There are different estrogen products available to manage vasomotor symptoms associated with menopause and several factors to consider in choosing which preparations to prescribe or to use.1 Transdermal E2 provides advantages over traditional oral therapy. Transdermal systems transfer bioactive hormone directly into the subcutaneous microcirculation, and steroid delivery is a closer simulation of natural E2 secretion than is traditional oral dosing. There is no first-pass hepatic transformation or deactivation of the dosed E2.2,3 Transdermal E2 has little or no effect on clotting factors, lipoproteins, sex hormone binding globulin, hepatic enzymes, or C-reactive protein.2–4 There are reports that have shown that there has been little or no increase in thromboembolic events with transdermal E2.5,6 Transdermal systems deliver therapeutic circulating E2 levels and demonstrate clinical efficacy for hot flushes at doses considerably lower than those reported with oral estrogens, probably because there is less interconversion into estrone and estrone sulfate pools.7–10 Transdermal E2 delivery simulates closely the circulating profiles of E2, estrone, and estrone sulfate normally observed in follicular phase premenopausal women than do oral systems.2 Clinical consensus with respect to vasomotor symptoms stipulates lowest possible estrogen dosing for the shortest time.11–15 It seems that transdermal E2 is currently the best strategy to meet the “lowest dose possible” standard.11–15
Skin patches, the first method of transdermal delivery allowed for effective therapy at lower estrogen doses but resulted in skin irritation and patch adhesion problems in approximately 20–30% of patients using the products.16 Estradiol patches, gels, and lotions are objectionable to some because they peel off due to adhesive failures, catch on clothing, irritate skin, and induce allergies.7–10 Some find patches unsightly because these get dirty after days of wear. Others consider gels and lotions messy and object to the finger contact in dispersing the medication.7–10
The E2 transdermal spray has several unique features. It goes on clear, dries in about 60 seconds, and has low reported skin irritation. The spray solution has ethanol and a skin-penetrating agent, octisalate, that facilitates incorporation of steroid below the skin’s surface, where it is retained in a depot that delivers slow release of E2 over a 24-hour period. The spray delivers a precisely metered dose of E2 to the ventral surface of the forearm, does not require a patch, and is touchless because there is no hand contact with the medication. It does not wash off or transfer to other people, is minimally affected by sunscreen, and delivers smooth, predictable, and sustainable circulating E2.17 This report presents the safety and efficacy of Evamist (Ther-Rx, St. Louis, MO), a transdermal E2 spray, in the treatment of postmenopausal vasomotor symptoms in a randomized, double-blind, multicenter, placebo-controlled study.
MATERIALS AND METHODS
This was a phase III, randomized, double-blind, placebo-controlled, parallel-group clinical trial conducted at 43 sites in the United States. There were three study periods (4-week baseline evaluation, 12-week treatment, and 4–6 week follow-up) and six study visits. The protocol was approved by the institutional review boards of St. Alexius Medical Center, Baylor College of Medicine and Affiliated Hospitals, Quorum Review Inc., Eastern Virginia Medical School, and the Greenville Hospital System. The study was conducted in accordance with the Declaration of Helsinki and in compliance with the Good Clinical Practice guidelines. All participants signed the informed consent form before undergoing any study procedures.
Participants were naturally or surgically postmenopausal women aged 35 years or older who were healthy, with an average of at least eight moderate-to-severe hot flushes per day (56 or more per week). Postmenopausal was defined as having 12 months of spontaneous amenorrhea or 6 months of amenorrhea with serum follicle-stimulating hormone (FSH) levels more than 40 international units/L or at least 6 weeks after surgical bilateral oophorectomy with or without hysterectomy. Other key inclusion criteria were adequate washout period from estrogen-containing medications before baseline assessments, Pap test with no dysplastic or malignant cells, screening mammogram and breast examination with no masses or other findings suspicious of malignancy, and endometrial biopsies showing no hyperplasia or cancer in women with a uterus.
Key exclusion criteria were known hypersensitivity or known reaction to estrogens or progestins; clinically relevant disease that might preclude safe participation; use of progestin implants or injectable drug therapy or estrogen injectable or pellet therapy within 1 year, body mass index more than 35 kg/m2; uncontrolled hypertension (diastolic blood pressure 95 mm Hg or more and/or systolic blood pressure 180 mm Hg or more); clinically relevant triglyceride levels 3.4 mmol/L or more (300 mg/dL or more); documented history of coagulopathy, thrombophlebitis, thrombosis, or thromboembolic disorders; history of cutaneous contact allergy to adhesives, cosmetics, or topical medications, including sunscreens; abnormal genital bleeding; and current dermatologic disease.
