Trial Outcomes & Findings for MsFLASH-03: Comparative Efficacy of Low-Dose Estradiol and Venlafaxine XR for Treatment of Menopausal Symptoms (NCT NCT01418209)

NCT ID: NCT01418209

Last Updated: 2014-08-27

Results Overview

Measured by self-report diary twice daily (day and night). The day and night frequencies were summed to produce a single number of hot flashes per day. The single number of hot flashes per day were summed and averaged for one week prior to the week 4 study assessment to produce a mean daily frequency for week 4.

• Recruitment status: COMPLETED
• Study phase: NA
• Target enrollment: 339 participants
• Primary outcome timeframe: Week 4
• Results posted on: 2014-08-27

Participant Flow

Participant milestones

Measure	Low-dose 17-ß-Estradiol With Progesterone Taper Low-dose 17-ß-estradiol oral (by mouth), 0.5 mg once per day for 8 (eight) weeks. 17-ß-estradiol is approved by the US Food and Drug Administration (FDA) and is indicated for the treatment of menopausal symptoms. ß is the Greek symbol for beta; the symbol and the word are used interchangeably. The 8 week estradiol treatment is followed 14 days (2 weeks) of progesterone taper (as medroxy-progesterone 10 mg/day).	Venlafaxine XR Venlafaxine XR: Venlafaxine oral (by mouth) 37.5 mg once per day for 1 (one) week, then 75 mg once per day for 7 (seven) weeks. Venlafaxine XR should not be taken while also taking monoamine oxidase inhibitors (MAOIs). Venlafaxine XR is approved by the US Food and Drug Administration (FDA) for treatment of depression, generalized anxiety disorder, social anxiety disorder, and panic disorder, and is available by prescription. Venlafaxine XR is not FDA-approved for the treatment of hot flashes, although prior studies have indicated that it is useful for treating hot flashes and vasomotor symptoms. After the 8-week venlafaxine XR study treatment period, women will receive a tapering dose of venlafaxine XR 37.5 mg once per day for 14 days (2 weeks).	Placebo Placebo: The placebo is an inactive pill that looks like the active medication.
Overall Study STARTED	97	96	146
Overall Study COMPLETED	95	93	142
Overall Study NOT COMPLETED	2	3	4

Reasons for withdrawal

Measure	Low-dose 17-ß-Estradiol With Progesterone Taper Low-dose 17-ß-estradiol oral (by mouth), 0.5 mg once per day for 8 (eight) weeks. 17-ß-estradiol is approved by the US Food and Drug Administration (FDA) and is indicated for the treatment of menopausal symptoms. ß is the Greek symbol for beta; the symbol and the word are used interchangeably. The 8 week estradiol treatment is followed 14 days (2 weeks) of progesterone taper (as medroxy-progesterone 10 mg/day).	Venlafaxine XR Venlafaxine XR: Venlafaxine oral (by mouth) 37.5 mg once per day for 1 (one) week, then 75 mg once per day for 7 (seven) weeks. Venlafaxine XR should not be taken while also taking monoamine oxidase inhibitors (MAOIs). Venlafaxine XR is approved by the US Food and Drug Administration (FDA) for treatment of depression, generalized anxiety disorder, social anxiety disorder, and panic disorder, and is available by prescription. Venlafaxine XR is not FDA-approved for the treatment of hot flashes, although prior studies have indicated that it is useful for treating hot flashes and vasomotor symptoms. After the 8-week venlafaxine XR study treatment period, women will receive a tapering dose of venlafaxine XR 37.5 mg once per day for 14 days (2 weeks).	Placebo Placebo: The placebo is an inactive pill that looks like the active medication.
Overall Study Withdrawal by Subject	1	0	1
Overall Study Did not provide hot flash diary data	1	3	3

Baseline Characteristics

MsFLASH-03: Comparative Efficacy of Low-Dose Estradiol and Venlafaxine XR for Treatment of Menopausal Symptoms

