Acquired Immunodeficiency Syndrome, HIV Infections
Conditions
Keywords
HIV-1, HIV, Treatment-Naive, Women, WAVES
Brief summary
The primary objective of this study is to evaluate the efficacy of a regimen containing elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF) versus ritonavir (RTV)-boosted atazanavir (ATV/r) plus emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) in HIV-1 infected, antiretroviral treatment-naive adult women.
Interventions
DRUGE/C/F/TDF
150/150/200/300 mg FDC tablet administered orally with food once daily
DRUGATV
300 mg capsule administered orally with food once daily
DRUGRTV
100 mg tablet administered orally with food once daily
DRUGFTC/TDF
200/300 mg tablet administered orally with food once daily
Tablet administered orally with food once daily
DRUGATV Placebo
Tablet administered orally with food once daily
DRUGRTV Placebo
Capsule administered orally with food once daily
DRUGFTC/TDF Placebo
Tablet administered orally with food once daily
DRUGE/C/F/TAF
150/150/200/10 mg FDC tablet administered orally with food once daily
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Female (at birth), age ≥ 18 years * Ability to understand and sign a written informed consent form * Plasma HIV-1 RNA levels ≥ 500 copies/mL * No prior use of any approved or investigational antiretroviral drug for any length of time * Screening genotype report must show sensitivity to emtricitabine (FTC), tenofovir disoproxil fumarate (TDF) and atazanavir (ATV) boosted with ritonavir (RTV) * Normal ECG * Adequate renal function: Estimated glomerular filtration rate ≥ 70 mL/min according to the Cockcroft Gault formula * Hepatic transaminases ≤ 5 x upper limit of normal (ULN) * Total bilirubin ≤ 1.5 mg/dL * Adequate hematologic function * Serum amylase ≤ 5 x ULN * Women of childbearing potential must agree to utilize protocol recommended contraception methods or be non-heterosexually active, or practice sexual abstinence from screening throughout the duration of the study period and for 30 days following the last dose of study drug * Women who utilize hormonal contraceptive as one of their birth control methods must have used the same method for at least three months prior to study dosing. Key
Exclusion criteria
* A new AIDS defining condition diagnosed within the 30 days * Females receiving drug treatment for Hepatitis C, or females who are anticipated to receive treatment for Hepatitis C during the course of the study * Females experiencing decompensated cirrhosis * Females who are breastfeeding * Positive serum pregnancy test (female of childbearing potential) * Have an implanted defibrillator or pacemaker * Have an ECG pulse rate interval ≥ 220 msec * Current alcohol or substance use which may potentially interfere with the female's study compliance * History of malignancy within the past 5 years or ongoing malignancy other than cutaneous Kaposi's sarcoma (KS), basal cell carcinoma, or resected, non-invasive cutaneous squamous carcinoma * Active, serious infections requiring parenteral antibiotic or antifungal therapy within 30 days prior to baseline * Participation in any other clinical trial without prior approval * Any other clinical condition or prior therapy that would make the female unsuitable for the study or unable to comply with the dosing requirements * Females receiving ongoing therapy with any disallowed medications, including drugs not to be used with elvitegravir, cobicistat, FTC, TDF, ATV, RTV; or females with any known allergies to the excipients of Stribild® tablets, Truvada® tablets, atazanavir capsules or ritonavir tablets Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 of the Double-Blind Phase as Determined by the US FDA-Defined Snapshot Algorithm | Week 48 | The percentage of participants with HIV-1 RNA \< 50 copies/mL at Week 48 of the double-blind phase was analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in CD4+ Cell Count at Week 48 of the Double-Blind Phase | Baseline; Week 48 | — |
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 96 for the STB Group as Determined by the US FDA-Defined Snapshot Algorithm | Week 96 | The percentage of participants with HIV-1 RNA \< 50 copies/mL at Week 96 was analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. |
| Percentage of Participants Receiving STB or ATV+RTV+TVD With HIV-1 RNA < 50 Copies/mL at Week 48 of the Open-Label Extension Phase | Open-Label Extension Week 48 | The percentage of participants with HIV-1 RNA \< 50 copies/mL at Week 48 of the open-label phase was analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. |
| Change in CD4+ Cell Count at Week 48 of the Open-Label Extension Phase | Baseline; Open-Label Extension Week 48 | — |
Countries
Belgium, Dominican Republic, France, Italy, Mexico, Portugal, Puerto Rico, Russia, Thailand, Uganda, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in North America, Europe, Dominican Republic, Thailand, and Uganda. The first participant was screened on 24 October 2012. The last study visit occurred on 06 September 2018.
