Clinical trial NCT04047875: Treatment of Prolonged Uterine Bleeding of Etonogestrel (ENG)-Releasing Implant
Official title: Treatment of Prolonged Uterine Bleeding of Etonogestrel (ENG)-Releasing Implant Using Norethisterone (NET)-Only Pill: a Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Breakthrough Bleeding
Keywords: norethisterone
uterine bleeding
progestogen-only contraceptives
etonogestrel-releasing implant
Lead sponsor: University of Sao Paulo
Sponsor class: OTHER
Collaborators: name: Organon
First posted: 2019-08-07
Enrollment: 114
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Percentage of women who will stop the prolonged uterine bleeding after 7 days of medication use.
timeFrame: 7 days
Secondary outcomes:
measure: Number of days of medication use until interruption of uterine bleeding episode
timeFrame: 30 days
measure: Percentage of women who will stop the prolonged uterine bleeding after 14 days of medication use.
timeFrame: 14 days
measure: The interval (number of days) to the recurrence of uterine bleeding after discontinuation of the first treatment cycle.
timeFrame: 6 months
measure: Bleeding patterns within 6 months after the end of the first treatment cycle
timeFrame: 6 months
measure: 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)
timeFrame: 6 months
measure: Relation between plasmatic levels of etonogestrel and bleeding patterns at baseline and at 7 days of randomized drug use
timeFrame: 7 days
measure: Treatment failure
timeFrame: 30 days
Other outcomes:
Locations:
city: Ribeirão Preto
country: Brazil
facility: Unidade de Pesquisa Clínica do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto
state: SP
city: São Paulo
country: Brazil
facility: UNIFESP
state: SP
Study officials:
affiliation: Professor
name: Carolina S Vieira, PhD, MD
role: STUDY_CHAIR
References: