HIV, HIV Infections
Conditions
Keywords
HIV 1 Infection, Treatment Naive
Brief summary
To evaluate the safety and efficacy of Stribild®, a single tablet regimen (STR) containing fixed doses of elvitegravir (EVG)/cobicistat (COBI \[GS-9350\])/emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) versus ritonavir-boosted atazanavir (ATV/r) plus the standard of care nucleoside reverse transcriptase inhibitor (NRTI) backbone FTC/TDF (Truvada®). ATV/r + FTC/TDF was selected as the active comparator for this study as it is a preferred protease inhibitor-based regimen in guidelines for the treatment of HIV-1 infected, antiretroviral treatment-naive adults.
Interventions
DRUGStribild
Stribild (EVG 150 mg/COBI 150 mg/FTC 200 mg/TDF 300 mg) STR administered orally once daily
DRUGATV
Atazanavir 300 mg capsule administered orally once daily
DRUGRitonavir
Ritonavir (RTV; /r) 100 mg tablet administered orally once daily
DRUGFTC/TDF
FTC/TDF 200/300 mg tablet administered orally once daily
DRUGStribild Placebo
Placebo to match Stribild administered orally once daily
DRUGATV Placebo
Placebo to match ATV administered orally once daily
DRUGRTV Placebo
Placebo to match RTV administered orally once daily
DRUGFTC/TDF Placebo
Placebo to match FTC/TDF administered orally once daily
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures * Plasma HIV-1 RNA levels ≥ 5,000 copies/mL at screening * No prior use of any approved or investigational antiretroviral drug for any length of time * Screening genotype report must show sensitivity to FTC, TDF, and ATV * Normal electrocardiogram (ECG) * Adequate renal function (estimated glomerular filtration rate ≥ 70 mL/min according to the Cockcroft Gault formula) * Hepatic transaminases (aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 x the upper limit of the normal range (ULN) * Total bilirubin ≤ 1.5 mg/dL, or normal direct bilirubin * Adequate hematologic function * Serum amylase ≤ 5 x ULN * Males and Females of childbearing potential must agree to utilize highly effective contraception methods from screening throughout the duration of study treatment and for 30 days following the last dose of study drug * Age ≥ 18 years * Life expectancy ≥ 1 year
Exclusion criteria
* A new acquired immunodeficiency syndrome (AIDS)-defining condition diagnosed within the 30 days prior to screening * Receiving drug treatment for hepatitis C, or anticipated to receive treatment for hepatitis C * Subjects experiencing decompensated cirrhosis * Females who are breastfeeding * Positive serum pregnancy test (female of childbearing potential) * Implanted defibrillator or pacemaker * Current alcohol or substance use judged by the Investigator to potentially interfere with subject study compliance * History of malignancy within the past 5 years or ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, noninvasive cutaneous squamous carcinoma * Active, serious infections (other than HIV-1 infection) requiring parenteral antibiotic or antifungal therapy within 30 days prior to baseline * Medications contraindicated for use with EVG, COBI, FTC, TDF, ATV, or ritonavir or subjects with any known allergies to the excipients of Stribild tablets, Truvada tablets, ATV capsules or ritonavir tablets * Participation in any other clinical trial without prior approval * Any other clinical condition or prior therapy that, in the opinion of the Investigator, would make the subject unsuitable for the study or unable to comply with the dosing requirements
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The Percentage of Participants With Virologic Success Using the Food and Drug Administration (FDA)-Defined Snapshot Analysis as Determined by the Achievement of HIV-1 Ribonucleic Acid (RNA) < 50 Copies/mL at Week 48 | Week 48 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage of Participants With Virologic Success Using the FDA-Defined Snapshot Analysis as Determined by the Achievement of HIV-1 RNA < 50 Copies/mL at Week 144 | Week 144 | — |
| The Percentage of Participants With Virologic Success Using the FDA-Defined Snapshot Analysis as Determined by the Achievement of HIV-1 RNA < 50 Copies/mL at Week 192 | Week 192 | — |
| The Percentage of Participants With Virologic Success Using the FDA-Defined Snapshot Analysis as Determined by the Achievement of HIV-1 RNA < 50 Copies/mL at Week 96 | Week 96 | — |
| The Change From Baseline in Cluster Determinant 4 (CD4) Cell Count at Weeks 48, 96, 144, and 192 | Baseline; Weeks 48, 96, 144, and 192 | Change = value of the relevant time point minus the baseline value |
| The Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 | Week 48 | — |
| The Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 50 Copies/mL at Week 48 Using the FDA-defined Time to Loss of Virologic Response (TLOVR) Algorithm | Week 48 | — |
Countries
Australia, Austria, Belgium, Canada, Denmark, France, Germany, Italy, Mexico, Netherlands, Portugal, Puerto Rico, Sweden, Switzerland, Thailand, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at 146 sites in 16 countries. The first participant was screened on 06 April 2010. The last study visit occurred on 18 September 2014.