Pre-assignment details
810 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Double-Blind STB to Open-Label STB Double-Blind Phase: STB 150/150/200/300 mg FDC + ATV placebo + RTV placebo + TVD placebo orally once daily with food for 48 weeks
Open-Label Extension Phase: After 48 weeks of blinded treatment participants continued on the blinded treatment for 12 weeks and returned for an unblinding visit at Week 60. Participants who were virologically suppressed at Week 48 during the double-blind phase had the option to receive open-label STB FDC orally once daily with food for 48 weeks. | 289 |
| Double-Blind ATV+RTV+TVD to OL GEN or OL ATV+ RTV+TVD Double-Blind Phase: ATV 300 mg + RTV 100 mg + TVD (200/300 mg) FDC + STB placebo orally once daily with food for 48 weeks
Open-Label Extension Phase: After 48 weeks of blinded treatment participants continued on the blinded treatment for 12 weeks and returned for an unblinding visit at Week 60. Participants who were virologically suppressed at Week 48 during the double-blind phase had the option to be re-randomized and either receive open-label GEN 150/150/200/10 mg FDC or open-label ATV 300 mg + RTV 100 mg + TVD 200/300 mg FDC orally once daily with food for 48 weeks. | 286 |
| Total | 575 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Double-Blind Phase | Adverse Event | 3 | 10 | 0 | 0 |
| Double-Blind Phase | Lost to Follow-up | 12 | 16 | 0 | 0 |
| Double-Blind Phase | Non-Compliance with Study Drug | 4 | 5 | 0 | 0 |
| Double-Blind Phase | Pregnancy | 1 | 1 | 0 | 0 |
| Double-Blind Phase | Protocol Violation | 1 | 0 | 0 | 0 |
| Double-Blind Phase | Randomized but Not Treated | 4 | 4 | 0 | 0 |
| Double-Blind Phase | Withdrew Consent | 8 | 5 | 0 | 0 |
| Open-Label Extension Phase | Adverse Event | 3 | 0 | 0 | 1 |
| Open-Label Extension Phase | Death | 2 | 0 | 1 | 0 |
| Open-Label Extension Phase | Lost to Follow-up | 6 | 0 | 2 | 2 |
| Open-Label Extension Phase | Non-Compliance with Study Drug | 0 | 0 | 1 | 0 |
| Open-Label Extension Phase | Physician Decision | 0 | 0 | 2 | 0 |
| Open-Label Extension Phase | Pregnancy | 0 | 0 | 1 | 1 |
| Open-Label Extension Phase | Withdrew Consent | 4 | 0 | 4 | 1 |
Baseline characteristics
| Characteristic | Double-Blind ATV+RTV+TVD to OL GEN or OL ATV+ RTV+TVD | Total | Double-Blind STB to Open-Label STB |
|---|---|---|---|
| Age, Continuous | 36 years STANDARD_DEVIATION 9.7 | 36 years STANDARD_DEVIATION 9.9 | 36 years STANDARD_DEVIATION 10.1 |
| CD4 Cell Count | 385 cells/µL STANDARD_DEVIATION 210.2 | 381 cells/µL STANDARD_DEVIATION 204.8 | 376 cells/µL STANDARD_DEVIATION 199.6 |
| HIV-1 RNA Category ≤ 100,000 copies/mL | 214 Participants | 434 Participants | 220 Participants |
| HIV-1 RNA Category > 100,000 to ≤400,000 copies/mL | 50 Participants | 94 Participants | 44 Participants |
| HIV-1 RNA Category > 400,000 copies/mL | 22 Participants | 47 Participants | 25 Participants |
| Race/Ethnicity, Customized Asian | 17 Participants | 26 Participants | 9 Participants |
| Race/Ethnicity, Customized Black | 133 Participants | 276 Participants | 143 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 24 Participants | 44 Participants | 20 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 262 Participants | 531 Participants | 269 Participants |
| Race/Ethnicity, Customized Not Permitted | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 15 Participants | 24 Participants | 9 Participants |
| Race/Ethnicity, Customized White | 119 Participants | 247 Participants | 128 Participants |
| Region of Enrollment Belgium | 5 participants | 8 participants | 3 participants |
| Region of Enrollment Dominican Republic | 13 participants | 19 participants | 6 participants |
| Region of Enrollment France | 1 participants | 2 participants | 1 participants |
| Region of Enrollment Italy | 1 participants | 5 participants | 4 participants |
| Region of Enrollment Mexico | 1 participants | 4 participants | 3 participants |
| Region of Enrollment Portugal | 13 participants | 21 participants | 8 participants |
| Region of Enrollment Russia | 91 participants | 192 participants | 101 participants |
| Region of Enrollment Thailand | 15 participants | 24 participants | 9 participants |
| Region of Enrollment Uganda | 74 participants | 161 participants | 87 participants |
| Region of Enrollment United Kingdom | 12 participants | 20 participants | 8 participants |
| Region of Enrollment United States | 60 participants | 119 participants | 59 participants |
| Sex: Female, Male Female | 286 Participants | 575 Participants | 289 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 176 / 289 | 194 / 286 | 118 / 246 | 68 / 159 | 20 / 53 |
| serious Total, serious adverse events | 25 / 289 | 29 / 286 | 13 / 246 | 12 / 159 | 4 / 53 |
Outcome results
Primary
Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 of the Double-Blind Phase as Determined by the US FDA-Defined Snapshot Algorithm
The percentage of participants with HIV-1 RNA \< 50 copies/mL at Week 48 of the double-blind phase was analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status.
