Evaluating Pharmacokinetic Interactions With Vaginal Ring Contraceptives and ART

NCT ID: NCT01903031

Last Updated: 2018-06-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 84 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-12-30
• Study Completion Date: 2016-10-10

Brief Summary

This study was done to look at a method of hormonal birth control, called the NuvaRing, and specific anti-HIV medications, called antiretrovirals (ARVs). Some studies of women who use a hormonal birth control method (specifically oral pills, patches, and injections) and take ARVs have shown that ARVs interact with the hormones released by the birth control medication. These interactions may cause the birth control to be less effective at preventing pregnancy. There is also concern that hormonal birth control can increase HIV spreading to others, but more studies are needed to determine if this is true. The investigators did not know whether the NuvaRing and ARVs interact when they are used together, so this study looked to see if certain ARVs (efavirenz and atazanavir/ritonavir) interact with the two hormones released by NuvaRing. This will help us to determine if NuvaRing is safe and effective for women with HIV infection who are taking ARVs. The study also included HIV-infected women who were not on ARVs but used the NuvaRing to show us what the hormone levels are like in a similar group of women not on ARVs.

Vaginal rings are also currently being studied to deliver anti-HIV medications that may prevent HIV acquisition, and to provide birth control over a longer period of time (more than 1 month). Since vaginal rings will become more commonly used to administer medications, the investigators wanted to better understand the potential for drug interactions with drugs given vaginally. This study will also help us understand the potential for drug interactions between ARVs given orally, and other drugs given through vaginal rings, like the NuvaRing. Additionally, this study will help us understand how hormones released from a vaginal ring affect the amount of HIV virus in the genital tract, the bacterial make-up (microbiome) of the female genital tract, and the immune system within the genital tract, all of which may affect the chances of spreading HIV.

Detailed Description

This was a 28 day study from study entry through the final clinic visit. Post-entry visits were scheduled at Days 7, 14, 21 and 28. The Nuvaring was put in place at study entry and removed on day 21. A single pharmacokinetic (PK) blood sample was collected for assay of etonogestrel (ENG) and ethinyl estradiol (EE) at entry (day 0, prior to NuvaRing placement), and on days 7, 14, and 21 after placement of the NuvaRing. For participants on the ARV arms, intensive, 8-hour PK sampling, for assay of efavirenz (EFV) and atazanavir/ritonavir (ATV/RTV) respectively, was performed at study entry (day 0, prior to NuvaRing placement) and 21 days later. ARV sampling was performed at pre-dose (hour 0), and 1, 3, 4, 5, and 8 hours post-dose. Safety was assessed at each study visit.

Conditions

HIV-1 Infection

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

NuvaRing and no ART (Arm A)

Once NuvaRing is inserted into the vagina, the ring should remain in place (not be removed) continuously for 3 weeks (21 days).

Group Type: EXPERIMENTAL

Nuvaring

Intervention Type: DEVICE

NuvaRing is made of ethylene vinylacetate copolymers (28% and 9% vinylacetate) and magnesium stearate, is latex free, and contains 11.7 mg etonogestrel and 2.7 mg ethinyl estradiol. NuvaRing has an outer diameter of 54 mm and a cross-sectional diameter of 4mm. Once NuvaRing is inserted into the vagina, the ring should remain in place (not be removed) continuously for 3 weeks (21 days). After being in place for the first 21 days of the study, the ring may be removed after the day 21 study visit evaluations have been completed.

NuvaRing with EFV plus ≥2 NRTIs (Arm B)

Once NuvaRing is inserted into the vagina, the ring should remain in place (not be removed) continuously for 3 weeks (21 days). EFV is a non-nucleoside reverse transcriptase inhibitor taken at a dose of 600 mg once daily.

Group Type: EXPERIMENTAL

Nuvaring

Intervention Type: DEVICE

NuvaRing is made of ethylene vinylacetate copolymers (28% and 9% vinylacetate) and magnesium stearate, is latex free, and contains 11.7 mg etonogestrel and 2.7 mg ethinyl estradiol. NuvaRing has an outer diameter of 54 mm and a cross-sectional diameter of 4mm. Once NuvaRing is inserted into the vagina, the ring should remain in place (not be removed) continuously for 3 weeks (21 days). After being in place for the first 21 days of the study, the ring may be removed after the day 21 study visit evaluations have been completed.

EFV

Intervention Type: DRUG

Participants received EFV 600 mg daily with two or more NRTIs

NRTIs

Intervention Type: DRUG

Participants received two or more NRTIs in Arm B and one or more NRTIs in Arm C

NuvaRing with ATV/r plus TDF + ≥1 NRTIs (Arm C)

Once NuvaRing is inserted into the vagina, the ring should remain in place (not be removed) continuously for 3 weeks (21 days). ATV/r is a combination protease inhibitor taken at a dose of 300/100 mg once daily. Tenofovir disoproxil fumarate (TDF) is a nucleoside reverse transcriptase inhibitor (NRTI) taken at a dose of 300 mg daily.

