Evaluating Pharmacokinetic Interactions With Vaginal Ring Contraceptives and ART

NCT01903031 | Completed Phase 2 Results DMC

• 2 other identifiers: ACTG A5316UM1AI068636
• Study Type: interventional
• Target: 84
• Locations: 8 countries
• Sites: 21

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.

Conditions

HIV-1 Infection

Outcome Measures

Primary Outcomes (2)

• Etonogestrel Concentrations at Study Day 21

  This evaluates the effect of EFV and ATV/r on etonogestrel by measuring etonogestrel concentrations on all three study arms 21 days after NuvaRing administration. The pharmacokinetic (PK) blood sample for measurement of etonogestrel on study day 21 was taken before the NuvaRing was removed. The assay lower limit of quantification for etonogestrel was 250 pg/mL; values \< 250 were assigned a value of half the lower limit (ie, 125 pg/mL).

  Day 21

• Ethinyl Estradiol Concentrations at Study Day 21

  This evaluates the effect of EFV and ATV/r on ethinyl estradiol by measuring ethinyl estradiol concentrations on all three study arms 21 days after NuvaRing administration. The PK blood sample for measurement of ethinyl estradiol on study day 21 was taken before the NuvaRing was removed. The assay lower limit of quantification for ethinyl estradiol was 5 pg/mL ; values \< 5 were assigned a value of half the lower limit (ie, 2.5 pg/mL).

  Day 21

Secondary Outcomes (19)

• Etonogestrel Concentrations Obtained on Study Days 7 and 14

  Study days 7 and 14

• Ethinyl Estradiol Concentrations Obtained on Study Days 7 and 14.

  Study days 7 and 14

• 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

  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).

• EFV PK Parameter Minimum Plasma Concentration (Cmin) Determined Based on EFV Levels From Individual Participants Enrolled in Arm B

  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).

• EFV PK Parameter Maximum Plasma Concentration (Cmax) Determined Based on EFV Levels From Individual Participants Enrolled in Arm B

  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).

Study Arms (3)

NuvaRing and no ART (Arm A)

EXPERIMENTAL

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

Device: Nuvaring

NuvaRing with EFV plus ≥2 NRTIs (Arm B)

EXPERIMENTAL

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.

Device: Nuvaring; Drug: EFV; Drug: NRTIs

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

EXPERIMENTAL

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.

Device: Nuvaring; Drug: ATV/r; Drug: TDF; Drug: NRTIs

Interventions

Nuvaring 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.

Also known as: Etonogestrel/ethinyl estradiol vaginal ring

NuvaRing and no ART (Arm A); NuvaRing with ATV/r plus TDF + ≥1 NRTIs (Arm C); NuvaRing with EFV plus ≥2 NRTIs (Arm B)

EFV DRUG

Participants received EFV 600 mg daily with two or more NRTIs

Also known as: Efavirenz

NuvaRing with EFV plus ≥2 NRTIs (Arm B)

ATV/r DRUG

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

Also known as: Atazanavir/Ritonavir

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

TDF DRUG

Participants received 300 mg of tenofovir in Arm C

Also known as: Tenofovir Disoproxil Fumarate

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

NRTIs DRUG

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

Also known as: Nucleoside Reverse Transcriptase Inhibitor

NuvaRing with ATV/r plus TDF + ≥1 NRTIs (Arm C); NuvaRing with EFV plus ≥2 NRTIs (Arm B)

Eligibility Criteria

• Age: 16 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (21)

31788 Alabama CRS

Birmingham, Alabama, 35294, United States

Location

University of Southern California LA (5048)

Los Angeles, California, 90033, United States

Location

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

Los Angeles, California, 90095-1752, United States

Location

University of Colorado Denver NICHD CRS (5052)

Aurora, Colorado, 80045, United States

Location

University of Florida Jacksonville (5051)

Jacksonville, Florida, 32209, United States

Location

Rush University Cook County Hospital Chicago NICHD CRS (5083)

Chicago, Illinois, 60612, United States

Location

31786 New Jersey Medical School Clinical Research Center CRS

Newark, New Jersey, 07103, United States

Location

Columbia Physicians and Surgeons CRS (30329)

New York, New York, 10032, United States

Location

Jacobi Medical Center Bronx

The Bronx, New York, 10461, United States

Location

The Miriam Hosp. ACTG CRS (2951)

Providence, Rhode Island, 02906, United States

Location

Gaborone Prevention/Treatment Trials CRS (12701)

Gaborone, Botswana

Location

Instituto de Pesquisa Clinica Evandro Chagas (12101)

Rio de Janeiro, 21045, Brazil

Location

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

Kisumu, 40100, Kenya

Location

Investigaciones Medicas en Salud (INMENSA) (11302)

San Isidro, Lima region, Peru

Location

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

Lima, 18 PE, Peru

Location

Puerto Rico-AIDS CRS (5401)

San Juan, 00935, Puerto Rico

Location

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

San Juan, 00935, Puerto Rico

Location

San Juan Hospital PR NICHD CRS (5031)

San Juan, 00936, Puerto Rico

Location

Shandukani Research CRS (8051)

Johannesburg, Gauteng, 2038, South Africa

Location

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

Bangkok, Patumwan, 10330, Thailand

Location

31784 Chiang Mai University HIV Treatment CRS

Chiang Mai, 50200, Thailand

Location

Related Publications (1)

• 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.

  PMID: 31498109 DERIVED

Related Links

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

MeSH Terms

Interventions

efavirenz; atazanavir, ritonavir drug combination; Tenofovir

Intervention Hierarchy (Ancestors)

Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: ACTG Clinicaltrials.gov Coordinator
• Organization: ACTG Network Coordinating Center, Social and Scientific Systems, Inc.

ACTGCT.Gov@s-3.com

(301) 628-3313

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 16, 2013
• First Posted: July 19, 2013
• Study Start: December 30, 2014
• Primary Completion: October 3, 2016
• Study Completion: October 10, 2016
• Last Updated: June 6, 2018
• Results First Posted: January 4, 2018

Record last verified: 2018-05

Locations

BO (1); TH (2); PR (3); ZA (1); KE (1); PE (2); BR (1); US (10)