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

NCT04047875 | Completed Phase 4

• 1 other identifier: 3.396.056
• Study Type: interventional
• Target: 114
• Locations: 1 country
• Sites: 2

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

Keywords

norethisterone; uterine bleeding; progestogen-only contraceptives; etonogestrel-releasing implant

Outcome Measures

Primary Outcomes (1)

• Percentage of women who will stop the prolonged uterine bleeding after 7 days of medication use.

  We will measure the percentage of women will stop the uterine bleeding after 7 days of norethisterone or placebo use. Participants will report their bleeding and/or spotting through text messages and daily diary.

  7 days

Secondary Outcomes (7)

• Number of days of medication use until interruption of uterine bleeding episode

  30 days

• Percentage of women who will stop the prolonged uterine bleeding after 14 days of medication use.

  14 days

• The interval (number of days) to the recurrence of uterine bleeding after discontinuation of the first treatment cycle.

  6 months

• Bleeding patterns within 6 months after the end of the first treatment cycle

  6 months

• Percentage of women who will need to repeat the treatment in order to stop the uterine bleeding (none vs. 1-2 times vs. 3 times)

  6 months

Study Arms (2)

Norethisterone 10mg/day

EXPERIMENTAL

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)

Drug: Norethisterone 10mg/day

Placebo

PLACEBO COMPARATOR

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)

Drug: Placebo

Interventions

Norethisterone 10mg/day DRUG

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

Also known as: Primolut-Nor®, 10 mg/day, 1 pill per day

Norethisterone 10mg/day

Placebo DRUG

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

Placebo

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Sao Paulo: lead
• Organon: collaborator

Study Sites (2)

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

Ribeirão Preto, São Paulo, 14015-010, Brazil

Location

UNIFESP

São Paulo, São Paulo, 04023-061, Brazil

Location

MeSH Terms

Conditions

Metrorrhagia; Uterine Hemorrhage

Interventions

Norethindrone

Condition Hierarchy (Ancestors)

Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Hemorrhage; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Norpregnenes; Norpregnanes; Norsteroids; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• Carolina S Vieira, PhD, MD

  Professor

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor, MD, PhD

Study Record Dates

• First Submitted: August 5, 2019
• First Posted: August 7, 2019
• Study Start: September 15, 2020
• Primary Completion: May 5, 2023
• Study Completion: May 5, 2023
• Last Updated: September 23, 2024

Record last verified: 2024-09

Locations

BR (2)