Progesterone for Perimenopausal Night Sweats

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to test whether a oral micronized progesterone reduces the Vasomotor Symptom Score comprised of the number and severity of hot flushes and night sweats in perimenopausal women. Oral micronized progesterone is molecularly identical to human progesterone, a steroid hormone. It is sold by prescription for use to prevent endometrial cancer in women taking estrogen in menopause. This research study will test whether progesterone reduces perimenopausal hot flushes and night sweats. It will also test whether progesterone improves sleep disturbances and anxiety.

Detailed Description
-----------------
This is a randomized, double-blind placebo-controlled trial of oral micronized progesterone (300 mg daily at bedtime) for perimenopausal women living anywhere in Canada. Using the self-reported maximum menstrual cycle length in the previous year, women will be stratified as in Early Perimenopause (<60 days) or Late Perimenopause (>=60 days). The design includes a 28-day baseline run-in followed by 12 weeks of randomized therapy.

Official Title
-----------------
Oral Micronized Progesterone for Perimenopausal Vasomotor Symptoms

Conditions
-----------------
Hot Flushes, Night Sweats

Intervention / Treatment
-----------------
* Drug: Oral micronized progesterone
* Drug: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Between 35-58 years of age At least 4 vasomotor symptoms (VMS) per day, on average, for at least 2/4 weeks or at least 56 over a four-week period. In addition, women should report having VMS of moderate or severe rather than mild intensity. Women reporting fewer VMS than this, but who report night sweats that awaken them from sleep on two or more nights per week will also be included. Perimenopausal status either based on irregularity of menstrual periods, or by onset of new perimenopausal symptoms in women with regular periods. At least one menstrual period within 12 months of study enrollment Ability and willingness to complete the Daily Perimenopause Hot Flush Calendar recording instrument. Ability to understand, speak, read and write English. Women who are at high risk for breast cancer (ie first degree relative with breast cancer, known/suspected history of breast cancer) will be required to have a normal mammogram and clinical breast examination within 12 months of study enrollment. Exclusion Criteria: VMS without perimenopausal etiology. Women who have had a hysterectomy and/or ovariectomy. Peanut allergy (because peanut oil is used in the progesterone formulation.) Current or recent (within the last 6-mos.) use of hormonal therapies (estrogen, progesterone, hormonal contraceptives, hormonal fertility treatments), or plans to initiate use during the study period. Two exceptions: women using progestin-releasing intrauterine device (IUD) will not be excluded as it is felt that level of hormone released will not have an effect on VMS and women taking very low-dose transdermal progesterone therapies who have VMS and meet inclusion criteria will be considered on a case-by-case basis. If enrolled, women with these exclusion exceptions will be required to continue and document use of these therapies throughout the entire trial. Planned pregnancy or fertility treatment during the study period. Women who are breastfeeding. Participants with a score greater or equal to 15 on the Personal Health Questionnaire (PHQ-9) will be assessed on a case-by-case basis. Women assessed as needing further investigation and/or treatment for depression will be excluded.

