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

Primary Purpose

Hot Flashes, Menopause, Vasomotor Disturbance

Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Low-dose 17-ß-estradiol with progesterone taper
Venlafaxine XR
Placebo
Sponsored by
Fred Hutchinson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hot Flashes focused on measuring Menopause, Vasomotor, Symptoms, Estradiol, Venlafaxine

Eligibility Criteria

40 Years - 62 Years (Adult)FemaleAccepts Healthy Volunteers

Inclusion Criteria:

  • Females aged 40-62 years
  • Postmenopausal or perimenopausal
  • Having bothersome hot flashes
  • In general good health
  • Signed informed consent

Exclusion Criteria:

  • Recent use of systemic hormone therapy or hormonal contraceptives
  • Recent use of any prescribed, over-the-counter or herbal therapies that are taken specifically for hot flashes
  • Recent use of selective estrogen receptor modulators (SERMS) or aromatase inhibitors
  • Recent use of psychotropic medications, including SSRIs (selective serotonin reuptake inhibitors), serotonin-norepinephrine reuptake inhibitors (SNRIs), MAOIs (monoamine oxidase inhibitors), and other antidepressants and anxiolytics.
  • Known hypersensitivity or contraindications (reasons not to take) to venlafaxine, estrogen, or progestins
  • Not using a medically approved method of birth control, if sexually active and not 12 or more months since last menstrual period
  • Recent drug or alcohol abuse
  • Lifetime diagnosis of psychosis or bipolar disorder
  • Suicide attempt in the past 3 years or any current suicidal ideation
  • Current major depression (assessed during screening)
  • Pregnancy, intending pregnancy, or breast feeding

  • History of:

    • Pre-breast cancer or high-risk breast cancer condition
    • Abnormal bleeding suggestive of endometrial pre-cancer or endometrial hyperplasia
    • Asthma, diabetes mellitus, epilepsy, and migraine disorders that are not stable or under medical management
  • Abnormal screening blood tests
  • Current participation in another drug trial or intervention study
  • Inability or unwillingness to complete the study procedures

Sites / Locations

  • Massachusetts General Hospital, Harvard Medical School (HU)
  • Brigham and Women's Hospital
  • University of Pennsylvania, UP
  • Group Health Research Institute (GHRI)

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

Placebo Comparator

Arm Label

Low-dose 17-ß-estradiol with progesterone taper

Venlafaxine XR

Placebo

Arm Description

Outcomes

Primary Outcome Measures

Frequency of Hot Flashes (Vasomotor Symptom [VMS] Frequency) -- Week 4
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.
Frequency of Hot Flashes (Daily Vasomotor Symptom [VMS] Frequency) -- Week 8
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.

Secondary Outcome Measures

Severity of Hot Flashes -- Week 4
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.
Severity of Hot Flashes -- Week 8
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.
Bothersomeness of Hot Flashes -- Week 4
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.
Bothersomeness of Hot Flashes -- Week 8
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.
Perceived Hot Flash Interference (Hot Flash Related Daily Interference Scale; HFRDIS) -- Week 4
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.
Perceived Hot Flash Interference (Hot Flash Related Daily Interference Scale; HFRDIS) -- Week 8
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.

Full Information

First Posted
August 15, 2011
Last Updated
August 20, 2014
Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Institute on Aging (NIA), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Center for Complementary and Integrative Health (NCCIH), Office of Research on Women's Health (ORWH)
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1. Study Identification

Unique Protocol Identification Number
NCT01418209
Brief Title
MsFLASH-03: Comparative Efficacy of Low-Dose Estradiol and Venlafaxine XR for Treatment of Menopausal Symptoms
Official Title
MsFLASH-03: Comparative Efficacy of Low-Dose Estradiol and the SNRI Venlafaxine XR for Treatment of Menopausal Symptoms
Study Type
Interventional

