Evaluating Pharmacokinetic Interactions With Vaginal Ring Contraceptives and ART

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT01903031
• Date of registration: 16/07/2013
• Prospective Registration: Yes
• Primary sponsor: AIDS Clinical Trials Group
• Public title: Evaluating Pharmacokinetic Interactions With Vaginal Ring Contraceptives and ART
• Scientific title: Evaluating Pharmacokinetic Interactions With Vaginal Ring Contraceptives and Antiretroviral Therapy (ART)
• Date of first enrolment: December 30, 2014
• Target sample size: 84
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT01903031
• Study type: Interventional
• Study design: Allocation: Non-Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 2

Countries of recruitment

Botswana, Brazil, Kenya, Peru, Puerto Rico, South Africa, Thailand, United States, Zimbabwe

Key inclusion & exclusion criteria

Inclusion Criteria:

- Documented HIV-1 infection.

- Participants must have been receiving either 1) EFV 600 mg daily with 2 or more NRTIs,
2) ATV/r 300 mg/ 100 mg daily with TDF 300 mg and 1 or more additional NRTIs, or 3) no
ART. ART regimens should have been stable for 30 days prior to study entry with no
plans to change therapy during the first 28 days of this study. Participants receiving
no ART should have had no plans to initiate ART during the first 28 days of the study.

NOTE: Participants must have had access to their ART regimens through their primary care
providers. ART medications were not supplied by this study.

- For participants on ART, documentation of plasma HIV-1 RNA =400 copies/mL was obtained
within 60 days prior to study entry.

- For participants not on ART, CD4+ cell count must have been =350 cells/mm^3, obtained
within 60 days prior to study entry.

- Laboratory values within 60 days prior to study entry:

- Platelet count =50,000 platelets/mm^3

- Hemoglobin =8.0 g/dL

- Aspartate transaminase (SGOT) and alanine aminotransferase (SGPT) <5 x upper
limit of normal (ULN)

- Creatinine =1.5 x ULN

- Total bilirubin =2.0 x ULN

- Last menstrual period =6 months prior to study entry. If last menstrual period >6
months prior to study entry without another cause for amenorrhea, such as recent
pregnancy, serum follicle-stimulating hormone (FSH) must have been checked and be =40
mIU/mL to be eligible for enrollment.

- Premenopausal females with at least one functioning ovary.

- Documentation of Pap smear within 1 year prior to study entry.

- Negative serum or urine-HCG pregnancy test with a sensitivity of =25 mIU/mL within 60
days prior to study entry and within 24 hours prior to study entry

- All participants must have agreed not to participate in a conception process (eg,
active attempt to become pregnant or in vitro fertilization) for the duration of the
study. Because it was unknown if ARVs adversely affect the efficacy of NuvaRing as a
contraceptive method, participants of reproductive potential, who were participating
in sexual activities that could lead to pregnancy, must have agreed to use an
additional reliable form of contraception while in the study. Acceptable additional
methods of contraception included:

- Condoms (male or female)

- Non-hormonal intrauterine device (IUD)

Other hormonal forms of contraception were not allowed during the study period.

Condoms should have been used to prevent transmission of HIV and sexually transmitted
diseases between sexual partners.

NOTE: Participants with bilateral tubal ligation or non-hormonal IUD were eligible to be
enrolled.

Exclusion Criteria:

- Received depot medroxyprogesterone acetate (DMPA) within 4 months prior to study
entry.

- Received other hormonal therapies (eg, oral contraceptive agents, hormone- containing
vaginal ring, contraceptive patch, hormone replacement therapy, anabolic therapies,
including nandrolone decanoate or megestrol acetate) within 30 days prior to study
entry.

- Breastfeeding.

- Less than 6 weeks postpartum at study entry.

- Use of any prohibited medications within 30 days prior to study entry.

- Initiated, discontinued, or changed doses of drugs that are CYP substrates or known to
have drug interactions with ethinyl estradiol or etonogestrel within 30 days prior to
study entry.

