HIV/AIDS, Contraception
Conditions
Keywords
etonogestrel, efavirenz, antiretroviral therapy, HIV
Brief summary
This study will evaluate the frequency of ovulation and cervical mucus quality of HIV-infected Ugandan women on efavirenz-based antiretroviral therapy using either a single etonogestrel implant or two etonogestrel implants for at least one year.
Detailed description
This study is being done to compare the rate of ovulation when women receive two subdermal implant contraception devices containing the hormone etonogestrel (instead of only one device) while taking the HIV drug efavirenz. The etonogestrel implant is a device that is inserted under the skin on the upper arm and releases a small amount of drug into the body every day over a long period of time to prevent pregnancy for 3 years. A total of 72 non-pregnant women in Uganda, who agree to use the copper intrauterine device throughout the study, will participate in this study. Half will be assigned by chance to use one implant and half will be assigned to use two implants at the entry visit. After the entry visit to place the implant, visits will be scheduled 1 week, 4 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 21 weeks, 22, weeks, 23 weeks, 24 weeks, 36 weeks, 45 weeks, 46 weeks, 47 weeks, and 48 weeks after the implant(s) were placed. The rate of ovulation (determined by weekly endogenous progesterone concentrations in the blood during months 3, 6, and 12) will be compared between women that receive two 68 mg etonogestrel implants compared to one 68 mg etonogestrel implant in combination with efavirenz-based antiretroviral therapy. Cervical mucus quality (from cervical mucus samples collected weekly at months 3, 6, and 12), the blood concentration of etonogestrel (from blood samples collected at day 3 and weeks 1, 4, 12, 24, 36, 48) and efavirenz (from blood samples collected at enrollment and weeks 4, 12, 24, 36, 48, and the number of adverse events deemed related to etonogestrel implant use through 48 weeks will also be compared between the one- and two-implant study arms.
Interventions
The etonogestrel implant is an contraceptive implant that is placed into the upper arm.
Sponsors
Infectious Disease Institute, Kampala, Uganda
University of Nebraska
Catherine Anne Chappell
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 40 Years
Healthy volunteers
No
Inclusion criteria
1. Evidence of a personally signed and dated informed consent document indicating that the participant has been informed of all pertinent aspects of the study. 2. Participants who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. 3. Women aged 18 years to 40 years. 4. Diagnosed with HIV infection. 5. Medically eligible for the etonogestrel subdermal implant as a contraceptive method. 6. Receiving efavirenz-based anti-retroviral therapy for a minimum of 3 months prior to screening. 7. Must agree to have concurrent highly effective non-hormonal contraception with a copper intrauterine device, if not previously medically sterilized. 8. Participants must report regular menses (bleeding for 4-8 days at 21- to 35-day intervals) for the preceding 2 months. 9. Participants must have a negative urine pregnancy test at entry and report no unprotected sex since the last menstrual period or in the last two weeks.
Exclusion criteria
1. HIV RNA \> 50 copies/mL at screening visit. 2. Serum hemoglobin \< 10.0 g/dL. 3. Elevations in serum levels of alanine transaminase above 5 times the upper limit of normal. 4. Elevations in serum creatinine above 2.5 times the upper limit of normal. 5. Use of drugs known to be contraindicated with etonogestrel or efavirenz within 30 days of study entry. Due to the dynamic nature of drug interactions related to antiretroviral therapy, the study team will review all concomitant medications at screening for drug interactions with efavirenz and the etonogestrel implant. 6. Currently pregnant or postpartum less than 30 days at study entry. 7. Breastfeeding women within 6 months of delivery. 8. Use of hormonal contraception in the preceding 3 months prior to entry 9. Participants determined to be ineligible for intrauterine device placement. 10. Patients with a history of hypersensitivity to etonogestrel implant, undiagnosed vaginal bleeding, diagnosed or suspected sex hormone dependent neoplasia, benign or malignant liver tumor, or thromboembolic disease. 11. Presence of any active clinically significant disease or life-threatening disease that, in the investigator's opinion, would compromise the subject's safety or outcome of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants That Ovulate During Month 3 | 3 months | Proportion of participants that experience at least one ovulation during month 3 of etonogestrel implant use. Serum progesterone concentrations are measured weekly during month 3 (weeks 9-12). Ovulation is defined as endogenous progesterone concentrations of \>3 ng/mL. |
