Evaluating Pharmacokinetic Interactions With Vaginal Ring... | NCT01903031

NCT01903031

ID	Type	Description	Link
UM1AI068636	U.S. NIH Grant/Contract		View source

Status Module

Sponsor/Collaborators Module

Name	Class
National Institute of Allergy and Infectious Diseases (NIAID)	NIH

Oversight Module

Description Module

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
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

Name	Type	Description	Arm Group Labels	Other Names
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.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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

Measure	Description	Time Frame
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).	Study days 7 and 14

Eligibility Module

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.

Contacts/Locations Module

Facility	Status	City	State	ZIP	Country	Contacts
31788 Alabama CRS		Birmingham	Alabama	35294	United States
University of Southern California LA (5048)

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
31498109	Derived	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.

Label	URL
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).	View source

ID	Title	Description
FG000	NuvaRing and no ART	Participants who were not on ART were prescribed NuvaRing, to be inserted at entry and removed at Day 21.
FG001	NuvaRing With EFV Plus ≥2 NRTIs	NuvaRing was inserted at entry and removed at Day 21. Participants also received EFV 600 mg daily with two or more NRTIs.

Categories

Title	Measurements
	BG00032(22 to 48) BG00136(17 to 55) BG00236(22 to 50) BG003

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG00027 BG00128 BG002

Race/Ethnicity, Customized

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
White Non-Hispanic	BG0001 BG0011 BG002

Region of Enrollment

Count of Participants

Participants

Title

Denominators

Categories

Puerto Rico

Title	Measurements
	BG0001 BG0010 BG002

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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).

Participants who provided the Etonogestrel PK sample at day 21 were included in the analysis.

Posted

Median

Full Range

pg/mL

Day 21

ID	Title	Description
OG000	NuvaRing and no ART	Participants who were not on ART were prescribed NuvaRing, to be inserted at entry and removed at Day 21.
OG001	NuvaRing With EFV Plus ≥2 NRTIs	NuvaRing was inserted at entry and removed at Day 21. Participants also received EFV 600 mg daily with two or more NRTIs.
OG002	NuvaRing With ATV/r Plus TDF and ≥1 NRTIs	NuvaRing was inserted at entry and removed at Day 21. Participants also received ATV/r 300 mg/ 100 mg daily with tenofovir (TDF) 300 mg and 1 or more additional NRTIs.

Units	Counts
Participants	OG00025 OG00125 OG00224

Title

Denominators

Categories

Title	Measurements
	OG0001860.00(665.00 to 3590.00) OG001429.00(125.00 to 1180.00) OG0023290.00(730.00 to 6920.00)

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	Null hypothesis: There is no difference in concentrations of Etonogestrel on day 21 between the control arm (NuvaRing and no ART) and NuvaRing with EFV plus ≥2 NRTIs.	Wilcoxon (Mann-Whitney)		<0.001	No adjustments for multiple comparisons were made. Statistical significance was declared if p<0.05.													Other

Primary

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).

Participants who provided the Ethinyl Estradiol PK sample at day 21 were included in the analysis.

Posted

Median

Full Range

pg/mL

Day 21

ID	Title	Description
OG000	NuvaRing and no ART	Participants who were not on ART were prescribed NuvaRing, to be inserted at entry and removed at Day 21.
OG001	NuvaRing With EFV Plus ≥2 NRTIs	NuvaRing was inserted at entry and removed at Day 21. Participants also received EFV 600 mg daily with two or more NRTIs.
OG002	NuvaRing With ATV/r Plus TDF and ≥1 NRTIs	NuvaRing was inserted at entry and removed at Day 21. Participants also received ATV/r 300 mg/ 100 mg daily with tenofovir (TDF) 300 mg and 1 or more additional NRTIs.

Secondary

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).

Participants who provided the Etonogestrel PK samples at day 7 and at day 14 were included in the analysis.

