Now Available: Final Rule for FDAAA 801 and NIH Policy on Clinical Trial Reporting

Mirena and Estrogen for Control of Perimenopause Symptoms and Ovulation Suppression

This study has been completed.
Sponsor:
Collaborator:
Bayer
Information provided by (Responsible Party):
University of Colorado, Denver
ClinicalTrials.gov Identifier:
NCT01613131
First received: June 4, 2012
Last updated: October 29, 2015
Last verified: October 2015
  Purpose

Hormonal treatment of perimenopausal women has frequently utilized oral contraceptive pills (OCPs). Because of their ability to suppress ovulation and establish cycle control, OCPs have become a popular option, and one that is FDA approved for use until menopause. However, use of OCPs in women in their 40's and 50's carries significant cardiovascular risks. Venous thromboembolism risk is 3-6 fold greater in OCP users, and the risk of myocardial infarction (MI) is approximately doubled in OCP users over the age of 40. This occurs at an age where the background population risk of MI begins to increase, such that the absolute number of cases rises substantially. Women with additional risk factors for cardiovascular disease have a much greater risk for MI (6-40-fold) in association with OCPs. There are also large subgroups of midlife women who are not candidates for OCP use, such a smokers and migraineurs. Moreover, the trend towards lower estrogen dosing with OCPs containing 20 micrograms of ethinyl estradiol has not led to a detectable decrease in thromboembolic risk.

Because of their increased potential risks, it is appropriate to seek alternatives to OCPs and to explore lower doses of hormones to relieve perimenopausal symptoms that occur prior to a woman's final menses. Recent evidence indicates that the hypothalamic-pituitary axis of reproductively aging women is more susceptible to suppression by sex steroids that previously believed. It is possible that hormone doses as low as 50 micrograms of transdermal estradiol (TDE) can suppress the hypothalamic-pituitary axis of midlife women. It is also tempting to speculate that the low but measurable circulating doses of levonorgestrel that are present when a woman uses the Mirena intrauterine system (IUS) can contribute to or even independently suppress the hypothalamic-pituitary axis, and reduce the hormonal fluctuations that result in worsening of perimenopausal symptoms. The combination of low dose TDE plus Mirena may therefore confer superior symptom control as well as contraceptive effectiveness, at far less risk.


Condition Intervention
Menopausal and Other Perimenopausal Disorders
Drug: Mirena
Drug: Estradiol
Drug: Placebo Gel

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Effectiveness of Perimenopausal Hormone Therapy in Suppression of Ovulation, Stabilization of Reproductive Hormones and Symptom Control

Resource links provided by NLM:


Further study details as provided by University of Colorado, Denver:

Primary Outcome Measures:
  • Hot Flashes [ Time Frame: Day 0 ] [ Designated as safety issue: No ]
    The Hot Flash Related Daily Interference Scale (HFRDIS) is a ten item scale measuring degree to which hot flashes interfere with 9 daily activities (work, social, leisure, sleep, mood, concentration, relations, sexuality, enjoyment of life, overall quality of life) over the prior week, each scored on a 10 point Likert scale. The total score is reported, and scores range from 0-100, 100 being the worst outcome.

  • Sleep [ Time Frame: Day 0 ] [ Designated as safety issue: No ]
    The Pittsburgh Sleep Quality Index (PSQI) is a 19-item scale designed to measure general sleep disturbances over the previous month (sleep wake patterns, duration of sleep, sleep latency, impact of poor sleep on daytime functioning, assesses specific problems contributing to poor sleep, including pain, urination, breathing difficulty, snoring, dreams, temperature). The global score is reported and ranges from 1-21, with higher scores being indicative of poorer sleep.

  • Depression [ Time Frame: Day 0 ] [ Designated as safety issue: No ]
    The Center for Epidemiologic Studies-Depression Scale (CES-D) is a 20-item scale with 4-point Likert responses indicating frequency of symptoms over past week. Scores range from 0-60, with scores >16 considered indicative of depressive symptoms.

