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

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
Hot Flashes; Menopause; Vasomotor Disturbance	Drug: Low-dose 17-ß-estradiol with progesterone taper; Drug: Venlafaxine XR; Drug: Placebo	Not Applicable

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	339 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	MsFLASH-03: Comparative Efficacy of Low-Dose Estradiol and the SNRI Venlafaxine XR for Treatment of Menopausal Symptoms
Study Start Date :	November 2011
Actual Primary Completion Date :	January 2013
Actual Study Completion Date :	January 2013

Arms and Interventions

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Arm	Intervention/treatment
Active Comparator: Low-dose 17-ß-estradiol with progesterone taper	Drug: 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).; Other Name: The brand name of estradiol being used in this study is Estrace®.
Active Comparator: Venlafaxine XR	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).; Other Name: The brand name of venlafaxine XR that is being used in this study is Effexor XR®
Placebo Comparator: Placebo	Drug: Placebo; The placebo is an inactive pill that looks like the active medication.

Outcome Measures

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Primary Outcome Measures :

1. Frequency of Hot Flashes (Vasomotor Symptom [VMS] Frequency) -- Week 4 [ Time Frame: 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.
2. Frequency of Hot Flashes (Daily Vasomotor Symptom [VMS] Frequency) -- Week 8 [ Time Frame: 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 :

1. Severity of Hot Flashes -- Week 4 [ Time Frame: 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.
2. Severity of Hot Flashes -- Week 8 [ Time Frame: 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.
3. Bothersomeness of Hot Flashes -- Week 4 [ Time Frame: 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.
4. Bothersomeness of Hot Flashes -- Week 8 [ Time Frame: 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.
5. Perceived Hot Flash Interference (Hot Flash Related Daily Interference Scale; HFRDIS) -- Week 4 [ Time Frame: 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.
6. Perceived Hot Flash Interference (Hot Flash Related Daily Interference Scale; HFRDIS) -- Week 8 [ Time Frame: 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.

Eligibility Criteria

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Ages Eligible for Study:	40 Years to 62 Years (Adult)
Sexes Eligible for Study:	Female
Accepts Healthy Volunteers:	Yes

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

Contacts and Locations

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Locations

United States, Massachusetts
Massachusetts General Hospital, Harvard Medical School (HU)
Boston, Massachusetts, United States, 02114
Brigham and Women's Hospital
Chestnut Hill, Massachusetts, United States, 02215
United States, Pennsylvania
University of Pennsylvania, UP
Philadelphia, Pennsylvania, United States, 19104
United States, Washington
Group Health Research Institute (GHRI)
Seattle, Washington, United States, 98101

Sponsors and Collaborators

Fred Hutchinson Cancer Research Center

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)

Investigators

Principal Investigator:	Andrea Z LaCroix, PhD	Fred Hutchinson Cancer Research Center
Principal Investigator:	Garnet Anderson, PhD	Fred Hutchinson Cancer Research Center
Principal Investigator:	Katherine Guthrie, PhD	Fred Hutchinson Cancer Research 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)
Study Director:	Janet Carpenter, PhD, RN, FAAN	Indiana University School of Medicine
Principal Investigator:	Ellen W Freeman, PhD	University of Pennsylvania School of Medicine (UP)

More Information

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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):413-22. doi: 10.1097/AOG.0000000000000927.

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.

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.

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):233-41. doi: 10.1097/AOG.0000000000000386.

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.

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.

Responsible Party:	Katherine Guthrie, Principal Investigator, Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:	NCT01418209 History of Changes
Other Study ID Numbers:	MsFLASH-03; 1U01AG032700-01 ( U.S. NIH Grant/Contract ); 1U01AG032699-01 ( U.S. NIH Grant/Contract )
First Posted:	August 17, 2011
Results First Posted:	August 20, 2014
Last Update Posted:	August 27, 2014
Last Verified:	August 2014

Keywords provided by Katherine Guthrie, Fred Hutchinson Cancer Research Center:

Menopause; Vasomotor; Symptoms; Estradiol; Venlafaxine

Additional relevant MeSH terms:

Hot Flashes; Signs and Symptoms; Estradiol; Polyestradiol phosphate; Progesterone; Estradiol 3-benzoate; Estradiol 17 beta-cypionate; Estradiol valerate; Venlafaxine Hydrochloride; Estrogens; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs	Contraceptive Agents; Reproductive Control Agents; Contraceptive Agents, Female; Progestins; Serotonin and Noradrenaline Reuptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Antidepressive Agents, Second-Generation; Antidepressive Agents; Psychotropic Drugs