Treatment of Prolonged Uterine Bleeding of Etonogestrel (ENG)-Releasing Implant

NCT ID: NCT04047875

Last Updated: 2024-09-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 114 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-09-15
• Study Completion Date: 2023-05-05

Brief Summary

Long-acting reversible contraceptives [LARC; copper-intrauterine devices (IUDs), the levonorgestrel-releasing intrauterine system (LNG-IUS) and subdermal implants] are the most effective reversible contraceptives available. A common side effect of these methods is changes in menstrual bleeding. Dissatisfaction with unpredictable bleeding is the main reason for early discontinuation of LARC methods.

The mechanism of unpredictable bleeding is unknown; it is likely related to the progestogen dilating superficial veins and capillaries, which are fragile and susceptible to focal bleeding. Other potential influences include changes in structural support of the endometrium, altered matrix metalloproteinase activity, and changes in endometrial perfusion and hemostasis. Local genetic alterations of the hormonal receptors of endometrium can also play a role in the etiology of the unpredictable bleeding experienced by some women.

Regarding etonogestrel (ENG)-releasing implant, some evidences suggest that the use of mefenamic acid, mifepristone with estradiol or doxycycline, or doxycycline alone can temporally stop the bleeding; however, all these therapies cannot avert the recurrence of the bleeding. Recently, a randomized clinical trial (RCT) evaluated the effectiveness of a short-term use of combined oral contraceptive (COC) in stopping bleeding episodes and preventing bleeding recurrence. The authors found that bothersome bleeding in ENG-implant users stopped within 14-day of COC treatment, but bleeding most often resumes within 10 days of treatment cessation.

Although COC can stop the bleeding, it is not known which component of the COC is responsible for this effect. There is evidence suggesting that estrogen alone is not effective in stopping the bleeding of progestogen-only contraceptives or a high dose of ethinyl estradiol is needed to obtain this effect. Furthermore, the recurrence of the bleeding shown with the COC use could be explained by the interruption of the estrogen. For this reason, our hypothesis is that a progestogen-only pill could be superior to placebo in stopping the bleeding associated with the ENG-implant use as well as being superior to placebo in recurrence of bleeding after discontinuation of the therapy.

Conditions

Breakthrough Bleeding

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Norethisterone 10mg/day

NET-only pill (Norethisterone, Primolut-Nor®), 10 mg/day, 1 pill per day until 2 consecutive days without bleeding/spotting (maximum use of 1 box of Primolut-Nor® per bleeding episode)

Group Type: EXPERIMENTAL

Norethisterone 10mg/day

Intervention Type: DRUG

NET-only pill (Norethisterone, Primolut-Nor®), 10 mg/day, 1 pill per day until 2 consecutive days without bleeding/spotting

Placebo

Identically appearing placebo to Primolut-Nor®, 1 pill per day until 2 consecutive days without bleeding/spotting (maximum use of 1 box of Placebo per bleeding episode)

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Identically appearing placebo to Primolut-Nor®, 1 pill per day until 2 consecutive days without bleeding/spotting

Interventions

Norethisterone 10mg/day

NET-only pill (Norethisterone, Primolut-Nor®), 10 mg/day, 1 pill per day until 2 consecutive days without bleeding/spotting

Intervention Type: DRUG

Placebo

Identically appearing placebo to Primolut-Nor®, 1 pill per day until 2 consecutive days without bleeding/spotting

Intervention Type: DRUG

Other Intervention Names

Primolut-Nor®, 10 mg/day, 1 pill per day

Eligibility Criteria

Inclusion Criteria

• To be an etonogestrel-releasing implant user for at least 40 days with a current bleeding/spotting episode of at least 7 consecutive days;
• Age between 18-40 years old;
• To have a mobile phone.

Exclusion Criteria

• Body mass index (BMI; kg/m2) ≥ 35;
• Pregnancy;
• To have a positive chlamydia test;
• To be unable or unwilling to swallow pills;
• To have a medical condition deemed severe by a physician investigator;
• To be in use of a hepatic enzyme inducing medication;
• To be in use of anticoagulant drug;
• To have findings on speculum examination indicating an anatomic source of bleeding (e.g., polyp, cervicitis);
• To be in the first 6 months of delivery;
• To be on a concurrent hormonal contraceptive, depot medroxyprogesterone acetate (DMPA) interruption ≤ 6 months;
• To be illiterate;
• To be in use of any drug to stop the bleeding associated with etonogestrel implant ≤ 15 days.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 40 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

Organon

INDUSTRY

Sponsor Role: collaborator

University of Sao Paulo

OTHER

Sponsor Role: lead

Responsible Party

Carolina Sales Vieira

Professor, MD, PhD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Carolina S Vieira, PhD, MD

Role: STUDY_CHAIR

Professor

Locations

Unidade de Pesquisa Clínica do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto

Ribeirão Preto, São Paulo, Brazil

UNIFESP

São Paulo, São Paulo, Brazil

Countries

Brazil

Other Identifiers

3.396.056

Identifier Type: -

Identifier Source: org_study_id