A combined, bioidentical, oral, 17β-estradiol and progesterone capsule for the treatment of moderate to severe vasomotor symptoms due to menopause

Figures & data

Figure 1. Mean steady-state serum (a) progesterone (P4) and (b) estradiol (E2) concentrations following daily oral administration of 1 mg E2/100 mg P4 (no baseline adjustment) at day 7.

Table 1. Main inclusion and exclusion criteria in the REPLENISH study.

Inclusion Criteria	Exclusion Criteria
Women Aged 40 to 65 years old Intact uterus Postmenopausal (defined as ≥12 months of spontaneous amenorrhea, or at least 6 months of spontaneous amenorrhea with screening follicle stimulating hormone > 40 mIU/ml, or ≥6 weeks’ postsurgical bilateral oophorectomy) Generally healthy BMI ≤34 kg/m^2 Seeking treatment for menopause-related VMS Willing to abstain from non-study hormone products Negative screening mammogram; normal breast and pelvic exams Normal PAP smear and endometrial biopsy	Contraindications to hormone use Heavy smoker (≥15 cigarettes/day) or user of electronic cigarettes History of endometrial hyperplasia or of undiagnosed vaginal bleeding History of melanoma or of breast, uterine, or ovarian cancer Thromboembolic disorder or other vascular disease, clotting or malabsorption disorder, estrogen-dependent neoplasia, or chronic kidney or liver disease Recent use of a CYP3A4 inhibitor, certain hormones, or an IUD Clinically significant uterine fibroids at screening Elevated fasting glucose (>125 mg/dL), triglyceride (≥300 mg/dL) or total cholesterol (≥300 mg/dL)
Additional Criteria for the VMS Substudy
14-day diary showing ≥7 moderate to severe hot flushes per day or ≥50 per week during screening	Use of medication in past 28 days that may affect VMS prior to screening

BMI, body mass index; IUD, intrauterine device; VMS, vasomotor symptoms.

Figure 2. Subject disposition in the REPLENISH trial.

Table 2. Participant demographics and baseline characteristics of the modified intent-to-treat (MITT)-VMS population.

	Estradiol/Progesterone
Characteristic	1 mg/ 100 mg	0.5 mg/ 100 mg	0.5 mg/ 50 mg	0.25 mg/ 50 mg	Placebo
n	141	149	147	154	135
Age, y	54.7 ± 4.8	54.9 ± 4.5	54.8 ± 4.6	54.5 ± 3.8	54.3 ± 4.3
Race, n (%) White African American Other*	95 (67.4) 45 (31.9) 1 (0.7)	99 (66.4) 48 (32.2) 2 (1.3)	99 (67.3) 43 (29.3) 5 (3.4)	102 (66.2) 48 (31.2) 4 (2.6)	91 (67.4) 41 (30.4) 3 (2.2)
BMI, kg/m^2	26.5 ± 3.9	27.1 ± 4.3	26.6 ± 3.9	26.4 ± 4.0	26.6 ± 3.8
Time since menopause, y	6.1 ± 5.5	6.5 ± 5.4	6.0 ± 4.8	5.2 ± 4.8	5.7 ± 4.9
Bilateral oophorectomy	3 (2.1)	3 (2.0)	1 (0.7)	1 (0.6)	0
Baseline VMS parameters Weekly frequency Weekly severity	74.4 ± 35.3 2.54 ± 0.32	72.1 ± 27.8 2.51 ± 0.25	75.9 ± 28.0 2.50 ± 0.23	77.0 ± 30.4 2.51 ± 0.26	72.4 ± 23.3 2.52 ± 0.25

Data presented as mean ± SD, unless stated otherwise.

SD, standard deviation; BMI, body mass index; VMS, vasomotor symptoms.

*Other includes: other (n = 10), American Indian or Alaska Native (n = 2), Native Hawaiian or Pacific Islander (n = 2), and unknown (n = 1).

