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

• Frequency of hot flashes [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
  Measured by self-report diary twice daily for 7 days
• Bothersomeness of hot flashes [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
  Measured by self-report diary twice daily for 7 days.
• Severity of hot flashes [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
  Measured by self-report diary twice daily for 7 days

• Sleep disturbance [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
  As measured by sleep diaries and possibly a sleep monitor wrist-device worn at home 7 days at the start and end of the study.
• Depression (depressive symptoms) [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
  Measured by self-report responses to questionnaire
• Anxiety [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
  Measured by self-report responses to questionnaire
• Sexual function [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
  Measured by self-report responses to questionnaire

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.

The MsFLASH-03 study, 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.

• Hot Flashes
• Menopause
• Vasomotor Disturbance

• Drug: Low-dose 17-ß-estradiol
  Low-dose 17-ß-estradiol oral (by mouth), 0.5 mg once per day for 8 (eight) weeks. After the 8-week treatment, women with a uterus will receive medroxyprogesterone 10 mg once per day for 2 weeks (14 days). 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.
  Other Name: The brand name of estradiol being used in this study is Estrace®.
• 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®
• Drug: Placebo
  The placebo is an inactive pill that looks like the active medication.

• Active Comparator: Low-dose 17-ß-estradiol
  Intervention: Drug: Low-dose 17-ß-estradiol
• Active Comparator: Venlafaxine XR
  Intervention: Drug: Venlafaxine XR
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo

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), SNRIs (serotonin-norepinephrine reuptake inhibitors), 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

• National Institute on Aging (NIA)
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• National Center for Complementary and Alternative Medicine (NCCAM)
• Office of Research on Women's Health (ORWH)