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SMART-1 [9–12, 100]
|
2-year, randomized, double-blind, multicenter, placebo- and active (RLX)-controlled, phase 3 trial
|
Age 40–75 years Postmenopausal (≥12 months amenorrhea, FSH ≥30 mIU/mL, and 17β-E2 ≤183.5 pmol/L)
|
3,544 OSS I: 1,454 OSS II: 861 [12]
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CE 0.625 mg/BZA 10 mg
|
Incidence of endometrial hyperplasia at 1 year
|
CE 0.45 and 0.625 mg/BZA 20 and 40 mg showed low rates (<1%) of endometrial hyperplasia [9]
|
|
With a uterus
|
|
No evidence of endometrial hyperplasia
|
CE 0.625 mg/BZA 20 mg
|
|
BMI ≤32.2 kg/m2
|
|
OSS I: >5 YSM with a baseline BMD T-score between -1 and -2.5 and ≥1 additional risk factor for osteoporosis [12]
|
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CE 0.625 mg/BZA 40 mg
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Other outcomes Incidence of abnormal mammograms at 2 years: 4.4% with CE 0.45 mg/BZA 20 mg, 4.2% with CE 0.625 mg/BZA 20 mg, 3.4% with RLX, and 2.6% with PBO [100]
|
|
OSS II: 1–5 YSM with ≥1 risk factor for osteoporosis [12]
|
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CE 0.625 and 0.45 mg/BZA 20 and 40 mg associated with rates of cumulative amenorrhea similar to PBO (>83% (cycles 1–13) and >93% (cycles 10–13)); bleeding and spotting rates similar to PBO [11]
|
|
CE 0.45 mg/BZA 10 mg
|
|
CE 0.45 mg/BZA 20 mg
|
|
CE 0.45 mg/BZA 40 mg
|
|
RLX 60 mg PBO
|
|
CE 0.45 and 0.625 mg/BZA 20 mg significantly reduced number (P <0.05 for both) and severity (P <0.001 for both) of hot flushes vs. PBO at week 12 [10]
|
|
CE 0.625 and 0.45 mg/BZA 20 mg significantly reduced VVA vs. PBO at month 24, and CE 0.625 mg/BZA 20 mg significantly reduced the incidence of dyspareunia at weeks 5–12 [10]
|
|
CE 0.45 and 0.625 mg/BZA 20 mg significantly improved LDL and HDL cholesterol vs. PBO (P <0.01 for all) at month 24 [10]
|
|
OSSs
|
|
In both OSSs, CE/BZA was associated with significant BMD increases at lumbar spine (P <0.001) and total hip (P <0.01), with significant decreases in bone turnover markers [12]
|
|
SMART-2 [13, 14]
|
12-week, multicenter, double-blind, randomized, placebo-controlled, phase 3 trial
|
Age 40–65 years
|
332
|
CE 0.45 mg/BZA 20 mg
|
Change from baseline in average daily number of moderate and severe hot flushes and the severity of hot flushes at weeks 4 and 12
|
CE/BZA at both doses significantly reduced the number and severity of hot flushes vs. PBO at weeks 4 and 12 (P <0.001 for all) [13]
|
|
Postmenopausal (≥12 months amenorrhea or 6 months amenorrhea with FSH >40 mIU/mL)
|
CE 0.625 mg/BZA 20 mg PBO
|
|
Other outcomes
|
|
With a uterus
|
|
BMI ≤34.0 kg/m2
|
Women treated with CE/BZA experienced significant improvements in sleep parameters and overall menopause-related and vasomotor HR-QOL [14]
|
|
≥7 moderate to severe hot flushes per day or ≥50 per week
|
|
SMART-3 [15, 16]
|
12-week, multicenter, double-blind, randomized, placebo- and active
|
Age 40–65 years
|
664
|
CE 0.45 mg/BZA 20 mg
|
4 co-primary endpoints: change from baseline in (1) proportion of vaginal superficial cells,
|
CE/BZA at both doses significantly (P <0.01) increased superficial cells and decreased parabasal cells vs. PBO [15]
|
|
Postmenopausal (≥12 months amenorrhea or 6 months amenorrhea with FSH >40 mIU/mL)
|