Figure 3. Weekly reduction in VMS (a) frequency and (b) severity in MITT-VMS population. For (a) p < 0.05 versus placebo from *weeks 3–12; †weeks 4–12; ‡weeks 6–12; for (b) p < 0.05 versus placebo from *weeks 3–12; †weeks 7, 9–12; ‡weeks 6, 7, 9. Weekly severity score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3]/(total number of mild, moderate and severe hot flushes over 7 days). E2: 17β-estradiol; MITT: modified intent-to-treat; P4: progesterone; VMS: vasomotor symptoms. Reprinted with permission from Lobo et al [30].

Figure 4. Mean reduction from baseline in Menopause-specific Quality of Life (MENQOL) (a) overall and (b) vasomotor domain scores in MITT-VMS population and in Medical Outcome Study (MOS)-Sleep (c) total and (d) Sleep Problems Index I scores in MITT population. *p < 0.05; †p < 0.01; ‡p < 0.001 vs placebo. Sleep Problems Index I based on the following questions: How often during the past 4 weeks did you: Get enough sleep to feel rested upon waking; Awaken short of breath or with a headache; Have trouble falling asleep; Awaken and have trouble falling asleep again; Have trouble staying awake during the day; Get the amount of sleep you needed? E2, 17β-estradiol; MITT, modified intent-to-treat; P4, progesterone; VMS: vasomotor symptoms. Figure 4(a,b) adapted with permission from Simon et al [36] Figure 4(c,d) adapted with permission from Kagan et al [37].

Table 3. Treatment-related TEAEs occurring in ≥3% in any treatment arm and more commonly than placebo and treatment-related serious AEs (safety population).

	Estradiol/Progesterone
N (%)	1 mg/ 100 mg n = 415	0.5 mg/ 100 mg n = 424	0.5 mg/ 50 mg n = 421	0.25 mg/ 50 mg n = 424	Placebo n = 151
Any treatment-related TEAE	170 (41)	143 (34)	133 (32)	134 (32)	27 (18)
Breast tenderness	43 (10)	17 (4)	25 (6)	10 (2)	1 (1)
Headache	14 (3)	17 (4)	22 (5)	24 (6)	1 (1)
Nausea	9 (2)	15 (4)	11 (3)	8 (2)	1 (1)
Pelvic pain	13 (3)	12 (3)	8 (2)	6 (1)	0
Vaginal hemorrhage	14 (3)	10 (2)	3 (1)	8 (2)	0
Vaginal discharge	14 (3)	8 (2)	6 (1)	6 (1)	1 (1)
At least 1 serious TEAE	9 (2)	13 (3)	8 (2)	8 (2)	2 (1)
Any treatment-related serious AE	3 (0.7)	2 (0.5)	2 (0.5)	2 (0.5)	1 (0.7)
Acute pancreatitis	1 (0.2)	0	0	0	0
Infective cholecystitis	0	0	0	0	1 (0.7)
Breast cancer/Invasive ductal carcinoma	2 (0.5)	2 (0.5)	1 (0.2)	1 (0.2)	0
Deep vein thrombosis	0	0	1 (0.2)	0	0
Chronic obstructive pulmonary disease	0	0	0	1 (0.2)	0

AE, adverse events; TEAE, treatment emergent adverse events.

Figure 5. Cumulative (a) amenorrhea and (b) no bleeding in safety population. *p < 0.05; †p ≤ 0.01; ‡p < 0.001 vs placebo. Cycles are 28 days in length. E2, 17β-estradiol; P4, progesterone.

Lobo RA, Archer DF, Kagan R, et al. A 17β-estradiol-progesterone oral capsule for vasomotor symptoms in postmenopausal women: a randomized controlled trial. Obstet Gynecol. 2018;132(1):161–170.

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Simon JA, Kaunitz A, Kroll R, et al. Oral 17β-estradiol-progesterone (TX-001HR) and quality of life in postmenopausal women with vasomotor symptoms. Menopause. 2019;26(5):506–512.

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Kagan R, Constantine G, Kaunitz AM, et al. Improvement in sleep outcomes with a 17β-estradiol-progesterone oral capsule (TX-001HR) for postmenopausal women. Menopause. 2019;26(6):622–628.

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