2. Study Status

Record Verification Date
August 2014
Overall Recruitment Status
Completed
Study Start Date
November 2011 (undefined)
Primary Completion Date
January 2013 (Actual)
Study Completion Date
January 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Institute on Aging (NIA), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Center for Complementary and Integrative Health (NCCIH), Office of Research on Women's Health (ORWH)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The primary objective of this study is to determine the efficacy of both low-dose oral (by mouth) 17-ß-estradiol and the non-hormonal drug venlafaxine XR compared to placebo in reducing hot flashes. Included in this objective is the intention to compare venlafaxine XR to estradiol therapy, to provide evidence of the relative efficacy of venlafaxine to what is currently considered the most established but also a controversial therapy. 17-ß-estradiol is a type of estrogen. Venlafaxine XR is the extended release (XR) version of venlafaxine. Venlafaxine XR is an serotonin-norepinephrine reuptake inhibitor (SNRI). A placebo is a substance containing no medication.
Detailed Description
The MsFLASH-03 study (Menopausal Strategies: Finding Lasting Answers for Symptoms and Health - 03), Comparative Efficacy of Low-Dose Estradiol and the SNRI Venlafaxine XR for Treatment of Menopausal Symptoms, is a randomized, double-blind, placebo-controlled, three arm clinical trial. The design includes: 3 weeks of daily recording of hot flashes prior to drug treatment; 8 weeks of double-blind treatment with oral estradiol, venlafaxine, or placebo; followed by 14 days of drug taper for those on venlafaxine and 14 days of progesterone treatment for those on estradiol; followed by 2 weeks with no treatment for all groups; and a telephone follow-up post-treatment.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hot Flashes, Menopause, Vasomotor Disturbance
Keywords
Menopause, Vasomotor, Symptoms, Estradiol, Venlafaxine

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
339 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Low-dose 17-ß-estradiol with progesterone taper
Arm Type
Active Comparator
Arm Title
Venlafaxine XR
Arm Type
Active Comparator
Arm Title
Placebo
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Low-dose 17-ß-estradiol with progesterone taper
Other Intervention Name(s)
The brand name of estradiol being used in this study is Estrace®.
Intervention Description
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 by 14 days (2 weeks) of progesterone taper (as medroxy-progesterone 10 mg/day).
Intervention Type
Drug
Intervention Name(s)
Venlafaxine XR
Other Intervention Name(s)
The brand name of venlafaxine XR that is being used in this study is Effexor XR®
Intervention Description
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).
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
The placebo is an inactive pill that looks like the active medication.
Primary Outcome Measure Information:
Title
Frequency of Hot Flashes (Vasomotor Symptom [VMS] Frequency) -- Week 4
Description
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.
Time Frame
Week 4
Title
Frequency of Hot Flashes (Daily Vasomotor Symptom [VMS] Frequency) -- Week 8
Description
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.
Time Frame
Week 8
Secondary Outcome Measure Information:
Title
Severity of Hot Flashes -- Week 4
Description
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.
Time Frame
Week 4
Title
Severity of Hot Flashes -- Week 8
Description
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.
Time Frame
Week 8
Title
Bothersomeness of Hot Flashes -- Week 4
Description
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.
Time Frame
Week 4
Title
Bothersomeness of Hot Flashes -- Week 8
Description
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.
Time Frame
Week 8
Title
Perceived Hot Flash Interference (Hot Flash Related Daily Interference Scale; HFRDIS) -- Week 4
Description
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.
Time Frame
Week 4
Title
Perceived Hot Flash Interference (Hot Flash Related Daily Interference Scale; HFRDIS) -- Week 8
Description
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.
Time Frame
Week 8