| Proportion of Participants That Ovulate During Month 6 | 6 months | Proportion of participants that experience at least one ovulation during month 6 of etonogestrel implant use. Serum progesterone concentrations are measured weekly during month 6 (weeks 21-24). Ovulation is defined as endogenous progesterone concentrations of \>3 ng/mL. |
| Proportion of Participants That Ovulate During Month 12 | 12 months | Proportion of participants that experience at least one ovulation during month 12 of etonogestrel implant use. Serum progesterone concentrations are measured weekly during month 12 (weeks 45-48). Ovulation is defined as endogenous progesterone concentrations of \>3 ng/mL. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Efavirenz Concentration at Week 12 | 12 weeks | Median efavirenz concentrations measured in plasma samples collected 12 weeks after insertion of the etonogestrel implant(s). Plasma efavirenz concentrations were quantified using a high-performance liquid chromatography assay with ultraviolet detection. |
| Median Efavirenz Concentration at Week 24 | 24 weeks | Median efavirenz concentrations measured in plasma samples collected 24 weeks after insertion of the etonogestrel implant(s). Plasma efavirenz concentrations were quantified using a high-performance liquid chromatography assay with ultraviolet detection. |
| Median Efavirenz Concentration at Week 36 | 36 weeks | Median efavirenz concentrations measured in plasma samples collected 36 weeks after insertion of the etonogestrel implant(s). Plasma efavirenz concentrations were quantified using a high-performance liquid chromatography assay with ultraviolet detection. |
| Median Efavirenz Concentration at Week 48 | 48 weeks | Median efavirenz concentrations measured in plasma samples collected 48 weeks after insertion of the etonogestrel implant(s). Plasma efavirenz concentrations were quantified using a high-performance liquid chromatography assay with ultraviolet detection. |
| Median Etonogestrel Concentration at Week 1 | 1 week | Median etonogestrel concentrations measured in plasma samples collected 1 week after insertion of the etonogestrel implant(s). Plasma etonogestrel concentrations were quantified using liquid chromatography tandem mass spectrometry. |
| Proportion of Cervical Mucus Scores Greater Than 10 | 12 months | The proportion of World Health Organization cervical mucus scores that are greater than 10 from weekly samples collected during months 3, 6 and 12 of etonogestrel implant use. A cervical mucus score greater than 10 indicates the mucus is favorable for sperm penetration or lack of contraceptive effect. The cervical mucus score ranges from 0 indicating least favorable for sperm penetration to 15 for most favorable for sperm penetration. |
| Median Etonogestrel Concentration at Week 12 | 12 weeks | Median etonogestrel concentrations measured in plasma samples collected 12 weeks after insertion of the etonogestrel implant(s). Plasma etonogestrel concentrations were quantified using liquid chromatography tandem mass spectrometry. |
| Median Etonogestrel Concentration at Week 24 | 24 weeks | Median etonogestrel concentrations measured in plasma samples collected 24 weeks after insertion of the etonogestrel implant(s). Plasma etonogestrel concentrations were quantified using liquid chromatography tandem mass spectrometry. |
| Median Etonogestrel Concentration at Week 36 | 36 weeks | Median etonogestrel concentrations measured in plasma samples collected 36 weeks after insertion of the etonogestrel implant(s). Plasma etonogestrel concentrations were quantified using liquid chromatography tandem mass spectrometry. |
| Median Etonogestrel Concentration at Week 48 | 48 weeks | Median etonogestrel concentrations measured in plasma samples collected 48 weeks after insertion of the etonogestrel implant(s). Plasma etonogestrel concentrations were quantified using liquid chromatography tandem mass spectrometry. |
| Median Etonogestrel Concentration at Week 4 | 4 weeks | Median etonogestrel concentrations measured in plasma samples collected 4 weeks after insertion of the etonogestrel implant(s). Plasma etonogestrel concentrations were quantified using liquid chromatography tandem mass spectrometry. |
| Median Efavirenz Concentration at Enrollment | Day 0 | Median efavirenz concentrations measured in plasma samples collected at enrollment, prior to insertion of the etonogestrel implant(s). Plasma efavirenz concentrations were quantified using a high-performance liquid chromatography assay with ultraviolet detection. |
| Median Efavirenz Concentration at Week 4 | 4 weeks | Median efavirenz concentrations measured in plasma samples collected 4 weeks after insertion of the etonogestrel implant(s). Plasma efavirenz concentrations were quantified using a high-performance liquid chromatography assay with ultraviolet detection. |
Countries
Uganda
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Standard Dose Etonogestrel Implant Single 68 mg etonogestrel implant
etonogestrel implant: The etonogestrel implant is an contraceptive implant that is placed into the upper arm. | 36 |
