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Evaluating Pharmacokinetic Interactions With Vaginal Ring Contraceptives and ART

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01903031
Recruitment Status : Completed
First Posted : July 19, 2013
Results First Posted : January 4, 2018
Last Update Posted : June 6, 2018
Sponsor:
Collaborator:
National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by (Responsible Party):
AIDS Clinical Trials Group

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition HIV-1 Infection
Interventions Device: Nuvaring
Drug: EFV
Drug: ATV/r
Drug: TDF
Drug: NRTIs
Enrollment 84
Recruitment Details The first participant enrolled in December 2014 and final participant enrolled in September 2016. Enrollment took place at 21 US and non-US clinical research sites.
Pre-assignment Details  
Arm/Group Title NuvaRing and no ART NuvaRing With EFV Plus ≥2 NRTIs NuvaRing With ATV/r Plus TDF and ≥1 NRTIs
Hide Arm/Group Description Participants who were not on ART were prescribed NuvaRing, to be inserted at entry and removed at Day 21. NuvaRing was inserted at entry and removed at Day 21. Participants also received EFV 600 mg daily with two or more 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.
Period Title: Overall Study
Started 27 28 29
Completed 25 25 24
Not Completed 2 3 5
Reason Not Completed
Not Able to Attend Clinic             1             1             0
Missed Day 21 Primary Endpoint Visit             1             0             0
Adverse Event             0             1             0
Withdrawal by Subject             0             1             1
Protocol Violation             0             0             2
Lost to Follow-up             0             0             1
NuvaRing removed prior to Day 21 visit             0             0             1
Arm/Group Title NuvaRing and no ART NuvaRing With EFV Plus ≥2 NRTIs NuvaRing With ATV/r Plus TDF and ≥1 NRTIs Total
Hide Arm/Group Description Participants who were not on ART were prescribed NuvaRing, to be inserted at entry and removed at Day 21. NuvaRing was inserted at entry and removed at Day 21. Participants also received EFV 600 mg daily with two or more 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. Total of all reporting groups
Overall Number of Baseline Participants 27 28 29 84
Hide Baseline Analysis Population Description
All participants enrolled.
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 27 participants 28 participants 29 participants 84 participants
32
(22 to 48)
36
(17 to 55)
36
(22 to 50)
35
(17 to 55)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 27 participants 28 participants 29 participants 84 participants
Female 27 28 29 84
Male 0 0 0 0
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 27 participants 28 participants 29 participants 84 participants
White Non-Hispanic
1
   3.7%
1
   3.6%
1
   3.4%
3
   3.6%
Black Non-Hispanic
12
  44.4%
18
  64.3%
14
  48.3%
44
  52.4%
Hispanic (Regardless of Race)
11
  40.7%
9
  32.1%
9
  31.0%
29
  34.5%
Asian, Pacific Islander
3
  11.1%
0
   0.0%
5
  17.2%
8
   9.5%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 27 participants 28 participants 29 participants 84 participants
Puerto Rico
1
   3.7%
0
   0.0%
2
   6.9%
3
   3.6%
United States
5
  18.5%
14
  50.0%
15
  51.7%
34
  40.5%
Botswana
4
  14.8%
1
   3.6%
0
   0.0%
5
   6.0%
Brazil
3
  11.1%
6
  21.4%
5
  17.2%
14
  16.7%
South Africa
2
   7.4%
0
   0.0%
0
   0.0%
2
   2.4%
Kenya
3
  11.1%
3
  10.7%
2
   6.9%
8
   9.5%
Thailand
3
  11.1%
0
   0.0%
5
  17.2%
8
   9.5%
Peru
6
  22.2%
4
  14.3%
0
   0.0%
10
  11.9%
1.Primary Outcome
Title Etonogestrel Concentrations at Study Day 21
Hide Description 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).
Time Frame Day 21
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who provided the Etonogestrel PK sample at day 21 were included in the analysis.
Arm/Group Title NuvaRing and no ART NuvaRing With EFV Plus ≥2 NRTIs NuvaRing With ATV/r Plus TDF and ≥1 NRTIs
Hide Arm/Group Description:
Participants who were not on ART were prescribed NuvaRing, to be inserted at entry and removed at Day 21.