Participants recorded, in a daily diary, the number and severity (0, none; 1, mild; 2, moderate; or 3, severe) of hot flushes during the 4-week baseline evaluation period. Eligible women were randomly assigned to one of the six treatment groups: one, two, or three sprays of E2 or placebo administered transdermally once daily to the inner forearm using a metered-dose pump. The E2 spray is composed of a single-phase solution containing E2 USP (17β-estradiol), octisalate, and alcohol (ethanol 95%), and the placebo spray consisted of the octisalate/alcohol vehicle. One E2 spray delivers 90 microliters containing 1.53 mg of E2. The application area (20 cm2 per spray) is controlled by a complete plastic housing, which directs the distance and angle of the spray from the skin surface, providing reproducible application of the solution to a specified area. If two or three sprays were employed, the sprays were applied to separate adjacent areas on the same forearm in the morning. Participants were instructed to air dry the site for two minutes before covering the area with clothing and to refrain from washing the site for 30 minutes after application.
The women were randomly assigned to treatment groups using a computer-generated central randomization schedule, and the applicator number was assigned through an interactive voice response system. All study site personnel and the participants were blinded as to the participant’s treatment group (active or placebo); however, both site personnel and the participants were aware of the number of sprays applied each day. Applicators containing E2 or placebo were identical in appearance. The pump’s dispensing volume variance is within ±10% (lot mean) and within ±15% (individual pump) of target volume. The between-assay variation for the high-performance liquid chromatography assay employed for spray content uniformity is approximately ±4–5%. For women with an intact uterus, a daily dose of medroxyprogesterone acetate 5 mg or 10 mg was prescribed for 2 weeks after the end of the 12-week treatment period.
The intent-to-treat/safety population was the primary basis for analysis. This included all participants who were randomly assigned and received at least one dose of study medication. The coprimary efficacy endpoints were mean change from baseline in frequency and severity of moderate-to-severe hot flushes at week 4 and week 12 of treatment as recommended by the U.S. Food and Drug Administration.18 The severity score was calculated using the formula (2×number of moderate hot flushes+3×number of severe hot flushes)/(number of moderate hot flushes+ number of severe hot flushes). Severity was defined as follows: mild, sensation of heat without sweating; moderate, sensation of heat with sweating, ability to continue activity; and severe, sensation of heat with sweating, causing discontinuation of activity. Baseline calculations were determined by considering the 14 days before first dose in which the diary was completed. Other efficacy evaluations included the mean change in frequency and severity of moderate-to-severe vasomotor symptoms weekly from baseline, the 50%, 75%, and 90% reduction of frequency, change in Greene Climacteric scale score, and participant assessment of overall treatment effect.
The Greene Climacteric scale was used to assess the climacteric symptoms of the postmenopausal women.19 Participants were asked to indicate the extent (1, not at all; 2, a little; 3, quite a bit; and 4, extremely) to which they are bothered by 21 specific symptoms. The women responded to a global assessment question to evaluate overall treatment effect at the end of the study. The question was “how would you describe the effect of study treatment on your menopausal symptoms (hot flushes and sweating)?” and the responses were: markedly improved, improved, no change, worse, or markedly worse.
Safety and tolerability were evaluated through adverse events; local skin tolerability; vital signs; physical examination; hematology, blood chemistry, and urinalysis; coagulation factors; lipid profile; Pap test, spontaneous vaginal bleeding (through adverse event reports), endometrial status (as determined by endometrial biopsy at screening and at end of study medication treatment, before medroxyprogesterone acetate dosing), and sex hormone binding globulin, which was measured for the three spray groups only (PPD Global Clinical Labs, LLC, Highland Heights, KY). Serum E2, estrone, and estrone sulfate levels (high-performance liquid chromatography with tandem mass spectrometry system detection method, PPD Analytical Laboratory, Richmond, VA) were measured at baseline and at weeks 4, 8, and 12 in all treatment groups. Samples were drawn at daytime, typically 2–6 hours after the dosing. The samples were obtained well before the peak levels (18–22 hours after the dose) and provide a reasonable estimate of the average concentration of each analyte during the 24-hour dosing cycle.
The sample size determination of 288 (48/group) was based on assumptions of a mean treatment difference between active and placebo of approximately four moderate-to-severe hot flushes per day and a standard deviation of the mean change from baseline of 6 at a 90% power using a 0.05 level two-tailed test in a one-way analysis of variance.20 The severity of hot flushes was assumed to have a similar effect size as the number of hot flushes, hence the sample size estimate for the frequency of hot flushes was considered sufficient to cover the severity of hot flushes endpoint. It was estimated that approximately 35% of participants would have some degree of incomplete data, thus the total sample size was calculated to be approximately 444 participants randomized (74/group).
For the primary efficacy endpoints, the mean change in frequency and severity of moderate-to-severe hot flushes from baseline to weeks 4 and 12 were compared between the treatment groups using the analysis of covariance model, where change from baseline was the dependent variable, treatment, region (study sites were grouped into four regions: North, South, East, and West), and treatment-by-region interaction were the independent variables, and baseline score was the covariate. Three pair-wise comparisons were conducted after the a priori sequence of three sprays, two sprays, one spray. The three-spray (E2/placebo) arms were compared first, then the two-spray arms, followed by the one-spray arms. The type I error rate was set at the 0.05 level at each dose comparison, and once a statistical test failed to reject the null hypothesis for any of the four endpoints, the testing was curtailed at that point from a confirmatory/regulatory perspective. A region-by-treatment interaction was examined. If a significant treatment-by-region interaction was observed and/or if distributional assumptions were violated, the Cochran-Mantel-Haenszel row mean score statistic was used to compare the treatment groups.21 The distributional assumptions were evaluated by considering stem-leaf and quantile-quantile plots as well as the Shapiro-Wilk statistics.
The analysis of the weekly changes in frequency and severity of hot flushes from baseline was carried out in the same manner as the primary endpoints. The 50%, 75%, and 90% reduction data were used to calculate the numbers needed to treat for benefit (number needed to treat=1/[percent E2 patients minus percent placebo patients]). The Greene Climacteric scale scores were evaluated in the same manner as the primary endpoints. Frequency counts were used to evaluate participant assessment of treatment effect. The demographic and other baseline characteristics tests for treatment differences used analysis of variance for continuous variables and Fisher exact test for categorical variables. Adverse events, laboratory measurements, and physical examination results were evaluated by descriptive statistics.
Statistical analyses were performed using SAS 8.2 (SAS Institute Inc., Cary, NC) on a PC platform. Statistical tests to evaluate treatment differences were two-tailed, with a significance level of 5% (α=0.05), and were declared statistically significant if the calculated P value was .05 or less. Treatment by region interaction analyses were performed at the .10 level. Adverse event terms were coded in Medical Dictionary for Regulatory Activities Version 7.1.
The study was completed in 15 months (December 2004 to March 2006). A total of 1,165 women underwent preliminary screening; 707 were screen failures, and 458 were randomly assigned. Of those assigned, 454 women administered at least one dose of the study drug and 377 participants (87.6% E2; 78.5% placebo) completed the study (Fig. 1).
There were no significant differences between E2 and placebo groups in the demographics and other baseline characteristics (Table 1). The mean age±standard deviation was 52.7±6.4 years for women on E2 and 52.3±6.7 years for women on placebo. The ages ranged from 36 years to 76 years, and most women (56.6%) were between 50 years and 59 years of age. The majority were white (69.0%, E2; 71.1%, placebo) and naturally menopausal (63.7%, E2; 59.6%, placebo).
The serum E2 levels for the different groups are shown in Figure 2. The overall mean (95% confidence interval) baseline E2 level of 5.8 (5.0–6.7) pg/mL for the active treatment group was similar to that of placebo 5.5 (4.8–6.3) pg/mL. The overall mean E2 level remained low (5.5 pg/mL or less) throughout the study in the placebo group. Marked increases in E2 levels were observed in the E2 groups, with posttreatment mean serum E2 levels of 30.7 (24.1–39.1) pg/mL to 40.1 (32.6–49.4) pg/mL observed in the three-spray group. In the two-spray group, mean serum E2 levels ranged between 24.0 (18.6–31.0) pg/mL and 32.1 (24.7–41.8) pg/mL. Mean E2 levels of 19.5 (15.3–25.0) pg/mL to 22.9 (17.9–29.3) pg/mL were observed in the one-spray group. The amount of E2 delivered to the systemic circulation was estimated by multiplying the average steady-state, baseline-adjusted E2 levels in serum (pg/mL) by the clearance rate of E2 in postmenopausal women (liters per day) by 1,000.22 Using the clearance rate of approximately 13.1 mL/(kg·min) (or 1,350 L/d) and the E2 serum values from the study, the systemic delivery rates were approximately 0.021 mg/d, 0.029 mg/d, and 0.040 mg/d of E2 for the one-, two-, and three-spray doses, respectively. The E2-treated women had an overall mean serum estrone level of 42.2 pg/mL and mean estrone sulfate level of 772.9 pg/mL at week 12.