| Increased Dose Etonogestrel Implant Two 68 mg (136 mg total) etonogestrel implants
etonogestrel implant: The etonogestrel implant is an contraceptive implant that is placed into the upper arm. | 36 |
| Total | 72 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Pregnancy | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Increased Dose Etonogestrel Implant | Standard Dose Etonogestrel Implant |
|---|---|---|---|
| Age, Continuous | 31 years | 30 years | 32 years |
| CD4+ cell count | 669 cells/mm3 | 700 cells/mm3 | 648 cells/mm3 |
| Prior live births | 3 births | 3 births | 3 births |
| Race/Ethnicity, Customized Ganda | 41 Participants | 19 Participants | 22 Participants |
| Race/Ethnicity, Customized Kiga | 4 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized Nkore | 6 Participants | 1 Participants | 5 Participants |
| Race/Ethnicity, Customized Nyarwanda | 5 Participants | 3 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 10 Participants | 6 Participants | 4 Participants |
| Race/Ethnicity, Customized Soga | 3 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Tooro | 3 Participants | 3 Participants | 0 Participants |
| Region of Enrollment Uganda | 72 participants | 36 participants | 36 participants |
| Sex: Female, Male Female | 72 Participants | 36 Participants | 36 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Weight | 60.0 kg | 59.2 kg | 60.2 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 36 | 0 / 36 |
| other Total, other adverse events | 35 / 36 | 35 / 36 |
| serious Total, serious adverse events | 0 / 36 | 0 / 36 |
Outcome results
Primary
Proportion of Participants That Ovulate During Month 12
Proportion of participants that experience at least one ovulation during month 12 of etonogestrel implant use. Serum progesterone concentrations are measured weekly during month 12 (weeks 45-48). Ovulation is defined as endogenous progesterone concentrations of \>3 ng/mL.
Time frame: 12 months
Population: One participant in the standard dose arm was withdrawn at week 1 of the study due to pregnancy, and one was withdrawn at week 45 due to a mental health condition.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard Dose Etonogestrel Implant | Proportion of Participants That Ovulate During Month 12 | 19 Participants |
| Increased Dose Etonogestrel Implant | Proportion of Participants That Ovulate During Month 12 | 2 Participants |
p-value: <0.001Fisher Exact
Primary
Proportion of Participants That Ovulate During Month 3
Proportion of participants that experience at least one ovulation during month 3 of etonogestrel implant use. Serum progesterone concentrations are measured weekly during month 3 (weeks 9-12). Ovulation is defined as endogenous progesterone concentrations of \>3 ng/mL.
Time frame: 3 months
Population: One participant in the standard dose arm was withdrawn at week 1 of the study due to pregnancy.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard Dose Etonogestrel Implant | Proportion of Participants That Ovulate During Month 3 | 11 Participants |
| Increased Dose Etonogestrel Implant | Proportion of Participants That Ovulate During Month 3 | 0 Participants |
p-value: <0.001Fisher Exact
Primary
Proportion of Participants That Ovulate During Month 6
Proportion of participants that experience at least one ovulation during month 6 of etonogestrel implant use. Serum progesterone concentrations are measured weekly during month 6 (weeks 21-24). Ovulation is defined as endogenous progesterone concentrations of \>3 ng/mL.
Time frame: 6 months
Population: One participant in the standard dose arm was withdrawn at week 1 of the study due to pregnancy.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard Dose Etonogestrel Implant | Proportion of Participants That Ovulate During Month 6 | 17 Participants |
| Increased Dose Etonogestrel Implant | Proportion of Participants That Ovulate During Month 6 | 0 Participants |
p-value: <0.001Fisher Exact
Secondary
Median Efavirenz Concentration at Enrollment
Median efavirenz concentrations measured in plasma samples collected at enrollment, prior to insertion of the etonogestrel implant(s). Plasma efavirenz concentrations were quantified using a high-performance liquid chromatography assay with ultraviolet detection.
Time frame: Day 0
Population: Efavirenz concentration not evaluated for 1 participant who was discontinued due to pregnancy at 1 week.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Standard Dose Etonogestrel Implant | Median Efavirenz Concentration at Enrollment | 2.26 µg/mL |
| Increased Dose Etonogestrel Implant | Median Efavirenz Concentration at Enrollment | 2.30 µg/mL |
p-value: 0.685Wilcoxon (Mann-Whitney)
Secondary
Median Efavirenz Concentration at Week 12
Median efavirenz concentrations measured in plasma samples collected 12 weeks after insertion of the etonogestrel implant(s). Plasma efavirenz concentrations were quantified using a high-performance liquid chromatography assay with ultraviolet detection.
