Bleeding, Breakthrough Bleeding, Implants
Conditions
Keywords
Unscheduled bleeding, Long acting contraception
Brief summary
The etonogestrel (ENG) subdermal contraceptive implant (ENG implant) is a highly effective method of preventing pregnancy, but it has bleeding side effects that make it unappealing for many women. The only study to demonstrate a sustained reduction in bleeding lasting for two months was the selective estrogen receptor modulator (SERM) tamoxifen in users of the levonogestrel (LNG) contraceptive implant. Based on the investigators encouraging preliminary data of tamoxifen and ENG implant users, the investigators plan to perform additional studies on the impact of tamoxifen on the breakthrough bleeding experience by ENG implant users.
Detailed description
The investigators will perform a 2 phase trial for treatment of women experiencing frequent or prolonged bleeding while using the ENG contraceptive implant. The first phase will consist of a randomized, controlled, double blind placebo-controlled clinical trial over a 90-day reference period and the second phase will allow both study arms to receive open-label treatment over an additional 90-day reference period. The primary outcome of the study will be the total number of consecutive bleeding-free days in first 30 days from Day 1 of first treatment (TX1).
Interventions
DRUGTamoxifen
Tamoxifen 10 mg orally twice daily for 7 days. Treatment to be started after 3 consecutive days of bleeding and can be repeated every 30 days two more times in the first 90 days of the study
DRUGPlacebo
Placebo orally twice daily for 7 days. Treatment to be started after 3 consecutive days of bleeding and can be repeated every 30 days two more times in the first 90 days of the study
DRUGTamoxifen (open label)
Tamoxifen 10 mg orally twice daily for 7 days. Treatment to be started after 3 consecutive days of bleeding and can be repeated every 30 days two more times in the second 90 days of the study
Sponsors
Merck Sharp & Dohme LLC
Oregon Health and Science University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
15 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* English or Spanish speaking * women aged 15-45 years of age * Currently using the ENG-implant for at least 1 month and use proven on exam (palpation of implant at screening visit) * Willing to continue using the implant for at least 6 months * \>7 days of continuous bleeding/spotting, or 2 or more episodes of bleeding/spotting in the last 30 days. * Cellphone that is able to receive and respond to a daily text or email message .
Exclusion criteria
* Postpartum within six months * post-abortion within six weeks * currently pregnant * currently breast-feeding * undiagnosed abnormal uterine bleeding pre-dating placement of contraceptive implant * bleeding dyscrasia * anticoagulation use * active cervicitis * allergy to tamoxifen * history of venous thromboembolism * current or past breast or uterine malignancy * use of medication contraindicated with tamoxifen (coumadin, letrozole, bromocriptine, rifampicin, aminoglutethimide, phenobarbital).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Number of Consecutive Bleeding-free Days in First 30 Days From Day 1 of First Treatment (TX1) | Day 1 to Day 30 | Bleeding free days in the first 30 days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Number of Bleeding Free Days Over the First 90 Day Reference Period From Day 1 of Treatment 1. | Day 1 to Day 90 | bleeding free days in the first 90 days |
Other
| Measure | Time frame | Description |
|---|---|---|
| Total Number of Bleeding Free Days Over the Second 90 Day Reference Period From Day 1 of Treatment Number 4 to Day 90 | Day 1 of treatment number 4 to Day 90 (second 90 day reference period) | bleeding free days in the second 90 days |
| Patient Satisfaction With Bleeding Pattern | Day 1 of treatment 1 to day 180 | Patient satisfaction with bleeding pattern. Assessed by visual analog scale to determine satisfaction with bleeding patterns on a scale of 0-100 mm, where 0 mm represents not satisfied at all and 100 mm is totally satisfied. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tamoxifen Tamoxifen 10 mg (oral) twice daily for 7 days to be started following 3 consecutive days of bleeding
