Contraceptives, Oral
Conditions
Keywords
birth control, continuous contraception, break-through bleeding
Brief summary
The purpose of this study is to learn if the study drug, doxycycline, can decrease the amount of unplanned vaginal bleeding that women commonly experience when taking combined oral contraception (COC)- pills with estrogen and progestin - in a continuous fashion - no hormone-free week. The study drug, doxycycline, is an antibiotic used commonly for many conditions (i.e. acne, Chlamydia infections, pneumonia) and can be safely used on a daily basis. Doxycycline has been shown to decrease unplanned vaginal bleeding in progestin-only contraception but has not been studied in combined hormonal contraception.
Detailed description
We intend to conduct a prospective, randomized, placebo controlled, double blind study at Oregon Health and Science University. This study will be conducted over four 28-day cycles (112 days of active COC hormone). All women enrolled in the study will take the same daily low dose COC. This protocol will be divided into two studies, a bleeding study and an endometrial biopsy study, each with two treatment arms; typical dose doxycycline (Arm 1), and controlled release subantimicrobial dose doxycycline (CRSD)(Arm 2). The first arm (Arm 1) of this study will constitute the typical dose doxycycline arm. In this arm, there will be two study groups. Group 1, the treatment group, will take doxycycline 100 mg orally twice a day for five days starting on the first day of bleeding if breakthrough bleeding occurs. The control group will take a placebo orally twice a day for five days starting on the first day of bleeding if breakthrough bleeding occurs. After three months, both groups will stop doxycycline (or placebo) and will continue on a COC alone for the remaining 28 days of the study. The second arm (Arm 2) of the study will constitute the controlled release subantimicrobial dose doxycycline (CRSD doxycycline)arm. Subjects in this arm of the study will be divided into Group 3 and Group 4. Group 3 will take CRSD doxycycline (40mg) daily for three months. Group 4 will take a daily placebo. Similarly to the first arm of the trial, after three months, both groups will stop doxycycline (or placebo) and will continue in a COC alone for the remaining 28 days of the study. This study also includes a endometrial biopsy sub-study: At the time of recruitment we will identify participants who are willing to undergo endometrial biopsy during the study period. These subjects will constitute a separate cohort who will enroll in the prospective, randomized, double blind, placebo controlled endometrial biopsy study.
Interventions
DRUGLybrel
All women enrolled in the study will take the same daily low dose oral contraceptive (20-mcg EE/90 mcg LNG) dosed in a continuous fashion.
DRUGDoxycycline
100 mg orally twice a day for five days starting on the first day of breakthrough bleeding. This regimen will be repeated if bleeding persists or recurs seven days after completing five-day course of doxycycline.
DRUGOracea
40-mg tablet daily for 84 days
DRUGPlacebo
Placebo pill orally twice a day for five days starting on the first day of breakthrough bleeding. This regimen will be repeated if bleeding persists or recurs seven days after completing five-day course of placebo
DRUGDoxycycline 100bid x5 days at the time of bleeding
Doxycycline 100 mg orally twice a day for five days starting on the first day of breakthrough bleeding. This regimen will be repeated if bleeding persists or recurs seven days after completing five-day course of doxycycline
DRUGSubantimicrobial doxycycline daily
Subantimicrobial dose doxycycline 40mg daily for the first 84 days of the study
DRUGplacebo daily
Placebo daily for the first 84 days of the study
Sponsors
Oregon Health and Science University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* General good health * Willing and able to agree to randomization and sign informed consent * Currently having regular menstrual cycles (24-36 days), with combined cyclic hormonal method (COCs, Nuva Ring, Ortho Evra), without intermenstrual bleeding in last 2 years.