Time frame: 12 weeks
Population: Efavirenz concentration not evaluated for 1 participant who was discontinued due to pregnancy at 1 week and 1 participant who missed the 12-week visit.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Standard Dose Etonogestrel Implant | Median Efavirenz Concentration at Week 12 | 2.10 µg/mL |
| Increased Dose Etonogestrel Implant | Median Efavirenz Concentration at Week 12 | 1.88 µg/mL |
p-value: 0.587Wilcoxon (Mann-Whitney)
Secondary
Median Efavirenz Concentration at Week 24
Median efavirenz concentrations measured in plasma samples collected 24 weeks after insertion of the etonogestrel implant(s). Plasma efavirenz concentrations were quantified using a high-performance liquid chromatography assay with ultraviolet detection.
Time frame: 24 weeks
Population: Efavirenz concentration not evaluated for 1 participant who was discontinued due to pregnancy at 1 week.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Standard Dose Etonogestrel Implant | Median Efavirenz Concentration at Week 24 | 2.26 µg/mL |
| Increased Dose Etonogestrel Implant | Median Efavirenz Concentration at Week 24 | 1.76 µg/mL |
p-value: 0.394Wilcoxon (Mann-Whitney)
Secondary
Median Efavirenz Concentration at Week 36
Median efavirenz concentrations measured in plasma samples collected 36 weeks after insertion of the etonogestrel implant(s). Plasma efavirenz concentrations were quantified using a high-performance liquid chromatography assay with ultraviolet detection.
Time frame: 36 weeks
Population: Efavirenz concentration not evaluated for 1 participant who was discontinued due to pregnancy at 1 week.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Standard Dose Etonogestrel Implant | Median Efavirenz Concentration at Week 36 | 1.97 µg/mL |
| Increased Dose Etonogestrel Implant | Median Efavirenz Concentration at Week 36 | 1.87 µg/mL |
p-value: 0.66Wilcoxon (Mann-Whitney)
Secondary
Median Efavirenz Concentration at Week 4
Median efavirenz concentrations measured in plasma samples collected 4 weeks after insertion of the etonogestrel implant(s). Plasma efavirenz concentrations were quantified using a high-performance liquid chromatography assay with ultraviolet detection.
Time frame: 4 weeks
Population: Efavirenz concentration not evaluated for 1 participant who was discontinued due to pregnancy at 1 and 1 participant who missed the 4-week visit.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Standard Dose Etonogestrel Implant | Median Efavirenz Concentration at Week 4 | 2.41 µg/mL |
| Increased Dose Etonogestrel Implant | Median Efavirenz Concentration at Week 4 | 2.23 µg/mL |
p-value: 0.784Wilcoxon (Mann-Whitney)
Secondary
Median Efavirenz Concentration at Week 48
Median efavirenz concentrations measured in plasma samples collected 48 weeks after insertion of the etonogestrel implant(s). Plasma efavirenz concentrations were quantified using a high-performance liquid chromatography assay with ultraviolet detection.
Time frame: 48 weeks
Population: Efavirenz concentration not evaluated for 1 participant who was discontinued due to pregnancy at 1 week and 1 participant who missed the 48-week visit.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Standard Dose Etonogestrel Implant | Median Efavirenz Concentration at Week 48 | 2.05 µg/mL |
| Increased Dose Etonogestrel Implant | Median Efavirenz Concentration at Week 48 | 1.72 µg/mL |
p-value: 0.29Wilcoxon (Mann-Whitney)
Secondary
Median Etonogestrel Concentration at Week 1
Median etonogestrel concentrations measured in plasma samples collected 1 week after insertion of the etonogestrel implant(s). Plasma etonogestrel concentrations were quantified using liquid chromatography tandem mass spectrometry.
Time frame: 1 week
Population: Etonogestrel concentration not evaluated for 1 participant who was discontinued due to pregnancy at 1 week.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Standard Dose Etonogestrel Implant | Median Etonogestrel Concentration at Week 1 | 182 pg/mL |
| Increased Dose Etonogestrel Implant | Median Etonogestrel Concentration at Week 1 | 439 pg/mL |
Secondary
Median Etonogestrel Concentration at Week 12
Median etonogestrel concentrations measured in plasma samples collected 12 weeks after insertion of the etonogestrel implant(s). Plasma etonogestrel concentrations were quantified using liquid chromatography tandem mass spectrometry.
