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Table 2 The SMART clinical trial program

From: Breast-related effects of selective estrogen receptor modulators and tissue-selective estrogen complexes

Study Study design Main inclusion criteria Number of patients randomly assigned Treatment groups Primary endpoint Key results
SMART-1 [912, 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] 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]
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]
  1. 17β-E2, 17β-estradiol; ASEX, Arizona Sexual Experiences Scale; BMD, bone mineral density; BMI, body mass index; BZA, bazedoxifene; CE, conjugated estrogens; FSH, follicle-stimulating hormone; HDL, high-density lipoprotein; HR-QOL, health-related quality of life; LDL, low-density lipoprotein; MENQOL, Menopause-specific Quality of Life; MPA, medroxyprogesterone acetate; OSS, Osteoporosis Substudy; PBO, placebo; RLX, raloxifene; SMART, Selective estrogens, Menopause, And Response to Therapy; VVA, vulvar-vaginal atrophy; YSM, years since menopause.
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