- Bilateral oophorectomy.

- For women older than 35 years of age, smoking 15 or more cigarettes per day.

- History of invasive cancer of the reproductive tract; known or suspected malignancy of
the breast, or known increased risk for breast cancer; undiagnosed abnormal vaginal
bleeding; liver tumors; or serious ocular disorders at any time prior to study entry.

- Chronic immunosuppressive conditions other than HIV.

- Use of systemic or inhaled corticosteroids such as for acute therapy for Pneumocystis
pneumonia (PCP) or asthma exacerbation and prednisone =10 mg (or equivalent) for any
reason other than a stable or tapering dose.

- History of deep venous thrombosis or pulmonary embolism.

- History of cerebral vascular or coronary artery disease.

- Severe uncontrolled hypertension within 60 days prior to study entry.

- Diabetes with vascular involvement.

- Clinically active cervical or vaginal infection at study entry. NOTE: Gonorrhea,
chlamydia, and trichomonas testing was performed during screening using techniques
available at the local sites and documented in source documentation and case report
forms (CRFs). Testing for bacterial vaginosis, performed using techniques available at
the local sites, was only necessary if the participant was symptomatic and the
provider felt treatment might be necessary. Women with genital herpes lesions waited
to be screened until the herpetic lesions had healed.

- Acute infections or other opportunistic diseases requiring medication within 14 days
prior to study entry.



Age minimum: 16 Years
Age maximum: N/A
Gender: Female

Health Condition(s) or Problem(s) studied

HIV-1 Infection

Intervention(s)

Device: Nuvaring

Drug: ATV/r

Drug: NRTIs

Drug: EFV

Drug: TDF

Primary Outcome(s)

Ethinyl Estradiol Concentrations at Study Day 21 [Time Frame: Day 21]

Etonogestrel Concentrations at Study Day 21 [Time Frame: Day 21]

Secondary Outcome(s)

EFV PK Parameter Area Under the Concentration-Time Curve (AUC0-24hours) Calculated Based on Intensive EFV PK Samples Obtained From Individual Participants Enrolled in Arm B [Time Frame: Intensive EFV PK samples at pre-dose, 1, 3, 4, 5, and 8 hours post-dose on study day 0 (before vaginal ring placement) and on study day 21 (3 weeks after vaginal ring placement).]

ATV PK Parameter Cmax Determined Based on ATV Levels From Individual Participants Enrolled in Arm C [Time Frame: Intensive ATV PK samples at pre-dose, 1, 3, 4, 5, and 8 hours post-dose on study day 0 (before vaginal ring placement) and on study day 21 (3 weeks after vaginal ring placement).]

RTV PK Parameter CLss/F Determined Based on RTV Levels From Individual Participants Enrolled in Arm C [Time Frame: Intensive RTV PK samples at pre-dose, 1, 3, 4, 5, and 8 hours post-dose on study day 0 (before vaginal ring placement) and on study day 21 (3 weeks after vaginal ring placement)]

ATV PK Parameter Time to Cmax (Tmax) Determined Based on ATV Levels From Individual Participants Enrolled in Arm C [Time Frame: Intensive ATV PK samples at pre-dose, 1, 3, 4, 5, and 8 hours post-dose on study day 0 (before vaginal ring placement) and on study day 21 (3 weeks after vaginal ring placement).]

Ethinyl Estradiol Concentrations Obtained on Study Days 7 and 14. [Time Frame: Study days 7 and 14]

RTV PK Parameter Cmax Determined Based on RTV Levels From Individual Participants Enrolled in Arm C [Time Frame: Intensive RTV PK samples at pre-dose, 1, 3, 4, 5, and 8 hours post-dose on study day 0 (before vaginal ring placement) and on study day 21 (3 weeks after vaginal ring placement)]

EFV PK Parameter Minimum Plasma Concentration (Cmin) Determined Based on EFV Levels From Individual Participants Enrolled in Arm B [Time Frame: Intensive EFV PK samples at pre-dose, 1, 3, 4, 5, and 8 hours post-dose on study day 0 (before vaginal ring placement) and on study day 21 (3 weeks after vaginal ring placement).]