NuvaRing was inserted at entry and removed at Day 21. Participants also received EFV 600 mg daily with two or more 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.
Overall Number of Participants Analyzed 25 25 24
Median (Full Range)
Unit of Measure: pg/mL
1860.00
(665.00 to 3590.00)
429.00
(125.00 to 1180.00)
3290.00
(730.00 to 6920.00)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection NuvaRing and no ART, NuvaRing With EFV Plus ≥2 NRTIs
Comments 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.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments No adjustments for multiple comparisons were made. Statistical significance was declared if p<0.05.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection NuvaRing and no ART, NuvaRing With ATV/r Plus TDF and ≥1 NRTIs
Comments Null hypothesis: There is no difference in concentrations of Etonogestrel on day 21 between the control arm (NuvaRing and no ART) and NuvaRing with ATV/r plus TDF and ≥1 NRTIs.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments No adjustments for multiple comparisons were made. Statistical significance was declared if p<0.05.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
2.Primary Outcome
Title Ethinyl Estradiol Concentrations at Study Day 21
Hide Description 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).
Time Frame Day 21
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who provided the Ethinyl Estradiol PK sample at day 21 were included in the analysis.
Arm/Group Title NuvaRing and no ART NuvaRing With EFV Plus ≥2 NRTIs NuvaRing With ATV/r Plus TDF and ≥1 NRTIs
Hide Arm/Group Description:
Participants who were not on ART were prescribed NuvaRing, to be inserted at entry and removed at Day 21.
NuvaRing was inserted at entry and removed at Day 21. Participants also received EFV 600 mg daily with two or more 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.
Overall Number of Participants Analyzed 25 25 24
Median (Full Range)
Unit of Measure: pg/mL
21.30
(6.46 to 51.00)
11.40
(2.50 to 21.00)
16.05
(2.50 to 26.40)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection NuvaRing and no ART, NuvaRing With EFV Plus ≥2 NRTIs
Comments Null hypothesis: There is no difference in concentrations of Ethinyl Estradiol on day 21 between the control arm (NuvaRing and no ART) and NuvaRing with EFV plus ≥2 NRTIs.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments No adjustments for multiple comparisons were made. Statistical significance was declared if p<0.05.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection NuvaRing and no ART, NuvaRing With ATV/r Plus TDF and ≥1 NRTIs
Comments Null hypothesis: There is no difference in concentrations of Ethinyl Estradiol on day 21 between the control arm (NuvaRing and no ART) and NuvaRing with ATV/r plus TDF and ≥1 NRTIs.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.004
Comments No adjustments for multiple comparisons were made. Statistical significance was declared if p<0.05.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
3.Secondary Outcome
Title Etonogestrel Concentrations Obtained on Study Days 7 and 14
Hide Description 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).
Time Frame Study days 7 and 14
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who provided the Etonogestrel PK samples at day 7 and at day 14 were included in the analysis.
Arm/Group Title NuvaRing and no ART NuvaRing With EFV Plus ≥2 NRTIs NuvaRing With ATV/r Plus TDF and ≥1 NRTIs
Hide Arm/Group Description:
Participants who were not on ART were prescribed NuvaRing, to be inserted at entry and removed at Day 21.
NuvaRing was inserted at entry and removed at Day 21. Participants also received EFV 600 mg daily with two or more 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.
Overall Number of Participants Analyzed 25 25 24
Median (Full Range)
Unit of Measure: pg/mL
Concentration at Day 7 Number Analyzed 24 participants 25 participants 24 participants
1970.00
(703.00 to 3220.00)
427.00
(125.00 to 916.00)
3250.00
(1330.00 to 4960.00)
Concentration at Day 14 Number Analyzed 23 participants 25 participants 24 participants
2070.00
(648.00 to 3720.00)
437.00
(125.00 to 1090.00)
3530.00
(725.00 to 6100.00)
4.Secondary Outcome
Title Ethinyl Estradiol Concentrations Obtained on Study Days 7 and 14.
Hide Description 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).
