopausal women. However, our analysis has some limitations. First, our secondary data analysis includes only women enrolled in three clinical trials, therefore the rates of adverse events reported herein may eventually differ from those encountered in larger real-world populations. Since the data analyzed were from relatively short (12-, 13- and 52-week) studies, additional long-term follow-up registry data analyzing distinct formulations (including various MHT combinations) can be used for a deeper critical appraisal of our findings, reinforcing the favorable safety profile of the estradiol and dydrogesterone formulations [Citation38–45]. Despite the limitations of our analysis, the safety profile of E0.5 mg/D2.5 mg in this pooled analysis is consistent with the individual studies of ultra-low dose estradiol plus dydrogesterone in postmenopausal women included in this analysis [Citation17–19].
Guidelines recommend that MHT dose, regimen and duration should be individualized, with regular evaluation of the advantages and disadvantages [Citation5–7,Citation11–13]. Our findings support the use of E0.5 mg/D2.5 mg as an alternative to higher dosage regimens to treat climacteric symptoms in postmenopausal women. Ultra-low-dose estradiol plus dydrogesterone was shown to have a good safety profile for the treatment of estrogen deficiency symptoms due to menopause. Long-term, real-world data analysis will be useful to provide further information on the safety and tolerability of E0.5 mg/D2.5 mg, and help to differentiate between distinct MHT combinations, dosages, and delivery systems.
Conclusions
This pooled safety analysis shows that ultra-low estradiol plus dydrogesterone is well tolerated among postmenopausal women, with no increase in the overall incidence of TEAEs or TESAEs compared with placebo treatment. Along with the previously reported beneficial impact on vasomotor symptoms and health-related quality of life, these findings support the use of ultra-low estradiol plus dydrogesterone in postmenopausal women.
Statement of authorship
Authors equally contributed to the conception, design and writing of the manuscript. All authors critically revised the manuscript, agreed to be fully accountable for ensuring the integrity and accuracy of the work, and read and approved the final manuscript.
Supplemental Material
Download PDF (100.9 KB)Acknowledgments
Editorial assistance was provided by Metamols Ltd, funded by Abbott Established Pharmaceuticals.
Disclosure statement
MR, QY, and TT declare no conflicts of interest; JCS has received grants/research support from Abbott, Mylan and Pfizer; consulting fees from Abbott, Mitsubishi Tanabe, Mylan and Pfizer; and speaker’s honoraria from Abbott, Bayer, Gedeon Richter, Menarini, Mylan, Pfizer and Viatris; EK is an employee of Abbott Laboratories GmbH, Hannover, Germany and owns shares in Abbott; MGC is an employee of Abbott Products Operations AG, Allschwil, Switzerland and owns shares in Abbott; REN has ongoing relationships with Abbott, Astellas, Bayer HealthCare AG, Besins Healthcare, Exeltis, Fidia, Gedeon Richter, HRA Pharma, Merck & Co, Novo Nordisk, Organon & Co, Shionogi Limited, Theramex, and Viatris; VK is an employee of Established Pharmaceuticals Division, Abbott Ukraine LLC, Kyiv, Ukraine; TS reports having received in the past three years consulting fees from Astellas, Gedeon Richter, Mitsubishi Tanabe, Sojournix, Estetra, Actavis, Abbott, Medtronic, Applied Medical, Johnson & Johnson and speaker’s honoraria from Shionogi, Gedeon Richter, Theramex, Abbott, Intuitive Surgical, and Applied Medical.
Data sharing
All relevant data are within the paper and its Supporting Information files.
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