The reduction in the frequency of moderate-to-severe hot flushes was statistically significant for all three E2 dose levels at weeks 4 and 12 (Fig. 3). In the three-spray E2 group, the frequency decreased from 10.78±3.58 flushes/d at baseline to 4.14±3.10 flushes/d at week 4, a change of –6.64±4.23 flushes/d. This was significantly (P<.001) greater than the change observed in placebo (–4.54±7.40). At week 12, the change was also significantly (P<.001) greater in women treated with three-spray E2 (–8.44±4.50) than those on placebo (–5.32±6.30). A –7.30±6.93 decrease was noted at week 4 in the two-spray E2 group compared with –4.74±4.38 in placebo (P=.003). Similarly, a significant (P=.010) decrease in frequency was reported at week 12 (E2, –8.66±6.65; placebo, –6.19±5.77). Reductions were significantly different between the one-spray E2 group and placebo at weeks 4 (–6.26±4.01 compared with –3.64±5.30, P=.001) and 12 (–8.10±4.02 compared with –4.76±5.84, P<.001). The weekly data showed that differences between E2 and placebo in the change in frequency of moderate-to-severe hot flushes became statistically significant (P<.050) relative to placebo by week 2 in all dose groups. By week 4, the difference in hot flush frequency between E2 and placebo exceeded two per day in all dose groups; the difference was maintained or increased in the subsequent weeks.
Significant reductions (P<.050) in the severity score of moderate-to-severe hot flushes was observed in the three-spray and two-spray E2 groups at both week 4 and week 12 (Fig. 4). The baseline severity score (2.58±0.25) was reduced to 2.15±0.73 at week 4 and 1.50±1.06 at week 12 in the three-spray E2 group. This change was significantly (week 4, P=.003; week 12, P<.001) greater than the three-spray placebo group (baseline, 2.54±.24; week 4, 2.41±0.58; week 12, 2.23±0.79). The baseline severity score (2.54±0.21) was reduced to 1.97±0.87 at week 4 and 1.63±1.07 at week 12 in the two-spray E2 group. These levels were significantly (P=.016 and P=.041, respectively) improved relative to placebo (week 4, 2.29±0.71; week 12, 2.00±0.96). The change in severity score at week 12 (–1.04±1.01) was significantly (P<.001) greater in the one-spray E2 group than in the one-spray placebo group (–0.26±0.60) and trended toward significance at week 4 (P=.057). A significant (P<.050) reduction in hot flush severity score was first achieved at weeks 3, 4, and 5 in the three-, two-, and one-spray E2 groups relative to placebo, respectively (Fig. 4). The difference was sustained throughout of the 12-week study period in all doses.
Between 74.3% and 85.5% of E2-treated women had a 50% or greater reduction in hot flush frequency relative to baseline at week 12 compared with 46.1% of women in the pooled placebo group. The 75% responder rates ranged from 59.2% to 65.8% for E2 (placebo, 28.1%). Participants on E2 had 90% responder rates that ranged from 39.2% to 47.4% (placebo, 18.0%). The number needed to treat at week 12 for decreases from baseline in frequency of vasomotor symptoms of 50%, 75%, and 90%, respectively, were 2.9, 2.9, and 3.3 for one-spray; 4.6, 5.4, and 7.0 for two-spray and 2.4, 2.5, and 3.2 for three-spray.
The supplemental endpoints also demonstrated significant differences between the E2 and the placebo groups. The Greene Climacteric Scale scores differed significantly between E2 and placebo groups for the vasomotor domain and for the individual questions from that domain (hot flush, night sweats). The mean reduction in hot flush score was 1.7 in the three-spray E2 group compared with 0.9 in the three-spray placebo (P<.001). These results were also observed in the two-spray (1.3 compared with 0.9, P=.018) and one-spray (1.3 compared with 0.8, P=.003) groups. The mean night sweat score decrease was 1.8 for the three-spray E2 and 0.8 for the placebo (P<.001). Similar reductions were observed in the two-spray (1.4 compared with 0.9, P<.001) and the one-spray (1.3 compared with 0.7, P=.003) groups. In the patient global assessment 64.5% of women in the three-spray E2 group reported marked improvement of vasomotor symptoms compared with 21.3% of women on placebo (P<.001). Similar trends were noted for the two-spray (43.2% compared with 30.3%, P=.039) and one-spray groups (47.4% compared with 23.4%, P=.003).