Time Frame Study days 7 and 14
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who provided the Ethinyl estradiol PK samples at day 7 and at day 14 were included in the analysis.
Arm/Group Title NuvaRing and no ART NuvaRing With EFV Plus ≥2 NRTIs NuvaRing With ATV/r Plus TDF and ≥1 NRTIs
Hide Arm/Group Description:
Participants who were not on ART were prescribed NuvaRing, to be inserted at entry and removed at Day 21.
NuvaRing was inserted at entry and removed at Day 21. Participants also received EFV 600 mg daily with two or more 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.
Overall Number of Participants Analyzed 25 25 24
Median (Full Range)
Unit of Measure: pg/mL
Concentration at Day 7 Number Analyzed 24 participants 25 participants 24 participants
18.05
(6.71 to 50.90)
9.98
(2.50 to 18.70)
15.70
(5.48 to 24.30)
Concentration at Day 14 Number Analyzed 23 participants 25 participants 24 participants
19.70
(6.51 to 47.90)
10.50
(2.50 to 18.60)
16.55
(6.76 to 26.90)
5.Secondary Outcome
Title 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
Hide Description 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).
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).
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title NuvaRing With EFV Plus ≥2 NRTIs
Hide Arm/Group Description:
NuvaRing was inserted at entry and removed at Day 21. Participants also received EFV 600 mg daily with two or more NRTIs.
Overall Number of Participants Analyzed 24
Median (Full Range)
Unit of Measure: h*ng/mL
AUC0-24h day 0
68949.1
(27114.3 to 367995.4)
AUC0-24h day 21
57795.9
(26326.3 to 362821.3)
6.Secondary Outcome
Title EFV PK Parameter Minimum Plasma Concentration (Cmin) Determined Based on EFV Levels From Individual Participants Enrolled in Arm B
Hide Description 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.
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).
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title NuvaRing With EFV Plus ≥2 NRTIs
Hide Arm/Group Description:
NuvaRing was inserted at entry and removed at Day 21. Participants also received EFV 600 mg daily with two or more NRTIs.
Overall Number of Participants Analyzed 24
Median (Full Range)
Unit of Measure: ng/mL
Cmin day 0
2121.5
(903.7 to 13620.0)
Cmin day 21
1766.0
(10.0 to 12930.0)
7.Secondary Outcome
Title EFV PK Parameter Maximum Plasma Concentration (Cmax) Determined Based on EFV Levels From Individual Participants Enrolled in Arm B
Hide Description 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.
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).
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title NuvaRing With EFV Plus ≥2 NRTIs
Hide Arm/Group Description:
NuvaRing was inserted at entry and removed at Day 21. Participants also received EFV 600 mg daily with two or more NRTIs.
Overall Number of Participants Analyzed 24
Median (Full Range)
Unit of Measure: ng/mL
Cmax day 0
4541.0
(1347.0 to 18670.0)
Cmax day 21
3786.0
(2231.0 to 19110.0)
8.Secondary Outcome
Title EFV PK Parameter Clearance (CLss/F) Determined Based on EFV Levels From Individual Participants Enrolled in Arm B
Hide Description 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
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).
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title NuvaRing With EFV Plus ≥2 NRTIs
Hide Arm/Group Description:
NuvaRing was inserted at entry and removed at Day 21. Participants also received EFV 600 mg daily with two or more NRTIs.
Overall Number of Participants Analyzed 24
Median (Full Range)
Unit of Measure: L/h
CLss/F day 0
8.7
(1.6 to 22.1)
CLss/F day 21
10.4
(1.7 to 22.8)
9.Secondary Outcome
Title ATV PK Parameter AUC(0-24h) Calculated Based on Intensive Atazanavir (ATV) PK Samples Obtained From Individual Participants Enrolled in Arm C
Hide Description 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).
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)
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title NuvaRing With ATV/r Plus TDF and ≥1 NRTIs
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 23
Median (Full Range)
Unit of Measure: h*ng/mL
AUC0-24h day 0
44313.7
(8802.3 to 91766.5)
AUC0-24h day 21
36764.7
(1346.9 to 108450.6)
10.Secondary Outcome
Title ATV PK Parameter Cmin Determined Based on ATV Levels From Individual Participants Enrolled in Arm C
Hide Description 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.
