Acquired Immunodeficiency Syndrome, HIV Infections
Conditions
Keywords
HIV-1, HIV, Treatment-Naive
Brief summary
This study is to evaluate the safety and efficacy darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) fixed dose combination (FDC) tablet versus darunavir (DRV)+cobicistat (COBI)+emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) in HIV-1 infected, antiretroviral treatment-naive adults as determined by the achievement of HIV-1 RNA \< 50 copies/mL at Week 24.
Interventions
DRUGD/C/F/TAF
DRV 800 mg/COBI 150 mg/FTC 200 mg/TAF 10 mg FDC tablet administered orally once daily
DRUGDRV
DRV 800 mg (2 × 400 mg tablets) administered orally once daily
DRUGCOBI
COBI 150 mg tablet administered orally once daily
DRUGFTC/TDF
FTC 200 mg/TDF 300 mg FDC tablet administered orally once daily
DRUGD/C/F/TAF Placebo
D/C/F/TAF placebo tablet administered orally once daily
DRUGDRV Placebo
DRV placebo tablet administered orally once daily
DRUGCOBI Placebo
COBI placebo tablet administered orally once daily
DRUGFTC/TDF Placebo
FTC/TDF placebo tablet administered orally once daily
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult (≥ 18 years) males or non-pregnant females * Ability to understand and sign a written informed consent form * General medical condition which does not interfere with the assessments and the completion of the trial * Plasma HIV-1 RNA levels ≥ 5,000 copies/mL * CD4+ cell count \> 50 cells/µL * Treatment-naive: No prior use of any approved or experimental anti-HIV drug for any length of time * Screening genotype report must show sensitivity to DRV, TDF and FTC * Normal ECG * Adequate renal function: Estimated glomerular filtration rate ≥ 70 mL/min according to the Cockcroft Gault formula * Hepatic transaminases ≤ 2.5 x upper limit of normal (ULN) * Total bilirubin ≤ 1.5 mg/dL * Serum amylase ≤ 5 x ULN * Adequate hematologic function * Normal thyroid-stimulating hormone (TSH) * Females of childbearing potential must have a negative serum pregnancy test * 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 drugs * Female subjects who are postmenopausal must have documentation of cessation of menses for ≥ 12 months and hormonal failure * Female subjects who have stopped menstruating for ≥ 12 months but do not have documentation of ovarian hormonal failure must have a serum follicle stimulating hormone (FSH) level test * Male subjects must agree to utilize a highly effective method of contraception during heterosexual intercourse throughout the study period and for 90 days following discontinuation of investigational medicinal product
Exclusion criteria
* A new AIDS defining condition diagnosed within the 30 days prior to screening * Hepatitis B surface antigen positive * Hepatitis C antibody positive * Proven acute hepatitis in the 30 days prior to study entry * Have a history or experiencing decompensated cirrhosis * Current alcohol or substance use that potentially interferes with study compliance * Any other clinical condition or prior therapy that would make the subject unsuitable for the study or unable to comply with the dosing requirements * 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 * Females who are breastfeeding * Positive serum pregnancy test (female of childbearing potential) * Female subjects who utilize non-estrogen hormonal contraceptive as one of their birth control methods must have used the same method for at least three months prior to study dosing * Have an implanted defibrillator or pacemaker * Active, serious infections (other than HIV-1 infection) requiring parenteral antibiotic or antifungal therapy within 30 days prior to Baseline * Participation in any other clinical trial without prior approval is prohibited while participating in this trial * Receiving ongoing therapy with any of the disallowed medications, including drugs not to be used with darunavir and cobicistat * Note: darunavir is a sulfonamide. Participants who previously experienced a sulfonamide allergy will be allowed to enter the trial. To date, no potential for cross sensitivity between drugs in the sulfonamide class and darunavir has been identified in patients participating in Phase 2 and Phase 3 trials.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 | Week 24 | The snapshot algorithm was used which defines a patient'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 |
|---|---|---|
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 | Week 48 | The snapshot algorithm was used which defines a patient'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 From Baseline in HIV-1 RNA at Week 24 | Baseline; Week 24 | — |
| Change From Baseline in HIV-1 RNA at Week 48 | Baseline; Week 48 | — |
| Change From Baseline in CD4+ Cell Count at Week 24 | Baseline; Week 24 | — |
| Change From Baseline in CD4+ Cell Count at Week 48 | Baseline; Week 48 | — |
Countries
Puerto Rico, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in the United States (including Puerto Rico). The first participant was screened on 16 April 2012. The last study visit occurred on 19 February 2014.