Ages Eligible for Study
-----------------
Minimum Age: 35 Years
Maximum Age: 58 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: oral micronized progesterone<br>Oral micronized progesterone is Prometrium 300 mg at bedtime daily | Drug: Oral micronized progesterone<br>* 300 mg as 3-100 mg capsules taken orally at bedtime daily for 12 weeks<br>* Other names: Utrogestan;|
| Placebo Comparator: Placebo Comparator<br>Placebo | Drug: placebo<br>* placebo comparator, taken as 3 round capsules at bedtime daily for 12 weeks<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vasomotor Symptoms (VMS)/ VMS Score - at 12 Weeks | Participants will complete a daily calendar (Daily Perimenopause Hot Flush Calendar) to record frequency (actual number) and severity (quantified by ordinal scale ie 0=none to 4=extreme) of hot flushes and night sweats. The VMS Score will be calculated as follows: Daily VMS Score = (# night sweats) x (severity) + (#hot flushes) x (severity). Outcome is the average daily VMS Score during the final 28 days of therapy, to be analysed with 28-day run-in scores as covariate. | 12 weeks | 
| Frequency of VMS | Frequency (count) of hot flushes/hot flashes and night sweats per day from prospective daily calendar records. Outcome is the average daily VMS Frequency (day + night) during the final 28 days of therapy, to be analysed with 28-day run-in scores as covariate. | 12 weeks | 
| Severity of VMS | Severity (0-4, 0=no intensity, 4=extreme intensity) of hot flushes/hot flashes and night sweats per day from prospective daily calendar records. Daily summary score is the maximum of daytime and nighttime severity. Outcome is the average daily severity during the final 28 days of therapy, to be analysed with 28-day run-in scores as covariate. | 12 weeks | 
| VMS Score by Early Perimenopause | subgroup analysis of VMS Score by Early Perimenopause (no skipped period or <60 day cycle length). Outcome is the average daily VMS Score during the final 28 days of therapy, to be analysed with 28-day run-in scores as covariate. Participants will complete a daily calendar (Daily Perimenopause Hot Flush Calendar) to record frequency (actual number) and severity (quantified by ordinal scale ie 0=none to 4=extreme) of hot flushes and night sweats. The VMS Score will be calculated as follows: Daily VMS Score = (# night sweats) x (severity) + (#hot flushes) x (severity). | 12 weeks | 
| VMS Score by Late Perimenopause | subgroup analysis of VMS Score by Late Perimenopause (those with skipped or ≥60 day cycle lengths). Outcome is the average daily VMS Score during the final 28 days of therapy, to be analysed with 28-day run-in scores as covariate. Participants will complete a daily calendar (Daily Perimenopause Hot Flush Calendar) to record frequency (actual number) and severity (quantified by ordinal scale ie 0=none to 4=extreme) of hot flushes and night sweats. The VMS Score will be calculated as follows: Daily VMS Score = (# night sweats) x (severity) + (#hot flushes) x (severity). | 12 weeks | 
| Subgroup Analysis for Those With Frequent and Severe VMS - VMS Score | VMS Score for those with more frequent (≥7 per day and moderate to severe episodes of intensity 2-4) at baseline. Participants will complete a daily calendar (Daily Perimenopause Hot Flush Calendar) to record frequency (actual number) and severity (quantified by ordinal scale ie 0=none to 4=extreme) of hot flushes and night sweats. The VMS Score will be calculated as follows: Daily VMS Score = (# night sweats) x (severity) + (#hot flushes) x (severity). | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sleep Problems | Daily average rating of sleep problems (0-4) from prospective daily calendar records. Outcome is the average daily rating during the final 28 days of therapy, to be analysed with 28-day run-in scores as covariate. Scale name: Sleep Problems (4=Worst, 0=None) | 12 weeks | 
| Anxiety | Daily average rating of anxiety (0-4) from prospective daily calendar records. Outcome is the average daily rating during the final 28 days of therapy, to be analysed with 28-day run-in scores as covariate. Scale name: Anxiety (4=Worst, 0=None) | 12 weeks | 
| Women's Perceived Changes in Daytime Hot Flushes for Whole Population | Women's Perceived Changes Questionnaire of changes (from -5 to 0 to +5) in Daytime Hot Flushes (both number and severity) as recorded on the Final Questionnaire. Scale Name: Daytime Hot Flush Change Decrease is -5 to -1; No change is 0; Increase is +1 to +5. This is women's perception of the change from run-in to when they recorded it at the end of the trial (at 12 weeks). No calculation is needed. | 12 weeks | 
| Women's Perceived Changes in Night Sweats for Whole Population | Women's Perceived Changes Questionnaire of changes (from -5 to 0 to +5) in Nighttime Night Sweats (both number and severity) as recorded on the Final Questionnaire. Scale Name: Night Sweats Change Decrease is -5 to -1; No change is 0; Increase is +1 to +5. This is women's perception of the change from run-in to when they recorded it at the end of the trial (at 12 weeks). No calculation is needed. | 12 weeks | 
| Women's Perceived Changes in Quality of Sleep for Whole Population | Women's Perceived Changes Questionnaire of changes (from -5 to 0 to +5) in the quality of sleep over the three months of the trial as assessed by the Final Questionnaire based on their random assignment to the progesterone or placebo arms of this RCT (Randomized Controlled Trial) and by Early/Late perimenopause. Scale Name: Quality of Sleep Change Decrease is -5 to -1; No change is 0; Increase is +1 to +5. This is women's perception of the change from run-in to when they recorded it at the end of the trial (at 12 weeks). No calculation is needed. | 12 weeks | 
