Breakthrough BleedingPhase 4NCT04047875
Treatment of Prolonged Uterine Bleeding of Etonogestrel (ENG)-Releasing Implant
A Phase 4 study testing Norethisterone 10mg/day in people with Breakthrough Bleeding, run by University of Sao Paulo at 2 sites in Brazil.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 40 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Breakthrough Bleeding
- What is being tested?
- Norethisterone 10mg/day
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 114 participants
- Where
- 2 sitesBrazil
- Study dates
- 15 Sep 2020to 5 May 2023
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 40 years
- Women only
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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.
Who cannot join
- 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;
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- 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.
Trial locations and contacts
2 sites in 1 country.
Brazil2 sites
Unidade de Pesquisa Clínica do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto
Ribeirão Preto, São Paulo, 14015-010
UNIFESP
São Paulo, São Paulo, 04023-061
About this study
Official title: Treatment of Prolonged Uterine Bleeding of Etonogestrel (ENG)-Releasing Implant Using Norethisterone (NET)-Only Pill: a Randomized Controlled Trial
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.
Read more
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
- Being tested
- Norethisterone 10mg/day, Placebo
- Keywords
- norethisterone, uterine bleeding, progestogen-only contraceptives, etonogestrel-releasing implant
- Medical subject headings
- Metrorrhagia, Uterine Hemorrhage
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Norethisterone 10mg/dayDrug
Also called Primolut-Nor®, 10 mg/day, 1 pill per day
NET-only pill (Norethisterone, Primolut-Nor®), 10 mg/day, 1 pill per day until 2 consecutive days without bleeding/spotting
PlaceboDrug
Identically appearing placebo to Primolut-Nor®, 1 pill per day until 2 consecutive days without bleeding/spotting
| Study group | Role | What they receive |
|---|---|---|
| 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) Receives: 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) Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 7 days
Secondary outcomes (7)
Number of days of medication use until interruption of uterine bleeding episode
We will analyze the mean (95%CI) number of days of placebo and norethisterone use until interruption of uterine bleeding episode. Participants will report their bleeding and/or spotting through text messages and daily diary. Women will use it until being 2 days without uterine bleeding/spotting or until the end of the box if the bleeding does not stop earlier.
Measured: 30 days
Percentage of women who will stop the prolonged uterine bleeding after 14 days of medication use.
We will measure the percentage of women will stop the uterine bleeding after 14 days of norethisterone or placebo use. Participants will report their bleeding and/or spotting through text messages and daily diary.
Measured: 14 days
The interval (number of days) to the recurrence of uterine bleeding after discontinuation of the first treatment cycle.
Participants will report their bleeding and/or spotting through text messages and daily diary. Women will use the randomized drug until being 2 days without uterine bleeding/spotting or until the end of the box if the bleeding does not stop earlier. We will assess the mean number of days (95%CI) until a new bleeding episode occur.
Measured: 6 months
Bleeding patterns within 6 months after the end of the first treatment cycle
We will summarize the bleeding patterns according to the World Health Organization terminology. Participants will report their bleeding and/or spotting through text messages and daily diary.
Measured: 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)
Women can repeat the same treatment 3 times in the following 6 months of follow-up in case of a new bleeding/spotting episode of at least 7 consecutive days. Participants will report their bleeding and/or spotting through text messages and daily diary. Women will the randomized drug until being 2 days without uterine bleeding/spotting or until the end of the box if the bleeding does not stop earlier. We will assess the percentage of women who will need to repeat the treatment in order to stop new uterine bleeding episodes (none vs. 1-2 times vs. 3 times)
Measured: 6 months
Relation between plasmatic levels of etonogestrel and bleeding patterns at baseline and at 7 days of randomized drug use
We will evaluate the etonogestrel level using Ultra Pressure Liquid Chromatography and will perform a multiple analysis to see if unfavorable bleeding patterns are related with etonogestrel levels.
Measured: 7 days
Treatment failure
Percentage of treatment failure in each study arm. Treatment failure is defined by the maintenance of the bleeding episode after 30 days of continuous drug use.
Measured: 30 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Aug 2019
- Study start15 Sep 2020
- Primary completion5 May 2023
- Study completion5 May 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Breakthrough BleedingStudies of the same condition, open and under way.
- More trials run by University of Sao PauloThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 114 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Sao Paulo
- Sponsor type
- University, hospital or other
- Collaborators
- Organon
- Responsible party
- Principal investigator, Carolina Sales Vieira, University of Sao Paulo
- Investigators
- Carolina S Vieira, PhD, MD, Study chair, Professor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04047875
- Sponsor's protocol ID
- 3.396.056
- Status last verified
- Sep 2024
- First submitted
- 5 Aug 2019
- Last updated
- 23 Sep 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 23 Sep 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Treatment of Prolonged Uterine Bleeding of Etonogestrel (ENG)-Releasing Implant Using Norethisterone (NET)-Only Pill: a Randomized Controlled Trial
- ClinicalTrials.gov ID
- NCT04047875
- Acronym / sponsor ID
- 3.396.056
- Conditions
- Breakthrough Bleeding
- Keywords
- norethisterone, uterine bleeding, progestogen-only contraceptives, etonogestrel-releasing implant
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 114 participants (actual)
- Lead sponsor
- University of Sao PauloUniversity, hospital or other
- Collaborators
- Organon
- Study start
- 15 Sep 2020 (actual)
- Primary completion
- 5 May 2023 (actual)
- Study completion
- 5 May 2023 (actual)
- First posted
- 7 Aug 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Norethisterone 10mg/day | Experimental | Drug: Norethisterone 10mg/dayNET-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) |
| Placebo | Placebo comparator | Drug: PlaceboIdentically 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) |
Who may qualify
- Ages
- 18 to 40 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (3 listed)
- 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.
Key exclusion criteria (12 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Norethisterone 10mg/dayAlso: Primolut-Nor®, 10 mg/day, 1 pill per dayNET-only pill (Norethisterone, Primolut-Nor®), 10 mg/day, 1 pill per day until 2 consecutive days without bleeding/spotting | Drug | Norethisterone 10mg/day |
| PlaceboIdentically appearing placebo to Primolut-Nor®, 1 pill per day until 2 consecutive days without bleeding/spotting | Drug | Placebo |
Primary outcome
Percentage of women who will stop the prolonged uterine bleeding after 7 days of medication use.
Time frame: 7 days
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 secondary outcomes
Number of days of medication use until interruption of uterine bleeding episode
Time frame: 30 days
Percentage of women who will stop the prolonged uterine bleeding after 14 days of medication use.
Time frame: 14 days
The interval (number of days) to the recurrence of uterine bleeding after discontinuation of the first treatment cycle.
Time frame: 6 months
Bleeding patterns within 6 months after the end of the first treatment cycle
Time frame: 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)
Time frame: 6 months
Relation between plasmatic levels of etonogestrel and bleeding patterns at baseline and at 7 days of randomized drug use
Time frame: 7 days
Treatment failure
Time frame: 30 days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Sep 2024.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Carolina S Vieira, PhD, MD study chair
Professor
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Norethisterone 10mg/day in people with Breakthrough Bleeding, run by University of Sao Paulo at 2 sites in Brazil.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 23 Sep 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Brazil. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage of women who will stop the prolonged uterine bleeding after 7 days of medication use. (time frame: 7 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Sep 2024.