WomenPhase 1NCT04290390
Annovera™ Drug-Drug Interaction Study
A Phase 1 study testing Segesterone Acetate and Ethinyl Estradiol, Rifampin and Itraconazole in people with Women and Contraception, run by TherapeuticsMD at 1 site in Canada.
Trial summary
A Drug-Drug Interaction (DDI) study to evaluate the effects of itraconazole and rifampin on the Pharmacokinetics of Segesterone Acetate and Ethinyl Estradiol from the Annovera Contraceptive Vaginal System (CVS) Read more about this study
- Who is it for?
- Ages 18 to 35 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Women, Contraception
- What is being tested?
- Segesterone Acetate and Ethinyl Estradiol, Rifampin and Itraconazole
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 67 participants
- Where
- 1 siteCanada
- Study dates
- 12 Feb 2020to 6 Jan 2021
- Phase
- Phase 1
- 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 35 years
- Women only
- Healthy volunteers accepted
- Adult
Who may be able to join
- All of the following criteria must be met for the participants to be eligible for the study:
- a. Healthy women, non-smoker (no use of tobacco or nicotine products within 3 months prior to screening) sterile or at risk of becoming pregnant, inclusive of ages 18 to 35* years at the enrollment visit.
- b. Body Mass Index (BMI) > 18.5 and ≤ 29.0 kg/m2 and body weight ≥ 45.0 kg.
- c. Intact uterus and both ovaries.
- d. Prior history of regular menstrual cycles that usually occur every 28 ± 7 days when not using hormonal contraception; if postpartum or post-abortal, history of regular menstrual cycles of 21 to 35 days in length and resumption of at least one cycle with a cycle length consistent with her past cycles.
- e. In the opinion of the Investigator, able to comply with the protocol, eg, live within the study site catchment area or within a reasonable distance from the study site.
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- f. If not sterile and sexually active with a non-sterile male partner, willing to use one of the following acceptable contraceptive methods throughout the study:
- intra-uterine contraceptive device without hormone release system placed at least 28 days prior to the start of the first treatment cycle;
- male condom with intravaginally applied spermicide starting at least 21 days prior to the start of the first treatment cycle;
- g. If not sterile and sexually active with a sterile male partner, the partner is at least 6 months post-vasectomy.
- h. Willing to abstain from Tylenol/acetaminophen use and from consuming grapefruit or grapefruit juice from 7 days pre-dose until after the last PK blood sample collection of each period.
- i. Willing to abstain from alcohol from 24 hours pre-dose until after the last PK blood sample collection of each period.
- j. Signed informed consent prior to entry into the trial.
- (Upper age limit based on normal ovarian changes (ovarian reserve) prevalent in women with advancing age (> 35 years of age) that may alter patterns of follicle development and/or confound interpretations of data regarding patterns of follicle development)
Who cannot join
- Contraindications for enrollment will be the same as those for use of CHCs and additional criteria important to the objectives of this study and include:
- a. Known hypersensitivity to estrogens or progestins.
- b. Pregnant, trying to become pregnant, or breastfeeding.
- c. Known hypersensitivity to silicone rubber.
- d. Undiagnosed abnormal vaginal bleeding.
- e. Undiagnosed vaginal discharge, vaginal lesions or abnormalities. Participants diagnosed at screening with a chlamydia or gonococcus infection may be included in the trial following treatment; partner treatment is also recommended. Investigators should make a determination if participants are at high risk for reinfection, eg, multiple sex partners, untreated partner, and whether such participants can be included.
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- f. History of pelvic inflammatory disease since the participant's last pregnancy.
- g. History of toxic shock syndrome.
- h. In accordance with the Bethesda system of classification: Women with a current (within the last 20 months) abnormal Papanicolaou smear (Pap smear) suggestive of high-grade pre-cancerous lesion(s), including high grade squamous intraepithelial lesion.
- i. Cystoceles or rectoceles or other anatomical abnormality that would preclude use of a vaginal ring.
- j. Women planning to undergo major surgery during the trial.
- k. Current or past thrombophlebitis or thromboembolic disorders.
- l. History of venous thrombosis or embolism in a first-degree relative, < 55 years of age suggesting a familial defect in the blood coagulation system, which in the opinion of the Principal Investigator (PI), suggests that use of a hormonal contraceptive could pose a significant risk.
- m. Cerebrovascular or cardiovascular disease.