| Perception of Interference of Overall Perimenopausal Changes With Usual Activities in Women | Final perceptions of interference of overall perimenopausal changes with usual activities (as recorded by the CeMCOR PIQ - Centre for Menstrual Cycle and Ovulation Research Perimenopause Interference Questionnaire) at 12 weeks in women randomized to the progesterone versus to placebo. Scale Name: Perceived Interference Score: 100 mm line (0 = No Interference; 100 = Severe Interference) | 12 weeks | 
| Perception of Interference of Overall Perimenopausal Changes With Usual Activities in Women - Early Perimenopause | Final perceptions of interference of overall perimenopausal changes with usual activities (as recorded by the CeMCOR Perimenopause Interference Questionnaire [CeMCOR PIQ]) at 12 weeks in women randomized to the progesterone versus to placebo. Scale Name: Perceived Interference Score: 100 mm line (0 = No Interference; 100 = Severe Interference) | 12 weeks | 
| Perception of Interference of Overall Perimenopausal Changes With Usual Activities in Women - Late Perimenopause | Final perceptions of interference of overall perimenopausal changes with usual activities (as recorded by the CeMCOR Perimenopause Interference Questionnaire [CeMCOR PIQ]) at 12 weeks in women randomized to the progesterone versus to placebo. Scale Name: Perceived Interference Score: 100 mm line (0 = No Interference; 100 = Severe Interference) | 12 weeks | 
| Perception of Interference of Perimenopausal Body Changes With Usual Activities in Women | Final perceptions of interference of perimenopausal body changes with usual activities (as recorded by the CeMCOR Perimenopause Interference Questionnaire [CeMCOR PIQ]) in women randomized to the progesterone versus to placebo. Scale Name: Perceived Interference Score: 100 mm line (0 = No Interference; 100 = Severe Interference) | 12 weeks | 
| Perception of Interference of Perimenopausal Mood Changes With Usual Activities in Women | Final perceptions of interference of perimenopausal mood changes with usual activities (as recorded by the CeMCOR Perimenopause Interference Questionnaire [CeMCOR PIQ]) in women randomized to the progesterone versus to placebo. Scale Name: Perceived Interference Score: 100 mm line (0 = No Interference; 100 = Severe Interference) | 12 weeks | 
| Women's Perceived Changes in Daytime Hot Flushes in Early Perimenopause | Women's Perceived Changes Questionnaire of changes (from -5 to 0 to +5) in Daytime Hot Flushes (both number and severity) as recorded on the Final Questionnaire and by subgroup for Early Perimenopause. Scale Name: Perceived Daytime Hot Flush Change Decrease is -5 to -1; No change is 0; Increase is +1 to +5. | 12 weeks | 
| Women's Perceived Changes in Night Sweats in Early Perimenopause | Women's Perceived Changes Questionnaire of changes (from -5 to 0 to +5) in Nighttime Night Sweats (both number and severity) as recorded on the Final Questionnaire and by subgroup for Early Perimenopause. Scale Name: Perceived Night Sweats Change Decrease is -5 to -1; No change is 0; Increase is +1 to +5. | 12 weeks | 
| Women's Perceived Changes in Daytime Hot Flushes in Late Perimenopause | Women's Perceived Changes Questionnaire of changes (from -5 to 0 to +5) in Daytime Hot Flushes (both number and severity) as recorded on the Final Questionnaire and by subgroup for Late Perimenopause. Scale Name: Perceived Daytime Hot Flush Change Decrease is -5 to -1; No change is 0; Increase is +1 to +5. | 12 weeks | 
| Women's Perceived Changes in Night Sweats in Late Perimenopause | Women's Perceived Changes Questionnaire of changes (from -5 to 0 to +5) in Nighttime Night Sweats (both number and severity) as recorded on the Final Questionnaire and by subgroup for Late Perimenopause. Scale Name: Perceived Night Sweats Change Decrease is -5 to -1; No change is 0; Increase is +1 to +5. | 12 weeks | 
| Depression Related to Progesterone Therapy in Whole Population | Final PHQ9 (Personal Health Questionnaire 9) Score for Depression related to progesterone therapy in perimenopause will be assessed based on the Personal Health Questionnaire-9 (PHQ-9) score changes within-woman from baseline to the end-of-trial on progesterone compared with placebo. Scale Name: PHQ9 Scale (0 = No Depression; 27 = Severe Depression) | 12 weeks | 
| Depression Related to Progesterone Therapy in Early Perimenopause | Final PHQ9 Score for Depression related to progesterone therapy in Early Perimenopause will be assessed based on the Personal Health Questionnaire-9 (PHQ-9) score changes within-woman from baseline to the end-of-trial on progesterone compared with placebo. Scale Name: PHQ9 Scale (0 = No Depression; 27 = Severe Depression) | 12 weeks | 
| Depression Related to Progesterone Therapy in Late Perimenopause | Final PHQ9 Score for Depression related to progesterone therapy in Late Perimenopause will be assessed based on the Personal Health Questionnaire-9 (PHQ-9) score changes within-woman from baseline to the end-of-trial on progesterone compared with placebo. Scale Name: PHQ9 Scale (0 = No Depression; 27 = Severe Depression) | 12 weeks | 
| Percentage of Women With Perceived Changes in Menstrual Flow | Menstrual flow related to progesterone therapy in perimenopause was assessed based on Women's Perceived Changes Questionnaire of changes in the experience of menstrual flow/vaginal bleeding from the Final Questionnaire. | 12 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
anxiety, hot flushes/hot flashes, night sweats, sleep problems, negative mood, perimenopause, progesterone, vasomotor symptoms, depression, women's perceived change, perimenopause interference questionnaire