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).
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title NuvaRing With ATV/r Plus TDF ≥1 NRTIs
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 23
Median (Full Range)
Unit of Measure: ng/mL
Cmin day 0
796.7
(10.0 to 2731.0)
Cmin day 21
599.4
(10.0 to 3599.0)
11.Secondary Outcome
Title ATV PK Parameter Cmax Determined Based on ATV Levels From Individual Participants Enrolled in Arm C
Hide Description 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.
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).
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title NuvaRing With ATV/r Plus TDF ≥1 NRTIs
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 23
Median (Full Range)
Unit of Measure: ng/mL
Cmax day 0
4291.0
(769.7 to 9440.0)
Cmax day 21
3583.0
(83.6 to 6578.0)
12.Secondary Outcome
Title ATV PK Parameter Time to Cmax (Tmax) Determined Based on ATV Levels From Individual Participants Enrolled in Arm C
Hide Description 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.
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).
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title NuvaRing With ATV/r Plus TDF ≥1 NRTIs
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 23
Median (Full Range)
Unit of Measure: hour
Tmax day 0
2.9
(0.9 to 4.0)
Tmax day 21
3.0
(0.0 to 5.0)
13.Secondary Outcome
Title ATV PK Parameter CLss/F Determined Based on ATV Levels From Individual Participants Enrolled in Arm C
Hide Description 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.
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).
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title NuvaRing With ATV/r Plus TDF ≥1 NRTIs
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 23
Median (Full Range)
Unit of Measure: L/h
CLss/F day 0
6.8
(3.3 to 34.1)
CLss/F day 21
8.2
(2.8 to 222.7)
14.Secondary Outcome
Title Ritonavir (RTV) PK Parameter AUC(0-24h) Calculated Based on Intensive RTV PK Samples Obtained From Individual Participants Enrolled in Arm C
Hide Description 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).
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)
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title NuvaRing With ATV/r Plus TDF and ≥1 NRTIs
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 23
Median (Full Range)
Unit of Measure: h*ng/mL
AUC0-24h day 0
10740.0
(3922.3 to 32632.7)
AUC0-24h day 21
7210.7
(240.0 to 31728.7)
15.Secondary Outcome
Title RTV PK Parameter Cmin Determined Based on RTV Levels From Individual Participants Enrolled in Arm C
Hide Description 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.
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)
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title NuvaRing With ATV/r Plus TDF and ≥1 NRTIs
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 23
Median (Full Range)
Unit of Measure: ng/mL
Cmin day 0
70.0
(10.0 to 1042.0)
Cmin day 21
51.9
(10.0 to 916.9)
16.Secondary Outcome
Title RTV PK Parameter Cmax Determined Based on RTV Levels From Individual Participants Enrolled in Arm C
Hide Description 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.
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)
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title NuvaRing With ATV/r Plus TDF and ≥1 NRTIs
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 23
Median (Full Range)
Unit of Measure: ng/mL
Cmax day 0
1437.0
(426.3 to 3078.0)
Cmax day 21
1063.0
(10.0 to 2297.0)
17.Secondary Outcome
Title RTV PK Parameter Tmax Determined Based on RTV Levels From Individual Participants Enrolled in Arm C
Hide Description 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.
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)
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title NuvaRing With ATV/r Plus TDF and ≥1 NRTIs
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 23
Median (Full Range)
Unit of Measure: hour
Tmax day 0
3.0
(0.9 to 5.0)
Tmax day 21
3.0
(0.0 to 5.0)
18.Secondary Outcome
Title RTV PK Parameter CLss/F Determined Based on RTV Levels From Individual Participants Enrolled in Arm C
Hide Description 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.
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)
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title NuvaRing With ATV/r Plus TDF and ≥1 NRTIs
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 23
Median (Full Range)
Unit of Measure: hour
CLss/F day 0
9.3
(3.1 to 25.5)
CLss/F day 21
13.9
(3.2 to 416.7)
19.Secondary Outcome
Title Proportion of Participants With Plasma HIV-1 RNA Levels <40 Copies/mL
Hide Description 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.
