Clinical trial NCT04290390: Annovera™ Drug-Drug Interaction 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Women
Contraception
Keywords: rifampin
itraconazole
CYP3A
Lead sponsor: TherapeuticsMD
Sponsor class: INDUSTRY
First posted: 2020-02-28
Enrollment: 67
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention 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.
Primary purpose: TREATMENT

Brief 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)


Eligibility criteria: Inclusion Criteria

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.
* 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)

Exclusion Criteria

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.
* 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.)

Primary outcomes:
measure: Area-under-the-curve (AUC) of rifampin and itraconzaole on Annovera (segesterone acetate and ethinyl estradiol)
timeFrame: Day 1 for itraconazole cohort, Day 11 for rifampin cohort
measure: Maximum concentration (Cmax) of rifampin and itraconzaole on Annovera (segesterone acetate and ethinyl estradiol)
timeFrame: Day 1 for itraconazole cohort, Day 11 for rifampin cohort
Secondary outcomes:
measure: Safety - Number of Participants with Adverse Events
timeFrame: Screening through 14 days following Annovera removal
measure: Safety - Vital signs - systolic and diastolic blood pressure
timeFrame: Through study completion, an average of 4 months
measure: Safety - Vital signs - pulse
timeFrame: Through study completion, an average of 4 months
measure: Tolerability -Discontinuation rates
timeFrame: Through study completion, an average of 4 months
Other outcomes:
Locations:
city: Quebec City
country: Canada
facility: Syneos Health
state: Quebec
Study officials:
affiliation: TherapeuticsMD
name: Sebastian Mirkin, MD
role: STUDY_CHAIR
References: