HIV-1 InfectionPhase 2NCT01903031
Evaluating Pharmacokinetic Interactions With Vaginal Ring Contraceptives and ART
A Phase 2 study testing Nuvaring, EFV and ATV/r in people with HIV-1 Infection, run by Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections at 21 sites in 8 countries.
Trial 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… Read more about this study
- Who is it for?
- Ages 16 years and older, women only
- Conditions the study is for
- HIV-1 Infection
- What is being tested?
- Nuvaring, EFV and ATV/r
- Type of treatment
- Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 84 participants
- Where
- 21 sitesin 8 countries
- Study dates
- 30 Dec 2014to 10 Oct 2016
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 16 years and older
- Women only
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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:
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- 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
21 sites in 8 countries.
21 sites in 8 countries
United States10 sites
University of Colorado Denver NICHD CRS (5052)
Aurora, Colorado, 80045
31788 Alabama CRS
Birmingham, Alabama, 35294
Rush University Cook County Hospital Chicago NICHD CRS (5083)
Chicago, Illinois, 60612
University of Florida Jacksonville (5051)
Jacksonville, Florida, 32209
University of Southern California LA (5048)
Los Angeles, California, 90033
David Geffen School of Medicine at UCLA NICHD CRS (5112)
Los Angeles, California, 90095-1752
Columbia Physicians and Surgeons CRS (30329)
New York, New York, 10032
31786 New Jersey Medical School Clinical Research Center CRS
Newark, New Jersey, 07103
The Miriam Hosp. ACTG CRS (2951)
Providence, Rhode Island, 02906
Jacobi Medical Center Bronx
The Bronx, New York, 10461
Puerto Rico3 sites
Puerto Rico-AIDS CRS (5401)
San Juan, 00935
University of Puerto Rico Pediatric HIV/AIDS Research Program CRS (6601)
San Juan, 00935
San Juan Hospital PR NICHD CRS (5031)
San Juan, 00936
Peru2 sites
Asociacion Civil Impacta Salud y Educacion - Miraf CRS (11301)
Lima, 18 PE
Investigaciones Medicas en Salud (INMENSA) (11302)
San Isidro, Lima region
Thailand2 sites
31802 Thai Red Cross AIDS Research Center Treatment (TRC-ARC Treatment) CRS
Bangkok, Patumwan, 10330
31784 Chiang Mai University HIV Treatment CRS
Chiang Mai, 50200
Brazil1 site
Instituto de Pesquisa Clinica Evandro Chagas (12101)
Rio de Janeiro, 21045
Kenya1 site
Kenya Medical Research Institute/Center for Disease Control (KEMRI/CDC) CRS (31460)
Kisumu, 40100
South Africa1 site
Shandukani Research CRS (8051)
Johannesburg, Gauteng, 2038
About this study
Official title: Evaluating Pharmacokinetic Interactions With Vaginal Ring Contraceptives and Antiretroviral Therapy (ART)
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.
Read the 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
- Being tested
- Nuvaring, EFV, ATV/r, TDF, NRTIs
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NuvaringDevice
Also called Etonogestrel/ethinyl estradiol vaginal ring
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.
EFVDrug
Also called Efavirenz
Participants received EFV 600 mg daily with two or more NRTIs
ATV/rDrug
Also called Atazanavir/Ritonavir
Participants received ATV/r 300 mg/ 100 mg daily with tenofovir and one or more additional NRTIs
TDFDrug
Also called Tenofovir Disoproxil Fumarate
Participants received 300 mg of tenofovir in Arm C
NRTIsDrug
Also called Nucleoside Reverse Transcriptase Inhibitor
Participants received two or more NRTIs in Arm B and one or more NRTIs in Arm C
| Study group | Role | What they receive |
|---|---|---|
| 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). Receives: 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. Receives: 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. Receives: Device: Nuvaring; Drug: ATV/r; Drug: TDF; Drug: NRTIs |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 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).
Measured: Day 21
Secondary outcomes (19)
Etonogestrel Concentrations Obtained on Study Days 7 and 14
This evaluates the effect of EFV and ATV/r on etonogestrel by measuring etonogestrel concentrations on all three study arms 7 and 14 days after NuvaRing administration. 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).
Measured: Study days 7 and 14
Ethinyl Estradiol Concentrations Obtained on Study Days 7 and 14.
This evaluates the effect of EFV and ATV/r on ethinyl estradiol by measuring ethinyl estradiol concentrations on all three study arms 7 and 14 days after NuvaRing administration. 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).
Measured: 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
This evaluates the effect of NuvaRing on the PK parameter AUC(0-24h) of EFV before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. AUC(0-24h) defines area under the concentration-time curve over the period of 24 hours (pre-dose concentration was used to impute concentration at 24h).