Group Type: EXPERIMENTAL

Nuvaring

Intervention Type: DEVICE

NuvaRing is made of ethylene vinylacetate copolymers (28% and 9% vinylacetate) and magnesium stearate, is latex free, and contains 11.7 mg etonogestrel and 2.7 mg ethinyl estradiol. NuvaRing has an outer diameter of 54 mm and a cross-sectional diameter of 4mm. Once NuvaRing is inserted into the vagina, the ring should remain in place (not be removed) continuously for 3 weeks (21 days). After being in place for the first 21 days of the study, the ring may be removed after the day 21 study visit evaluations have been completed.

ATV/r

Intervention Type: DRUG

Participants received ATV/r 300 mg/ 100 mg daily with tenofovir and one or more additional NRTIs

TDF

Intervention Type: DRUG

Participants received 300 mg of tenofovir in Arm C

NRTIs

Intervention Type: DRUG

Participants received two or more NRTIs in Arm B and one or more NRTIs in Arm C

Interventions

Nuvaring

NuvaRing is made of ethylene vinylacetate copolymers (28% and 9% vinylacetate) and magnesium stearate, is latex free, and contains 11.7 mg etonogestrel and 2.7 mg ethinyl estradiol. NuvaRing has an outer diameter of 54 mm and a cross-sectional diameter of 4mm. Once NuvaRing is inserted into the vagina, the ring should remain in place (not be removed) continuously for 3 weeks (21 days). After being in place for the first 21 days of the study, the ring may be removed after the day 21 study visit evaluations have been completed.

Intervention Type: DEVICE

EFV

Participants received EFV 600 mg daily with two or more NRTIs

Intervention Type: DRUG

ATV/r

Participants received ATV/r 300 mg/ 100 mg daily with tenofovir and one or more additional NRTIs

Intervention Type: DRUG

TDF

Participants received 300 mg of tenofovir in Arm C

Intervention Type: DRUG

NRTIs

Participants received two or more NRTIs in Arm B and one or more NRTIs in Arm C

Intervention Type: DRUG

Other Intervention Names

Etonogestrel/ethinyl estradiol vaginal ring; Efavirenz; Atazanavir/Ritonavir; Tenofovir Disoproxil Fumarate; Nucleoside Reverse Transcriptase Inhibitor

Eligibility 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.

• Minimum Eligible Age: 16 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: collaborator

Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

31788 Alabama CRS

Birmingham, Alabama, United States

University of Southern California LA (5048)

Los Angeles, California, United States

David Geffen School of Medicine at UCLA NICHD CRS (5112)

Los Angeles, California, United States

University of Colorado Denver NICHD CRS (5052)

Aurora, Colorado, United States

University of Florida Jacksonville (5051)

Jacksonville, Florida, United States

Rush University Cook County Hospital Chicago NICHD CRS (5083)

Chicago, Illinois, United States

31786 New Jersey Medical School Clinical Research Center CRS

Newark, New Jersey, United States

Columbia Physicians and Surgeons CRS (30329)

New York, New York, United States

Jacobi Medical Center Bronx

The Bronx, New York, United States

The Miriam Hosp. ACTG CRS (2951)

Providence, Rhode Island, United States

Gaborone Prevention/Treatment Trials CRS (12701)

Gaborone, , Botswana

Instituto de Pesquisa Clinica Evandro Chagas (12101)

Rio de Janeiro, , Brazil

Kenya Medical Research Institute/Center for Disease Control (KEMRI/CDC) CRS (31460)

Kisumu, , Kenya

Investigaciones Medicas en Salud (INMENSA) (11302)

San Isidro, Lima region, Peru

Asociacion Civil Impacta Salud y Educacion - Miraf CRS (11301)

Lima, , Peru

Puerto Rico-AIDS CRS (5401)

San Juan, , Puerto Rico

University of Puerto Rico Pediatric HIV/AIDS Research Program CRS (6601)

San Juan, , Puerto Rico

San Juan Hospital PR NICHD CRS (5031)

San Juan, , Puerto Rico

Shandukani Research CRS (8051)

Johannesburg, Gauteng, South Africa

31802 Thai Red Cross AIDS Research Center Treatment (TRC-ARC Treatment) CRS

Bangkok, Patumwan, Thailand

31784 Chiang Mai University HIV Treatment CRS

Chiang Mai, , Thailand

Countries

United States; Botswana; Brazil; Kenya; Peru; Puerto Rico; South Africa; Thailand

References

Scarsi KK, Cramer YS, Rosenkranz SL, Aweeka F, Berzins B, Coombs RW, Coughlin K, Moran LE, Zorrilla CD, Akelo V, Aziz M, Friedman RK, Gingrich D, Swaminathan S, Godfrey C, Cohn SE; AIDS Clinical Trials Group A5316 Study Team. Antiretroviral therapy and vaginally administered contraceptive hormones: a three-arm, pharmacokinetic study. Lancet HIV. 2019 Sep;6(9):e601-e612. doi: 10.1016/S2352-3018(19)30155-9.

Reference Type: DERIVED

PMID: 31498109 (View on PubMed)

Related Links

http://rsc.tech-res.com/safetyandpharmacovigilance/

Location of DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004 (Clarification, August 2009).

http://rsc.tech-res.com/clinical-research-sites/safety-reporting/manual

Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010

Other Identifiers

UM1AI068636

Identifier Type: NIH

Identifier Source: secondary_id

View Link

ACTG A5316

Identifier Type: -

Identifier Source: org_study_id