Posted

Median

Full Range

pg/mL

Study days 7 and 14

ID	Title	Description
OG000	NuvaRing and no ART	Participants who were not on ART were prescribed NuvaRing, to be inserted at entry and removed at Day 21.
OG001	NuvaRing With EFV Plus ≥2 NRTIs	NuvaRing was inserted at entry and removed at Day 21. Participants also received EFV 600 mg daily with two or more NRTIs.
OG002	NuvaRing With ATV/r Plus TDF and ≥1 NRTIs	NuvaRing was inserted at entry and removed at Day 21. Participants also received ATV/r 300 mg/ 100 mg daily with tenofovir (TDF) 300 mg and 1 or more additional NRTIs.

Secondary

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).

Participants who provided the Ethinyl estradiol PK samples at day 7 and at day 14 were included in the analysis.

Posted

Median

Full Range

pg/mL

Study days 7 and 14

ID	Title	Description
OG000	NuvaRing and no ART	Participants who were not on ART were prescribed NuvaRing, to be inserted at entry and removed at Day 21.
OG001	NuvaRing With EFV Plus ≥2 NRTIs	NuvaRing was inserted at entry and removed at Day 21. Participants also received EFV 600 mg daily with two or more NRTIs.
OG002	NuvaRing With ATV/r Plus TDF and ≥1 NRTIs	NuvaRing was inserted at entry and removed at Day 21. Participants also received ATV/r 300 mg/ 100 mg daily with tenofovir (TDF) 300 mg and 1 or more additional NRTIs.

Secondary

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).

The analysis population is the 24 A5316 participants enrolled in Arm B (NuvaRing with EFV arm plus 2 or more NRTIs) eligible for the secondary outcome of EFV PK parameters.

Posted

Median

Full Range

h*ng/mL

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).

ID	Title	Description
OG000	NuvaRing With EFV Plus ≥2 NRTIs	NuvaRing was inserted at entry and removed at Day 21. Participants also received EFV 600 mg daily with two or more NRTIs.

Units	Counts
Participants	OG000

Secondary

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.

The analysis population is the 24 A5316 participants enrolled in Arm B (NuvaRing with EFV arm plus 2 or more NRTIs) eligible for the secondary outcome of EFV PK parameters.

Posted

Median

Full Range

ng/mL

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).

ID	Title	Description
OG000	NuvaRing With EFV Plus ≥2 NRTIs	NuvaRing was inserted at entry and removed at Day 21. Participants also received EFV 600 mg daily with two or more NRTIs.

Units	Counts
Participants	OG000

Secondary

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.

The analysis population is the 24 A5316 participants enrolled in Arm B (NuvaRing with EFV arm plus 2 or more NRTIs) eligible for the secondary outcome of EFV PK parameters.

Posted

Median

Full Range

ng/mL

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).

ID	Title	Description
OG000	NuvaRing With EFV Plus ≥2 NRTIs	NuvaRing was inserted at entry and removed at Day 21. Participants also received EFV 600 mg daily with two or more NRTIs.

Units	Counts
Participants	OG000

Secondary

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

The analysis population is the 24 A5316 participants enrolled in Arm B (NuvaRing with EFV arm plus 2 or more NRTIs) eligible for the secondary outcome of EFV PK parameters.

Posted

Median

Full Range

L/h

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).

ID	Title	Description
OG000	NuvaRing With EFV Plus ≥2 NRTIs	NuvaRing was inserted at entry and removed at Day 21. Participants also received EFV 600 mg daily with two or more NRTIs.

Units	Counts
Participants	OG000

Secondary

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).

The analysis population is the 23 A5316 participants enrolled in Arm C (NuvaRing with ATV/r arm plus TDF and one or more NRTIs) eligible for the secondary outcome of ATV PK parameters.

Posted

Median

Full Range

h*ng/mL

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)

ID	Title	Description
OG000	NuvaRing With ATV/r Plus TDF and ≥1 NRTIs	NuvaRing was inserted at entry and removed at Day 21. Participants also received ATV/r 300 mg/ 100 mg daily with tenofovir (TDF) 300 mg and 1 or more additional NRTIs.

Units	Counts
Participants	OG000

Secondary

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.

The analysis population is the 23 A5316 participants enrolled in Arm C (NuvaRing with ATV/r arm plus TDF and one or more NRTIs) eligible for the secondary outcome of ATV PK parameters.

Posted

Median

Full Range

ng/mL

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).

