Clinical trial NCT01418209: 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
Overall status: COMPLETED
Phase: NA
Conditions: Hot Flashes
Menopause
Vasomotor Disturbance
Keywords: Menopause
Vasomotor
Symptoms
Estradiol
Venlafaxine
Lead sponsor: Fred Hutchinson Cancer Center
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: National Center for Complementary and Integrative Health (NCCIH)
name: Office of Research on Women's Health (ORWH)
First posted: 2011-08-17
Enrollment: 339
Sex: FEMALE
Minimum age (years): 40
Maximum age (years): 62
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Frequency of Hot Flashes (Vasomotor Symptom [VMS] Frequency) -- Week 4
timeFrame: Week 4
measure: Frequency of Hot Flashes (Daily Vasomotor Symptom [VMS] Frequency) -- Week 8
timeFrame: Week 8
Secondary outcomes:
measure: Severity of Hot Flashes -- Week 4
timeFrame: Week 4
measure: Severity of Hot Flashes -- Week 8
timeFrame: Week 8
measure: Bothersomeness of Hot Flashes -- Week 4
timeFrame: Week 4
measure: Bothersomeness of Hot Flashes -- Week 8
timeFrame: Week 8
measure: Perceived Hot Flash Interference (Hot Flash Related Daily Interference Scale; HFRDIS) -- Week 4
timeFrame: Week 4
measure: Perceived Hot Flash Interference (Hot Flash Related Daily Interference Scale; HFRDIS) -- Week 8
timeFrame: Week 8
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital, Harvard Medical School (HU)
state: Massachusetts
city: Chestnut Hill
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Philadelphia
country: United States
facility: University of Pennsylvania, UP
state: Pennsylvania
city: Seattle
country: United States
facility: Group Health Research Institute (GHRI)
state: Washington
Study officials:
affiliation: Fred Hutchinson Cancer Center
name: Andrea Z LaCroix, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Fred Hutchinson Cancer Center
name: Garnet Anderson, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Fred Hutchinson Cancer Center
name: Katherine Guthrie, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Massachusetts General Hospital/Harvard Medical School (HU)
name: Lee S Cohen, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Massachusetts General Hospital/Harvard Medical School (HU)
name: Hadine Joffe, MD, MSc
role: PRINCIPAL_INVESTIGATOR
affiliation: Group Health Research Institute (GHRI)
name: Katherine M Newton, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Washington/Group Health Research Institute (GHRI)
name: Susan D Reed, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Indiana University School of Medicine
name: Janet Carpenter, PhD, RN, FAAN
role: STUDY_DIRECTOR
affiliation: University of Pennsylvania School of Medicine (UP)
name: Ellen W Freeman, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.