14 CLINICAL STUDIES
14.1 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause in Women with a Uterus
The safety and efficacy of DUAVEE as a treatment for moderate to severe vasomotor symptoms associated with menopause was established in a 12-week randomized, double-blind, placebo-controlled study (Study 3). Study 3 enrolled a total of 318 women, age 42–64 (mean age of 53 years), who had at least 7 moderate to severe hot flushes per day or at least 50 per week at baseline. The mean number of years since menopause was 4.5 years with all women undergoing natural menopause. A total of 127 women were assigned to DUAVEE and 63 women were assigned to placebo.
In Study 3, DUAVEE significantly reduced the number and severity of moderate to severe hot flushes, as measured by the daily severity score, compared with placebo at Weeks 4 and 12. The change from baseline in the number and severity of moderate to severe hot flushes observed and the difference from placebo in Study 3 are shown in Table 3.
|Treatment Difference†||-3.1 (-4.4, -1.7)‡||--||-0.5 (-0.7, -0.3)‡||--|
|Treatment Difference†||-2.7 (-3.8, -1.6)‡||--||-0.6 (-0.9, -0.4)‡||--|
14.2 Prevention of Postmenopausal Osteoporosis in Women with a Uterus
The safety and efficacy of DUAVEE for the prevention of postmenopausal osteoporosis was demonstrated in Study 1 and Study 2.
Study 1 was a 24-month, double-blind, randomized, placebo- and active-controlled study evaluating the safety and efficacy of multiple combinations of conjugated estrogen/bazedoxifene (including conjugated estrogens 0.45 mg/bazedoxifene 20 mg) compared to placebo. The primary endpoint of the study was the incidence of endometrial hyperplasia at Year 1. Bone mineral density change at the lumbar spine at Year 2 was the key secondary endpoint, assessed in two subsets of patients (Substudy I and Substudy II). Patients enrolled into Substudy I had to be more than 5 years postmenopausal, have a lumbar spine or total hip T-score of -1 to -2.5, and have at least one additional risk factor for osteoporosis (e.g., Caucasian race, family history of osteoporosis, early menopause, thin/small frame, inactive lifestyle, tobacco abuse). Those enrolled into Substudy II had to be 1–5 years postmenopausal with at least one additional risk factor for osteoporosis. A total of 3,397 women age 40–75 (mean age of 56 years) were enrolled in the overall study. Substudy I enrolled a total of 1,454 women (182 women receiving DUAVEE) with mean baseline T-scores of -1.43 and -1.52 in the DUAVEE and placebo groups, respectively. Substudy II enrolled a total of 861 women (with 111 women receiving DUAVEE) with mean baseline T-scores of -0.81 and -0.94 in the DUAVEE and placebo groups, respectively. Women also took calcium (600–1200 mg) and vitamin D (200–400 IU) daily.
In these substudies, treatment with DUAVEE significantly increased lumbar spine bone mineral density (BMD) at 24 months compared to placebo in both groups of postmenopausal women (Table 4).
|** Adjusted mean changes, confidence intervals, and p-values based on an ANCOVA model with treatment and region (U.S. or non-U.S.) as factors and baseline BMD value and years since menopause as covariates using the Modified Intention to Treat population with Last Observation Carried Forward. Study 1 excludes those subjects with missing source documentation.|
|Between 1 and 5 Years Postmenopausal|
|% Mean Change||1.72||-1.90|
|Difference from Placebo (95% C.I.)||3.62 (2.64, 4.60)*|
|More Than 5 Years Postmenopausal|
|% Mean Change||1.64||-1.47|
|Difference from Placebo (95% C.I.)||3.11 (2.29, 3.93)*||–|
In Study 1, treatment with DUAVEE also significantly increased total hip BMD. The treatment difference (or difference from placebo) in total hip BMD at 24 months was 1.96% (DUAVEE minus placebo) in women who had been postmenopausal between 1 and 5 years and 1.73% (DUAVEE minus placebo) in women who had been postmenopausal for more than 5 years.
Study 2 was a 12-month, double-blind, randomized, placebo- and active-controlled study. The primary endpoint was the incidence of endometrial hyperplasia at 12 months. The prevention of osteoporosis was assessed in a substudy that enrolled women (n=590) who were less than 5 years postmenopausal (mean 2.5 years). The mean baseline T-score in the substudy was -0.91 in the DUAVEE group and -0.95 in the placebo group. The mean age of women (n=135) taking DUAVEE was 53 years (range 46–60 years). Women also took calcium (600 mg) and vitamin D (400 IU) daily.