ID	Title	Description
OG000	NuvaRing With ATV/r Plus TDF ≥1 NRTIs	NuvaRing was inserted at entry and removed at Day 21. Participants also received ATV/r 300 mg/ 100 mg daily with tenofovir (TDF) 300 mg and 1 or more additional NRTIs.

Units	Counts
Participants	OG000

Secondary

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.

The analysis population is the 23 A5316 participants enrolled in Arm C (NuvaRing with ATV/r arm plus TDF and one or more NRTIs) eligible for the secondary outcome of ATV PK parameters.

Posted

Median

Full Range

ng/mL

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).

ID	Title	Description
OG000	NuvaRing With ATV/r Plus TDF ≥1 NRTIs	NuvaRing was inserted at entry and removed at Day 21. Participants also received ATV/r 300 mg/ 100 mg daily with tenofovir (TDF) 300 mg and 1 or more additional NRTIs.

Units	Counts
Participants	OG000

Secondary

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.

The analysis population is the 23 A5316 participants enrolled in Arm C (NuvaRing with ATV/r arm plus TDF and one or more NRTIs) eligible for the secondary outcome of ATV PK parameters.

Posted

Median

Full Range

hour

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).

ID	Title	Description
OG000	NuvaRing With ATV/r Plus TDF ≥1 NRTIs	NuvaRing was inserted at entry and removed at Day 21. Participants also received ATV/r 300 mg/ 100 mg daily with tenofovir (TDF) 300 mg and 1 or more additional NRTIs.

Units	Counts
Participants	OG000

Secondary

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.

The analysis population is the 23 A5316 participants enrolled in Arm C (NuvaRing with ATV/r arm plus TDF and one or more NRTIs) eligible for the secondary outcome of ATV PK parameters.

Posted

Median

Full Range

L/h

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).

ID	Title	Description
OG000	NuvaRing With ATV/r Plus TDF ≥1 NRTIs	NuvaRing was inserted at entry and removed at Day 21. Participants also received ATV/r 300 mg/ 100 mg daily with tenofovir (TDF) 300 mg and 1 or more additional NRTIs.

Units	Counts
Participants	OG000

Secondary

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).

The analysis population is the 23 A5316 participants enrolled in Arm C (NuvaRing with ATV/r arm plus TDF and one or more NRTIs) eligible for the secondary outcome of RTV PK parameters.

Posted

Median

Full Range

h*ng/mL

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)

ID	Title	Description
OG000	NuvaRing With ATV/r Plus TDF and ≥1 NRTIs	NuvaRing was inserted at entry and removed at Day 21. Participants also received ATV/r 300 mg/ 100 mg daily with tenofovir (TDF) 300 mg and 1 or more additional NRTIs.

Units	Counts
Participants	OG000

Secondary

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.

The analysis population is the 23 A5316 participants enrolled in Arm C (NuvaRing with ATV/r arm plus TDF and one or more NRTIs) eligible for the secondary outcome of RTV PK parameters.

Posted

Median

Full Range

ng/mL

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)

ID	Title	Description
OG000	NuvaRing With ATV/r Plus TDF and ≥1 NRTIs	NuvaRing was inserted at entry and removed at Day 21. Participants also received ATV/r 300 mg/ 100 mg daily with tenofovir (TDF) 300 mg and 1 or more additional NRTIs.

Units	Counts
Participants	OG000

Secondary

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.

The analysis population is the 23 A5316 participants enrolled in Arm C (NuvaRing with ATV/r arm plus TDF and one or more NRTIs) eligible for the secondary outcome of RTV PK parameters.

Posted

Median

Full Range

ng/mL

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)

ID	Title	Description
OG000	NuvaRing With ATV/r Plus TDF and ≥1 NRTIs	NuvaRing was inserted at entry and removed at Day 21. Participants also received ATV/r 300 mg/ 100 mg daily with tenofovir (TDF) 300 mg and 1 or more additional NRTIs.

Units	Counts
Participants	OG000

Secondary

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.

The analysis population is the 23 A5316 participants enrolled in Arm C (NuvaRing with ATV/r arm plus TDF and one or more NRTIs) eligible for the secondary outcome of RTV PK parameters.

