Pilot Study of Femring Estrogen Supplementation During Depo-Provera Initiation

Study Overview
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Brief Summary
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Many women choose Depo-Provera for birth control because it is easy to use and very effective. However, a significant number of Depo-Provera users experience irregular bleeding during the first 90 days. Many users discontinue after their first injection due to irregular bleeding. This study will evaluate the effect of using an estrogen vaginal ring during the first 90 days of Depo-Provera use to see if it is acceptable to women and whether it decreases irregular bleeding during the first 90 days of use and increases continuation to a second injection.

Detailed Description
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Many women choose depot medroxyprogesterone acetate (DMPA) for contraception because it is long-acting, highly effective, and requires minimal user involvement. One of the most common side effects of DMPA use during the first 90 day cycle is irregular bleeding. There are few studies that report mean number of bleeding days among DMPA users. A large World Health Organization (WHO) trial including ten international centers and menstrual data on 748 women using DMPA including 372 woman-years of follow-up reported 23.6 mean days of spotting and bleeding during the first cycle with a standard deviation of 18.9 days (WHO). Another study sponsored by WHO (n=575) reported that 25% of subjects had bleeding/spotting episodes during the first cycle of DMPA that exceeded 13 days. The number of bleeding/spotting days and number of bleeding/spotting episodes decreased over successive reference periods (Said 1987). Discontinuation rates are high after the first injection and related to irregular bleeding. Rates of discontinuation after the first injection range from 15-60% but were around 30% in most studies (Harel, Paul, Polaneczy, Lim, Hubacher, Sangi, Rickert). Several studies noted that the largest percentage of discontinuation during the first year of DMPA use occurs after the first injection (Rickert, Hubacher, Lim). Irregular bleeding is uniformly cited as one of the most common reasons for discontinuation, accounting for 17-60% of all reasons given (Harel, Paul, Polaneczy, Lim, Sangi). An intervention to prevent or minimize irregular bleeding during the first 90 days of DMPA use could potentially minimize or prevent this bothersome side effect and thus improve continuation. Few studies have examined the effect of prophylactic or therapeutic estrogen supplementation on irregular bleeding in DMPA users. A randomized trial (n=132) of cyclic transdermal estradiol 0.1 mg/day (Climara) for 3 months versus placebo in women initiating DMPA immediately post-abortion showed no difference in continuation rates at 12 months; however, the authors of this study reported a high rate of non-compliance with the study protocol and lacked an adequate sample size to detect a difference (Goldberg). This is the only study to report on prophylactic estrogen supplementation in DMPA users. Two studies evaluated therapeutic estrogen supplementation in DMPA users. In 1996, WHO published results of a trial in which women using DMPA and experiencing a bleeding episode greater than 7 days during the first or second injection interval were offered treatment. Subjects (n=278) were randomized to a 14 day course of 50 mcg ethinyl estradiol, 2.5 mg oestrone sulphate, or placebo. The authors found that subjects treated with ethinyl estradiol had shorter median time to cessation of bleeding and fewer bleeding/spotting days (Said 1996). An observational study (n=131) of adolescents reporting vaginal bleeding on DMPA who were treated with monophasic oral contraceptive pills identified improvement of bleeding patterns and a high rate of continuation in those receiving treatment (Rager). Estrogen supplementation appears to be more effective than placebo in stopping and decreasing bleeding in Norplant users. Women who presented with a spontaneous complaint of prolonged or irregular bleeding were randomly assigned to receive 20 days of treatment with a combined oral contraceptive, 50 mcg ethinyl estradiol, or placebo. Both combined oral contraceptive pills and estradiol were significantly more effective than placebo in stopping bleeding and decreasing the mean number of bleeding days during treatment (Alvarez). To summarize, prior studies have not identified an acceptable or effective prophylactic intervention to prevent or minimize irregular bleeding or improve continuation rates in DMPA users. The first cycle of DMPA is a critical time for such an intervention. Our study will evaluate estrogen supplementation with an estrogen vaginal ring during the first 90 days of DMPA use versus no estrogen supplementation and report on acceptability, bleeding patterns, and continuation rates. Femring®, an estradiol vaginal ring currently used for treatment of postmenopausal symptoms, provides 100 mcg of estradiol per day with one ring designed for 90 days of consecutive use. This dose provides systemic levels sufficient to suppress vasomotor symptoms in postmenopausal women (Speroff). The vaginal ring would require minimal user involvement when placed at the time of DMPA initiation. If acceptable and effective, this intervention could prevent or minimize irregular bleeding and improve continuation rates of this highly effective contraceptive method.

Official Title
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Pilot Study of Femring Estrogen Supplementation During Depo-Provera Initiation

Conditions
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Metrorrhagia

Intervention / Treatment
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* Drug: Femring®
* Drug: DepoProvera ®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women age 18 or older who are initiating Depo-Provera for contraception English or Spanish-speaking Have a negative urine pregnancy test Exclusion Criteria: Contraindications to either Depo-Provera or Femring (estrogen vaginal ring) Have used Depo-Provera or Mirena in the prior 6 months Have had an induced abortion, spontaneous abortion, or birth in prior 8 weeks

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Depo-Provera/Femring<br>Subjects will receive an estrogen vaginal ring (100 mcg) during the first 90 days of Depo-Provera use. | Drug: Femring®<br>* Estrogen vaginal ring (100 mcg) placed for the first 90 days of Depo-Provera use. Femring® (estradiol acetate vaginal ring) is a flexible off-white ring designed for vaginal insertion with measurements that include an outer diameter of 56 mm, cross-sectional diameter of 7.6 mm, and core diameter of 2 mm. Femring® 0.1 mg/day has a central core containing 24.8 mg of estradiol acetate which releases at a rate equivalent to 0.1 mg of estradiol per day for 3 months.<br>* Other names: Estradiol Acetate Vaginal Ring;Drug: DepoProvera ®<br>* Medroxyprogesterone intramuscular injection comes as a suspension (liquid) to be injected into the buttocks or upper arm. It is usually given once every 3 months (13 weeks), and the recommended dose is 150 mg.<br>* Other names: Depot Medroxyprogesterone Acetate (DMPA);|
| Other: Depo-Provera Injection Alone<br>Subjects will receive Depo-Provera intramuscular injection. | Drug: DepoProvera ®<br>* Medroxyprogesterone intramuscular injection comes as a suspension (liquid) to be injected into the buttocks or upper arm. It is usually given once every 3 months (13 weeks), and the recommended dose is 150 mg.<br>* Other names: Depot Medroxyprogesterone Acetate (DMPA);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Number of Bleeding or Spotting Days | Bleeding and spotting were defined using World Health Organization criteria and measured through daily diaries given to participants and collected at the 3 and 6 month followup. In addition, a study staff member called participants weekly to collect the daily bleeding and spotting calendar for that week to optimize the accuracy of this information. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Users Who Were Satisfied With Femring | Acceptability was measured using questionnaires that assessed satisfaction of Femring and usage of the ring. This outcome was only measured among the intervention group of women who actually were randomized to use of Femring. Acceptability of the vaginal ring was high among those in the intervention group. | 3 months | 
| Number of Subjects Who Receive a 2nd Injection of Depo-Provera |  | 3 months | 
| Percentage of Subjects Who Receive a 3rd Injection |  | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Depo-Provera, Medroxyprogesterone Acetate, Metrorrhagia, Irregular Bleeding