Time Frame Study day 0 and study day 21
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in whom NuvaRing was inserted and with HIV-1 RNA data available.
Arm/Group Title NuvaRing and no ART NuvaRing With EFV Plus ≥2 NRTIs NuvaRing With ATV/r Plus TDF and ≥1 NRTIs
Hide Arm/Group Description:
Participants who were not on ART were prescribed NuvaRing, to be inserted at entry and removed at Day 21.
NuvaRing was inserted at entry and removed at Day 21. Participants also received EFV 600 mg daily with two or more 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.
Overall Number of Participants Analyzed 27 28 28
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: proportion of participants
Proportion with HIV-1 RNA <40 copies/mL at day 0 Number Analyzed 23 participants 27 participants 28 participants
0.22
(0.07 to 0.44)
0.93
(0.76 to 0.99)
0.89
(0.72 to 0.98)
Proportion with HIV-1 RNA <40 copies/mL at day 21 Number Analyzed 24 participants 26 participants 27 participants
0.17
(0.05 to 0.37)
0.85
(0.65 to 0.96)
0.85
(0.66 to 0.96)
20.Secondary Outcome
Title Percentage of Participants With Signs and Symptoms of Grade 2 or Higher Deemed Possibly, Probably or Definitely Related to Study Treatment
Hide Description 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.
Time Frame From day 0 to day 28
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in whom NuvaRing was inserted
Arm/Group Title NuvaRing and no ART NuvaRing With EFV Plus ≥2 NRTIs NuvaRing With ATV/r Plus TDF and ≥1 NRTIs
Hide Arm/Group Description:
Participants who were not on ART were prescribed NuvaRing, to be inserted at entry and removed at Day 21.
NuvaRing was inserted at entry and removed at Day 21. Participants also received EFV 600 mg daily with two or more 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.
Overall Number of Participants Analyzed 27 28 28
Measure Type: Number
Unit of Measure: Percent of Participants
7.4 3.6 3.6
21.Secondary Outcome
Title Proportion of Participants With Progesterone Levels Greater Than 5 ng/mL.
Hide Description 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.
Time Frame Study days 0, 7, 14, 21 and 28
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title NuvaRing and no ART NuvaRing With EFV Plus ≥2 NRTIs NuvaRing With ATV/r Plus TDF and ≥1 NRTIs
Hide Arm/Group Description:
Participants who were not on ART were prescribed NuvaRing, to be inserted at entry and removed at Day 21.
NuvaRing was inserted at entry and removed at Day 21. Participants also received EFV 600 mg daily with two or more 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.
Overall Number of Participants Analyzed 25 25 24
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: proportion of participants
Proportion with progesterone >5 at day 0 Number Analyzed 25 participants 25 participants 24 participants
0.08
(0.01 to 0.26)
0.04
(0.00 to 0.20)
0.25
(0.10 to 0.47)
Proportion with progesterone >5 at day 7 Number Analyzed 24 participants 25 participants 24 participants
0.08
(0.01 to 0.27)
0.24
(0.09 to 0.45)
0.08
(0.01 to 0.27)
Proportion with progesterone >5 at day 14 Number Analyzed 24 participants 24 participants 24 participants
0.00
(0.00 to 0.14)
0.04
(0.00 to 0.21)
0.00
(0.00 to 0.14)
Proportion with progesterone >5 at day 21 Number Analyzed 25 participants 25 participants 24 participants
0.00
(0.00 to 0.14)
0.00
(0.00 to 0.14)
0.00
(0.00 to 0.14)
Proportion with progesterone >5 at day 28 Number Analyzed 24 participants 24 participants 24 participants
0.00
(0.00 to 0.14)
0.00
(0.00 to 0.14)
0.00
(0.00 to 0.14)
Time Frame From Day 0 to Day 28.
Adverse Event Reporting Description Protocol required reporting: diagnoses (identified by ACTG criteria for clinical events and other diseases); signs/symptoms of grade ≥3; selected signs/symptoms of grade ≤2 (gynecological and/or deemed related to the NuvaRing or study procedures); hematology, LFTs and chemistry findings of grade ≥2. The DAIDS AE Grading Table and Version 2.0 of the DAIDS EAE Manual were used. One participant on ATV/r arm was excluded from AE analyses because insertion of NuvaRing could not be confirmed.