Baseline characteristics by cohort

Measure	Low-dose 17-ß-estradiol With Progesterone Taper n=97 Participants Low-dose 17-ß-estradiol: Low-dose 17-ß-estradiol oral (by mouth), 0.5 mg once per day for 8 (eight) weeks. After the 8-week treatment, women with a uterus will receive medroxyprogesterone 10 mg once per day for 2 weeks (14 days). 17-ß-estradiol is approved by the US Food and Drug Administration (FDA) and is indicated for the treatment of menopausal symptoms. ß is the Greek symbol for beta; the symbol and the word are used interchangeably.	Venlafaxine XR n=96 Participants Venlafaxine XR: Venlafaxine oral (by mouth) 37.5 mg once per day for 1 (one) week, then 75 mg once per day for 7 (seven) weeks. Venlafaxine XR should not be taken while also taking monoamine oxidase inhibitors (MAOIs). Venlafaxine XR is approved by the US Food and Drug Administration (FDA) for treatment of depression, generalized anxiety disorder, social anxiety disorder, and panic disorder, and is available by prescription. Venlafaxine XR is not FDA-approved for the treatment of hot flashes, although prior studies have indicated that it is useful for treating hot flashes and vasomotor symptoms. After the 8-week venlafaxine XR study treatment period, women will receive a tapering dose of venlafaxine XR 37.5 mg once per day for 14 days (2 weeks).	Placebo n=146 Participants Placebo: The placebo is an inactive pill that looks like the active medication.	Total n=339 Participants Total of all reporting groups
Age, Continuous	54.9 years STANDARD_DEVIATION 4.1 • n=5 Participants	54.8 years STANDARD_DEVIATION 3.7 • n=7 Participants	54.3 years STANDARD_DEVIATION 3.8 • n=5 Participants	54.6 years STANDARD_DEVIATION 3.8 • n=4 Participants
Sex: Female, Male Female	97 Participants n=5 Participants	96 Participants n=7 Participants	146 Participants n=5 Participants	339 Participants n=4 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Region of Enrollment United States	97 participants n=5 Participants	96 participants n=7 Participants	146 participants n=5 Participants	339 participants n=4 Participants
Smoking Past	30 participants n=5 Participants	27 participants n=7 Participants	50 participants n=5 Participants	107 participants n=4 Participants
Body Mass Index (BMI)	28.5 kg/m^2 STANDARD_DEVIATION 6.5 • n=5 Participants	29.3 kg/m^2 STANDARD_DEVIATION 6.9 • n=7 Participants	27.6 kg/m^2 STANDARD_DEVIATION 6.8 • n=5 Participants	28.3 kg/m^2 STANDARD_DEVIATION 6.8 • n=4 Participants
Smoking Never	50 participants n=5 Participants	54 participants n=7 Participants	70 participants n=5 Participants	174 participants n=4 Participants
Smoking Current	17 participants n=5 Participants	14 participants n=7 Participants	24 participants n=5 Participants	55 participants n=4 Participants
Smoking Missing	0 participants n=5 Participants	1 participants n=7 Participants	2 participants n=5 Participants	3 participants n=4 Participants
Alcohol use (drinks/week) <7	71 participants n=5 Participants	77 participants n=7 Participants	117 participants n=5 Participants	265 participants n=4 Participants
Alcohol use (drinks/week) >=7	21 participants n=5 Participants	13 participants n=7 Participants	27 participants n=5 Participants	61 participants n=4 Participants
Alcohol use (drinks/week) Missing	5 participants n=5 Participants	6 participants n=7 Participants	2 participants n=5 Participants	13 participants n=4 Participants
Marital status Never married / Divorced / Widowed	38 participants n=5 Participants	40 participants n=7 Participants	49 participants n=5 Participants	127 participants n=4 Participants
Marital status Married / living with partner	58 participants n=5 Participants	56 participants n=7 Participants	96 participants n=5 Participants	210 participants n=4 Participants
Marital status Missing	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants	2 participants n=4 Participants
Education <College graduate	48 participants n=5 Participants	48 participants n=7 Participants	70 participants n=5 Participants	166 participants n=4 Participants
Education College graduate	49 participants n=5 Participants	48 participants n=7 Participants	75 participants n=5 Participants	172 participants n=4 Participants
Education Missing	0 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants	1 participants n=4 Participants
Menopause status Perimenopausal	14 participants n=5 Participants	16 participants n=7 Participants	22 participants n=5 Participants	52 participants n=4 Participants
Menopause status Postmenopausal	74 participants n=5 Participants	72 participants n=7 Participants	110 participants n=5 Participants	256 participants n=4 Participants
Menopause status Indeterminate	9 participants n=5 Participants	8 participants n=7 Participants	14 participants n=5 Participants	31 participants n=4 Participants
Years since final menstrual period (postmenopausal only) 0 - 5	35 participants n=5 Participants	39 participants n=7 Participants	68 participants n=5 Participants	142 participants n=4 Participants
Years since final menstrual period (postmenopausal only) 6 - 10	23 participants n=5 Participants	20 participants n=7 Participants	29 participants n=5 Participants	72 participants n=4 Participants
Years since final menstrual period (postmenopausal only) > 10	16 participants n=5 Participants	13 participants n=7 Participants	13 participants n=5 Participants	42 participants n=4 Participants
Years since final menstrual period (postmenopausal only) Not postmenopausal	23 participants n=5 Participants	24 participants n=7 Participants	36 participants n=5 Participants	83 participants n=4 Participants
Vasomotor symptom (VMS) number of participants with number of hot flashes / day < 6	36 participants n=5 Participants	36 participants n=7 Participants	67 participants n=5 Participants	139 participants n=4 Participants
Vasomotor symptom (VMS) number of participants with number of hot flashes / day 6 - < 9	32 participants n=5 Participants	31 participants n=7 Participants	39 participants n=5 Participants	102 participants n=4 Participants
Vasomotor symptom (VMS) number of participants with number of hot flashes / day 9 - < 12	11 participants n=5 Participants	15 participants n=7 Participants	19 participants n=5 Participants	45 participants n=4 Participants