Posted

Median

Full Range

hour

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)

ID	Title	Description
OG000	NuvaRing With ATV/r Plus TDF and ≥1 NRTIs	NuvaRing was inserted at entry and removed at Day 21. Participants also received ATV/r 300 mg/ 100 mg daily with tenofovir (TDF) 300 mg and 1 or more additional NRTIs.

Units	Counts
Participants	OG000

Secondary

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.

The analysis population is the 23 A5316 participants enrolled in Arm C (NuvaRing with ATV/r arm plus TDF and one or more NRTIs) eligible for the secondary outcome of RTV PK parameters.

Posted

Median

Full Range

hour

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)

ID	Title	Description
OG000	NuvaRing With ATV/r Plus TDF and ≥1 NRTIs	NuvaRing was inserted at entry and removed at Day 21. Participants also received ATV/r 300 mg/ 100 mg daily with tenofovir (TDF) 300 mg and 1 or more additional NRTIs.

Units	Counts
Participants	OG000

Secondary

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.

All participants in whom NuvaRing was inserted and with HIV-1 RNA data available.

Posted

Number

95% Confidence Interval

proportion of participants

Study day 0 and study day 21

ID	Title	Description
OG000	NuvaRing and no ART	Participants who were not on ART were prescribed NuvaRing, to be inserted at entry and removed at Day 21.
OG001	NuvaRing With EFV Plus ≥2 NRTIs	NuvaRing was inserted at entry and removed at Day 21. Participants also received EFV 600 mg daily with two or more NRTIs.
OG002	NuvaRing With ATV/r Plus TDF and ≥1 NRTIs	NuvaRing was inserted at entry and removed at Day 21. Participants also received ATV/r 300 mg/ 100 mg daily with tenofovir (TDF) 300 mg and 1 or more additional NRTIs.

Secondary

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.

All participants in whom NuvaRing was inserted

Posted

Number

Percent of Participants

From day 0 to day 28

ID	Title	Description
OG000	NuvaRing and no ART	Participants who were not on ART were prescribed NuvaRing, to be inserted at entry and removed at Day 21.
OG001	NuvaRing With EFV Plus ≥2 NRTIs	NuvaRing was inserted at entry and removed at Day 21. Participants also received EFV 600 mg daily with two or more NRTIs.
OG002	NuvaRing With ATV/r Plus TDF and ≥1 NRTIs	NuvaRing was inserted at entry and removed at Day 21. Participants also received ATV/r 300 mg/ 100 mg daily with tenofovir (TDF) 300 mg and 1 or more additional NRTIs.

Secondary

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.

All participants included in the primary analyses who had progesterone data available. One participant on the EFV arm is excluded at day 14 visit because NuvaRing was out of the body for >3 hours leading up to the visit.

Posted

Number

95% Confidence Interval

proportion of participants

Study days 0, 7, 14, 21 and 28

ID	Title	Description
OG000	NuvaRing and no ART	Participants who were not on ART were prescribed NuvaRing, to be inserted at entry and removed at Day 21.
OG001	NuvaRing With EFV Plus ≥2 NRTIs	NuvaRing was inserted at entry and removed at Day 21. Participants also received EFV 600 mg daily with two or more NRTIs.
OG002	NuvaRing With ATV/r Plus TDF and ≥1 NRTIs	NuvaRing was inserted at entry and removed at Day 21. Participants also received ATV/r 300 mg/ 100 mg daily with tenofovir (TDF) 300 mg and 1 or more additional NRTIs.

Arm/Groups

ID	Title	Description	Deaths (At Risk)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	NuvaRing and no ART	Participants who were not on ART were prescribed NuvaRing, to be inserted at entry and removed at Day 21.	27	27	10	27
EG001	NuvaRing With EFV Plus ≥2 NRTIs	NuvaRing was inserted at entry and removed at Day 21. Participants also received EFV 600 mg daily with two or more NRTIs.	28	28	20	28
EG002	NuvaRing With ATV/r Plus TDF and ≥1 NRTIs	NuvaRing was inserted at entry and removed at Day 21. Participants also received ATV/r 300 mg/ 100 mg daily with tenofovir (TDF) 300 mg and 1 or more additional NRTIs.	28	28	18	28