- n. History of retinal vascular lesions, unexplained partial or complete loss of vision.
- o. Known or suspected carcinoma of the breast.
- p. Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia.
- q. Past history of any other carcinoma unless in remission for more than five years.
- r. Current or history of medically diagnosed severe depression, which, in the opinion of the Investigator, could be exacerbated by the use of a hormonal contraceptive.
- s. Has a Type D personality type as assessed by the DS14 test (Standard Assessment of Negative Affectivity, Social Inhibition and Type D Personality).
- t. Headaches with focal neurological symptoms.
- u. Severe constipation in the opinion of the Investigator.
- v. History of cholestatic jaundice of pregnancy or jaundice with prior steroid use.
- w. Benign or malignant liver tumors; active liver disease.
- x. Diastolic blood pressure (BP) > 85 mm Hg and/or systolic BP > 135 mm Hg after 5 to 10 minutes rest (at Screening).
- y. Known or suspected alcoholism or drug abuse within their lifetime, or use of soft drugs (such as marijuana) within 3 months prior to the screening visit or hard drugs (such as cocaine, phencyclidine, crack, opioid derivatives including heroin, and amphetamine derivatives) within 1 year prior to screening.
- z. Elevated serum fasting clinical chemistry values or complete blood count (CBC) values designated clinically significant by the Investigator and/or medically qualified Sub-Investigator.
- aa. Screening hemoglobin levels less than 115 g/L or hematocrit less than 0.32 L/L.
- bb. Participation in another clinical trial involving the administration of an investigational drug or marketed drug or device within the last 30 days prior to the first dosing, administration of a biological product in the context of a clinical research study within 90 days prior to the first dosing, or concomitant participation in an investigational study involving no drug or device administration.
- cc. Use of liver enzyme inducers on a regular basis and sex steroid hormone treatments (see Section 8.3 for list of exclusionary medications).
- dd. Use of monthly injectable contraceptives, unless suspended 2 months before initiation of the treatment. Use of Depo-Provera® [depot medroxyprogesterone acetate] unless suspended 9 months before treatment.
- ee. Current use of implanted hormonal contraceptives, including Mirena® [progestin containing intrauterine system], Jadelle®, Norplant®, Implanon® or Nexplanon (if now available in the USA).**
- ff. Known HIV, Hepatitis B or Hepatitis C infection.
- gg. History of frequent vaginal infections in the opinion of the Investigator.
- hh. Known hypersensitivity or prior adverse reaction to itraconazole, or to any of the other azoles or to rifampin, or to any of the rifamycins.
- (Women using non-hormonal intrauterine devices are permitted to enroll in the study.) (Participants using any of the implanted hormonal methods who request removal for reasons unrelated to the purpose of enrollment in this study may be considered for participation.)
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Drug-Drug Interaction Study to Evaluate the Effects of Strong CYP3A Induction and Inhibition on the Pharmacokinetics of Segesterone Acetate and Ethinyl Estradiol From the Annovera™ Contraceptive Vaginal System
A Drug-Drug Interaction (DDI) study to evaluate the effects of itraconazole and rifampin on the Pharmacokinetics of Segesterone Acetate and Ethinyl Estradiol from the Annovera Contraceptive Vaginal System (CVS)
- Conditions
- Women, Contraception
- Being tested
- Segesterone Acetate and Ethinyl Estradiol, Rifampin, Itraconazole
- Keywords
- rifampin, itraconazole, CYP3A
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Segesterone Acetate and Ethinyl EstradiolDrug
Also called Annovera
Contraceptive Vaginal System
RifampinDrug
CYP3A inducer
ItraconazoleDrug
CYP3A inhibitor
| Study group | Role | What they receive |
|---|---|---|
| Annovera (alone) | Active comparator | Annovera taken alone (without itraconazole or rifampin) Receives: Drug: Segesterone Acetate and Ethinyl Estradiol |
| Annovera with itraconazole use | Active comparator | Subjects will dose with 200 mg/day of itraconazole for five days before Annovera insertion and through Days 1 to 8 of Annovera use Receives: Drug: Segesterone Acetate and Ethinyl Estradiol; Drug: Itraconazole |
