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

NCT ID: NCT01418209

Last Updated: 2014-08-27

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

NA

Total Enrollment

339 participants

Study Classification

INTERVENTIONAL

Study Start Date

2011-11-30

Study Completion Date

2013-01-31

Brief Summary

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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

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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.

Conditions

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Hot Flashes Menopause Vasomotor Disturbance

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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Low-dose 17-ß-estradiol with progesterone taper

Group Type ACTIVE_COMPARATOR

Low-dose 17-ß-estradiol with progesterone taper

Intervention Type DRUG

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).

Venlafaxine XR

Group Type ACTIVE_COMPARATOR

Venlafaxine XR

Intervention Type DRUG

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

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

The placebo is an inactive pill that looks like the active medication.

Interventions

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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 by 14 days (2 weeks) of progesterone taper (as medroxy-progesterone 10 mg/day).

Intervention Type DRUG

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).

Intervention Type DRUG

Placebo

The placebo is an inactive pill that looks like the active medication.

Intervention Type DRUG

Other Intervention Names

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The brand name of estradiol being used in this study is Estrace®. The brand name of venlafaxine XR that is being used in this study is Effexor XR®

Eligibility Criteria

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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
Minimum Eligible Age

40 Years

Maximum Eligible Age

62 Years

Eligible Sex

FEMALE

Accepts Healthy Volunteers

Yes

Sponsors

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National Institute on Aging (NIA)

NIH

Sponsor Role collaborator

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

NIH

Sponsor Role collaborator

National Center for Complementary and Integrative Health (NCCIH)

NIH

Sponsor Role collaborator

Office of Research on Women's Health (ORWH)

NIH

Sponsor Role collaborator

Fred Hutchinson Cancer Center

OTHER

Sponsor Role lead

Responsible Party

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Katherine Guthrie

Principal Investigator

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Andrea Z LaCroix, PhD

Role: PRINCIPAL_INVESTIGATOR

Fred Hutchinson Cancer Center

Garnet Anderson, PhD

Role: PRINCIPAL_INVESTIGATOR

Fred Hutchinson Cancer Center

Katherine Guthrie, PhD

Role: PRINCIPAL_INVESTIGATOR

Fred Hutchinson Cancer Center

Lee S Cohen, MD

Role: PRINCIPAL_INVESTIGATOR

Massachusetts General Hospital/Harvard Medical School (HU)

Hadine Joffe, MD, MSc

Role: PRINCIPAL_INVESTIGATOR

Massachusetts General Hospital/Harvard Medical School (HU)

Katherine M Newton, PhD

Role: PRINCIPAL_INVESTIGATOR

Group Health Research Institute (GHRI)

Susan D Reed, MD

Role: PRINCIPAL_INVESTIGATOR

University of Washington/Group Health Research Institute (GHRI)

Janet Carpenter, PhD, RN, FAAN

Role: STUDY_DIRECTOR

Indiana University School of Medicine

Ellen W Freeman, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Pennsylvania School of Medicine (UP)

Locations

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Massachusetts General Hospital, Harvard Medical School (HU)

Boston, Massachusetts, United States

Site Status

Brigham and Women's Hospital

Chestnut Hill, Massachusetts, United States

Site Status

University of Pennsylvania, UP

Philadelphia, Pennsylvania, United States

Site Status

Group Health Research Institute (GHRI)

Seattle, Washington, United States

Site Status

Countries

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United States

References

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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.

Reference Type DERIVED
PMID: 35969887 (View on PubMed)

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.

Reference Type DERIVED
PMID: 33367735 (View on PubMed)

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.

Reference Type DERIVED
PMID: 32701665 (View on PubMed)

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.

Reference Type DERIVED
PMID: 29206774 (View on PubMed)

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.

Reference Type DERIVED
PMID: 29165623 (View on PubMed)

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.

Reference Type DERIVED
PMID: 26241433 (View on PubMed)

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.

Reference Type DERIVED
PMID: 25405571 (View on PubMed)

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.

Reference Type DERIVED
PMID: 25325454 (View on PubMed)

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.

Reference Type DERIVED
PMID: 25004335 (View on PubMed)

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.

Reference Type DERIVED
PMID: 24861828 (View on PubMed)

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.

Reference Type DERIVED
PMID: 23760428 (View on PubMed)

Other Identifiers

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1U01AG032700-01

Identifier Type: NIH

Identifier Source: secondary_id

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1U01AG032699-01

Identifier Type: NIH

Identifier Source: secondary_id

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MsFLASH-03

Identifier Type: -

Identifier Source: org_study_id

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