Intervention to End Recurrent Unscheduled Bleeding Trial
Condition: Contraception; Bleeding
MeSH terms: Hemorrhage
Study type: Interventional
Phase: Phase 3

Summary: 
      The subdermal etonogestrel (ENG) implant, a long-acting reversible contraceptive (LARC)
      method, is among the most effective forms of reversible contraception and thus, an important
      tool in the quest to reduce unintended pregnancy. However, despite overall increases in LARC
      use in the United States from 1.5% in 2002 to 7.2% in 2011, and 11.6% most recently in 2015,
      implant use continues to make up a small proportion of LARC use. While evidence to explain
      this low uptake of implants is lacking, one potential reason is patient and provider concerns
      about unpredictable bleeding.

      As a result of this, many studies have been performed in attempts to discover therapies for
      unscheduled bleeding in progestin-only contraceptive users. Some of these studies include
      those investigating selective progesterone receptor modulators, such as mifepristone and
      ulipristal acetate (UPA), which did find some benefit. Although a previous study showed mixed
      benefit, the investigators feel that this medication has demonstrated both biologic
      plausibility as well as clinically important outcomes. This previous study may not be
      entirely translatable to the proposed research as therapies were used for different
      indications (prophylaxis vs. treatment) and different progestins and delivery systems were
      studied. Therefore, the investigators believe UPA should not be discounted as a potential
      therapy. UPA may provide an additional safe and effective option for treatment of irregular
      bleeding with implants in women. In addition, UPA is currently available in outpatient
      pharmacies in the U.S. as a single 30mg oral tablet.

      The investigators propose to investigate UPA for the treatment of unscheduled and troublesome
      bleeding in ENG implant users.
    

Detailed description: 
      The subdermal etonogestrel (ENG) implant, a long-acting reversible contraceptive (LARC)
      method, is among the most effective forms of reversible contraception and thus, an important
      tool in the quest to reduce unintended pregnancy. Despite this, ENG implant users make up a
      small percent of overall women that use LARC in the United States. Previous studies have
      demonstrated that among women dissatisfied with their implant, the majority cite
      unpredictable and irregular bleeding as a primary reason. Dissatisfaction with a
      contraceptive method can lead to discontinuation, which can put a woman at risk for unplanned
      pregnancy. Although irregular bleeding is a common side effect of all progestin-only
      contraceptives, there are significant gaps in our knowledge regarding the etiology of and
      effective therapies for unscheduled bleeding. While several mechanisms have been proposed and
      therapies have been studied, lack of convincing scientific evidence, in addition to possible
      contraindications to these therapies, demonstrates the need to investigate additional
      effective interventions.

      Studies evaluating interventions for abnormal uterine bleeding resulting from uterine
      leiomyoma provide insight into potential therapies for progestin-mediated bleeding. In prior
      studies, ulipristal acetate (UPA) has been shown to reduce bleeding symptoms associated with
      uterine leiomyoma, including decreasing or stopping excessive bleeding. Progestin-associated
      irregular bleeding has been proposed to be secondary to a disruption in endometrial
      angiogenesis, therefore creating a fragile venous network. UPA may displace local progestin
      to counteract this effect. Thus, this medication has demonstrated both biologic plausibility
      as well as clinically important benefits. UPA may provide an additional safe and effective
      option for treatment of irregular bleeding in implant users. As women are often dissatisfied
      with irregular bleeding with the implant as noted above, improving bleeding profiles could
      potentially improve uptake and continuation of the device.

      The investigators will perform a double blinded, randomized, placebo-controlled trial. Women
      will be randomized to receive either 15mg of UPA daily for 7 days or placebo for the same
      duration. The investigators hypothesize that UPA will decrease bleeding and spotting days in
      users of the ENG implant with unscheduled bleeding when compared to placebo as assessed by
      daily bleeding diaries.
    

Intervention name(s): Ulipristal Acetate; Placebo oral capsule
Intervention type(s): Drug; Drug
Intervention description(s): Women who have bothersome bleeding with the etonogestrel implant will be randomized to receive ulipristal acetate versus placebo daily for 7 days.; Women who have bothersome bleeding with the etonogestrel implant will be randomized to receive ulipristal acetate versus placebo daily for 7 days.
Intervention MeSH terms: Ulipristal acetate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Etonogestrel Implant