CE 0.625 mg/BZA 20 mg
|
|
(BZA)-controlled, phase 3 trial
|
|
BZA 20 mg
|
|
With a uterus
|
PBO
|
(2) proportion of parabasal cells, (3) vaginal pH, and (4) severity of the most bothersome vulvar-vaginal symptom at week 12
|
CE 0.625 mg/BZA 20 mg was associated with a significant decrease in vaginal pH from baseline (P <0.001), a decrease that was significantly greater than that seen with placebo (P <0.001) [15]
|
|
BMI ≤34.0 kg/m2
|
|
≤5% or less superficial cells on vaginal cytological smear
|
|
CE 0.625 mg/BZA 20 mg was associated with improvement in most bothersome vulvar-vaginal symptom at week 12 vs. PBO (P <0.05) [15]
|
|
Vaginal pH >5
|
|
≥1 moderate to severe bothersome vulvar-vaginal symptom
|
|
Other outcomes
|
|
No endometrial hyperplasia, estrogen-dependent neoplasia, undiagnosed vaginal bleeding, or focal endometrial abnormality on transvaginal ultrasound
|
CE 0.45 and 0.625 mg/BZA 20 mg significantly improved sexual function measured by ASEX (P <0.05) vs. PBO [16]
|
|
CE 0.45 and 0.625 mg/BZA 20 mg significantly improved vasomotor function, sexual function, and overall menopause-related HR-QOL measured by MENQOL (P <0.01) vs. PBO [16]
|
|
SMART-4 [17]
|
1-year, multicenter, double-blind, randomized, placebo- and active- (CE/MPA) controlled, phase 3 study
|
Age 40–59 years
|
1,083
|
CE 0.45 mg/BZA 20 mg
|
Incidence of endometrial hyperplasia at 1 year
|
There were 3 cases of endometrial hyperplasia in the CE 0.625 mg/BZA 20 mg group and none in the other groups
|
|
OSS: mean percentage change from baseline in lumbar spine BMD at 1 year
|
|
All active treatments produced significant increases from baseline in lumbar spine and total hip BMD compared with PBO (P <0.001)
|
|
Postmenopausal (≥12 months amenorrhea or 6 months amenorrhea with FSH >40 mIU/mL)
|
CE 0.625 mg/BZA 20 mg
|
|
CE 0.45 mg/MPA 1.5 mg PBO
|
|
With a uterus
|
|
BMI ≤34.0 kg/m2
|
|
No history of endometrial hyperplasia or undiagnosed vaginal bleeding
|
|
OSS: ≤5 years amenorrhea 2 evaluable BMD scans of lumbar spine differing by <5% and hip differing by <7.5%
|
|
No osteoporosis or fragility fractures
|
|
SMART-5 [18, 19, 101, 102]
|
1-year, multicenter, double-blind, randomized, placebo-, and active- (CE/MPA) controlled, phase 3 trial
|
Aged 40–65 years
|
1,843
|
CE 0.45 mg/BZA 20 mg
|
Incidence of endometrial hyperplasia and mean percentage change in lumbar spine BMD at 12 months
|
Incidence of endometrial hyperplasia with CE 0.45 and 0.625 mg/BZA 20 mg was low (≤0.3%) and similar to that with PBO and CE 0.45 mg/MPA 1.5 mg [102]
|
|
Postmenopausal (≥12 months amenorrhea or 6 months amenorrhea with FSH >40 mIU/mL)
|
|
CE 0.625 mg/BZA 20 mg
|
|
With a uterus
|
|
BMI ≤34.0 kg/m2
|
BZA 20 mg
|
|
Acceptable endometrial biopsy
|
CE 0.45 mg/MPA 1.5 mg PBO
|
|
Seeking treatment for menopausal symptoms
|
|
Sleep/HR-QOL substudy: bothered by hot flushes/night sweats plus sleep interruptions
|
|
CE 0.45 and 0.625 mg/BZA 20 mg were associated with significant improvements in lumbar spine BMD vs. PBO at 1 year (P <0.001) [101]
|
|
Other outcomes
|
|
CE 0.45 and 0.625 mg/BZA 20 mg were non-inferior to PBO in percentage change in mammographic breast density [18]
|
|
In the sleep/HR-QOL substudy, both doses of CE/BZA were associated with significant improvements in sleep parameters and HRQOL at 1 year [19]
|
