Estradiol (Page 6 of 8)

14 CLINICAL STUDIES

14.1 Effects on Atrophic Vaginitis in Postmenopausal Women

A 12-month double-blind, randomized, parallel group, placebo-controlled multicenter study was conducted in the U.S. and Canada to evaluate the efficacy and safety of estradiol 10 mcg in the treatment of atrophic vaginitis in 309 postmenopausal women between 46 and 81 years of age (mean 57.6 years of age) who at baseline identified their most bothersome symptom of atrophic vaginitis from among six symptoms (vaginal dryness, vaginal and/or vulvar irritation/itching, vaginal soreness, dysuria, dyspareunia and vaginal bleeding associated with intercourse). Women inserted one insert intravaginally each day for 14 days, then one insert twice weekly for the remaining 50 weeks. The majority (92.9 percent) of the women were Caucasian (n=287), 3.2 percent were Black (n=10), 1.6 percent were Asian (n=5) and 2.2 percent were Other (n=7). All participants were assessed for improvement in the mean change from baseline to Week 12 for co-primary efficacy variables of: a composite of most bothersome symptoms of atrophic vaginitis; percentage of vaginal superficial cells and percentage of vaginal parabasal cells on a vaginal smear; and vaginal pH.

Relief of Vaginal Symptoms

Estradiol 10 mcg was statistically superior to placebo in reducing the severity of a composite score of most bothersome symptoms associated with atrophic vaginitis at Week 12 (see Table 3).

Table 3: Mean Change from Baseline to Week 12 in a Composite Score of Most Bothersome Symptoms Compared to Placebo – ITT Population
Placebo Estradiol 10 mcg
ITT Populationa
a All randomized subjects who received at least one dose of study drug and had at least one post-baseline evaluation.
N 93 190
Baseline mean composite score 2.29 2.35
Change from baseline at Week 12 (LOCF) -0.84 -1.20
p-value versus Placebo 0.002

Also demonstrated for estradiol 10 mcg compared to placebo was a statistically significant increase in the percentage of superficial cells at Week 12 (13.2 percent compared to 3.8 percent for matching placebo, p<0.001), a statistically significant decrease in parabasal cells at Week 12 (-37 percent compared to -9.3 percent for matching placebo, p<0.001), and a statistically significant mean reduction between baseline and Week 12 in vaginal pH score (-1.3 compared to -0.4 for matching placebo, p<0.001).

Endometrial safety was assessed by endometrial biopsy at the screening and final study visit. Of the 172 women in the estradiol 10 mcg group who had a biopsy performed at end of study, 92 women had endometrial tissue that was atrophic or inactive and 73 women had no tissue or tissue insufficient for diagnosis. There was one case of adenocarcinoma grade 2 and one case of complex hyperplasia without atypia. Three women exhibited polyps (two atrophic polyps and one adenomyomatus type polyp) and two others had adenomyosis and an atypical epithelial proliferation.

Endometrial safety of estradiol 10 mcg was additionally evaluated in a second, 12 month, open-label, multicenter safety study. Of the 297 women who had a biopsy performed at end of study, 183 women had endometrial tissue that was atrophic or inactive and 111 women had no tissue or tissue insufficient for diagnosis. There was one case of complex hyperplasia without atypia. Two women exhibited polyps.

14.2 Women’s Health Initiative Studies

The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 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, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other causes. These substudies did not evaluate the effects of CE-alone or CE plus MPA on menopausal symptoms.

WHI Estrogen-Alone Substudy

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 4.

Table 4: Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHI
Event Relative Risk CE vs. Placebo (95% nCIb) CE n = 5,310 Placebo n = 5,429
Absolute Risk per 10,000 Women-Years
a Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi.
b Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
c Results are based on centrally adjudicated data for an average follow-up of 7.1 years.
d Not included in “global index”.
e Results are based on an average follow-up of 6.8 years.
f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease.
g A subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes.
CHD eventsc 0.95 (0.78 to 1.16) 54 57
Non-fatal MI c 0.91 (0.73 to 1.14) 40 43
CHD death c 1.01 (0.71 to 1.43) 16 16
All Strokesc 1.33 (1.05 to 1.68) 45 33
Ischemic stroke c 1.55 (1.19 to 2.01) 38 25
Deep vein thrombosisc,d 1.47 (1.06 to 2.06) 23 15
Pulmonary embolismc 1.37 (0.90 to 2.07) 14 10
Invasive breast cancerc 0.80 (0.62 to 1.04) 28 34
Colorectal cancere 1.08 (0.75 to 1.55) 17 16
Hip fracturec 0.65 (0.45 to 0.94) 12 19
Vertebral fracturesc,d 0.64 (0.44 to 0.93) 11 18
Lower arm/wrist fracturesc,d 0.58 (0.47 to 0.72) 35 59
Total fracturesc,d 0.71 (0.64 to 0.80) 144 197
Death due to other causese,f 1.08 (0.88 to 1.32) 53 50
Overall mortalityc,d 1.04 (0.88 to 1.22) 79 75
Global Indexg 1.02 (0.92 to 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.9 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 CE-alone compared with 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 difference in distribution of stroke subtype or severity, including fatal strokes, in women receiving CE-alone compared to placebo. Estrogen-alone increased the risk for ischemic stroke, and this excess risk was present in all subgroups of women examined.10

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 to 1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46 to 1.11)].

WHI Estrogen Plus Progestin Substudy

The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years.

For those outcomes included in the WHI “global index” that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures.

Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 5. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.

Table 5: Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Years
Event Relative Risk CE/MPA vs Placebo (95% nCI c) CE/MPA n = 8,506 Placebo n = 8,102
Absolute Risk per 10,000 Women-Years
a Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi.
b Results are based on centrally adjudicated data.
c Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
d Not included in “global index”.
e Includes metastatic and non-metastatic breast cancer, with the exception of in situ cancer.
f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease.
g A subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes.
CHD events 1.23 (0.99 to 1.53) 41 34
Non-fatal MI 1.28 (1 to 1.63) 31 25
CHD death 1.10 (0.70 to 1.75) 8 8
All Strokes 1.31 (1.03 to 1.68) 33 25
Ischemic stroke 1.44 (1.09 to 1.90) 26 18
Deep vein thrombosisd 1.95 (1.43 to 2.67) 26 13
Pulmonary embolism 2.13 (1.45 to 3.11) 18 8
Invasive breast cancere 1.24 (1.01 to 1.54) 41 33
Colorectal cancer 0.61 (0.42 to 0.87) 10 16
Endometrial cancerd 0.81 (0.48 to 1.36) 6 7
Cervical cancerd 1.44 (0.47 to 4.42) 2 1
Hip fracture 0.67 (0.47 to 0.96) 11 16
Vertebral fracturesd 0.65 (0.46 to 0.92) 11 17
Lower arm/wrist fracturesd 0.71 (0.59 to 0.85) 44 62
Total fracturesd 0.76 (0.69 to 0.83) 152 199
Overall Mortalityf 1 (0.83 to 1.19) 52 52
Global Indexg 1.13 (1.02 to 1.25) 184 165

Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age showed in women 50 to 59 years of age, a non-significant trend toward reduced risk for overall mortality [HR 0.69 (95 percent CI, 0.44 to 1.07)].

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