 
Arm/Group Title NuvaRing and no ART NuvaRing With EFV Plus ≥2 NRTIs NuvaRing With ATV/r Plus TDF and ≥1 NRTIs
Hide Arm/Group Description Participants who were not on ART were prescribed NuvaRing, to be inserted at entry and removed at Day 21. NuvaRing was inserted at entry and removed at Day 21. Participants also received EFV 600 mg daily with two or more 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.
All-Cause Mortality
NuvaRing and no ART NuvaRing With EFV Plus ≥2 NRTIs NuvaRing With ATV/r Plus TDF and ≥1 NRTIs
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/27 (0.00%)   0/28 (0.00%)   0/28 (0.00%) 
Hide Serious Adverse Events
NuvaRing and no ART NuvaRing With EFV Plus ≥2 NRTIs NuvaRing With ATV/r Plus TDF and ≥1 NRTIs
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/27 (0.00%)   0/28 (0.00%)   0/28 (0.00%) 
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
NuvaRing and no ART NuvaRing With EFV Plus ≥2 NRTIs NuvaRing With ATV/r Plus TDF and ≥1 NRTIs
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   10/27 (37.04%)   20/28 (71.43%)   18/28 (64.29%) 
Infections and infestations       
Bacterial vaginosis  1  1/27 (3.70%)  3/28 (10.71%)  1/28 (3.57%) 
Vulvovaginal candidiasis  1  1/27 (3.70%)  2/28 (7.14%)  0/28 (0.00%) 
Investigations       
Blood bicarbonate decreased  1  0/27 (0.00%)  2/28 (7.14%)  0/28 (0.00%) 
Blood bilirubin increased  1  0/27 (0.00%)  0/28 (0.00%)  3/28 (10.71%) 
Blood glucose increased  1  2/27 (7.41%)  0/28 (0.00%)  1/28 (3.57%) 
Blood sodium decreased  1  3/27 (11.11%)  3/28 (10.71%)  2/28 (7.14%) 
Menstruation normal  1  1/27 (3.70%)  5/28 (17.86%)  8/28 (28.57%) 
Psychiatric disorders       
Libido decreased  1  0/27 (0.00%)  0/28 (0.00%)  2/28 (7.14%) 
Reproductive system and breast disorders       
Dysmenorrhoea  1  1/27 (3.70%)  1/28 (3.57%)  2/28 (7.14%) 
Metrorrhagia  1  1/27 (3.70%)  2/28 (7.14%)  1/28 (3.57%) 
Vaginal discharge  1  4/27 (14.81%)  8/28 (28.57%)  4/28 (14.29%) 
Vaginal haemorrhage  1  0/27 (0.00%)  4/28 (14.29%)  1/28 (3.57%) 
Vulvovaginal pruritus  1  2/27 (7.41%)  4/28 (14.29%)  1/28 (3.57%) 
1
Term from vocabulary, MedDRA 20.1
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
In accordance with the Clinical Trials Agreement between NIAID (DAIDS) and company collaborators, NIAID (DAIDS) provides companies with a copy of any abstract, press release, or manuscript prior to submission for publication with sufficient time for company review and comment. The publication/other disclosure can be delayed for up to 30 additional business days for manuscripts and five (5) business days for abstracts, to preserve U.S. or foreign patent or other intellectual property rights.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: ACTG Clinicaltrials.gov Coordinator
Organization: ACTG Network Coordinating Center, Social and Scientific Systems, Inc.
Phone: (301) 628-3313
EMail: ACTGCT.Gov@s-3.com
Layout table for additonal information
Responsible Party: AIDS Clinical Trials Group
ClinicalTrials.gov Identifier: NCT01903031    
Other Study ID Numbers: ACTG A5316
UM1AI068636 ( U.S. NIH Grant/Contract )
First Submitted: July 16, 2013
First Posted: July 19, 2013
Results First Submitted: December 1, 2017
Results First Posted: January 4, 2018
Last Update Posted: June 6, 2018