Pre-assignment details
1017 subjects were screened.
Participants by arm
| Arm | Count |
|---|---|
| Stribild Stribild (EVG 150 mg/COBI 150 mg/FTC 200 mg/TDF 300 mg) plus placebo to match ATV/r + FTC/TDF once daily | 353 |
| ATV/r + FTC/TDF ATV/r 300/100 mg tablet plus FTC 200 mg/TDF 300 mg tablet plus placebo to match Stribild once daily | 355 |
| Total | 708 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 9 | 15 |
| Overall Study | Death | 1 | 3 |
| Overall Study | Investigator's Discretion | 5 | 8 |
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Lost to Follow-up | 24 | 20 |
| Overall Study | Participant Noncompliance | 12 | 10 |
| Overall Study | Participant Transferred to Another Study | 212 | 197 |
| Overall Study | Pregnancy | 2 | 2 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrew Consent | 18 | 30 |
Baseline characteristics
| Characteristic | Total | Stribild | ATV/r + FTC/TDF |
|---|---|---|---|
| Age, Continuous | 38 years STANDARD_DEVIATION 10.2 | 38 years STANDARD_DEVIATION 10.5 | 39 years STANDARD_DEVIATION 9.8 |
| CD4 Cell Count (/µL) 201 to ≤ 350 μL | 246 participants | 122 participants | 124 participants |
| CD4 Cell Count (/µL) 351 to ≤ 500 μL | 244 participants | 122 participants | 122 participants |
| CD4 Cell Count (/µL) > 500 μL | 125 participants | 55 participants | 70 participants |
| CD4 Cell Count (/µL) ≤ 50 μL | 17 participants | 12 participants | 5 participants |
| CD4 Cell Count (/µL) 51 to ≤ 200 μL | 76 participants | 42 participants | 34 participants |
| Hepatitis B Virus (HBV) Infection Status Indeterminate | 1 participants | 0 participants | 1 participants |
| Hepatitis B Virus (HBV) Infection Status Negative | 693 participants | 347 participants | 346 participants |
| Hepatitis B Virus (HBV) Infection Status Not done | 2 participants | 1 participants | 1 participants |
| Hepatitis B Virus (HBV) Infection Status Positive | 12 participants | 5 participants | 7 participants |
| Hepatitis C Virus (HCV) Infection Status Indeterminate | 0 participants | 0 participants | 0 participants |
| Hepatitis C Virus (HCV) Infection Status Negative | 679 participants | 335 participants | 344 participants |
| Hepatitis C Virus (HCV) Infection Status Not done | 1 participants | 0 participants | 1 participants |
| Hepatitis C Virus (HCV) Infection Status Positive | 28 participants | 18 participants | 10 participants |
| HIV-1 RNA Category (copies/mL) ≤ 100,000 copies/mL | 417 participants | 203 participants | 214 participants |
| HIV-1 RNA Category (copies/mL) > 100,000 copies/mL | 291 participants | 150 participants | 141 participants |
| HIV Disease Status AIDS | 56 participants | 32 participants | 24 participants |
| HIV Disease Status Asymptomatic | 578 participants | 285 participants | 293 participants |
| HIV Disease Status Symptomatic HIV Infections | 74 participants | 36 participants | 38 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 5 participants | 2 participants | 3 participants |
| Race/Ethnicity, Customized Asian | 34 participants | 17 participants | 17 participants |
| Race/Ethnicity, Customized Black or African Heritage | 119 participants | 72 participants | 47 participants |
| Race/Ethnicity, Customized Native Hawaiian or Pacific Islander | 3 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Other | 20 participants | 11 participants | 9 participants |
| Race/Ethnicity, Customized White | 527 participants | 250 participants | 277 participants |
| Region of Enrollment Australia | 62 participants | 30 participants | 32 participants |
| Region of Enrollment Austria | 20 participants | 12 participants | 8 participants |
| Region of Enrollment Belgium | 21 participants | 9 participants | 12 participants |
| Region of Enrollment Canada | 41 participants | 19 participants | 22 participants |
| Region of Enrollment Denmark | 3 participants | 1 participants | 2 participants |
| Region of Enrollment France | 46 participants | 23 participants | 23 participants |
| Region of Enrollment Germany | 65 participants | 29 participants | 36 participants |
