A randomized, double-blind, placebo-controlled, multi-center clinical study was conducted to evaluate the safety and effectiveness of ENJUVIA 0.3 mg tablets for the treatment of symptoms of vulvar and vaginal atrophy in 248 naturally or surgically postmenopausal women between 32 to 81 years of age (mean 58.6 years) who at baseline had ≤ 5% superficial cells on a vaginal smear, a vaginal pH > 5.0, and who identified their most bothersome moderate to severe symptom of vulvar and vaginal atrophy. The majority (82%) of the women were Caucasian (n=203), 11% were Hispanic (n=26), 4% were Black (n=9) and 3% were Asian (n=6). All patients were assessed for improvement in the mean change from baseline to Week 12 for three co-primary efficacy variables: most bothersome symptom of vulvar and vaginal atrophy (defined as the moderate to severe symptom that had been identified by the patient as most bothersome to her at baseline); percentage of vaginal superficial cells and percentage of vaginal parabasal cells; and vaginal pH.
In this study, a statistically significant mean change between baseline and week 12 for the group treated with ENJUVIA 0.3 mg tablets compared to placebo was observed for the symptoms, vaginal dryness and pain with intercourse. See Table 5. ENJUVIA 0.3 mg tablets increased superficial cells by a mean of 17.1% as compared to 2.0% for placebo (statistically significant). A corresponding statistically significant mean reduction from baseline in parabasal cells (41.7% for ENJUVIA 0.3 mg tablets and 6.8% for placebo) was observed at week 12. The mean reduction between baseline and week 12 in the pH was 1.69 in the ENJUVIA 0.3 mg tablets group and 0.45 in the placebo group (statistically significant).
|* Treatment differences assessed by ANCOVA or rank ANCOVA (% cell data) with baseline as covariate for the modified intent-to-treat population, last-observation-carried-forward data set.|
|Most Bothersome Symptom at Baseline *||ENJUVIA 0.3 mg||Placebo|
|Mean Severity at Week 12||0.80||1.81|
|Mean Change in Severity from Baseline (s.d.)|| |
|p-value vs. placebo||<0.001||—|
|Pain With Intercourse|
|Mean Severity at Week 12||0.94||1.95|
|Mean Change in Severity from Baseline (s.d.)||-1.80 (1.02)||-0.75 (0.95)|
|p-value vs. placebo||<0.001||—|
The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of either the use of oral conjugated estrogens (CE 0.625 mg) alone per day or in combination with medroxyprogesterone acetate (CE 0.625 mg/MPA 2.5 mg) per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction (MI), silent MI and CHD death), with invasive breast cancer as the primary adverse outcome studied. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer (only in the estrogen plus progestin substudy), colorectal cancer, hip fracture, or death due to other causes. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.
The 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 age of 63 years, range 50 to 79; 75.3% White, 15.1% Black, 6.1% Hispanic, 3.6% Other), after an average follow-up of 6.8 years are presented in Table 6.
|Event||Relative Risk CE vs. Placebo(95% nCI * )||Placebon = 5,429||CE n = 5,310|
|Absolute Risk per 10,000Women-Years|
|CHD events † Nonfatal MI † CHD death †||0.95 (0.79- 1.16)0.91 (0.73-1.14) 1.01(0.71- 1.43)||564316||534016|
|Stroke ‡||1.39 (1.10-1.77)||32||44|
|Deep vein thrombosis †,§||1.47 (1.06-2.06)||15||23|
|Pulmonary embolism †||1.37 (0.90-2.07)||10||14|
|Invasive breast cancer †||0.80 (0.62-1.04)||34||28|
|Colorectal cancer ‡||1.08 (0.75-1.55)||16||17|
|Hip fracture ‡||0.61 (0.41-0.91)||17||11|
|Vertebral fractures ‡, §||0.62 (0.42-0.93)||17||11|
|Total fractures ‡, §||0.70 (0.63-0.79)||195||139|
|Death due to other causes ‡,||1.08 (0.88-1.32)||50||53|
|Overall mortality ‡, §||1.04 (0.88-1.32)||78||81|
|Global index ‡,||1.01 (0.91-1.12)||190||192|
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 estrogen-alone was 12 more strokes, while the absolute risk reduction per 10,000 women-years was 6 fewer hip fractures. The absolute excess risk of events included in the “global index” was a nonsignificant 2 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)
Final centrally adjudicated results for CHD events and centrally adjudicated results for invasive breast cancer incidence from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported 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 (see Table 6).
The estrogen-plus-progestin substudy was also stopped early because, according to the predefined stopping rule, after an average follow-up of 5.2 years of treatment, the increased risk of 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 (RR 1.15, 95% nCI 1.03-1.28).
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/MPA were 6 more CHD events, 7 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 7 fewer colorectal cancers and 5 fewer hip fractures. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)
Results of the estrogen-plus-progestin substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.8% Black, 5.4% Hispanic, 3.9% Other) are presented in Table 7 below.
|Event||Relative RiskCE/MPA vs. Placebo(95% nCI )||Placebon = 8102||CE/MPAn = 8506|
|Absolute Risk per 10,000 Women-Years|
|CHD events Non-fatal MI CHD death||1.24 (1.00-1.54)1.28 (1.00-1.63)1.10 (0.70-1.75)||33258||39318|
|All strokes||1.31 (1.02-1.68)||24||31|
|Ischemic stroke||1.44 (1.09 -1.90 )||18||26|
|Deep vein thrombosis||1.95 (1.43 – 2.67)||13||26|
|Pulmonary embolism||2.13 (1.45-3.11)||8||18|
|Invasive breast cancer||1.24 (1.01-1.54)||3||41|
|Invasive colorectal cancer||0.56 (0.38-0.81)||16||9|
|Endometrial cancer||0.81 (0.48-1.36)||7||6|
|Cervical cancer||1.44 (0.47-4.42)||1||2|
|Hip fracture||0.67 (0.47-0.96)||16||11|
|Vertebral fractures||0.65 (0.46-0.92)||17||11|
|Lower arm/wrist fractures||0.71 (0.59-0.85)||62||44|
|Total fractures||0.76 (0.69-0.83)||199||152|
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