Intervention to End Recurrent Unscheduled Bleeding Trial (INTERRUPT)

• ClinicalTrials.gov Identifier: NCT03118297
• Recruitment Status: Completed
• First Posted: April 18, 2017
• Results First Posted: August 31, 2018
• Last Update Posted: August 31, 2018
• Sponsor: Washington University School of Medicine
• Information provided by (Responsible Party): Rachel Zigler, MD MSCI, Washington University School of Medicine

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Contraception; Bleeding	Drug: Ulipristal Acetate; Drug: Placebo oral capsule	Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 65 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Intervention to End Recurrent Unscheduled Bleeding Trial: A Randomized-controlled Trial of Ulipristal Acetate for Unscheduled Bleeding in Etonogestrel Implant Users
• Actual Study Start Date: May 1, 2017
• Actual Primary Completion Date: January 31, 2018
• Actual Study Completion Date: January 31, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Ulipristal Acetate; 15mg ulipristal acetate (capsule) daily for 7 days	Drug: Ulipristal Acetate; Women who have bothersome bleeding with the etonogestrel implant will be randomized to receive ulipristal acetate versus placebo daily for 7 days.
Placebo Comparator: Placebo; Identical placebo (capsule) daily for 7 days	Drug: Placebo oral capsule; Women who have bothersome bleeding with the etonogestrel implant will be randomized to receive ulipristal acetate versus placebo daily for 7 days.

Outcome Measures

Primary Outcome Measures :

1. Number of Bleeding/Spotting Days With Use of Ulipristal Acetate as Measured by Daily Bleeding Diaries [ Time Frame: 30 days ]
   To evaluate the effectiveness of ulipristal acetate (15mg) in decreasing bleeding/spotting days due to the ENG implant over a 30-day period as compared to placebo.

Secondary Outcome Measures :

1. Number of Participants With Bleeding Cessation by Day 10 [ Time Frame: 10 days ]
   To evaluate bleeding cessation rates by day 10 following seven days of treatment with either ulipristal acetate or placebo.
2. Participant Satisfaction With Bleeding Pattern at 30 Days [ Time Frame: 30 days ]
   To evaluate participant satisfaction with regards to bleeding pattern after use of ulipristal acetate.
3. Number of Participants With Medication Side Effects by 30 Days [ Time Frame: 30 days ]
   To evaluate participant satisfaction with regards to medication side effects.
4. Ovulation Status Measured by Weekly Serum Progesterone Levels [ Time Frame: Baseline, weeks 1, 2, 3, 4 ]
   To evaluate effect, if any, of ulipristal acetate on ovulation status. Data in the table represent the lowest and highest values that were recorded over all of the measurements for each arm as a whole.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Women age 18-45
• Implant placed >90 days and <3 years prior to enrollment
• Patient complaint of bothersome irregular bleeding with implant
• Willing to be abstinent or use condoms during study period
• Willing to complete 30-day bleeding diary
• Willing to be randomized to placebo or ulipristal acetate
• Ability to send/receive SMS text message

Exclusion Criteria:

• Non-English speaking
• Implant placed >3 years prior to enrollment
• Contraindication to ulipristal acetate (current use of barbiturates, bosentan, carbamazepine, felbamate, griseofulvin, oxcarbazepine, phenytoin, rifampin, St. John's Wort, topiramate, known or suspected pregnancy, hypersensitivity to active substance or excipients, uterine/cervical/ovarian/breast cancer, severe asthma insufficiently controlled by oral glucocorticoids)
• Inability or unwillingness to comply with medication protocol
• Inability or unwillingness to comply with bleeding diary
• Breastfeeding

Contacts and Locations

Locations

United States, Missouri

Washington University School of Medicine in St. Louis

Saint Louis, Missouri, United States, 63110

Sponsors and Collaborators

Washington University School of Medicine

Investigators

• Principal Investigator: Rachel Zigler, MD; Washington University School of Medicine

  Study Documents (Full-Text)

Documents provided by Rachel Zigler, MD MSCI, Washington University School of Medicine:

Study Protocol and Statistical Analysis Plan  [PDF] February 9, 2018

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Zigler RE, Madden T, Ashby C, Wan L, McNicholas C. Ulipristal Acetate for Unscheduled Bleeding in Etonogestrel Implant Users: A Randomized Controlled Trial. Obstet Gynecol. 2018 Oct;132(4):888-894. doi: 10.1097/AOG.0000000000002810.

• Responsible Party: Rachel Zigler, MD MSCI, Clinical Fellow, Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT03118297
• Other Study ID Numbers: 201612002
• First Posted: April 18, 2017
• Results First Posted: August 31, 2018
• Last Update Posted: August 31, 2018
• Last Verified: August 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Rachel Zigler, MD MSCI, Washington University School of Medicine:

Etonogestrel Implant

Additional relevant MeSH terms:

Hemorrhage; Pathologic Processes; Ulipristal acetate; Contraceptive Agents, Female; Contraceptive Agents; Reproductive Control Agents; Physiological Effects of Drugs