| Annovera with rifampin use | Active comparator | Subjects will dose with 600 mg/day rifampin for 8 days, between Days 4 to 11 of Annovera use during their respective treatment cycles Receives: Drug: Segesterone Acetate and Ethinyl Estradiol; Drug: Rifampin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Area-under-the-curve (AUC) of rifampin and itraconzaole on Annovera (segesterone acetate and ethinyl estradiol)
AUC for 24 hours for segesterone acetate and ethinyl estradiol
Measured: Day 1 for itraconazole cohort, Day 11 for rifampin cohort
Maximum concentration (Cmax) of rifampin and itraconzaole on Annovera (segesterone acetate and ethinyl estradiol)
Cmax for segesterone acetate and ethinyl estradiol
Measured: Day 1 for itraconazole cohort, Day 11 for rifampin cohort
Secondary outcomes (4)
Safety - Number of Participants with Adverse Events
Serious adverse events (SAEs) and adverse events (AEs)
Measured: Screening through 14 days following Annovera removal
Safety - Vital signs - systolic and diastolic blood pressure
Measurements of systolic and diastolic blood pressure will be compared from Screening to end of treatment/end of study
Measured: Through study completion, an average of 4 months
Safety - Vital signs - pulse
Measurements of pulse will be compared from Screening to end of treatment/end of study
Measured: Through study completion, an average of 4 months
Tolerability -Discontinuation rates
Participant rates of discontinuation due to AEs will provide information regarding tolerability
Measured: Through study completion, an average of 4 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Feb 2020
- Study start12 Feb 2020
- Primary completion6 Jan 2021
- Study completion6 Jan 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for WomenStudies of the same condition, open and under way.
- 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 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- Two cohort, open label, randomized, two period (Cycle 1 and Cycle 2) crossover study. Subjects may only participate in one randomized sequence of one cohort. Subjects will be assigned to either Cohort 1 (itraconazole) or Cohort 2 (rifampin). Once assigned, a subject will then be randomized to a Sequence Group within the cohort. There will be at least a 4-week washout between Treatment Cycle 1 and Cycle 2.
- Masking
- None (open label)
- Enrolment
- 67 participants (actual)
Sponsor and investigators
- Lead sponsor
- TherapeuticsMD
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Sebastian Mirkin, MD, Study chair, TherapeuticsMD
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04290390
- Sponsor's protocol ID
- ANNOV3454-2 PMR
- Status last verified
- Jan 2021
- First submitted
- 10 Feb 2020
- Last updated
- 29 Jan 2021
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Plagianos M, Lansiaux M, Kumar N, Graham S, Sussman H, Kushner H, Creasy G, Bernick B, Haddad LB. A drug-drug interaction study to evaluate the effects of strong CYP3A4 inducer on the pharmacokinetics of segesterone acetate and ethinyl estradiol in a contraceptive vaginal system. Contracept Reprod Med. 2025 Nov 26;10(1):78. doi: 10.1186/s40834-025-00414-y.
PubMed 41291952
Study at a glance
From the registry record, last updated by the sponsor on 29 Jan 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Drug-Drug Interaction Study to Evaluate the Effects of Strong CYP3A Induction and Inhibition on the Pharmacokinetics of Segesterone Acetate and Ethinyl Estradiol From the Annovera™ Contraceptive Vaginal System
- ClinicalTrials.gov ID
- NCT04290390
- Acronym / sponsor ID
- ANNOV3454-2 PMR
- Conditions
- Women, Contraception
- Keywords
- rifampin, itraconazole, CYP3A
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 67 participants (actual)
- Lead sponsor
- TherapeuticsMDIndustry (pharma, biotech, devices)
- Study start
- 12 Feb 2020 (actual)
- Primary completion
- 6 Jan 2021 (actual)
- Study completion
- 6 Jan 2021 (actual)
- First posted
- 28 Feb 2020 (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.
A Drug-Drug Interaction (DDI) study to evaluate the effects of itraconazole and rifampin on the Pharmacokinetics of Segesterone Acetate and Ethinyl Estradiol from the Annovera Contraceptive Vaginal System (CVS)
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 3
- Model description
- Two cohort, open label, randomized, two period (Cycle 1 and Cycle 2) crossover study. Subjects may only participate in one randomized sequence of one cohort. Subjects will be assigned to either Cohort 1 (itraconazole) or Cohort 2 (rifampin). Once assigned, a subject will then be randomized to a Sequence Group within the cohort. There will be at least a 4-week washout between Treatment Cycle 1 and Cycle 2.
