Pilot Study of Femring Estrogen Supplementation During Depo-Provera Initiation

Metrorrhagia Clinical Trial

Official title:

Pilot Study of Femring Estrogen Supplementation During Depo-Provera Initiation

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00563576
• Other study ID #: AAAC6363
• Status: Completed
• Phase: N/A
• Start date: September 2007
• Est. completion date: February 2009

Study information

• Verified date: December 2021
• Source: Columbia University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 71
• Est. completion date: February 2009
• Est. primary completion date: February 2009
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Metrorrhagia

Intervention

Drug:
• Femring®
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.
• DepoProvera ®
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.

Locations

Country	Name	City	State
United States	Title X Family Planning Clinic	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
Columbia University

Country where clinical trial is conducted

United States, 

References & Publications (17)

Alvarez-Sanchez F, Brache V, Thevenin F, Cochon L, Faundes A. Hormonal treatment for bleeding irregularities in Norplant implant users. Am J Obstet Gynecol. 1996 Mar;174(3):919-22. — View Citation

Belsey EM, Machin D, d'Arcangues C. The analysis of vaginal bleeding patterns induced by fertility regulating methods. World Health Organization Special Programme of Research, Development and Research Training in Human Reproduction. Contraception. 1986 Sep;34(3):253-60. — View Citation

Dieben TO, Roumen FJ, Apter D. Efficacy, cycle control, and user acceptability of a novel combined contraceptive vaginal ring. Obstet Gynecol. 2002 Sep;100(3):585-93. — View Citation

Goldberg AB, Cardenas LH, Hubbard AE, Darney PD. Post-abortion depot medroxyprogesterone acetate continuation rates: a randomized trial of cyclic estradiol. Contraception. 2002 Oct;66(4):215-20. — View Citation

Harel Z, Biro FM, Kollar LM, Rauh JL. Adolescents' reasons for and experience after discontinuation of the long-acting contraceptives Depo-Provera and Norplant. J Adolesc Health. 1996 Aug;19(2):118-23. — View Citation

Hubacher D, Goco N, Gonzalez B, Taylor D. Factors affecting continuation rates of DMPA. Contraception. 1999 Dec;60(6):345-51. — View Citation

Lim SW, Rieder J, Coupey SM, Bijur PE. Depot medroxyprogesterone acetate use in inner-city, minority adolescents: continuation rates and characteristics of long-term users. Arch Pediatr Adolesc Med. 1999 Oct;153(10):1068-72. — View Citation

Multinational comparative clinical evaluation of two long-acting injectable contraceptive steroids: noresthisterone oenanthate and medroxyprogesterone acetate. 2. Bleeding patterns and side effects. Contraception. 1978 May;17(5):395-406. — View Citation

Novák A, de la Loge C, Abetz L, van der Meulen EA. The combined contraceptive vaginal ring, NuvaRing: an international study of user acceptability. Contraception. 2003 Mar;67(3):187-94. — View Citation

Paul C, Skegg DC, Williams S. Depot medroxyprogesterone acetate. Patterns of use and reasons for discontinuation. Contraception. 1997 Oct;56(4):209-14. — View Citation

Polaneczky M, Liblanc M. Long-term depot medroxyprogesterone acetate (Depo-Provera) use in inner-city adolescents. J Adolesc Health. 1998 Aug;23(2):81-8. — View Citation

Rager KM, Fowler A, Omar HA. Successful treatment of depot medroxyprogesterone acetate-related vaginal bleeding improves continuation rates in adolescents. ScientificWorldJournal. 2006 Mar 19;6:353-5. — View Citation

Rickert VI, Tiezzi L, Lipshutz J, León J, Vaughan RD, Westhoff C. Depo Now: preventing unintended pregnancies among adolescents and young adults. J Adolesc Health. 2007 Jan;40(1):22-8. — View Citation

Said S, Omar K, Koetsawang S, Kiriwat O, Srisatayapan Y, Kazi A, Ajmal F, Wynter HH, Pretnar-Darovec A, Benitez IB. A multicentered phase III comparative clinical trial of depot-medroxyprogesterone acetate given three-monthly at doses of 100 mg or 150 mg: II. The comparison of bleeding patterns. World Health Organization. Task Force on Long-Acting Systemic Agents for Fertility Regulation Special Programme of Research, Development and Research Training in Human Reproduction. Contraception. 1987 Jun;35(6):591-610. — View Citation

Said S, Sadek W, Rocca M, Koetsawang S, Kirwat O, Piya-Anant M, Dusitsin N, Sethavanich S, Affandi B, Hadisaputra W, Kazi A, Ramos RM, d'Arcangues C, Belsey EM, Noonan E, Olayinka I, Pinol A. Clinical evaluation of the therapeutic effectiveness of ethinyl oestradiol and oestrone sulphate on prolonged bleeding in women using depot medroxyprogesterone acetate for contraception. World Health Organization, Special Programme of Research, Development and Research Training in Human Reproduction, Task Force on Long-acting Systemic Agents for Fertility Regulation. Hum Reprod. 1996 Oct;11 Suppl 2:1-13. — View Citation

Sangi-Haghpeykar H, Poindexter AN 3rd, Bateman L, Ditmore JR. Experiences of injectable contraceptive users in an urban setting. Obstet Gynecol. 1996 Aug;88(2):227-33. — View Citation

Speroff L. Efficacy and tolerability of a novel estradiol vaginal ring for relief of menopausal symptoms. Obstet Gynecol. 2003 Oct;102(4):823-34. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Number of Subjects Who Receive a 2nd Injection of Depo-Provera		3 months
Secondary	Percentage of Subjects Who Receive a 3rd Injection		6 months