Pre-assignment details
232 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| D/C/F/TAF D/C/F/TAF (800/150/200/10 mg) FDC tablet plus DRV placebo plus COBI placebo plus FTC/TDF placebo once daily | 103 |
| DRV+COBI+FTC/TDF DRV 800 mg tablet plus COBI 150 mg tablet plus FTC/TDF 200/300 mg FDC tablet plus D/C/F/TAF placebo once daily | 50 |
| Total | 153 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Investigator's Discretion | 2 | 1 |
| Overall Study | Lost to Follow-up | 12 | 4 |
| Overall Study | Participant noncompliance | 2 | 0 |
| Overall Study | Withdrew Consent | 4 | 2 |
Baseline characteristics
| Characteristic | DRV+COBI+FTC/TDF | Total | D/C/F/TAF |
|---|---|---|---|
| Age, Continuous | 37 years STANDARD_DEVIATION 10.9 | 35 years STANDARD_DEVIATION 11.2 | 35 years STANDARD_DEVIATION 11.3 |
| CD4 Cell Count | 464 cells/µL STANDARD_DEVIATION 261.6 | 417 cells/µL STANDARD_DEVIATION 205.7 | 395 cells/µL STANDARD_DEVIATION 169.3 |
| CD4 Cell Count Category 200 to ≤ 349 cells/µL | 8 participants | 45 participants | 37 participants |
| CD4 Cell Count Category 351 to ≤ 499 cells/µL | 12 participants | 39 participants | 27 participants |
| CD4 Cell Count Category ≥ 500 cells/μL | 20 participants | 48 participants | 28 participants |
| CD4 Cell Count Category < 50 cells/μL | 1 participants | 2 participants | 1 participants |
| CD4 Cell Count Category 50 to ≤ 199 cells/µL | 9 participants | 19 participants | 10 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 32 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 41 Participants | 121 Participants | 80 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| HIV-1 RNA | 4.65 log10 copies/mL STANDARD_DEVIATION 0.514 | 4.68 log10 copies/mL STANDARD_DEVIATION 0.515 | 4.70 log10 copies/mL STANDARD_DEVIATION 0.516 |
| HIV-1 RNA Category ≤ 100,000 copies/mL | 43 participants | 123 participants | 80 participants |
| HIV-1 RNA Category > 100,000 to ≤ 400,000 copies/mL | 5 participants | 22 participants | 17 participants |
| HIV-1 RNA Category > 400,000 copies/mL | 2 participants | 8 participants | 6 participants |
| Race/Ethnicity, Customized Asian | 1 participants | 3 participants | 2 participants |
| Race/Ethnicity, Customized Black or African American | 17 participants | 53 participants | 36 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 participants | 2 participants | 1 participants |
| Race/Ethnicity, Customized Other | 1 participants | 3 participants | 2 participants |
| Race/Ethnicity, Customized White | 30 participants | 92 participants | 62 participants |
| Region of Enrollment United States | 50 participants | 153 participants | 103 participants |
| Sex: Female, Male Female | 3 Participants | 11 Participants | 8 Participants |
| Sex: Female, Male Male | 47 Participants | 142 Participants | 95 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 77 / 103 | 40 / 50 |
| serious Total, serious adverse events | 5 / 103 | 2 / 50 |
Outcome results
Primary
Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24
The snapshot algorithm was used which defines a patient'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 24
Population: Full Analysis Set: participant who were randomized;enrolled and received at least one dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| D/C/F/TAF | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 | 74.8 percentage of participants |
| DRV+COBI+FTC/TDF | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 | 74.0 percentage of participants |
Comparison: The null hypothesis was that the D/C/F/TAF group is at least 12% worse than the DRV+COBI+FTC/TDF group with respect to the percentage of participants achieving HIV-1 RNA \< 50 copies/mL (response rate as defined by the snapshot analysis algorithm) at Week 24; the alternative hypothesis was that the response rate in the D/C/F/TAF group is less than 12% worse than that in the DRV+COBI +FTC/TDF group.p-value: 0.6495% CI: [-11.4, 18.1]Cochran-Mantel-Haenszel
Secondary
Change From Baseline in CD4+ Cell Count at Week 24
Time frame: Baseline; Week 24
Population: Participants in the Full Analysis Set with Week 24 data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| D/C/F/TAF | Change From Baseline in CD4+ Cell Count at Week 24 | 186 cells/µL | Standard Deviation 137.9 |
| DRV+COBI+FTC/TDF | Change From Baseline in CD4+ Cell Count at Week 24 | 139 cells/µL | Standard Deviation 185.8 |
p-value: 0.1195% CI: [-10, 101]ANOVA
Secondary
Change From Baseline in CD4+ Cell Count at Week 48
Time frame: Baseline; Week 48
Population: Participants in the Full Analysis Set with Week 48 data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| D/C/F/TAF | Change From Baseline in CD4+ Cell Count at Week 48 | 231 cells/µL | Standard Deviation 141.9 |
| DRV+COBI+FTC/TDF | Change From Baseline in CD4+ Cell Count at Week 48 | 212 cells/µL | Standard Deviation 151.5 |
p-value: 0.595% CI: [-35, 72]ANOVA
Secondary
Change From Baseline in HIV-1 RNA at Week 24
Time frame: Baseline; Week 24
Population: Participants in the Full Analysis Set with Week 24 data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| D/C/F/TAF | Change From Baseline in HIV-1 RNA at Week 24 | -3.20 log10 copies/mL | Standard Deviation 0.653 |
| DRV+COBI+FTC/TDF | Change From Baseline in HIV-1 RNA at Week 24 | -3.18 log10 copies/mL | Standard Deviation 0.416 |
p-value: 0.6795% CI: [-0.14, 0.21]ANOVA
Secondary
Change From Baseline in HIV-1 RNA at Week 48
Time frame: Baseline; Week 48
Population: Participants in the Full Analysis Set with Week 48 data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| D/C/F/TAF | Change From Baseline in HIV-1 RNA at Week 48 | -3.27 log10 copies/mL | Standard Deviation 0.668 |
| DRV+COBI+FTC/TDF | Change From Baseline in HIV-1 RNA at Week 48 | -3.26 log10 copies/mL | Standard Deviation 0.521 |
p-value: 0.595% CI: [-0.11, 0.23]ANOVA
Secondary
Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48
The snapshot algorithm was used which defines a patient'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: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| D/C/F/TAF | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 | 76.7 percentage of participants |
| DRV+COBI+FTC/TDF | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 | 84.0 percentage of participants |
p-value: 0.3595% CI: [-19.9, 7.4]Cochran-Mantel-Haenszel