Exclusion criteria
* Intrauterine device (IUD) in place * Abnormal pap smear that has not been treated or followed up * Those with hypersensitivity reactions to doxycycline or any of the tetracyclines * Use of depomedroxyprogesterone acetate within 9 months of the start of the study. * Use of hormonal medications (excluding cyclic contraceptives and plan B) within 2 months of the start of the study. * Any one unwilling to keep a daily menstrual diary or otherwise unwilling to follow the study criteria * Currently taking medications that interfere with COCs (rifampin, carbamazepine, St. Johns wort) * Currently has a progestin implant * Positive Gonorrhea or Chlamydia cultures at enrollment examination * Smoking more than 5 cigarettes per month * Any medical condition that is a contraindication to the use of COCs in accordance with product labeling including: * History of thrombophlebitis, deep venous thrombosis, thrombogenic vasculopathies, thrombogenic rhythm disorders or thromboembolic disorders * Current or past history of cerebrovascular or coronary artery disease * Scheduled major surgery in the next six months with prolonged immobilization * Diabetes with vascular involvement * Headache with focal neurologic symptoms * Uncontrolled hypertension * Suspected or known carcinoma of the breast or personal history of breast cancer * Carcinoma of the endometrium or other known or suspected estrogen dependent neoplasms * Undiagnosed genital bleeding * History of cholestatic jaundice of pregnancy or cholestatic jaundice with prior oral contraceptive use * Hepatic adenoma or carcinoma or active liver disease if liver function has not returned to normal * Known or suspected pregnancy * Hypersensitivity to estrogen or progesterone containing products
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Differences in Bleeding Patterns Between Study Groups. | The outcome was also assessed for day 1 to 84 | number of days of bleeding and spotting, self reported on calendar |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Subject Satisfaction. | Assessed on day 112 of the study (the end of the study period). This outcome does not represent a change from baseline. It was assessed at the end of the study period. | measured using 100 mm visual analog scale. anchors of not at all satisfied (0mm) extremely satisfied (100mm) |
| Subject Compliance | Assessed on day 112 of the study (the end of the study period). The outcome reflects the number of subjects who did not miss pills during the entire 112 day study. It does not represent a change from baseline. | measured by self report of pill intake on daily diary (yes/no), and reported as percentage with no missed pills over entire study |
Countries
United States
Participant flow
Recruitment details
Recruitment at Oregon Health and Science University (OHSU) and University of Hawaii (UH
Participants by arm
| Arm | Count |
|---|---|
| Placebo (Treatment) Placebo (for treatment portion of the study) | 33 |
| Doxy (7 Day Treatment Arm) Doxycycline 100 mg po bid x 7 days taken when bleeding occurred | 33 |
| Placebo (Prevention) Placebo for prevention portion of the study | 33 |
| Subantibmicrobial Dose Doxy Doxycycline 40mg (sustained release) once daily for 84 days | 32 |
| Total | 131 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Protocol Violation | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 4 | 3 | 1 |
Baseline characteristics
| Characteristic | Doxy (7 Day Treatment Arm) | Placebo (Prevention) | Placebo (Treatment) | Subantibmicrobial Dose Doxy | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 33 Participants | 33 Participants | 33 Participants | 31 Participants | 130 Participants |
| Age, Continuous | 27.5 years STANDARD_DEVIATION 6.8 | 27.8 years STANDARD_DEVIATION 5.4 | 28.0 years STANDARD_DEVIATION 6.6 | 28.6 years STANDARD_DEVIATION 6.1 | 28.0 years STANDARD_DEVIATION 7 |
| Region of Enrollment United States | 33 participants | 33 participants | 33 participants | 32 participants | 131 participants |
| Sex: Female, Male Female | 33 Participants | 33 Participants | 33 Participants | 32 Participants | 131 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 33 | 0 / 33 | 0 / 32 | 0 / 32 |
| serious Total, serious adverse events | 0 / 33 | 0 / 33 | 0 / 32 | 0 / 32 |
Outcome results
Primary
Differences in Bleeding Patterns Between Study Groups.
number of days of bleeding and spotting, self reported on calendar
Time frame: The outcome was also assessed for day 1 to 84
Population: All participants analyzed in the groups to which they were randomized except for 1 subject in prevention placebo group who was erroneously enrolled although she did not meet enrollment entry criteria
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Treatment) | Differences in Bleeding Patterns Between Study Groups. | 26.72 days | Standard Error 4.89 |
| Doxy (7 Day Treatment Arm) | Differences in Bleeding Patterns Between Study Groups. | 31.86 days | Standard Error 5.08 |
| Placebo (Prevention) | Differences in Bleeding Patterns Between Study Groups. | 25.69 days | Standard Error 3.24 |
| Subantibmicrobial Dose Doxy | Differences in Bleeding Patterns Between Study Groups. | 18.84 days | Standard Error 3.3 |
Secondary
Subject Compliance
measured by self report of pill intake on daily diary (yes/no), and reported as percentage with no missed pills over entire study
Time frame: Assessed on day 112 of the study (the end of the study period). The outcome reflects the number of subjects who did not miss pills during the entire 112 day study. It does not represent a change from baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (Treatment) | Subject Compliance | 25 number of participants with no missed pi |
| Doxy (7 Day Treatment Arm) | Subject Compliance | 21 number of participants with no missed pi |
| Placebo (Prevention) | Subject Compliance | 19 number of participants with no missed pi |
| Subantibmicrobial Dose Doxy | Subject Compliance | 20 number of participants with no missed pi |
Secondary
Subject Satisfaction.
measured using 100 mm visual analog scale. anchors of not at all satisfied (0mm) extremely satisfied (100mm)
Time frame: Assessed on day 112 of the study (the end of the study period). This outcome does not represent a change from baseline. It was assessed at the end of the study period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Treatment) | Subject Satisfaction. | 63.9 mm | Standard Deviation 41.1 |
| Doxy (7 Day Treatment Arm) | Subject Satisfaction. | 64.2 mm | Standard Deviation 33 |
| Placebo (Prevention) | Subject Satisfaction. | 72.0 mm | Standard Deviation 30.9 |
| Subantibmicrobial Dose Doxy | Subject Satisfaction. | 67.0 mm | Standard Deviation 35.3 |