| Arm | Type | Receives |
|---|---|---|
| Annovera (alone) | Active comparator | Drug: Segesterone Acetate and Ethinyl EstradiolAnnovera taken alone (without itraconazole or rifampin) |
| Annovera with itraconazole use | Active comparator | Drug: Segesterone Acetate and Ethinyl Estradiol, Drug: ItraconazoleSubjects will dose with 200 mg/day of itraconazole for five days before Annovera insertion and through Days 1 to 8 of Annovera use |
| Annovera with rifampin use | Active comparator | Drug: Segesterone Acetate and Ethinyl Estradiol, Drug: RifampinSubjects will dose with 600 mg/day rifampin for 8 days, between Days 4 to 11 of Annovera use during their respective treatment cycles |
Who may qualify
- Ages
- 18 to 35 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (14 listed)
- All of the following criteria must be met for the participants to be eligible for the study:
- a. Healthy women, non-smoker (no use of tobacco or nicotine products within 3 months prior to screening) sterile or at risk of becoming pregnant, inclusive of ages 18 to 35* years at the enrollment visit.
- b. Body Mass Index (BMI) > 18.5 and ≤ 29.0 kg/m2 and body weight ≥ 45.0 kg.
- c. Intact uterus and both ovaries.
- d. Prior history of regular menstrual cycles that usually occur every 28 ± 7 days when not using hormonal contraception; if postpartum or post-abortal, history of regular menstrual cycles of 21 to 35 days in length and resumption of at least one cycle with a cycle length consistent with her past cycles.
Key exclusion criteria (36 listed)
- Contraindications for enrollment will be the same as those for use of CHCs and additional criteria important to the objectives of this study and include:
- a. Known hypersensitivity to estrogens or progestins.
- b. Pregnant, trying to become pregnant, or breastfeeding.
- c. Known hypersensitivity to silicone rubber.
- d. Undiagnosed abnormal vaginal bleeding.
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 |
|---|---|---|
| Segesterone Acetate and Ethinyl EstradiolAlso: AnnoveraContraceptive Vaginal System | Drug | Annovera (alone), Annovera with itraconazole use, Annovera with rifampin use |
| RifampinCYP3A inducer | Drug | Annovera with rifampin use |
| ItraconazoleCYP3A inhibitor | Drug | Annovera with itraconazole use |
Primary outcome
Area-under-the-curve (AUC) of rifampin and itraconzaole on Annovera (segesterone acetate and ethinyl estradiol)
Time frame: Day 1 for itraconazole cohort, Day 11 for rifampin cohort
AUC for 24 hours for segesterone acetate and ethinyl estradiol
Maximum concentration (Cmax) of rifampin and itraconzaole on Annovera (segesterone acetate and ethinyl estradiol)
Time frame: Day 1 for itraconazole cohort, Day 11 for rifampin cohort
Cmax for segesterone acetate and ethinyl estradiol
4 secondary outcomes
Safety - Number of Participants with Adverse Events
Time frame: Screening through 14 days following Annovera removal
Safety - Vital signs - systolic and diastolic blood pressure
Time frame: Through study completion, an average of 4 months
Safety - Vital signs - pulse
Time frame: Through study completion, an average of 4 months
Tolerability -Discontinuation rates
Time frame: Through study completion, an average of 4 months
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 29 Jan 2021.
- Derived from this study: PubMed 41291952Plagianos M, Lansiaux M, Kumar N, Graham S, Sussman H, Kushner H, Creasy G, Bernick B, Haddad LB. A drug-drug interaction study to evaluate the effects of strong CYP3A4 inducer on the pharmacokinetics of segesterone acetate and ethinyl estradiol in a contraceptive vaginal system. Contracept Reprod Med. 2025 Nov 26;10(1):78. doi: 10.1186/s40834-025-00414-y.
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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.
Sebastian Mirkin, MD study chair
TherapeuticsMD
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Segesterone Acetate and Ethinyl Estradiol, Rifampin and Itraconazole in people with Women and Contraception, run by TherapeuticsMD at 1 site in Canada.
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 14 inclusion and 36 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 29 Jan 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. 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. 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 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
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?
Area-under-the-curve (AUC) of rifampin and itraconzaole on Annovera (segesterone acetate and ethinyl estradiol) (time frame: Day 1 for itraconazole cohort, Day 11 for rifampin cohort). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04290390, which also lists 1 linked publication.
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 29 Jan 2021.