A Randomized Controlled Trial of Oral Naproxen and Transdermal Estradiol for Bleeding in LNG-IUC
We hypothesize that the addition of oral naproxen or transdermal estradiol will decrease the number of days of unscheduled bleeding experienced by first-time users of the levonorgestrel intrauterine system (LNG-IUC) during the first 12 weeks of use compared to an oral placebo. The objective of this study is to compare the total number of days of bleeding experienced by first time users of the LNG-IUC randomized to oral naproxen or estradiol patch compared to those randomized to placebo for the first 12 weeks of use. We will enroll women initiating LNG-IUC to one of 3 groups, transdermal estrogen, oral naproxen or oral placebo. We will enroll a total of 114 women, 38 in each group. Women will keep bleeding diaries for 16 weeks which will be used to calculate the total number of bleeding or spotting days. Statistical analysis will be performed to evaluate if there is less bleeding among the treatment arms then the placebo arm.
Drug: transdermal estradiol
Drug: oral placebo
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single Blind (Outcomes Assessor)
Primary Purpose: Prevention
|Official Title:||A Randomized, Controlled Trial of Oral Naproxen and Transdermal Estradiol for Prevention of Unscheduled Bleeding in New Users of Levonorgestrel Intrauterine Contraception|
- Number of Bleeding and Spotting Days [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]The median number of bleeding and spotting days was 27.5 (range 5-83) in the naproxen group, 44 (2-82) in the estradiol group, and 32 (9-84) in the placebo group.
- To Describe and Compare the Bleeding Patterns Observed in Women With a LNG-IUC Treated With Naproxen, Estradiol and Placebo. [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
- To Compare the Level of Patient Satisfaction With the LNG-IUC at the End of the 16 Week and 12 Months Periods Between the 3 Study Groups. [ Time Frame: 16 week ] [ Designated as safety issue: No ]
- To Compare Continuation Rates of the LNG-IUC at the End of the 16 Week and 12 Month Periods Between the 3 Study Groups [ Time Frame: 12 months ] [ Designated as safety issue: No ]
|Study Start Date:||November 2008|
|Study Completion Date:||January 2011|
|Primary Completion Date:||January 2010 (Final data collection date for primary outcome measure)|
Experimental: transdermal estradiol
participants will be randomized to transdermal estradiol
Drug: transdermal estradiol
transdermal estradiol 0.1mg patch to be changed weekly for 12 weeks.
Other Name: Climara
Experimental: oral naproxen
participants will be randomized to oral naproxen
naproxen 500mg by mouth twice daily for the first 5 days of every 4 week period for a total of 12 weeks
Other Name: Naprosyn, Anaprox
|Placebo Comparator: oral placebo||
Drug: oral placebo
oral placebo to be taken by mouth twice daily for the first 5 days of a 4 week block for a total of 5 weeks
The levonorgestrel intrauterine system (LNG-IUC) is one of the most effective, reversible methods of contraception currently available in the United States. User satisfaction is overall high , however the most often cited reason for discontinuation is irregular bleeding . The LNG-IUC has mainly progesteronic effects on the uterine cavity. Morphological changes of the endometrium are observed, including stromal pseudo-decidualization and glandular atrophy . These endometrial changes may contribute to the irregular uterine bleeding experienced by women using the LNG-IUC. Up to 14% of women will discontinue the LNG-IUC within the 5-year period due to abnormal bleeding and up to 66% of woman who request removal of the LNG-IUC will do so in the first 6 months of use . Women may be less likely to discontinue the LNG-IUC due to abnormal bleeding patterns if they are counseled appropriately beforehand, however the prospect of irregular bleeding with few options for management may dissuade some women from even trying the LNG-IUC. A recent Cochrane review identified the need for further investigation into the treatment of irregular uterine bleeding caused by progestin only contraception .
One treatment for progestin-induced irregular bleeding is the administration of nonsteroidal anti-inflammatory agents (NSAIDs). A 1999 study showed a significant decrease in the number of bleeding days in women using the levonorgestrel sub-dermal implant randomized to mefenamic acid 500 mg compared to placebo . A 2004 study found a 50% reduction in bleeding in depot medroxyprogesterone (DPMA) users randomized to mefenamic acid versus placebo . There have been no studies looking specifically at NSAIDs for the prevention or treatment of LNG-IUC related irregular bleeding. Naproxen is an antiprostaglandin that is commonly used in gynecological practice for relief of dysmenorrhea and has been used to treat menorrhagia. It is widely available, inexpensive, well-tolerated and has a low incidence of side effects.
Previous studies have also shown the administration of estrogen alone and estrogen-containing oral contraceptives to users of subdermal levonorgestrel implants (Norplant®) resulted in decreased frequency of irregular uterine bleeding , . A prior randomized, controlled trial found a 0.1mg estradiol patch resulted in the clinical improvement of abnormal bleeding, however this finding was not statistically significant . A randomized, controlled trial of DMPA users found the cyclic administration of 0.1mg estradiol patches did not decreases irregular menstrual bleeding . In this study, the cyclic use of estrogen may have resulted in lower or inconsistent serum estradiol levels. Additionally, the progestational mechanism of action is more similar between levonorgestrel subdermal implants and LNG-IUC than depot medroxyprogesterone. No study has specifically addressed estrogen for treatment of irregular bleeding with the LNG-IUC.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00789802
|United States, Missouri|
|Washington University School fo Medicine|
|Saint Louis, Missouri, United States, 63110|
|Principal Investigator:||Tessa E Madden, MD||Washington University School of Medicine|