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
40 Years
Maximum Age & Unit of Time
62 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Females aged 40-62 years Postmenopausal or perimenopausal Having bothersome hot flashes In general good health Signed informed consent Exclusion Criteria: Recent use of systemic hormone therapy or hormonal contraceptives Recent use of any prescribed, over-the-counter or herbal therapies that are taken specifically for hot flashes Recent use of selective estrogen receptor modulators (SERMS) or aromatase inhibitors Recent use of psychotropic medications, including SSRIs (selective serotonin reuptake inhibitors), serotonin-norepinephrine reuptake inhibitors (SNRIs), MAOIs (monoamine oxidase inhibitors), and other antidepressants and anxiolytics. Known hypersensitivity or contraindications (reasons not to take) to venlafaxine, estrogen, or progestins Not using a medically approved method of birth control, if sexually active and not 12 or more months since last menstrual period Recent drug or alcohol abuse Lifetime diagnosis of psychosis or bipolar disorder Suicide attempt in the past 3 years or any current suicidal ideation Current major depression (assessed during screening) Pregnancy, intending pregnancy, or breast feeding History of: Pre-breast cancer or high-risk breast cancer condition Abnormal bleeding suggestive of endometrial pre-cancer or endometrial hyperplasia Asthma, diabetes mellitus, epilepsy, and migraine disorders that are not stable or under medical management Abnormal screening blood tests Current participation in another drug trial or intervention study Inability or unwillingness to complete the study procedures
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Andrea Z LaCroix, PhD
Organizational Affiliation
Fred Hutchinson Cancer Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Garnet Anderson, PhD
Organizational Affiliation
Fred Hutchinson Cancer Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Katherine Guthrie, PhD
Organizational Affiliation
Fred Hutchinson Cancer Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Lee S Cohen, MD
Organizational Affiliation
Massachusetts General Hospital/Harvard Medical School (HU)
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Hadine Joffe, MD, MSc
Organizational Affiliation
Massachusetts General Hospital/Harvard Medical School (HU)
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Katherine M Newton, PhD
Organizational Affiliation
Group Health Research Institute (GHRI)
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Susan D Reed, MD
Organizational Affiliation
University of Washington/Group Health Research Institute (GHRI)
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Janet Carpenter, PhD, RN, FAAN
Organizational Affiliation
Indiana University School of Medicine
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Ellen W Freeman, PhD
Organizational Affiliation
University of Pennsylvania School of Medicine (UP)
Official's Role
Principal Investigator
Facility Information:
Facility Name
Massachusetts General Hospital, Harvard Medical School (HU)
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Brigham and Women's Hospital
City
Chestnut Hill
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
University of Pennsylvania, UP
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Group Health Research Institute (GHRI)
City
Seattle
State/Province
Washington
ZIP/Postal Code
98101
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
35969887
Citation
Ensrud KE, Larson JC, Guthrie KA, Crandall CJ, LaCroix AZ, Reed SD, Bhasin S, Mitchell CM, Joffe H. Changes in serum endogenous estrogen concentrations are mediators of the effect of low-dose oral estradiol on vasomotor symptoms. Menopause. 2022 Sep 1;29(9):1014-1020. doi: 10.1097/GME.0000000000002026. Epub 2022 Aug 16.
Results Reference
derived
PubMed Identifier
33367735
Citation
Hudson PL, Ling W, Wu MC, Hayward MR, Mitchell AJ, Larson J, Guthrie KA, Reed SD, Kwon DS, Mitchell CM. Comparison of the Vaginal Microbiota in Postmenopausal Black and White Women. J Infect Dis. 2021 Dec 1;224(11):1945-1949. doi: 10.1093/infdis/jiaa780.
