A Randomized Controlled Trial of Oral Naproxen and Transdermal Estradiol for Bleeding in LNG-IUC

A Randomized, Controlled Trial of Oral Naproxen and Transdermal Estradiol for Prevention of Unscheduled Bleeding in New Users of Levonorgestrel Intrauterine Contraception

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.

Study Overview

• Status: Completed
• Conditions: Bleeding; Contraception
• Intervention / Treatment: Drug: transdermal estradiol; Drug: naproxen; Drug: oral placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 129
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School fo Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Must be of reproductive age from 18 to 45 years
• Must be choosing LNG-IUC for contraception
• Must be English-speaking
• Be willing to avoid additional use of exogenous hormones, such as oral contraceptives, for the duration of the study
• Be willing to avoid additional use of nonsteroidal antiinflammatory drugs, such as ibuprofen or aspirin for the duration of the study
• Be willing to comply with the study protocol, keep the bleeding diary and comply with follow-up visits and telephone interviews as scheduled
• Be willing and able to provide informed consent

Exclusion Criteria:

• Known or suspected pregnancy

• Contraindication to estrogen use, such as presence or history of:

  • venous thromboembolism
  • Arterial thrombosis
  • Thrombophilia disorders, or known family history of
  • Hypertension
  • Migraine headaches with aura or focal neurologic involvement, or any migraine over age 35 years
• Recent or planned future major surgery which will result in prolonged immobilization during the study period
• Presence or history of severe hepatic disease or liver tumors
• Known or suspected estrogen-dependent neoplasm
• Vaginal bleeding of unknown etiology
• Any cigarette smoking and age over 35 years

• Contraindications to nonsteroidal anti-inflammatory use, such as presence or history of:

  • Gastrointestinal ulcer disease
  • Renal insufficiency or failure
  • Aspirin-induced asthma or hypersensitivity reaction
  • Systemic lupus erythematosus (SLE) and mixed connective tissue disorders
  • Use of anticoagulants
  • Cardiovascular disease
• Use of medications that alter estrogen metabolism, i.e. rifampin, certain anti-seizure medications
• Regular use of an NSAID
• Current diagnosis of menorrhagia, metrorrhagia, symptomatic uterine fibroids, or endometrial polyp
• Hypersensitivity or allergy to any of the components of the estradiol patch
• Use of injectable contraception within 6 months of the start of the study medication
• Delivery or abortion in the previous 4 weeks
• Prior use of LNG-IUD
• Any condition, that in the opinion of the investigator, would contraindicate study participation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 Names: Climara
Experimental: oral naproxen; participants will be randomized to oral naproxen	Drug: naproxen; naproxen 500mg by mouth twice daily for the first 5 days of every 4 week period for a total of 12 weeks; Other Names: Naprosyn, Anaprox
Placebo Comparator: oral placebo; participants will be randomized to 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Bleeding and Spotting Days	The median number of bleeding and spotting days reported at 12 weeks.	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Bleeding Days Observed in Women With a LNG-IUC Treated With Naproxen, Estradiol and Placebo.	Median number of bleeding days observed in women with a LNG-IUC treated with naproxen, estradiol and placebo at 16 weeks.	16 weeks
Patient Satisfaction With the LNG-IUC at the End of the 12 Weeks Between the 3 Study Groups.	To compare the level of patient satisfaction with the LNG-IUC at the end of the 12 weeks between the 3 study groups.	12 weeks
Continuation Rates of the LNG-IUC at the End of the 12 Week Between the 3 Study Groups	To compare continuation rates of the LNG-IUC at the end of the 12 week between the 3 study groups	12 weeks

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: American College of Obstetricians and Gynecologists
• Investigators: Principal Investigator: Tessa E Madden, MD, Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start: November 1, 2008
• Primary Completion (Actual): January 1, 2010
• Study Completion (Actual): January 1, 2011

Study Registration Dates

• First Submitted: November 11, 2008
• First Submitted That Met QC Criteria: November 12, 2008
• First Posted (Estimate): November 13, 2008

Study Record Updates

• Last Update Posted (Actual): March 20, 2018
• Last Update Submitted That Met QC Criteria: March 19, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: placebo; contraception; progestin contraception; intrauterine contraception; unscheduled bleeding
• Additional Relevant MeSH Terms: Pathologic Processes; Hemorrhage; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Estrogens; Gout Suppressants; Estradiol; Naproxen
• Other Study ID Numbers: 07-1026