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

NCT01418209 | Completed Results DMC

• 3 other identifiers: MsFLASH-031U01AG032700-011U01AG032699-01
• Study Type: interventional
• Target: 339
• Locations: 1 country
• Sites: 4

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.

Conditions

Hot Flashes; Menopause; Vasomotor Disturbance

Keywords

Menopause; Vasomotor; Symptoms; Estradiol; Venlafaxine

Outcome Measures

Primary Outcomes (2)

• 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.

  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.

  Week 8

Secondary Outcomes (6)

• Severity of Hot Flashes -- Week 4

  Week 4

• Severity of Hot Flashes -- Week 8

  Week 8

• Bothersomeness of Hot Flashes -- Week 4

  Week 4

• Bothersomeness of Hot Flashes -- Week 8

  Week 8

• Perceived Hot Flash Interference (Hot Flash Related Daily Interference Scale; HFRDIS) -- Week 4

  Week 4

Study Arms (3)

Low-dose 17-ß-estradiol with progesterone taper

ACTIVE COMPARATOR

Drug: Low-dose 17-ß-estradiol with progesterone taper

Venlafaxine XR

ACTIVE COMPARATOR

Drug: Venlafaxine XR

Placebo

PLACEBO COMPARATOR

Drug: Placebo

Interventions

Low-dose 17-ß-estradiol with progesterone taper 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).

Also known as: The brand name of estradiol being used in this study is Estrace®.

Low-dose 17-ß-estradiol with progesterone taper

Venlafaxine XR 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).

Also known as: The brand name of venlafaxine XR that is being used in this study is Effexor XR®

Venlafaxine XR

Placebo DRUG

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

Placebo

Eligibility Criteria

• Age: 40 Years - 62 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• Fred Hutchinson Cancer Center: lead
• National Institute on Aging (NIA): collaborator
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator
• National Center for Complementary and Integrative Health (NCCIH): collaborator
• Office of Research on Women's Health (ORWH): collaborator

Study Sites (4)

Massachusetts General Hospital, Harvard Medical School (HU)

Boston, Massachusetts, 02114, United States

Location

Brigham and Women's Hospital

Chestnut Hill, Massachusetts, 02215, United States

Location

University of Pennsylvania, UP

Philadelphia, Pennsylvania, 19104, United States

Location

Group Health Research Institute (GHRI)

Seattle, Washington, 98101, United States

Location

Related Publications (11)

• 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.

  PMID: 35969887 DERIVED

• 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.

  PMID: 33367735 DERIVED

• 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.

  PMID: 32701665 DERIVED

• 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.

  PMID: 29206774 DERIVED

• 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.

  PMID: 29165623 DERIVED

• 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.

  PMID: 26241433 DERIVED

• 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.

  PMID: 25405571 DERIVED

• 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.

  PMID: 25325454 DERIVED

• 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.

  PMID: 25004335 DERIVED

• 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.

  PMID: 24861828 DERIVED

• 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.

  PMID: 23760428 DERIVED

MeSH Terms

Conditions

Hot Flashes

Condition Hierarchy (Ancestors)

Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Limitations and Caveats

Findings may be specific to the particular dose of each agent used, treatment period, as well as the preparation and oral administration of estrogen therapy.

Results Point of Contact

• Title: Hadine Joffe, MD, MSc
• Organization: Brigham and Women's Hospital

hjoffe@partners.org

617-732-4906

Study Officials

• Andrea Z LaCroix, PhD

  Fred Hutchinson Cancer Center

  PRINCIPAL INVESTIGATOR

• Garnet Anderson, PhD

  Fred Hutchinson Cancer Center

  PRINCIPAL INVESTIGATOR

• Katherine Guthrie, PhD

  Fred Hutchinson Cancer Center

  PRINCIPAL INVESTIGATOR

• Lee S Cohen, MD

  Massachusetts General Hospital/Harvard Medical School (HU)

  PRINCIPAL INVESTIGATOR

• Hadine Joffe, MD, MSc

  Massachusetts General Hospital/Harvard Medical School (HU)

  PRINCIPAL INVESTIGATOR

• Katherine M Newton, PhD

  Group Health Research Institute (GHRI)

  PRINCIPAL INVESTIGATOR

• Susan D Reed, MD

  University of Washington/Group Health Research Institute (GHRI)

  PRINCIPAL INVESTIGATOR

• Janet Carpenter, PhD, RN, FAAN

  Indiana University School of Medicine

  STUDY DIRECTOR

• Ellen W Freeman, PhD

  University of Pennsylvania School of Medicine (UP)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: August 15, 2011
• First Posted: August 17, 2011
• Study Start: November 1, 2011
• Primary Completion: January 1, 2013
• Study Completion: January 1, 2013
• Last Updated: August 27, 2014
• Results First Posted: August 20, 2014

Record last verified: 2014-08

Locations

US (4)