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

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.

Study Type: Interventional

Study Design: Prevention, Randomized, Open Label, Parallel Assignment, Efficacy Study

Study Primary Completion Date: March 2009

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 0.1mg/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 50mcg 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, 50mcg 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 100mcg 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.

Intervention(s) in this Clinical Trial

• Drug: Femring
  • Estrogen vaginal ring (100mcg) placed for the first 90 days of Depo-Provera use.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • Subjects will receive an estrogen vaginal ring (100mcg) during the first 90 days of Depo-Provera use.
• No Intervention: 2
  • Subjects will receive Depo-Provera intramuscular injection.

Primary Measures

• Mean Number of Bleeding or Spotting Days
  • Time Frame: 6 months
    Safety Issue?: No

Secondary Measures

• Acceptability of Femring in Users
  • Time Frame: 3 months
    Safety Issue?: No
• Percentage of Subjects who receive a 2nd injection of Depo-Provera
  • Time Frame: 3 months
    Safety Issue?: No
• Percentage of subjects who receive a 3rd injection
  • Time Frame: 6 months
    Safety Issue?: No

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

Gender Eligibility for this Clinical Trial: Female

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Columbia University

Overall Clinical Trial Officials and Contacts

Angela R Dempsey-Fanning, MD Principal Investigator Columbia University Medical Center  

Overall Contact: Angela R Dempsey-Fanning, MD 212-305-4938 ard2117@columbia.edu

Information obtained from ClinicalTrials.gov on October 10, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00563576

Study ID Number: AAAC6363

ClinicalTrials.gov Identifier: NCT00563576

Health Authority: United States: Institutional Review Board