Vasomotor symptom (VMS) number of participants with number of hot flashes / day >= 12	18 participants n=5 Participants	14 participants n=7 Participants	21 participants n=5 Participants	53 participants n=4 Participants
Age at starting vasomotor symptoms (VMS), years of age < 50	47 participants n=5 Participants	51 participants n=7 Participants	73 participants n=5 Participants	171 participants n=4 Participants
Age at starting vasomotor symptoms (VMS), years of age >= 50	48 participants n=5 Participants	44 participants n=7 Participants	71 participants n=5 Participants	163 participants n=4 Participants
Age at starting vasomotor symptoms (VMS), years of age Missing	2 participants n=5 Participants	1 participants n=7 Participants	2 participants n=5 Participants	5 participants n=4 Participants
Insomnia Severity Index (ISI) Score	11.0 units on a scale STANDARD_DEVIATION 6.3 • n=5 Participants	11.7 units on a scale STANDARD_DEVIATION 6.0 • n=7 Participants	10.4 units on a scale STANDARD_DEVIATION 5.8 • n=5 Participants	11.0 units on a scale STANDARD_DEVIATION 6.0 • n=4 Participants
Insomnia Severity Index (ISI) Score No clinically significant insomnia (<= 7)	28 participants n=5 Participants	26 participants n=7 Participants	52 participants n=5 Participants	106 participants n=4 Participants
Insomnia Severity Index (ISI) Score Subthreshold insomnia (8 - 14)	40 participants n=5 Participants	39 participants n=7 Participants	54 participants n=5 Participants	133 participants n=4 Participants
Insomnia Severity Index (ISI) Score Clinical insomnia (moderate, 15 - 21)	21 participants n=5 Participants	25 participants n=7 Participants	32 participants n=5 Participants	78 participants n=4 Participants
Insomnia Severity Index (ISI) Score Clinical insomnia (severe, >= 22)	5 participants n=5 Participants	5 participants n=7 Participants	4 participants n=5 Participants	14 participants n=4 Participants
Insomnia Severity Index (ISI) Score Missing	3 participants n=5 Participants	1 participants n=7 Participants	4 participants n=5 Participants	8 participants n=4 Participants
Pittsburgh Sleep Quality Index (PSQI) Score	7.6 units on a scale STANDARD_DEVIATION 3.6 • n=5 Participants	7.6 units on a scale STANDARD_DEVIATION 3.2 • n=7 Participants	7.3 units on a scale STANDARD_DEVIATION 3.5 • n=5 Participants	7.5 units on a scale STANDARD_DEVIATION 3.4 • n=4 Participants
Pittsburgh Sleep Quality Index (PSQI) Score Good quality sleep (< 5)	23 participants n=5 Participants	14 participants n=7 Participants	30 participants n=5 Participants	67 participants n=4 Participants
Pittsburgh Sleep Quality Index (PSQI) Score Moderate sleep quality (5 - < 8)	21 participants n=5 Participants	35 participants n=7 Participants	46 participants n=5 Participants	102 participants n=4 Participants
Pittsburgh Sleep Quality Index (PSQI) Score Poor sleep quality (>= 8)	46 participants n=5 Participants	40 participants n=7 Participants	65 participants n=5 Participants	151 participants n=4 Participants
Pittsburgh Sleep Quality Index (PSQI) Score Missing	7 participants n=5 Participants	7 participants n=7 Participants	5 participants n=5 Participants	19 participants n=4 Participants
Patient Health Questionnaire (PHQ-9) Depression Score	3.9 units on a scale STANDARD_DEVIATION 4.4 • n=5 Participants	3.0 units on a scale STANDARD_DEVIATION 2.9 • n=7 Participants	3.4 units on a scale STANDARD_DEVIATION 3.7 • n=5 Participants	3.4 units on a scale STANDARD_DEVIATION 3.7 • n=4 Participants
PHQ-9 Depression Score No depression (0 - 4)	68 participants n=5 Participants	70 participants n=7 Participants	108 participants n=5 Participants	246 participants n=4 Participants
PHQ-9 Depression Score Mild depression (5 - 9)	18 participants n=5 Participants	23 participants n=7 Participants	23 participants n=5 Participants	64 participants n=4 Participants
PHQ-9 Depression Score Moderate depression (>= 10)	11 participants n=5 Participants	3 participants n=7 Participants	15 participants n=5 Participants	29 participants n=4 Participants
Generalized Anxiety Disorder 7 (GAD-7) Score	3.0 units on a scale STANDARD_DEVIATION 4.3 • n=5 Participants	2.2 units on a scale STANDARD_DEVIATION 3.0 • n=7 Participants	2.4 units on a scale STANDARD_DEVIATION 3.4 • n=5 Participants	2.5 units on a scale STANDARD_DEVIATION 3.6 • n=4 Participants
Generalized Anxiety Disorder 7 (GAD-7) Score No anxiety (0 - 4)	73 participants n=5 Participants	76 participants n=7 Participants	116 participants n=5 Participants	265 participants n=4 Participants
Generalized Anxiety Disorder 7 (GAD-7) Score Mild anxiety (5 - 9)	15 participants n=5 Participants	17 participants n=7 Participants	19 participants n=5 Participants	51 participants n=4 Participants
Generalized Anxiety Disorder 7 (GAD-7) Score Moderate anxiety (>= 10)	9 participants n=5 Participants	3 participants n=7 Participants	11 participants n=5 Participants	23 participants n=4 Participants
Vasomotor Symptoms (VMS) as number of hot flashes	8.5 Number of hot flashes per day STANDARD_DEVIATION 5.7 • n=5 Participants	8.2 Number of hot flashes per day STANDARD_DEVIATION 5.5 • n=7 Participants	7.7 Number of hot flashes per day STANDARD_DEVIATION 4.8 • n=5 Participants	8.1 Number of hot flashes per day STANDARD_DEVIATION 5.3 • n=4 Participants
Severity of Hot Flashes	1.1 units on a scale STANDARD_DEVIATION 0.5 • n=5 Participants	1.0 units on a scale STANDARD_DEVIATION 0.5 • n=7 Participants	1.0 units on a scale STANDARD_DEVIATION 0.4 • n=5 Participants	1.0 units on a scale STANDARD_DEVIATION 0.5 • n=4 Participants
Bothersomeness of Hot Flashes	2.1 units on a scale STANDARD_DEVIATION 0.5 • n=5 Participants	2.0 units on a scale STANDARD_DEVIATION 0.5 • n=7 Participants	2.0 units on a scale STANDARD_DEVIATION 0.5 • n=5 Participants	2.0 units on a scale STANDARD_DEVIATION 0.5 • n=4 Participants
Perceived Hot Flash Interference (Hot Flash Related Daily Interference Scale; HFRDIS)	36.9 units on a scale STANDARD_DEVIATION 23.8 • n=5 Participants	36.8 units on a scale STANDARD_DEVIATION 23.4 • n=7 Participants	32.8 units on a scale STANDARD_DEVIATION 21.3 • n=5 Participants	35.1 units on a scale STANDARD_DEVIATION 22.6 • n=4 Participants