Measured: 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
This evaluates the effect of NuvaRing on the EFV PK parameter Cmin obtained from both sampling periods, before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. Cmin defines minimum concentration observed within the first 8 hours of the 24 hour dosing interval.
Measured: 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
This evaluates the effect of NuvaRing on the EFV PK parameter Cmax obtained from both sampling periods, before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. Cmax defines maximum concentration observed within the first 8 hours of the 24 hour dosing interval.
Measured: 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 Clearance (CLss/F) Determined Based on EFV Levels From Individual Participants Enrolled in Arm B
This evaluates the effect of NuvaRing on the EFV PK parameter CLss/F obtained from both sampling periods, before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. CLss/F defines apparent oral clearance
Measured: 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
This evaluates the effect of NuvaRing on the PK parameter AUC(0-24h) of ATV before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. AUC(0-24h) defines area under the concentration-time curve over the period of 24 hours (pre-dose concentration was used to impute concentration at 24h).
Measured: 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
This evaluates the effect of NuvaRing on the ATV PK parameter Cmin obtained from both sampling periods, before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. Cmin defines minimum concentration observed within the first 8 hours of the 24 hour dosing interval.
Measured: 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 Cmax Determined Based on ATV Levels From Individual Participants Enrolled in Arm C
This evaluates the effect of NuvaRing on the ATV PK parameter Cmax obtained from both sampling periods, before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. Cmax defines maximum concentration observed within the first 8 hours of the 24 hour dosing interval.
Measured: 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 Time to Cmax (Tmax) Determined Based on ATV Levels From Individual Participants Enrolled in Arm C
This evaluates the effect of NuvaRing on the ATV PK parameter Tmax obtained from both sampling periods, before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. Tmax defines time to maximum concentration since dose is initiated.
Measured: 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 CLss/F Determined Based on ATV Levels From Individual Participants Enrolled in Arm C
This evaluates the effect of NuvaRing on the ATV PK parameter CLss/F obtained from both sampling periods, before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. CLss/f defines apparent oral clearance.
Measured: 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).
Ritonavir (RTV) PK Parameter AUC(0-24h) Calculated Based on Intensive RTV PK Samples Obtained From Individual Participants Enrolled in Arm C
This evaluates the effect of NuvaRing on the PK parameter AUC(0-24h) of RTV before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. AUC(0-24h) defines area under the concentration-time curve over the period of 24 hours (pre-dose concentration was used to impute concentration at 24h).
Measured: 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)
RTV PK Parameter Cmin Determined Based on RTV Levels From Individual Participants Enrolled in Arm C
This evaluates the effect of NuvaRing on the PK parameter Cmin of RTV before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. Cmin defines minimum concentration observed within the first 8 hours of the 24 hour dosing interval.
Measured: 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)
RTV PK Parameter Cmax Determined Based on RTV Levels From Individual Participants Enrolled in Arm C
This evaluates the effect of NuvaRing on the PK parameter Cmax of RTV before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. Cmax defines maximum concentration observed within the first 8 hours of the 24 hour dosing interval.
Measured: 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)
RTV PK Parameter Tmax Determined Based on RTV Levels From Individual Participants Enrolled in Arm C
This evaluates the effect of NuvaRing on the PK parameter Tmax of RTV before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. Tmax defines time to maximum concentration since dose is initiated.
Measured: 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)
RTV PK Parameter CLss/F Determined Based on RTV Levels From Individual Participants Enrolled in Arm C
This evaluates the effect of NuvaRing on the PK parameter CLss/F of RTV before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. CLss/F defines apparent oral clearance.
Measured: 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 Plasma HIV-1 RNA Levels <40 Copies/mL
This evaluates the short-term impact of Nuvaring on virologic suppression in participants who have been administered Nuvaring alone or together with EFV or ATV/r by measuring proportion of participants with plasma HIV-1 RNA levels <40 copies/mL at study day 0 (before vaginal ring placement) and study day 21 (three weeks after vaginal ring placement). An FDA-approved HIV-1 RNA assay was required.
Measured: Study day 0 and study day 21
Percentage of Participants With Signs and Symptoms of Grade 2 or Higher Deemed Possibly, Probably or Definitely Related to Study Treatment
This evaluates toxicity and safety of NuvaRing alone, NuvaRing with EFV, and NuvaRing with ATV/r. Signs/symptoms were graded using the DAIDS AE Grading Table was used. Participants with sign(s)/symptom(s) of grade 2 (moderate), 3 (severe), 4 (potentially life-threatening) or 5 (death) are included in the percentage. Relationship to study treatment was determined by the study co-chairs and DAIDS clinical representative.
Measured: From day 0 to day 28
Proportion of Participants With Progesterone Levels Greater Than 5 ng/mL.
This evaluates alterations in progesterone levels due to the potential PK interaction between NuvaRing and the ARVs EFV and ATV/r by examining progesterone levels at study days 0 (before vaginal ring placement), 7, 14, and 21 (before vaginal ring removal), and study day 28, without regard to menstrual cycle status at study entry.