Tamoxifen: Tamoxifen 10 mg orally twice daily for 7 days. Treatment to be started after 3 consecutive days of bleeding and can be repeated every 30 days two more times in the first 90 days of the study
Tamoxifen (open label): Tamoxifen 10 mg orally twice daily for 7 days. Treatment to be started after 3 consecutive days of bleeding and can be repeated every 30 days two more times in the second 90 days of the study | 55 |
| Placebo Placebo (oral) twice daily for 7 days to be started following 3 consecutive days of bleeding
Placebo: Placebo orally twice daily for 7 days. Treatment to be started after 3 consecutive days of bleeding and can be repeated every 30 days two more times in the first 90 days of the study | 52 |
| Total | 107 |
Baseline characteristics
| Characteristic | Total | Placebo | Tamoxifen |
|---|---|---|---|
| Age, Continuous | 23.9 Years STANDARD_DEVIATION 4.8 | 23.4 Years STANDARD_DEVIATION 4.5 | 24.5 Years STANDARD_DEVIATION 5.1 |
| Days of implant use at study entry | 418.6 Days STANDARD_DEVIATION 274.2 | 469.1 Days STANDARD_DEVIATION 274.5 | 370.8 Days STANDARD_DEVIATION 267.7 |
| Education College (any or more) | 90 Participants | 45 Participants | 45 Participants |
| Education High school or less | 17 Participants | 7 Participants | 10 Participants |
| Marital Status Partnered or Married | 76 Participants | 34 Participants | 42 Participants |
| Marital Status Single or divorced | 31 Participants | 18 Participants | 13 Participants |
| Race/Ethnicity, Customized Asian | 11 Participants | 4 Participants | 7 Participants |
| Race/Ethnicity, Customized Black | 3 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Hispanic | 18 Participants | 10 Participants | 8 Participants |
| Race/Ethnicity, Customized More than one | 11 Participants | 4 Participants | 7 Participants |
| Race/Ethnicity, Customized Other or unspecified | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 62 Participants | 32 Participants | 30 Participants |
| Sex: Female, Male Female | 107 Participants | 52 Participants | 55 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 55 | 0 / 52 |
| other Total, other adverse events | 45 / 55 | 12 / 52 |
| serious Total, serious adverse events | 0 / 55 | 0 / 52 |
Outcome results
Primary
Total Number of Consecutive Bleeding-free Days in First 30 Days From Day 1 of First Treatment (TX1)
Bleeding free days in the first 30 days
Time frame: Day 1 to Day 30
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tamoxifen | Total Number of Consecutive Bleeding-free Days in First 30 Days From Day 1 of First Treatment (TX1) | 18.5 days | Standard Deviation 17 |
| Placebo | Total Number of Consecutive Bleeding-free Days in First 30 Days From Day 1 of First Treatment (TX1) | 8.7 days | Standard Deviation 8.4 |
Secondary
Total Number of Bleeding Free Days Over the First 90 Day Reference Period From Day 1 of Treatment 1.
bleeding free days in the first 90 days
Time frame: Day 1 to Day 90
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tamoxifen | Total Number of Bleeding Free Days Over the First 90 Day Reference Period From Day 1 of Treatment 1. | 60 days |
| Placebo | Total Number of Bleeding Free Days Over the First 90 Day Reference Period From Day 1 of Treatment 1. | 52 days |
Other Pre-specified
Patient Satisfaction With Bleeding Pattern
Patient satisfaction with bleeding pattern. Assessed by visual analog scale to determine satisfaction with bleeding patterns on a scale of 0-100 mm, where 0 mm represents not satisfied at all and 100 mm is totally satisfied.
Time frame: Day 1 of treatment 1 to day 180
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tamoxifen | Patient Satisfaction With Bleeding Pattern | 67.5 mm |
| Placebo | Patient Satisfaction With Bleeding Pattern | 54.25 mm |
Other Pre-specified
Total Number of Bleeding Free Days Over the Second 90 Day Reference Period From Day 1 of Treatment Number 4 to Day 90
bleeding free days in the second 90 days
Time frame: Day 1 of treatment number 4 to Day 90 (second 90 day reference period)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tamoxifen | Total Number of Bleeding Free Days Over the Second 90 Day Reference Period From Day 1 of Treatment Number 4 to Day 90 | 56 days |
| Placebo | Total Number of Bleeding Free Days Over the Second 90 Day Reference Period From Day 1 of Treatment Number 4 to Day 90 | 67.5 days |