Adverse events were reported in 129 (57.1%) women on E2 and 114 (50.0%) women on placebo. At least one adverse event was reported by 60.5%, 55.4%, and 55.3% of women in the three-, two-, and one-spray E2 treatment groups, respectively, and by 50.7%, 53.9%, and 45.5% of women in the three-, two-, and one-spray placebo groups, respectively. Adverse events rates of 5% or more in any group are shown in Table 2. Headache was the most frequently reported adverse event. The most commonly reported events are known effects of E2 treatment. Treatment-related application site events were reported in three (1.3%) women on E2 and in four (1.8%) women on placebo. Twelve women (2.6%) withdrew from the study due to an adverse event; (6, E2; 6, placebo). Nine serious adverse events were reported in eight women (7, E2; 1, placebo); all were assessed as not related to study medication. There were no deaths, nor pulmonary emboli, venous thromboemboli, myocardial infarctions, or strokes reported.
Application site erythema was evaluated. The mean erythema score ranged from no erythema to very slight (barely perceptible) erythema. This indicated that the spray did not cause or was associated with very slight erythema at the application site. There were no clinically significant differences between the E2 and placebo groups in the vital signs, physical examination, hematology, clinical chemistry, urinalysis, coagulation measurements, and lipid profile results. Eleven participants (5, E2; 6, placebo) were found to be heterozygous for the R506Q factor V Leiden mutation; coagulation values for these participants were unremarkable. A single abnormal endometrial biopsy, simple hyperplasia without atypia, was identified in the two-spray E2 group at the end of treatment (before medroxyprogesterone acetate dosing). The follow-up biopsy performed 6 months after end of treatment was reported by the site as atrophic. Three women on E2 and eight women on placebo had reports of cervical test abnormalities at the end of treatment. The baseline sex hormone binding globulin was 49.1 nmol/L for the three-spray E2 group and 63.8 nmol/L for the placebo. The week 12 sex hormone binding globulin was 53.8 nmol/L for the three-spray E2 group and 66.1 nmol/L for the placebo; the difference between the three-spray E2 and placebo group in serum sex hormone binding globulin level was not significant (P=.143).
Like other transdermal delivery systems, the new E2 spray significantly reduced the frequency and severity of moderate-to-severe hot flushes in menopausal women.7–10 A significant decrease in frequency was already evident on the second week of treatment for all the three doses and was sustained throughout the 12 weeks of treatment. The vasomotor domain of Greene climacteric scale provided additional support of effective symptom relief at all three doses. The participants’ perception of the overall effect of the treatment after 12 weeks significantly favored E2 over placebo.
Estradiol spray achieved efficacy at 0.021–0.040 mg/d delivery rates. Currently, the lowest effective transdermal patch indicated to treat vasomotor symptoms is 0.025 mg/d; the lowest dose delivered for a transdermal E2 gel is approximately 0.012 mg/d.7 Thus, the addition of this E2 spray to the current armamentarium of E2 therapies allows for a low dose of E2 as endorsed by clinical and regulatory authorities, with the added flexibility of dose titration when individual needs necessitate.11–15
Adverse events observed with the spray were comparable to what have been reported with other low-dose transdermal systems.7–10 Adverse effects on skin, however, seem to be considerably lower than have been reported previously with patches and comparable or lower than with gels and emulsions.7–10 As with other transdermal E2 studies, there were no clinically significant differences observed in clotting factors, lipoproteins, sex hormone binding globulin, or liver function tests.2,3
A limitation of the study was that it was not feasible to blind the number of sprays that the participant received. This was mitigated by having corresponding placebo groups for each dose level of the E2 spray and by the availability of serial serum E2 levels that provided data on the systemic exposure and response relationship. The study was not designed or powered to demonstrate a dose response, and no proportionality analysis was conducted in this trial, but serum E2 levels increased with dose.
The E2 spray capitalizes on the advantages of transdermal over oral hormone therapy2,3 and differentiates itself from other transdermal systems in terms of convenience and tidiness of application. The spray is delivered in a closed system that applies the treatment to a precisely defined area of forearm skin. Unlike E2 gels and emulsions currently available, there is no need for the woman to touch the medication and to wash her fingers after application.7–9 The dispersal of drug is over a very small area and when used as instructed is not expected to be transferred to other people or to clothing through skin contact.
This study supports the efficacy and safety of the first transdermal E2 spray approved in the United States for the treatment of moderate-to-severe vasomotor symptoms in healthy menopausal women. The dose regimen starts with one spray per day and can be increased to a maximum of three sprays per day in women for whom higher E2 levels may be necessary to achieve an acceptable reduction in vasomotor symptom frequency. This E2 “spray-on patch” is a treatment option for women who will benefit from the advantages of transdermal E2 delivery but are intolerant of or are not inclined to use patches, gels, or emulsions. For many users, the spray will be an attractive first choice for transdermal E2 delivery.
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