| Region of Enrollment Italy | 14 participants | 9 participants | 5 participants |
| Region of Enrollment Mexico | 5 participants | 3 participants | 2 participants |
| Region of Enrollment Netherlands | 6 participants | 2 participants | 4 participants |
| Region of Enrollment Portugal | 3 participants | 1 participants | 2 participants |
| Region of Enrollment Sweden | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Switzerland | 2 participants | 0 participants | 2 participants |
| Region of Enrollment Thailand | 11 participants | 7 participants | 4 participants |
| Region of Enrollment United Kingdom | 26 participants | 11 participants | 15 participants |
| Region of Enrollment United States | 382 participants | 197 participants | 185 participants |
| Sex: Female, Male Female | 68 Participants | 29 Participants | 39 Participants |
| Sex: Female, Male Male | 640 Participants | 324 Participants | 316 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 326 / 353 | 326 / 355 |
| serious Total, serious adverse events | 58 / 353 | 62 / 355 |
Outcome results
Primary
The Percentage of Participants With Virologic Success Using the Food and Drug Administration (FDA)-Defined Snapshot Analysis as Determined by the Achievement of HIV-1 Ribonucleic Acid (RNA) < 50 Copies/mL at Week 48
Time frame: Week 48
Population: ITT analysis set: participants who were randomized into the study and received at least 1 dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stribild | The Percentage of Participants With Virologic Success Using the Food and Drug Administration (FDA)-Defined Snapshot Analysis as Determined by the Achievement of HIV-1 Ribonucleic Acid (RNA) < 50 Copies/mL at Week 48 | 89.5 percentage of participants |
| ATV/r + FTC/TDF | The Percentage of Participants With Virologic Success Using the Food and Drug Administration (FDA)-Defined Snapshot Analysis as Determined by the Achievement of HIV-1 Ribonucleic Acid (RNA) < 50 Copies/mL at Week 48 | 86.8 percentage of participants |
Comparison: The null hypothesis was that the Stribild group is at least 12% worse than the ATV/r + Truvada group with respect to percentage of participants achieving HIV-1 RNA \< 50 copies/mL (response rate as defined by the snapshot analysis algorithm) at Week 48; the alternative hypothesis was that the response rate in the Stribild group is less than 12% worse than that in the ATV/r + Truvada Group.95.2% CI: [-1.9, 7.8]
Secondary
The Change From Baseline in Cluster Determinant 4 (CD4) Cell Count at Weeks 48, 96, 144, and 192
Change = value of the relevant time point minus the baseline value
Time frame: Baseline; Weeks 48, 96, 144, and 192
Population: ITT analysis set. The missing = excluded (M = E) method was used in which participants with missing data were excluded from analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stribild | The Change From Baseline in Cluster Determinant 4 (CD4) Cell Count at Weeks 48, 96, 144, and 192 | Change at Wk 48 (Stribild, n=334; ATV/r, n=321) | 207 cells/µL | Standard Deviation 164.2 |
| Stribild | The Change From Baseline in Cluster Determinant 4 (CD4) Cell Count at Weeks 48, 96, 144, and 192 | Change at Wk 96 (Stribild, n=317; ATV/r, n=315) | 256 cells/µL | Standard Deviation 166.8 |
| Stribild | The Change From Baseline in Cluster Determinant 4 (CD4) Cell Count at Weeks 48, 96, 144, and 192 | Change at Wk 144 (Stribild, n=297; ATV/r, n=286) | 280 cells/µL | Standard Deviation 159.8 |
| Stribild | The Change From Baseline in Cluster Determinant 4 (CD4) Cell Count at Weeks 48, 96, 144, and 192 | Change at Wk 192 (Stribild, n=69; ATV/r, n=72) | 338 cells/µL | Standard Deviation 186.8 |
| ATV/r + FTC/TDF | The Change From Baseline in Cluster Determinant 4 (CD4) Cell Count at Weeks 48, 96, 144, and 192 | Change at Wk 192 (Stribild, n=69; ATV/r, n=72) | 340 cells/µL | Standard Deviation 224.2 |
| ATV/r + FTC/TDF | The Change From Baseline in Cluster Determinant 4 (CD4) Cell Count at Weeks 48, 96, 144, and 192 | Change at Wk 48 (Stribild, n=334; ATV/r, n=321) | 211 cells/µL | Standard Deviation 160.3 |
