Table 2 The SMART clinical trial program

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]

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]

CE 0.625 mg/BZA 40 mg

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]

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]

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

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]

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

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]