Results Reference
derived
PubMed Identifier
32701665
Citation
Diem SJ, LaCroix AZ, Reed SD, Larson JC, Newton KM, Ensrud KE, Woods NF, Guthrie KA. Effects of pharmacologic and nonpharmacologic interventions on menopause-related quality of life: a pooled analysis of individual participant data from four MsFLASH trials. Menopause. 2020 Oct;27(10):1126-1136. doi: 10.1097/GME.0000000000001597.
Results Reference
derived
PubMed Identifier
29206774
Citation
Mitchell CM, Srinivasan S, Plantinga A, Wu MC, Reed SD, Guthrie KA, LaCroix AZ, Fiedler T, Munch M, Liu C, Hoffman NG, Blair IA, Newton K, Freeman EW, Joffe H, Cohen L, Fredricks DN. Associations between improvement in genitourinary symptoms of menopause and changes in the vaginal ecosystem. Menopause. 2018 May;25(5):500-507. doi: 10.1097/GME.0000000000001037.
Results Reference
derived
PubMed Identifier
29165623
Citation
Guthrie KA, Larson JC, Ensrud KE, Anderson GL, Carpenter JS, Freeman EW, Joffe H, LaCroix AZ, Manson JE, Morin CM, Newton KM, Otte J, Reed SD, McCurry SM. Effects of Pharmacologic and Nonpharmacologic Interventions on Insomnia Symptoms and Self-reported Sleep Quality in Women With Hot Flashes: A Pooled Analysis of Individual Participant Data From Four MsFLASH Trials. Sleep. 2018 Jan 1;41(1):zsx190. doi: 10.1093/sleep/zsx190.
Results Reference
derived
PubMed Identifier
26241433
Citation
Guthrie KA, LaCroix AZ, Ensrud KE, Joffe H, Newton KM, Reed SD, Caan B, Carpenter JS, Cohen LS, Freeman EW, Larson JC, Manson JE, Rexrode K, Skaar TC, Sternfeld B, Anderson GL. Pooled Analysis of Six Pharmacologic and Nonpharmacologic Interventions for Vasomotor Symptoms. Obstet Gynecol. 2015 Aug;126(2):413-422. doi: 10.1097/AOG.0000000000000927.
Results Reference
derived
PubMed Identifier
25405571
Citation
Caan B, LaCroix AZ, Joffe H, Guthrie KA, Larson JC, Carpenter JS, Cohen LS, Freeman EW, Manson JE, Newton K, Reed S, Rexrode K, Shifren J, Sternfeld B, Ensrud K. Effects of estrogen and venlafaxine on menopause-related quality of life in healthy postmenopausal women with hot flashes: a placebo-controlled randomized trial. Menopause. 2015 Jun;22(6):607-15. doi: 10.1097/GME.0000000000000364.
Results Reference
derived
PubMed Identifier
25325454
Citation
Ensrud KE, Guthrie KA, Hohensee C, Caan B, Carpenter JS, Freeman EW, LaCroix AZ, Landis CA, Manson J, Newton KM, Otte J, Reed SD, Shifren JL, Sternfeld B, Woods NF, Joffe H. Effects of estradiol and venlafaxine on insomnia symptoms and sleep quality in women with hot flashes. Sleep. 2015 Jan 1;38(1):97-108. doi: 10.5665/sleep.4332.
Results Reference
derived
PubMed Identifier
25004335
Citation
Reed SD, Mitchell CM, Joffe H, Cohen L, Shifren JL, Newton KM, Freeman EW, Larson JC, Manson JE, LaCroix AZ, Guthrie KA. Sexual function in women on estradiol or venlafaxine for hot flushes: a randomized controlled trial. Obstet Gynecol. 2014 Aug;124(2 Pt 1):233-241. doi: 10.1097/AOG.0000000000000386.
Results Reference
derived
PubMed Identifier
24861828
Citation
Joffe H, Guthrie KA, LaCroix AZ, Reed SD, Ensrud KE, Manson JE, Newton KM, Freeman EW, Anderson GL, Larson JC, Hunt J, Shifren J, Rexrode KM, Caan B, Sternfeld B, Carpenter JS, Cohen L. Low-dose estradiol and the serotonin-norepinephrine reuptake inhibitor venlafaxine for vasomotor symptoms: a randomized clinical trial. JAMA Intern Med. 2014 Jul;174(7):1058-66. doi: 10.1001/jamainternmed.2014.1891.
Results Reference
derived
PubMed Identifier
23760428
Citation
Newton KM, Carpenter JS, Guthrie KA, Anderson GL, Caan B, Cohen LS, Ensrud KE, Freeman EW, Joffe H, Sternfeld B, Reed SD, Sherman S, Sammel MD, Kroenke K, Larson JC, Lacroix AZ. Methods for the design of vasomotor symptom trials: the menopausal strategies: finding lasting answers to symptoms and health network. Menopause. 2014 Jan;21(1):45-58. doi: 10.1097/GME.0b013e31829337a4.
Results Reference
derived

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

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