  • Fatigue [ Time Frame: Day 0 ] [ Designated as safety issue: No ]
    The Fatigue Severity Scale (FSS) was used to determine the degree to which night-time sleep difficulty manifested as daytime sleepiness. The FSS is a 9-item scale assessing fatigue over the past week, on a 7-point Likert scale (ranging from 1-7). It is scored by averaging the individual item scores, with higher scores indicating greater fatigue. Scores greater than or equal to 5.5 are generally indicative of insomnia with impaired daytime functioning.

  • Sleep [ Time Frame: Day 90 ] [ Designated as safety issue: No ]
    The Pittsburgh Sleep Quality Index (PSQI) is a 19-item scale designed to measure general sleep disturbances over the previous month (sleep wake patterns, duration of sleep, sleep latency, impact of poor sleep on daytime functioning, assesses specific problems contributing to poor sleep, including pain, urination, breathing difficulty, snoring, dreams, temperature). The global score is reported and ranges from 1-21, with higher scores being indicative of poorer sleep.

  • Sleep [ Time Frame: Day 140 ] [ Designated as safety issue: No ]
    The Pittsburgh Sleep Quality Index (PSQI) is a 19-item scale designed to measure general sleep disturbances over the previous month (sleep wake patterns, duration of sleep, sleep latency, impact of poor sleep on daytime functioning, assesses specific problems contributing to poor sleep, including pain, urination, breathing difficulty, snoring, dreams, temperature). The global score is reported and ranges from 1-21, with higher scores being indicative of poorer sleep.

  • Hot Flashes [ Time Frame: Day 90 ] [ Designated as safety issue: No ]
    The Hot Flash Related Daily Interference Scale (HFRDIS) is a ten item scale measuring degree to which hot flashes interfere with 9 daily activities (work, social, leisure, sleep, mood, concentration, relations, sexuality, enjoyment of life, overall quality of life) over the prior week, each scored on a 10 point Likert scale. The total score is reported, and scores range from 0-100, 100 being the worst outcome.

  • Hot Flashes [ Time Frame: Day 140 ] [ Designated as safety issue: No ]
    The Hot Flash Related Daily Interference Scale (HFRDIS) is a ten item scale measuring degree to which hot flashes interfere with 9 daily activities (work, social, leisure, sleep, mood, concentration, relations, sexuality, enjoyment of life, overall quality of life) over the prior week, each scored on a 10 point Likert scale. The total score is reported, and scores range from 0-100, 100 being the worst outcome.

  • Depression [ Time Frame: Day 90 ] [ Designated as safety issue: No ]
    The Center for Epidemiologic Studies-Depression Scale (CES-D) is a 20-item scale with 4-point Likert responses indicating frequency of symptoms over past week. Scores range from 0-60, with scores >16 considered indicative of depressive symptoms.

  • Depression [ Time Frame: Day 140 ] [ Designated as safety issue: No ]
    The Center for Epidemiologic Studies-Depression Scale (CES-D) is a 20-item scale with 4-point Likert responses indicating frequency of symptoms over past week. Scores range from 0-60, with scores >16 considered indicative of depressive symptoms.

  • Fatigue [ Time Frame: Day 90 ] [ Designated as safety issue: No ]
    The Fatigue Severity Scale (FSS) was used to determine the degree to which night-time sleep difficulty manifested as daytime sleepiness. The FSS is a 9-item scale assessing fatigue over the past week, on a 7-point Likert scale (ranging from 1-7). It is scored by averaging the individual item scores, with higher scores indicating greater fatigue. Scores greater than or equal to 5.5 are generally indicative of insomnia with impaired daytime functioning.