Time frame: Week 48
Population: Participants in the Intent-to-Treat (ITT) Analysis Set (randomized and received at least one dose of study drug) were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double-Blind STB | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 of the Double-Blind Phase as Determined by the US FDA-Defined Snapshot Algorithm | 87.2 percentage of participants |
| Double-Blind ATV+RTV+TVD | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 of the Double-Blind Phase as Determined by the US FDA-Defined Snapshot Algorithm | 80.8 percentage of participants |
95.2% CI: [0.4, 12.6]
Comparison: If noninferiority of STB versus ATV+RTV+TVD was established, the same 95.2% CI used in evaluating noninferiority was used to evaluate superiority. The baseline HIV-1 RNA and race stratum-stratified, 2-sided CMH test was also used to assess superiority as a secondary assessment.p-value: 0.03495.2% CI: [0.4, 12.6]Cochran-Mantel-Haenszel
Secondary
Change From Baseline in CD4+ Cell Count at Week 48 of the Double-Blind Phase
Time frame: Baseline; Week 48
Population: Participants in the ITT Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double-Blind STB | Change From Baseline in CD4+ Cell Count at Week 48 of the Double-Blind Phase | 221 cells/μL | Standard Deviation 165.1 |
| Double-Blind ATV+RTV+TVD | Change From Baseline in CD4+ Cell Count at Week 48 of the Double-Blind Phase | 212 cells/μL | Standard Deviation 176.8 |
Secondary
Change in CD4+ Cell Count at Week 48 of the Open-Label Extension Phase
Time frame: Baseline; Open-Label Extension Week 48
Population: Participants in the OLE ITT Analysis Set with available on-treatment data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double-Blind STB | Change in CD4+ Cell Count at Week 48 of the Open-Label Extension Phase | 265 cells/uL | Standard Deviation 190.4 |
| Double-Blind ATV+RTV+TVD | Change in CD4+ Cell Count at Week 48 of the Open-Label Extension Phase | 35 cells/uL | Standard Deviation 137.5 |
| Open-Label ATV + RTV + TVD | Change in CD4+ Cell Count at Week 48 of the Open-Label Extension Phase | 49 cells/uL | Standard Deviation 204.8 |
Secondary
Percentage of Participants Receiving STB or ATV+RTV+TVD With HIV-1 RNA < 50 Copies/mL at Week 48 of the Open-Label Extension Phase
The percentage of participants with HIV-1 RNA \< 50 copies/mL at Week 48 of the open-label phase was analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status.
Time frame: Open-Label Extension Week 48
Population: Participants in the OLE ITT Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double-Blind STB | Percentage of Participants Receiving STB or ATV+RTV+TVD With HIV-1 RNA < 50 Copies/mL at Week 48 of the Open-Label Extension Phase | 94.3 Percentage of participants |
| Double-Blind ATV+RTV+TVD | Percentage of Participants Receiving STB or ATV+RTV+TVD With HIV-1 RNA < 50 Copies/mL at Week 48 of the Open-Label Extension Phase | 86.8 Percentage of participants |
Secondary
Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 96 for the STB Group as Determined by the US FDA-Defined Snapshot Algorithm
The percentage of participants with HIV-1 RNA \< 50 copies/mL at Week 96 was analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status.
Time frame: Week 96
Population: Participants in the ITT Analysis Set who received STB through 96 weeks were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double-Blind STB | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 96 for the STB Group as Determined by the US FDA-Defined Snapshot Algorithm | 84.5 Percentage of participants |