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Bacterial vaginosis	Infections and infestations	MedDRA 20.1	Systematic Assessment	EG0001 affected27 at risk EG0013 affected28 at risk EG0021 affected28 at risk
Vulvovaginal candidiasis	Infections and infestations	MedDRA 20.1	Systematic Assessment	EG0001 affected27 at risk EG0012 affected28 at risk EG0020 affected28 at risk
Blood bicarbonate decreased	Investigations	MedDRA 20.1	Systematic Assessment	EG0000 affected27 at risk EG0012 affected28 at risk EG0020 affected28 at risk
Blood bilirubin increased	Investigations	MedDRA 20.1	Systematic Assessment	EG0000 affected27 at risk EG0010 affected28 at risk EG0023 affected28 at risk
Blood glucose increased	Investigations	MedDRA 20.1	Systematic Assessment	EG0002 affected27 at risk EG0010 affected28 at risk EG0021 affected28 at risk
Blood sodium decreased	Investigations	MedDRA 20.1	Systematic Assessment	EG0003 affected27 at risk EG0013 affected28 at risk EG0022 affected28 at risk
Menstruation normal	Investigations	MedDRA 20.1	Systematic Assessment	EG0001 affected27 at risk EG0015 affected28 at risk EG0028 affected28 at risk
Libido decreased	Psychiatric disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected27 at risk EG0010 affected28 at risk EG0022 affected28 at risk
Dysmenorrhoea	Reproductive system and breast disorders	MedDRA 20.1	Systematic Assessment	EG0001 affected27 at risk EG0011 affected28 at risk EG0022 affected28 at risk
Metrorrhagia	Reproductive system and breast disorders	MedDRA 20.1	Systematic Assessment	EG0001 affected27 at risk EG0012 affected28 at risk EG0021 affected28 at risk
Vaginal discharge	Reproductive system and breast disorders	MedDRA 20.1	Systematic Assessment	EG0004 affected27 at risk EG0018 affected28 at risk EG0024 affected28 at risk
Vaginal haemorrhage	Reproductive system and breast disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected27 at risk EG0014 affected28 at risk EG0021 affected28 at risk
Vulvovaginal pruritus	Reproductive system and breast disorders	MedDRA 20.1	Systematic Assessment	EG0002 affected27 at risk EG0014 affected28 at risk EG0021 affected28 at risk

ID	Term
C098320	efavirenz
C000718687	atazanavir, ritonavir drug combination
D000068698	Tenofovir

Ancestor Terms

ID	Term
D063065	Organophosphonates
D009943	Organophosphorus Compounds
D009930	Organic Chemicals
D000225	Adenine
D011687	Purines
D006574	Heterocyclic Compounds, 2-Ring
D000072471	Heterocyclic Compounds, Fused-Ring
D006571	Heterocyclic Compounds

Units	Counts
Participants	OG00025 OG00125 OG00224

Units	Counts
Participants	OG00025 OG00125 OG00224

OG001437.00(125.00 to 1090.00)

OG0023530.00(725.00 to 6100.00)

OG00110.50(2.50 to 18.60)

OG00216.55(6.76 to 26.90)

OG0010.85(0.65 to 0.96)

OG0020.85(0.66 to 0.96)

OG0010.24(0.09 to 0.45)

OG0020.08(0.01 to 0.27)

OG0010.04(0.00 to 0.21)

OG0020.00(0.00 to 0.14)

OG0010.00(0.00 to 0.14)

OG0020.00(0.00 to 0.14)

OG0010.00(0.00 to 0.14)

OG0020.00(0.00 to 0.14)

ID	Title	Description
BG000	NuvaRing and no ART	Participants who were not on ART were prescribed NuvaRing, to be inserted at entry and removed at Day 21.
BG001	NuvaRing With EFV Plus ≥2 NRTIs	NuvaRing was inserted at entry and removed at Day 21. Participants also received EFV 600 mg daily with two or more NRTIs.
BG002	NuvaRing With ATV/r Plus TDF and ≥1 NRTIs	NuvaRing was inserted at entry and removed at Day 21. Participants also received ATV/r 300 mg/ 100 mg daily with tenofovir (TDF) 300 mg and 1 or more additional NRTIs.
BG003	Total	Total of all reporting groups