  • Fatigue [ Time Frame: Day 140 ] [ Designated as safety issue: No ]
    The Fatigue Severity Scale (FSS) was used to determine the degree to which night-time sleep difficulty manifested as daytime sleepiness. The FSS is a 9-item scale assessing fatigue over the past week, on a 7-point Likert scale (ranging from 1-7). It is scored by averaging the individual item scores, with higher scores indicating greater fatigue. Scores greater than or equal to 5.5 are generally indicative of insomnia with impaired daytime functioning.


Enrollment: 39
Study Start Date: April 2012
Study Completion Date: June 2014
Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Mirena + Estradiol Gel
Subjects will be assigned to use of Estradiol gel for use with Mirena.
Drug: Mirena
Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months).
Other Name: IUD
Drug: Estradiol
Topical, .06%, Applied once daily for 50 days.
Other Name: TDE
Placebo Comparator: Mirena + Placebo Gel
Subjects will be assigned to use of placebo gel for use with Mirena.
Drug: Mirena
Mirena (levonorgestrel-releasing intrauterine system), 52 mg (20 mcg/day), 5 year duration (study duration 6 months).
Other Name: IUD
Drug: Placebo Gel
Topical Gel, Applied once daily for 50 days, Placebo comparator.
Other Name: placebo

Detailed Description:

The Specific Aims of the present proposal are therefore as follows:

Aim 1: To test the hypothesis that low dose estrogen therapy in concert with the low doses of levonorgestrel that circulate when Mirena is used will suppress ovulation in perimenopausal women.

Aim 2: To examine ovulation rates and symptom control with Mirena alone, and to assess the tolerability of combined estrogen therapy plus the Mirena IUS as a treatment option for symptomatic perimenopausal women.

The proposed pilot study is designed to test the feasibility and tolerability of the proposed regimens: Mirena alone or Mirena plus low-dose TDE in treating symptoms in perimenopausal women and to provide the preliminary data for a larger, comparative effectiveness study of optimal symptom control and provision of long term contraception for midlife women within 5 years of their final menstrual period.

  Eligibility

Ages Eligible for Study:   40 Years to 52 Years   (Adult)
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age 40-52
  • History of regular menstrual cycles every 20-35 days in mid-reproductive life (20-35 years of age)
  • At least 1 period within the past 3 months
  • BMI less than 35 kg/m2
  • Presence of at least one of the following perimenopausal symptoms:

    1. Hot flashes (vasomotor symptoms)
    2. Cyclical headache, bloating or adverse mood
    3. Self-reported poor quality of sleep

Exclusion Criteria:

  • Age < 40 years
  • Hysterectomy or bilateral oophorectomy
  • Cigarette smoking
  • Signs or symptoms of restless leg syndrome or sleep apnea
  • Any chronic renal or hepatic disease that might interfere with excretion of gonadotropins or sex steroids
  • Moderate/vigorous aerobic exercise > 4 hours per week
  • Inability to read/write English
  • Pregnant Women
  • Prisoners
  • Decisionally challenged subjects
  • Any medical condition that makes use of Topical estradiol or Mirena contraindicated.
  • Sex hormone use within the past 30 days
  • History of cancer, blood clots or blood clotting disorder
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01613131

Locations
United States, Colorado
University of Colorado
Aurora, Colorado, United States, 80045
Sponsors and Collaborators
University of Colorado, Denver
Bayer
Investigators
Principal Investigator: Nanette Santoro, MD University of Colorado, Denver
  More Information

Responsible Party: University of Colorado, Denver
ClinicalTrials.gov Identifier: NCT01613131     History of Changes
Other Study ID Numbers: 11-1711 
Study First Received: June 4, 2012
Results First Received: August 11, 2015
Last Updated: October 29, 2015
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Estradiol
Polyestradiol phosphate
Estradiol 3-benzoate
Estradiol 17 beta-cypionate
Estradiol valerate
Levonorgestrel
Estrogens
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Contraceptive Agents
Reproductive Control Agents
Contraceptive Agents, Female
Contraceptives, Oral, Synthetic
Contraceptives, Oral

ClinicalTrials.gov processed this record on December 08, 2016