In Study 2, treatment with DUAVEE significantly increased mean lumbar spine BMD (treatment difference, 1.51%), at 12 months compared to placebo in women who had been postmenopausal between 1 and 5 years. Treatment with DUAVEE also increased total hip BMD. The treatment difference in total hip BMD at 12 months was 1.21%.
14.3 Effects on the Endometrium
Effects of DUAVEE on endometrial hyperplasia and endometrial malignancy were assessed in Study 1 and Study 2. The Efficacy Evaluable population included patients who had taken at least one dose of DUAVEE, had baseline and post baseline endometrial biopsies, or had been diagnosed with hyperplasia. By endometrial biopsy, the incidence of endometrial hyperplasia or malignancy for DUAVEE was below 1% in both studies (see Table 5).
|STUDY 1*||STUDY 2*|
|Treatment Group||Month||% (n/N)||1 – Sided 95% UL||% (n/N)||1 – Sided 95% UL|
|UL = Upper limit|
|DUAVEE||12||0.00% (0/336)||0.89||0.30% (1/335)||1.41|
14.4 Effects on Uterine Bleeding and Spotting
Uterine bleeding or spotting were evaluated in two clinical studies (Studies 1 and 2) by daily diary. In Study 1, cumulative amenorrhea at Year 1 was 83% in women treated with DUAVEE and 85% in women who received placebo. In Study 2, cumulative amenorrhea at Year 1 was 88% in women treated with DUAVEE and 84% in women who received placebo.
14.5 Women's Health Initiative Studies
The WHI enrolled approximately 11,000 predominantly healthy postmenopausal women to assess the risks and benefits of daily oral conjugated estrogens 0.625 mg compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of CHD (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, colorectal cancer, hip fracture, or death due to other cause. These substudies did not evaluate the effects of conjugated estrogens on menopausal symptoms.
The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen-alone in predetermined primary endpoints.
Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other), after an average follow- up of 7.1 years are presented in Table 6.
CE vs. Placebo
n = 5,310
N = 5,429
|Absolute Risk per 10,000 Women-Years|
|CHD events‡||0.95 (0.78–1.16)||54||57|
|Non-fatal MI‡||0.91 (0.73–1.14)||40||43|
|CHD death‡||1.01 (0.71–1.43)||16||16|
|All strokes‡||1.33 (1.15–1.68)||45||33|
|Ischemic stroke‡||1.55 (1.19–2.01)||38||25|
|Deep vein thrombosis‡,§||1.47 (1.06–2.06)||23||15|
|Pulmonary embolism‡||1.37 (0.90–2.07)||14||10|
|Invasive breast cancer‡||0.80 (0.62–1.04)||28||34|
|Colorectal cancer¶||1.08 (0.75–1.55)||17||16|
|Hip fracture‡||0.65 (0.45–0.94)||12||19|
|Vertebral fractures‡,§||0.64 (0.44–0.93)||11||18|
|Lower arm/wrist fractures‡,§||0.58 (0.47–0.72)||35||59|
|Total fractures‡,§||0.71 (0.64–0.80)||144||197|
|Death due to other causes¶,#||1.08 (0.88–1.32)||53||50|
|Overall mortality‡,§||1.04 (0.88–1.22)||79||75|
|Global IndexÞ||1.02 (0.92–1.13)||206||201|
For those outcomes included in the WHI "global index" that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE-alone was 12 more strokes, while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures. The absolute excess risk of events included in the "global index" was a non-significant 5 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality.
No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving conjugated estrogens-alone compared to placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow-up of 7.1 years.
Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant differences in distribution of stroke subtype or severity, including fatal strokes, in women receiving conjugated estrogens-alone compared to placebo. Estrogen-alone increased the risk for ischemic stroke, and this excess risk was present in all subgroups of women examined.
Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy, stratified by age, showed in women 50 to 59 years of age a non-significant trend toward reduced risk for CHD [hazard ratio (HR) 0.63 (95 percent CI, 0.36–1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46–1.11)].
14.6 Women's Health Initiative Memory Study
The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age (45 percent were 65 to 69 years of age, 36 percent were 70 to 74 years of age, and 19 percent were 75 years of age and older) to evaluate the effects of daily conjugated estrogens (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo.
After an average follow-up of 5.2 years, the relative risk of probable dementia for conjugated estrogens-alone versus placebo was 1.49 (95 percent CI, 0.83–2.66). The absolute risk of probable dementia for conjugated estrogens-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as defined in this study included Alzheimer's disease (AD), vascular dementia (VaD) and mixed type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions (5.4) and Use in Specific Populations (8.5)].