ATV PK Parameter CLss/F Determined Based on ATV Levels From Individual Participants Enrolled in Arm C [Time Frame: Intensive ATV PK samples at pre-dose, 1, 3, 4, 5, and 8 hours post-dose on study day 0 (before vaginal ring placement) and on study day 21 (3 weeks after vaginal ring placement).]

Etonogestrel Concentrations Obtained on Study Days 7 and 14 [Time Frame: Study days 7 and 14]

RTV PK Parameter Tmax Determined Based on RTV Levels From Individual Participants Enrolled in Arm C [Time Frame: Intensive RTV PK samples at pre-dose, 1, 3, 4, 5, and 8 hours post-dose on study day 0 (before vaginal ring placement) and on study day 21 (3 weeks after vaginal ring placement)]

EFV PK Parameter Maximum Plasma Concentration (Cmax) Determined Based on EFV Levels From Individual Participants Enrolled in Arm B [Time Frame: Intensive EFV PK samples at pre-dose, 1, 3, 4, 5, and 8 hours post-dose on study day 0 (before vaginal ring placement) and on study day 21 (3 weeks after vaginal ring placement).]

RTV PK Parameter Cmin Determined Based on RTV Levels From Individual Participants Enrolled in Arm C [Time Frame: Intensive RTV PK samples at pre-dose, 1, 3, 4, 5, and 8 hours post-dose on study day 0 (before vaginal ring placement) and on study day 21 (3 weeks after vaginal ring placement)]

EFV PK Parameter Clearance (CLss/F) Determined Based on EFV Levels From Individual Participants Enrolled in Arm B [Time Frame: Intensive EFV PK samples at pre-dose, 1, 3, 4, 5, and 8 hours post-dose on study day 0 (before vaginal ring placement) and on study day 21 (3 weeks after vaginal ring placement).]

ATV PK Parameter AUC(0-24h) Calculated Based on Intensive Atazanavir (ATV) PK Samples Obtained From Individual Participants Enrolled in Arm C [Time Frame: Intensive ATV PK samples at pre-dose, 1, 3, 4, 5, and 8 hours post-dose on study day 0 (before vaginal ring placement) and on study day 21 (3 weeks after vaginal ring placement)]

ATV PK Parameter Cmin Determined Based on ATV Levels From Individual Participants Enrolled in Arm C [Time Frame: Intensive ATV PK samples at pre-dose, 1, 3, 4, 5, and 8 hours post-dose on study day 0 (before vaginal ring placement) and on study day 21 (3 weeks after vaginal ring placement).]

Percentage of Participants With Signs and Symptoms of Grade 2 or Higher Deemed Possibly, Probably or Definitely Related to Study Treatment [Time Frame: From day 0 to day 28]

Proportion of Participants With Plasma HIV-1 RNA Levels <40 Copies/mL [Time Frame: Study day 0 and study day 21]

Ritonavir (RTV) PK Parameter AUC(0-24h) Calculated Based on Intensive RTV PK Samples Obtained From Individual Participants Enrolled in Arm C [Time Frame: Intensive RTV PK samples at pre-dose, 1, 3, 4, 5, and 8 hours post-dose on study day 0 (before vaginal ring placement) and on study day 21 (3 weeks after vaginal ring placement)]

Proportion of Participants With Progesterone Levels Greater Than 5 ng/mL. [Time Frame: Study days 0, 7, 14, 21 and 28]

Secondary ID(s)

UM1AI068636

ACTG A5316

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

National Institute of Allergy and Infectious Diseases (NIAID)

Results

• Results available: Yes
• Date Posted: 04/01/2018
• URL: https://clinicaltrials.gov/ct2/show/results/NCT01903031