PRIMARY outcome

Timeframe: Week 4

Population: Intention-to-treat, i.e., all participants with follow-up data were included.

Measured by self-report diary twice daily (day and night). The day and night frequencies were summed to produce a single number of hot flashes per day. The single number of hot flashes per day were summed and averaged for one week prior to the week 4 study assessment to produce a mean daily frequency for week 4.

Outcome measures

Measure	Low-dose 17-ß-estradiol With Progesterone Taper n=91 Participants Low-dose 17-ß-estradiol: Low-dose 17-ß-estradiol oral (by mouth), 0.5 mg once per day for 8 (eight) weeks. After the 8-week treatment, women with a uterus will receive medroxyprogesterone 10 mg once per day for 2 weeks (14 days). 17-ß-estradiol is approved by the US Food and Drug Administration (FDA) and is indicated for the treatment of menopausal symptoms. ß is the Greek symbol for beta; the symbol and the word are used interchangeably.	Venlafaxine XR n=93 Participants Venlafaxine XR: Venlafaxine oral (by mouth) 37.5 mg once per day for 1 (one) week, then 75 mg once per day for 7 (seven) weeks. Venlafaxine XR should not be taken while also taking monoamine oxidase inhibitors (MAOIs). Venlafaxine XR is approved by the US Food and Drug Administration (FDA) for treatment of depression, generalized anxiety disorder, social anxiety disorder, and panic disorder, and is available by prescription. Venlafaxine XR is not FDA-approved for the treatment of hot flashes, although prior studies have indicated that it is useful for treating hot flashes and vasomotor symptoms. After the 8-week venlafaxine XR study treatment period, women will receive a tapering dose of venlafaxine XR 37.5 mg once per day for 14 days (2 weeks).	Placebo n=139 Participants Placebo: The placebo is an inactive pill that looks like the active medication.
Frequency of Hot Flashes (Vasomotor Symptom [VMS] Frequency) -- Week 4	5.3 number of hot flashes per day Interval 4.2 to 6.5	5.1 number of hot flashes per day Interval 4.1 to 6.0	5.8 number of hot flashes per day Interval 4.9 to 6.7

PRIMARY outcome

Timeframe: Week 8

Population: Intention-to-treat, i.e., all participants with follow-up data were included.

Measured by self-report diary twice daily (day and night). The day and night frequencies were summed to produce a single number of hot flashes per day. The single number of hot flashes per day were summed and averaged for one week prior to the week 8 study assessment to produce a mean daily frequency for week 8.

Outcome measures

Measure	Low-dose 17-ß-estradiol With Progesterone Taper n=92 Participants Low-dose 17-ß-estradiol: Low-dose 17-ß-estradiol oral (by mouth), 0.5 mg once per day for 8 (eight) weeks. After the 8-week treatment, women with a uterus will receive medroxyprogesterone 10 mg once per day for 2 weeks (14 days). 17-ß-estradiol is approved by the US Food and Drug Administration (FDA) and is indicated for the treatment of menopausal symptoms. ß is the Greek symbol for beta; the symbol and the word are used interchangeably.	Venlafaxine XR n=89 Participants Venlafaxine XR: Venlafaxine oral (by mouth) 37.5 mg once per day for 1 (one) week, then 75 mg once per day for 7 (seven) weeks. Venlafaxine XR should not be taken while also taking monoamine oxidase inhibitors (MAOIs). Venlafaxine XR is approved by the US Food and Drug Administration (FDA) for treatment of depression, generalized anxiety disorder, social anxiety disorder, and panic disorder, and is available by prescription. Venlafaxine XR is not FDA-approved for the treatment of hot flashes, although prior studies have indicated that it is useful for treating hot flashes and vasomotor symptoms. After the 8-week venlafaxine XR study treatment period, women will receive a tapering dose of venlafaxine XR 37.5 mg once per day for 14 days (2 weeks).	Placebo n=137 Participants Placebo: The placebo is an inactive pill that looks like the active medication.
Frequency of Hot Flashes (Daily Vasomotor Symptom [VMS] Frequency) -- Week 8	3.9 number of hot flashes per day Interval 2.9 to 4.9	4.4 number of hot flashes per day Interval 3.5 to 5.3	5.5 number of hot flashes per day Interval 4.7 to 6.3

