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

Study Overview
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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.

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

Conditions
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Hot Flashes, Menopause, Vasomotor Disturbance

Intervention / Treatment
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* Drug: Low-dose 17-ß-estradiol with progesterone taper
* Drug: Venlafaxine XR
* Drug: Placebo


Participation Criteria
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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

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 62 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Severity of Hot Flashes -- 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. | Week 4 | 
| Severity of Hot Flashes -- 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. | Week 8 | 
| Bothersomeness of Hot Flashes -- 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. | Week 4 | 
| Bothersomeness of Hot Flashes -- 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. | Week 8 | 
| Perceived Hot Flash Interference (Hot Flash Related Daily Interference Scale; HFRDIS) -- 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. | Week 4 | 
| Perceived Hot Flash Interference (Hot Flash Related Daily Interference Scale; HFRDIS) -- 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. | Week 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Menopause, Vasomotor, Symptoms, Estradiol, Venlafaxine