Annovera™ Drug-Drug Interaction Study

NCT04290390 | Completed Phase 1 FDA Drug

• 1 other identifier: ANNOV3454-2 PMR
• Study Type: interventional
• Target: 67
• Locations: 1 country
• Sites: 1

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)

Conditions

Women; Contraception

Keywords

rifampin; itraconazole; CYP3A

Outcome Measures

Primary Outcomes (2)

• 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

  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

  Day 1 for itraconazole cohort, Day 11 for rifampin cohort

Secondary Outcomes (4)

• Safety - Number of Participants with Adverse Events

  Screening through 14 days following Annovera removal

• Safety - Vital signs - systolic and diastolic blood pressure

  Through study completion, an average of 4 months

• Safety - Vital signs - pulse

  Through study completion, an average of 4 months

• Tolerability -Discontinuation rates

  Through study completion, an average of 4 months

Study Arms (3)

Annovera (alone)

ACTIVE COMPARATOR

Annovera taken alone (without itraconazole or rifampin)

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

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

Drug: Segesterone Acetate and Ethinyl Estradiol; Drug: Rifampin

Interventions

Segesterone Acetate and Ethinyl Estradiol DRUG

Contraceptive Vaginal System

Also known as: Annovera

Annovera (alone); Annovera with itraconazole use; Annovera with rifampin use

Rifampin DRUG

CYP3A inducer

Annovera with rifampin use

Itraconazole DRUG

CYP3A inhibitor

Annovera with itraconazole use

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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)

You may not qualify if:

• 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.

Sponsors & Collaborators

• TherapeuticsMD: lead

Study Sites (1)

Syneos Health

Québec, Quebec, G1P OA2, Canada

Location

MeSH Terms

Interventions

segesterone acetate and ethinyl estradiol vaginal system; Rifampin; Itraconazole

Intervention Hierarchy (Ancestors)

Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Piperazines

Study Officials

• Sebastian Mirkin, MD

  TherapeuticsMD

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: February 10, 2020
• First Posted: February 28, 2020
• Study Start: February 12, 2020
• Primary Completion: January 6, 2021
• Study Completion: January 6, 2021
• Last Updated: January 29, 2021

Record last verified: 2021-01

Locations

CA (1)