SECONDARY outcome

Timeframe: Week 4

Population: Intention-to-treat, i.e., all participants with follow-up data were included.

Measured by self-report diary twice daily (day and night) for 7 days. Severity ratings ranged from 0 to 3 with lower numbers being less severe and higher numbers being more severe. Data from the day and night severity ratings were averaged for a single daily score. The single daily scores for the week prior to the week 4 study assessment were summed and averaged to produce a mean daily VMS severity for week 4.

Outcome measures

Measure	Low-dose 17-ß-estradiol With Progesterone Taper n=81 Participants Low-dose 17-ß-estradiol: Low-dose 17-ß-estradiol oral (by mouth), 0.5 mg once per day for 8 (eight) weeks. After the 8-week treatment, women with a uterus will receive medroxyprogesterone 10 mg once per day for 2 weeks (14 days). 17-ß-estradiol is approved by the US Food and Drug Administration (FDA) and is indicated for the treatment of menopausal symptoms. ß is the Greek symbol for beta; the symbol and the word are used interchangeably.	Venlafaxine XR n=86 Participants Venlafaxine XR: Venlafaxine oral (by mouth) 37.5 mg once per day for 1 (one) week, then 75 mg once per day for 7 (seven) weeks. Venlafaxine XR should not be taken while also taking monoamine oxidase inhibitors (MAOIs). Venlafaxine XR is approved by the US Food and Drug Administration (FDA) for treatment of depression, generalized anxiety disorder, social anxiety disorder, and panic disorder, and is available by prescription. Venlafaxine XR is not FDA-approved for the treatment of hot flashes, although prior studies have indicated that it is useful for treating hot flashes and vasomotor symptoms. After the 8-week venlafaxine XR study treatment period, women will receive a tapering dose of venlafaxine XR 37.5 mg once per day for 14 days (2 weeks).	Placebo n=134 Participants Placebo: The placebo is an inactive pill that looks like the active medication.
Severity of Hot Flashes -- Week 4	0.7 units on a scale Interval 0.6 to 0.9	0.7 units on a scale Interval 0.5 to 0.8	0.8 units on a scale Interval 0.7 to 0.9

SECONDARY outcome

Timeframe: Week 8

Population: Intention-to-treat, i.e., all participants with follow-up data were included.

Measured by self-report diary twice daily (day and night) for 7 days. Severity ratings ranged from 0 to 3 with lower numbers being less severe and higher numbers being more severe. Data from the day and night severity ratings were averaged for a single daily score. The single daily scores for the week prior to the week 8 study assessment were summed and averaged to produce a mean daily VMS severity for week 8.

Outcome measures

Measure	Low-dose 17-ß-estradiol With Progesterone Taper n=73 Participants Low-dose 17-ß-estradiol: Low-dose 17-ß-estradiol oral (by mouth), 0.5 mg once per day for 8 (eight) weeks. After the 8-week treatment, women with a uterus will receive medroxyprogesterone 10 mg once per day for 2 weeks (14 days). 17-ß-estradiol is approved by the US Food and Drug Administration (FDA) and is indicated for the treatment of menopausal symptoms. ß is the Greek symbol for beta; the symbol and the word are used interchangeably.	Venlafaxine XR n=86 Participants Venlafaxine XR: Venlafaxine oral (by mouth) 37.5 mg once per day for 1 (one) week, then 75 mg once per day for 7 (seven) weeks. Venlafaxine XR should not be taken while also taking monoamine oxidase inhibitors (MAOIs). Venlafaxine XR is approved by the US Food and Drug Administration (FDA) for treatment of depression, generalized anxiety disorder, social anxiety disorder, and panic disorder, and is available by prescription. Venlafaxine XR is not FDA-approved for the treatment of hot flashes, although prior studies have indicated that it is useful for treating hot flashes and vasomotor symptoms. After the 8-week venlafaxine XR study treatment period, women will receive a tapering dose of venlafaxine XR 37.5 mg once per day for 14 days (2 weeks).	Placebo n=133 Participants Placebo: The placebo is an inactive pill that looks like the active medication.
Severity of Hot Flashes -- Week 8	0.6 units on a scale Interval 0.4 to 0.7	0.6 units on a scale Interval 0.4 to 0.7	0.7 units on a scale Interval 0.6 to 0.8

SECONDARY outcome

Timeframe: Week 4

Population: Intention-to-treat, i.e., all participants with follow-up data were included.

Measured by self-report diary twice daily (day and night) for 7 days. Bothersomeness ratings ranged from 0 to 3 with lower numbers being less bothersome and higher numbers being more bothersome. Data from the day and night bothersomeness ratings were averaged for a single daily score. The single daily scores for the week prior to the week 4 study assessment were summed and averaged to produce a mean daily VMS bothersomeness for week 4.

Outcome measures

Measure	Low-dose 17-ß-estradiol With Progesterone Taper n=82 Participants Low-dose 17-ß-estradiol: Low-dose 17-ß-estradiol oral (by mouth), 0.5 mg once per day for 8 (eight) weeks. After the 8-week treatment, women with a uterus will receive medroxyprogesterone 10 mg once per day for 2 weeks (14 days). 17-ß-estradiol is approved by the US Food and Drug Administration (FDA) and is indicated for the treatment of menopausal symptoms. ß is the Greek symbol for beta; the symbol and the word are used interchangeably.	Venlafaxine XR n=88 Participants Venlafaxine XR: Venlafaxine oral (by mouth) 37.5 mg once per day for 1 (one) week, then 75 mg once per day for 7 (seven) weeks. Venlafaxine XR should not be taken while also taking monoamine oxidase inhibitors (MAOIs). Venlafaxine XR is approved by the US Food and Drug Administration (FDA) for treatment of depression, generalized anxiety disorder, social anxiety disorder, and panic disorder, and is available by prescription. Venlafaxine XR is not FDA-approved for the treatment of hot flashes, although prior studies have indicated that it is useful for treating hot flashes and vasomotor symptoms. After the 8-week venlafaxine XR study treatment period, women will receive a tapering dose of venlafaxine XR 37.5 mg once per day for 14 days (2 weeks).	Placebo n=135 Participants Placebo: The placebo is an inactive pill that looks like the active medication.
Bothersomeness of Hot Flashes -- Week 4	1.6 units on a scale Interval 1.4 to 1.7	1.6 units on a scale Interval 1.4 to 1.7	1.7 units on a scale Interval 1.6 to 1.8

SECONDARY outcome

Timeframe: Week 8

Population: Intention-to-treat, i.e., all participants with follow-up data were included.

Measured by self-report diary twice daily (day and night) for 7 days. Bothersomeness ratings ranged from 0 to 3 with lower numbers being less bothersome and higher numbers being more bothersome. Data from the day and night bothersomeness ratings were averaged for a single daily score. The single daily scores for the week prior to the week 8 study assessment were summed and averaged to produce a mean daily VMS bothersomeness for week 8.

Outcome measures

Measure	Low-dose 17-ß-estradiol With Progesterone Taper n=73 Participants Low-dose 17-ß-estradiol: Low-dose 17-ß-estradiol oral (by mouth), 0.5 mg once per day for 8 (eight) weeks. After the 8-week treatment, women with a uterus will receive medroxyprogesterone 10 mg once per day for 2 weeks (14 days). 17-ß-estradiol is approved by the US Food and Drug Administration (FDA) and is indicated for the treatment of menopausal symptoms. ß is the Greek symbol for beta; the symbol and the word are used interchangeably.	Venlafaxine XR n=86 Participants Venlafaxine XR: Venlafaxine oral (by mouth) 37.5 mg once per day for 1 (one) week, then 75 mg once per day for 7 (seven) weeks. Venlafaxine XR should not be taken while also taking monoamine oxidase inhibitors (MAOIs). Venlafaxine XR is approved by the US Food and Drug Administration (FDA) for treatment of depression, generalized anxiety disorder, social anxiety disorder, and panic disorder, and is available by prescription. Venlafaxine XR is not FDA-approved for the treatment of hot flashes, although prior studies have indicated that it is useful for treating hot flashes and vasomotor symptoms. After the 8-week venlafaxine XR study treatment period, women will receive a tapering dose of venlafaxine XR 37.5 mg once per day for 14 days (2 weeks).	Placebo n=133 Participants Placebo: The placebo is an inactive pill that looks like the active medication.
Bothersomeness of Hot Flashes -- Week 8	1.4 units on a scale Interval 1.2 to 1.6	1.4 units on a scale Interval 1.3 to 1.6	1.6 units on a scale Interval 1.5 to 1.7

SECONDARY outcome

Timeframe: Week 4

Population: Intention-to-treat, i.e., all participants with follow-up data were included.

The perceived hot flash related daily interference scale (HFRDIS) is a tool for assessing the impact of hot flashes on quality of life. There are 10 questions with each having a score ranging from 0 to 10. The scores from each question are summed for a total score ranging from 0 to 100. Lower numbers indicate less interference and higher numbers indicate more interference.