Time frame: 12 weeks
Population: Etonogestrel concentration not evaluated for 1 participant who was discontinued due to pregnancy at 1 week and 1 participant who missed the 12-week visit.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Standard Dose Etonogestrel Implant | Median Etonogestrel Concentration at Week 12 | 83 pg/mL |
| Increased Dose Etonogestrel Implant | Median Etonogestrel Concentration at Week 12 | 214 pg/mL |
Secondary
Median Etonogestrel Concentration at Week 24
Median etonogestrel concentrations measured in plasma samples collected 24 weeks after insertion of the etonogestrel implant(s). Plasma etonogestrel concentrations were quantified using liquid chromatography tandem mass spectrometry.
Time frame: 24 weeks
Population: Etonogestrel concentration not evaluated for 1 participant who was discontinued due to pregnancy at 1 week.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Standard Dose Etonogestrel Implant | Median Etonogestrel Concentration at Week 24 | 69 pg/mL |
| Increased Dose Etonogestrel Implant | Median Etonogestrel Concentration at Week 24 | 168 pg/mL |
Secondary
Median Etonogestrel Concentration at Week 36
Median etonogestrel concentrations measured in plasma samples collected 36 weeks after insertion of the etonogestrel implant(s). Plasma etonogestrel concentrations were quantified using liquid chromatography tandem mass spectrometry.
Time frame: 36 weeks
Population: Etonogestrel concentration not evaluated for 1 participant who was discontinued due to pregnancy at 1 week.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Standard Dose Etonogestrel Implant | Median Etonogestrel Concentration at Week 36 | 54 pg/mL |
| Increased Dose Etonogestrel Implant | Median Etonogestrel Concentration at Week 36 | 132 pg/mL |
Secondary
Median Etonogestrel Concentration at Week 4
Median etonogestrel concentrations measured in plasma samples collected 4 weeks after insertion of the etonogestrel implant(s). Plasma etonogestrel concentrations were quantified using liquid chromatography tandem mass spectrometry.
Time frame: 4 weeks
Population: Etonogestrel concentration not evaluated for 1 participant who was discontinued due to pregnancy at 1 week and 1 participant who missed the 4-week visit.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Standard Dose Etonogestrel Implant | Median Etonogestrel Concentration at Week 4 | 115 pg/mL |
| Increased Dose Etonogestrel Implant | Median Etonogestrel Concentration at Week 4 | 282 pg/mL |
Secondary
Median Etonogestrel Concentration at Week 48
Median etonogestrel concentrations measured in plasma samples collected 48 weeks after insertion of the etonogestrel implant(s). Plasma etonogestrel concentrations were quantified using liquid chromatography tandem mass spectrometry.
Time frame: 48 weeks
Population: Etonogestrel concentration not evaluated for 1 participant who was discontinued due to pregnancy at 1 week and 1 participant who missed the 48-week visit.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Standard Dose Etonogestrel Implant | Median Etonogestrel Concentration at Week 48 | 39 pg/mL |
| Increased Dose Etonogestrel Implant | Median Etonogestrel Concentration at Week 48 | 95 pg/mL |
Secondary
Proportion of Cervical Mucus Scores Greater Than 10
The proportion of World Health Organization cervical mucus scores that are greater than 10 from weekly samples collected during months 3, 6 and 12 of etonogestrel implant use. A cervical mucus score greater than 10 indicates the mucus is favorable for sperm penetration or lack of contraceptive effect. The cervical mucus score ranges from 0 indicating least favorable for sperm penetration to 15 for most favorable for sperm penetration.
Time frame: 12 months
Population: Evaluable cervical mucus samples collected from participants over 48 weeks of etonogestrel implant use. One participant in the standard dose arm was withdrawn at week 1 of the study due to pregnancy.
| Arm | Measure | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Standard Dose Etonogestrel Implant | Proportion of Cervical Mucus Scores Greater Than 10 | Cervical mucus score greater than 10 | 1 Cervical mucus samples |
| Standard Dose Etonogestrel Implant | Proportion of Cervical Mucus Scores Greater Than 10 | Cervical mucus score of 10 or less | 248 Cervical mucus samples |
| Increased Dose Etonogestrel Implant | Proportion of Cervical Mucus Scores Greater Than 10 | Cervical mucus score greater than 10 | 1 Cervical mucus samples |
| Increased Dose Etonogestrel Implant | Proportion of Cervical Mucus Scores Greater Than 10 | Cervical mucus score of 10 or less | 233 Cervical mucus samples |
p-value: >0.99Fisher Exact