Measured: Study days 0, 7, 14, 21 and 28
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Jul 2013 (estimated)
- Study start30 Dec 2014
- Primary completion3 Oct 2016
- Study completion10 Oct 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for HIV-1 InfectionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 84 participants (actual)
Sponsor and investigators
- Lead sponsor
- Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
- Sponsor type
- Research network
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01903031
- Sponsor's protocol ID
- ACTG A5316
- Other IDs
- UM1AI068636
- Status last verified
- May 2018
- First submitted
- 16 Jul 2013
- Last updated
- 6 Jun 2018
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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.
PubMed 31498109
Study at a glance
From the registry record, last updated by the sponsor on 6 Jun 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Evaluating Pharmacokinetic Interactions With Vaginal Ring Contraceptives and Antiretroviral Therapy (ART)
- ClinicalTrials.gov ID
- NCT01903031
- Acronym / sponsor ID
- ACTG A5316
- Conditions
- HIV-1 Infection
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 84 participants (actual)
- Lead sponsor
- Advancing Clinical Therapeutics Globally for HIV/AIDS and Other InfectionsResearch network
- Collaborators
- National Institute of Allergy and Infectious Diseases (NIAID)
- Study start
- 30 Dec 2014 (actual)
- Primary completion
- 3 Oct 2016 (actual)
- Study completion
- 10 Oct 2016 (actual)
- First posted
- 19 Jul 2013 (estimated)
- Results
- Posted 4 Jan 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| NuvaRing and no ART (Arm A) | Experimental | Device: NuvaringOnce NuvaRing is inserted into the vagina, the ring should remain in place (not be removed) continuously for 3 weeks (21 days). |
| NuvaRing with EFV plus ≥2 NRTIs (Arm B) | Experimental | Device: Nuvaring, Drug: EFV, Drug: NRTIsOnce 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. |
| NuvaRing with ATV/r plus TDF + ≥1 NRTIs (Arm C) | Experimental | Device: Nuvaring, Drug: ATV/r, Drug: TDF, Drug: NRTIsOnce 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. |
Who may qualify
- Ages
- 16 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (21 listed)
- 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.
Key exclusion criteria (17 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| NuvaringAlso: Etonogestrel/ethinyl estradiol vaginal ringNuvaRing 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. | Device | NuvaRing and no ART (Arm A), NuvaRing with ATV/r plus TDF + ≥1 NRTIs (Arm C), NuvaRing with EFV plus ≥2 NRTIs (Arm B) |
| EFVAlso: EfavirenzParticipants received EFV 600 mg daily with two or more NRTIs | Drug | NuvaRing with EFV plus ≥2 NRTIs (Arm B) |
| ATV/rAlso: Atazanavir/RitonavirParticipants received ATV/r 300 mg/ 100 mg daily with tenofovir and one or more additional NRTIs | Drug | NuvaRing with ATV/r plus TDF + ≥1 NRTIs (Arm C) |
| TDFAlso: Tenofovir Disoproxil FumarateParticipants received 300 mg of tenofovir in Arm C | Drug | NuvaRing with ATV/r plus TDF + ≥1 NRTIs (Arm C) |
| NRTIsAlso: Nucleoside Reverse Transcriptase InhibitorParticipants received two or more NRTIs in Arm B and one or more NRTIs in Arm C | Drug | NuvaRing with ATV/r plus TDF + ≥1 NRTIs (Arm C), NuvaRing with EFV plus ≥2 NRTIs (Arm B) |
Primary outcome
Etonogestrel Concentrations at Study Day 21
Time frame: 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).
Ethinyl Estradiol Concentrations at Study Day 21
Time frame: 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).
19 secondary outcomes
Etonogestrel Concentrations Obtained on Study Days 7 and 14
Time frame: Study days 7 and 14
Ethinyl Estradiol Concentrations Obtained on Study Days 7 and 14.
Time frame: 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
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).
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).
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).
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).
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).
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).
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).
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)
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)
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)
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)
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)
Proportion of Participants With Plasma HIV-1 RNA Levels <40 Copies/mL
Time frame: Study day 0 and study day 21
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 Progesterone Levels Greater Than 5 ng/mL.
Time frame: Study days 0, 7, 14, 21 and 28
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Jun 2018.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 31498109Scarsi 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.
- 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).Link provided by the sponsor.
- Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010Link provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
21 sites in 8 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Nuvaring, EFV and ATV/r in people with HIV-1 Infection, run by Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections at 21 sites in 8 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 21 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 6 Jun 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 21 sites in United States, Puerto Rico, Peru, Thailand, Botswana and 3 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 4 Jan 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Etonogestrel Concentrations at Study Day 21 (time frame: Day 21). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01903031, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Jun 2018.