Outcome measures

Measure	Low-dose 17-ß-estradiol With Progesterone Taper n=84 Participants Low-dose 17-ß-estradiol: Low-dose 17-ß-estradiol oral (by mouth), 0.5 mg once per day for 8 (eight) weeks. After the 8-week treatment, women with a uterus will receive medroxyprogesterone 10 mg once per day for 2 weeks (14 days). 17-ß-estradiol is approved by the US Food and Drug Administration (FDA) and is indicated for the treatment of menopausal symptoms. ß is the Greek symbol for beta; the symbol and the word are used interchangeably.	Venlafaxine XR n=83 Participants Venlafaxine XR: Venlafaxine oral (by mouth) 37.5 mg once per day for 1 (one) week, then 75 mg once per day for 7 (seven) weeks. Venlafaxine XR should not be taken while also taking monoamine oxidase inhibitors (MAOIs). Venlafaxine XR is approved by the US Food and Drug Administration (FDA) for treatment of depression, generalized anxiety disorder, social anxiety disorder, and panic disorder, and is available by prescription. Venlafaxine XR is not FDA-approved for the treatment of hot flashes, although prior studies have indicated that it is useful for treating hot flashes and vasomotor symptoms. After the 8-week venlafaxine XR study treatment period, women will receive a tapering dose of venlafaxine XR 37.5 mg once per day for 14 days (2 weeks).	Placebo n=128 Participants Placebo: The placebo is an inactive pill that looks like the active medication.
Perceived Hot Flash Interference (Hot Flash Related Daily Interference Scale; HFRDIS) -- Week 4	18.3 units on a scale Interval 13.8 to 22.8	19.8 units on a scale Interval 15.6 to 23.9	24.2 units on a scale Interval 20.7 to 27.7

SECONDARY outcome

Timeframe: Week 8

Population: Intention-to-treat, i.e., all participants with follow-up data were included.

The perceived hot flash related daily interference scale (HFRDIS) is a tool for assessing the impact of hot flashes on quality of life. There are 10 questions with each having a score ranging from 0 to 10. The scores from each question are summed for a total score ranging from 0 to 100. Lower numbers indicate less interference and higher numbers indicate more interference.

Outcome measures

Measure	Low-dose 17-ß-estradiol With Progesterone Taper n=92 Participants Low-dose 17-ß-estradiol: Low-dose 17-ß-estradiol oral (by mouth), 0.5 mg once per day for 8 (eight) weeks. After the 8-week treatment, women with a uterus will receive medroxyprogesterone 10 mg once per day for 2 weeks (14 days). 17-ß-estradiol is approved by the US Food and Drug Administration (FDA) and is indicated for the treatment of menopausal symptoms. ß is the Greek symbol for beta; the symbol and the word are used interchangeably.	Venlafaxine XR n=86 Participants Venlafaxine XR: Venlafaxine oral (by mouth) 37.5 mg once per day for 1 (one) week, then 75 mg once per day for 7 (seven) weeks. Venlafaxine XR should not be taken while also taking monoamine oxidase inhibitors (MAOIs). Venlafaxine XR is approved by the US Food and Drug Administration (FDA) for treatment of depression, generalized anxiety disorder, social anxiety disorder, and panic disorder, and is available by prescription. Venlafaxine XR is not FDA-approved for the treatment of hot flashes, although prior studies have indicated that it is useful for treating hot flashes and vasomotor symptoms. After the 8-week venlafaxine XR study treatment period, women will receive a tapering dose of venlafaxine XR 37.5 mg once per day for 14 days (2 weeks).	Placebo n=137 Participants Placebo: The placebo is an inactive pill that looks like the active medication.
Perceived Hot Flash Interference (Hot Flash Related Daily Interference Scale; HFRDIS) -- Week 8	14.6 units on a scale Interval 10.6 to 18.7	18.3 units on a scale Interval 13.8 to 22.7	21.5 units on a scale Interval 18.1 to 24.9