| ATV/r + FTC/TDF | The Change From Baseline in Cluster Determinant 4 (CD4) Cell Count at Weeks 48, 96, 144, and 192 | Change at Wk 144 (Stribild, n=297; ATV/r, n=286) | 293 cells/µL | Standard Deviation 211.5 |
| ATV/r + FTC/TDF | The Change From Baseline in Cluster Determinant 4 (CD4) Cell Count at Weeks 48, 96, 144, and 192 | Change at Wk 96 (Stribild, n=317; ATV/r, n=315) | 261 cells/µL | Standard Deviation 188 |
Secondary
The Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 50 Copies/mL at Week 48 Using the FDA-defined Time to Loss of Virologic Response (TLOVR) Algorithm
Time frame: Week 48
Population: ITT analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stribild | The Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 50 Copies/mL at Week 48 Using the FDA-defined Time to Loss of Virologic Response (TLOVR) Algorithm | 86.1 percentage of participants |
| ATV/r + FTC/TDF | The Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 50 Copies/mL at Week 48 Using the FDA-defined Time to Loss of Virologic Response (TLOVR) Algorithm | 84.8 percentage of participants |
Secondary
The Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48
Time frame: Week 48
Population: ITT analysis set. The missing = failure (M = F) method was used in which all missing data were considered as failure (HIV-1 RNA ≥ 50 copies/mL).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stribild | The Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 | 91.5 percentage of participants |
| ATV/r + FTC/TDF | The Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 | 88.5 percentage of participants |
Secondary
The Percentage of Participants With Virologic Success Using the FDA-Defined Snapshot Analysis as Determined by the Achievement of HIV-1 RNA < 50 Copies/mL at Week 144
Time frame: Week 144
Population: ITT Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stribild | The Percentage of Participants With Virologic Success Using the FDA-Defined Snapshot Analysis as Determined by the Achievement of HIV-1 RNA < 50 Copies/mL at Week 144 | 77.6 percentage of participants |
| ATV/r + FTC/TDF | The Percentage of Participants With Virologic Success Using the FDA-Defined Snapshot Analysis as Determined by the Achievement of HIV-1 RNA < 50 Copies/mL at Week 144 | 74.6 percentage of participants |
Secondary
The Percentage of Participants With Virologic Success Using the FDA-Defined Snapshot Analysis as Determined by the Achievement of HIV-1 RNA < 50 Copies/mL at Week 192
Time frame: Week 192
Population: Week 192 modified intent-to-treat (MITT) Analysis Set: Participants in the ITT analysis set, excluding those who either 1) transferred to other Gilead-sponsored studies after completing their Week 144 Visit and before the lower limit of the Week 192 analysis window, or 2) prematurely discontinued study drug prior to the Week 144 Visit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stribild | The Percentage of Participants With Virologic Success Using the FDA-Defined Snapshot Analysis as Determined by the Achievement of HIV-1 RNA < 50 Copies/mL at Week 192 | 78.4 percentage of participants |
| ATV/r + FTC/TDF | The Percentage of Participants With Virologic Success Using the FDA-Defined Snapshot Analysis as Determined by the Achievement of HIV-1 RNA < 50 Copies/mL at Week 192 | 73.1 percentage of participants |
Secondary
The Percentage of Participants With Virologic Success Using the FDA-Defined Snapshot Analysis as Determined by the Achievement of HIV-1 RNA < 50 Copies/mL at Week 96
Time frame: Week 96
Population: ITT Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stribild | The Percentage of Participants With Virologic Success Using the FDA-Defined Snapshot Analysis as Determined by the Achievement of HIV-1 RNA < 50 Copies/mL at Week 96 | 83.3 percentage of participants |
| ATV/r + FTC/TDF | The Percentage of Participants With Virologic Success Using the FDA-Defined Snapshot Analysis as Determined by the Achievement of HIV-1 RNA < 50 Copies/mL at Week 96 | 82.3 percentage of participants |