Adverse Events

Low-dose 17-ß-estradiol

Serious events: 0 serious events

Other events: 53 other events

Deaths: 0 deaths

Venlafaxine XR

Serious events: 0 serious events

Other events: 65 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 88 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Low-dose 17-ß-estradiol n=97 participants at risk Low-dose 17-ß-estradiol: Low-dose 17-ß-estradiol oral (by mouth), 0.5 mg once per day for 8 (eight) weeks. After the 8-week treatment, women with a uterus will receive medroxyprogesterone 10 mg once per day for 2 weeks (14 days). 17-ß-estradiol is approved by the US Food and Drug Administration (FDA) and is indicated for the treatment of menopausal symptoms. ß is the Greek symbol for beta; the symbol and the word are used interchangeably.	Venlafaxine XR n=96 participants at risk Venlafaxine XR: Venlafaxine oral (by mouth) 37.5 mg once per day for 1 (one) week, then 75 mg once per day for 7 (seven) weeks. Venlafaxine XR should not be taken while also taking monoamine oxidase inhibitors (MAOIs). Venlafaxine XR is approved by the US Food and Drug Administration (FDA) for treatment of depression, generalized anxiety disorder, social anxiety disorder, and panic disorder, and is available by prescription. Venlafaxine XR is not FDA-approved for the treatment of hot flashes, although prior studies have indicated that it is useful for treating hot flashes and vasomotor symptoms. After the 8-week venlafaxine XR study treatment period, women will receive a tapering dose of venlafaxine XR 37.5 mg once per day for 14 days (2 weeks).	Placebo n=146 participants at risk Placebo: The placebo is an inactive pill that looks like the active medication.
General disorders Any fatigue/arousal symptom	23.5% 20/85 • 8 weeks At 1-, 4, and 8-weeks, potential adverse events were assessed by a Management and Safety Interview. Symptoms data were collected at screening and weeks 4 and 8. Data are reported as newly emergent adverse events.	32.1% 26/81 • 8 weeks At 1-, 4, and 8-weeks, potential adverse events were assessed by a Management and Safety Interview. Symptoms data were collected at screening and weeks 4 and 8. Data are reported as newly emergent adverse events.	26.0% 33/127 • 8 weeks At 1-, 4, and 8-weeks, potential adverse events were assessed by a Management and Safety Interview. Symptoms data were collected at screening and weeks 4 and 8. Data are reported as newly emergent adverse events.
Nervous system disorders Any central nervous system symptom	23.9% 22/92 • 8 weeks At 1-, 4, and 8-weeks, potential adverse events were assessed by a Management and Safety Interview. Symptoms data were collected at screening and weeks 4 and 8. Data are reported as newly emergent adverse events.	31.9% 30/94 • 8 weeks At 1-, 4, and 8-weeks, potential adverse events were assessed by a Management and Safety Interview. Symptoms data were collected at screening and weeks 4 and 8. Data are reported as newly emergent adverse events.	25.4% 36/142 • 8 weeks At 1-, 4, and 8-weeks, potential adverse events were assessed by a Management and Safety Interview. Symptoms data were collected at screening and weeks 4 and 8. Data are reported as newly emergent adverse events.
Gastrointestinal disorders Any GI symptom	24.5% 23/94 • 8 weeks At 1-, 4, and 8-weeks, potential adverse events were assessed by a Management and Safety Interview. Symptoms data were collected at screening and weeks 4 and 8. Data are reported as newly emergent adverse events.	26.9% 25/93 • 8 weeks At 1-, 4, and 8-weeks, potential adverse events were assessed by a Management and Safety Interview. Symptoms data were collected at screening and weeks 4 and 8. Data are reported as newly emergent adverse events.	31.0% 44/142 • 8 weeks At 1-, 4, and 8-weeks, potential adverse events were assessed by a Management and Safety Interview. Symptoms data were collected at screening and weeks 4 and 8. Data are reported as newly emergent adverse events.
Reproductive system and breast disorders Breast tenderness	5.6% 5/90 • 8 weeks At 1-, 4, and 8-weeks, potential adverse events were assessed by a Management and Safety Interview. Symptoms data were collected at screening and weeks 4 and 8. Data are reported as newly emergent adverse events.	0.00% 0/93 • 8 weeks At 1-, 4, and 8-weeks, potential adverse events were assessed by a Management and Safety Interview. Symptoms data were collected at screening and weeks 4 and 8. Data are reported as newly emergent adverse events.	5.6% 8/142 • 8 weeks At 1-, 4, and 8-weeks, potential adverse events were assessed by a Management and Safety Interview. Symptoms data were collected at screening and weeks 4 and 8. Data are reported as newly emergent adverse events.
Reproductive system and breast disorders Vaginal secretions	2.2% 2/90 • 8 weeks At 1-, 4, and 8-weeks, potential adverse events were assessed by a Management and Safety Interview. Symptoms data were collected at screening and weeks 4 and 8. Data are reported as newly emergent adverse events.	3.3% 3/90 • 8 weeks At 1-, 4, and 8-weeks, potential adverse events were assessed by a Management and Safety Interview. Symptoms data were collected at screening and weeks 4 and 8. Data are reported as newly emergent adverse events.	2.2% 3/139 • 8 weeks At 1-, 4, and 8-weeks, potential adverse events were assessed by a Management and Safety Interview. Symptoms data were collected at screening and weeks 4 and 8. Data are reported as newly emergent adverse events.
Musculoskeletal and connective tissue disorders Any musculoskeletal symptom	9.8% 9/92 • 8 weeks At 1-, 4, and 8-weeks, potential adverse events were assessed by a Management and Safety Interview. Symptoms data were collected at screening and weeks 4 and 8. Data are reported as newly emergent adverse events.	5.3% 5/94 • 8 weeks At 1-, 4, and 8-weeks, potential adverse events were assessed by a Management and Safety Interview. Symptoms data were collected at screening and weeks 4 and 8. Data are reported as newly emergent adverse events.	9.2% 13/141 • 8 weeks At 1-, 4, and 8-weeks, potential adverse events were assessed by a Management and Safety Interview. Symptoms data were collected at screening and weeks 4 and 8. Data are reported as newly emergent adverse events.
General disorders Any miscellaneous symptom	29.8% 28/94 • 8 weeks At 1-, 4, and 8-weeks, potential adverse events were assessed by a Management and Safety Interview. Symptoms data were collected at screening and weeks 4 and 8. Data are reported as newly emergent adverse events.	38.3% 36/94 • 8 weeks At 1-, 4, and 8-weeks, potential adverse events were assessed by a Management and Safety Interview. Symptoms data were collected at screening and weeks 4 and 8. Data are reported as newly emergent adverse events.	30.3% 43/142 • 8 weeks At 1-, 4, and 8-weeks, potential adverse events were assessed by a Management and Safety Interview. Symptoms data were collected at screening and weeks 4 and 8. Data are reported as newly emergent adverse events.

Additional Information

Hadine Joffe, MD, MSc

Brigham and Women's Hospital

Phone: 617-732-4906

Email: hjoffe@partners.org

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place