HIV-1, HIV Infections, Acquired Immunodeficiency Syndrome
Conditions
Keywords
HIV-1, HIV, Treatment-Experienced
Brief summary
The primary objective of this study is to evaluate the efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) fixed dose combination (FDC) plus darunavir (DRV) relative to current antiretroviral regimens (ARV) in virologically suppressed, HIV-1 positive participants with HIV-1 RNA \<50 copies/mL at Week 24. This study consists of 48 weeks of open-label phase followed by an optional Extension Phase in which all the participants will receive E/C/F/TAF+DRV.
Interventions
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Ability to understand and sign a written informed consent form * History of at least two prior antiretroviral regimens, and history of resistance to at least two different classes of antiretroviral agents * Plasma HIV-1 RNA levels \< 50 copies/mL at screening. Virologically suppressed on the current antiretroviral regimen containing darunavir 600 mg twice a day or 800 mg once daily continuously for ≥ 4 months preceding the screening visit and have maintained documented undetectable plasma HIV-1 RNA levels (\< 50 copies/mL) and must have documentation of genotype/phenotype prior to current regimen which shows no darunavir associated resistance mutation. * Currently receiving raltegravir, elvitegravir, or dolutegravir (50 mg once daily, but not twice daily), or have never received integrase inhibitor, or have documentation of genotype/phenotype within 12 months prior to current regimen which must show no evidence of resistance to integrase inhibitors * Normal ECG * Estimated glomerular filtration rate (eGFR) ≥ 50 mL/min according to the Cockcroft Gault formula for creatinine clearance * Hepatic transaminases (AST and ALT) ≤ 5 × upper limit of normal (ULN) * Total bilirubin ≤ 1.5 mg/dL, or normal direct bilirubin * Adequate hematologic function (absolute neutrophil count ≥ 1,000/mm\^3; platelets ≥ 50,000/mm\^3; hemoglobin ≥ 8.5 g/dL) * Serum amylase ≤ 5 × ULN (individuals with serum amylase \> 5 × ULN will remain eligible if serum lipase is ≤ 5 × ULN) * A female individual is eligible to enter the study if it is confirmed that she is: * Not pregnant or nursing * Of non-childbearing potential (i.e., women who have had a hysterectomy, have had both ovaries removed or medically documented ovarian failure, or are postmenopausal women \> 54 years of age with cessation (for ≥ 12 months) of previously occurring menses), or * Of childbearing potential and agrees to utilize highly effective contraception methods or be non-heterosexually active or practice sexual abstinence from screening throughout the duration of study treatment and for 30 days following the last study drug dose. * Female individuals 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. * Male individuals must agree to utilize a highly effective method of contraception during heterosexual intercourse or be non-heterosexually active, or practice sexual abstinence from first dose throughout the study period and for 30 days following the last study drug dose. * Male individuals must agree to refrain from sperm donation from first dose until at least 30 days after the last study drug dose. Key
Exclusion criteria
* A new AIDS-defining condition diagnosed within the 30 days prior to screening (except CD4 cell count and/or percentage criteria) * Hepatitis B surface antigen (HBsAg) positive * Individuals receiving drug treatment for Hepatitis C, or individuals who are anticipated to receive treatment for Hepatitis C during the course of the study. * Must not have Q151M, T69ins, or \> 3 thymidine analogue mutations (TAMS) present on documented historic genotype report * Individuals experiencing decompensated cirrhosis * Females who are breastfeeding * Positive serum pregnancy test * Have an implanted defibrillator or pacemaker * Current alcohol or substance use that may interfere with individual's study compliance * A 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 (other than HIV-1 infection) requiring parenteral antibiotic or antifungal therapy within 30 days prior to Day 1 visit * Any other clinical condition or prior therapy that would make the individual unsuitable for the study or unable to comply with dosing requirements * Participation in any other clinical trial (including observational trials) without prior approval from the sponsor is prohibited while participating in this trial * Individuals receiving ongoing therapy with any of the disallowed medications, including drugs not to be used with elvitegravir, cobicistat, emtricitabine, TAF, or DRV; or individuals with any known allergies to the study drugs. Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants in Each Treatment Arm in Cohort 2 With HIV-1 RNA < 50 Copies/mL at Week 24 | Week 24 | The percentage of participants achieving HIV-1 RNA \< 50 copies/mL at Week 24 was analyzed using the snapshot algorithm, 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 in Each Treatment Arm in Cohort 2 With HIV-1 RNA < 50 Copies/mL at Week 48 | Week 48 | The percentage of participants achieving HIV-1 RNA \< 50 copies/mL at Week 48 was analyzed using the snapshot algorithm, 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 CD4+ Cell Count at Week 24 | Baseline; Week 24 | — |
| Change From Baseline in CD4+ Cell Count at Week 48 | Baseline; Week 48 | — |
Countries
Canada, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in the United States and Canada. The first participant was screened on 3 September 2013. The last study visit occurred on 09 July 2016.
Pre-assignment details
231 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: E/C/F/TAF+DRV Open-Label Phase: E/C/F/TAF (150/150/200/10 mg) FDC tablet plus DRV (800 mg) tablet administered orally once daily with food for up to 48 weeks
Open-Label Extension Phase: E/C/F/TAF (150/150/200/10 mg) FDC tablet plus DRV (800 mg) tablet administered orally once daily | 21 |
| Cohort 2: E/C/F/TAF+DRV Open-Label Phase: E/C/F/TAF (150/150/200/10 mg) FDC tablet plus DRV (800 mg) tablet administered orally once daily with food for up to 48 weeks
Open-Label Extension Phase: E/C/F/TAF (150/150/200/10 mg) FDC tablet plus DRV (800 mg) tablet administered orally once daily | 89 |
| Cohort 2: SBR Open-Label Phase: Participants stayed on their baseline DRV- containing regimen administered according to the prescribing information for up to 48 weeks
Open-Label Extension Phase: E/C/F/TAF (150/150/200/10 mg) FDC tablet plus DRV (800 mg) tablet administered orally once daily | 46 |
| Total | 156 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Extension Phase | Adverse Event | 0 | 0 | 2 |
| Extension Phase | Death | 0 | 1 | 0 |
| Extension Phase | Lost to Follow-up | 1 | 0 | 1 |
| Extension Phase | Withdrew Consent | 0 | 0 | 1 |
| Open Label Phase (48 Weeks) | Investigator's Discretion | 0 | 1 | 0 |
| Open Label Phase (48 Weeks) | Lost to Follow-up | 0 | 0 | 2 |
| Open Label Phase (48 Weeks) | Randomized but Never Treated | 1 | 1 | 0 |
| Open Label Phase (48 Weeks) | Withdrew Consent | 1 | 1 | 3 |
Baseline characteristics
| Characteristic | Cohort 1: E/C/F/TAF+DRV | Total | Cohort 2: SBR | Cohort 2: E/C/F/TAF+DRV |
|---|---|---|---|---|
| Age, Continuous | 53 Years STANDARD_DEVIATION 5.7 | 49 Years STANDARD_DEVIATION 8.4 | 47 Years STANDARD_DEVIATION 9.4 | 49 Years STANDARD_DEVIATION 8.2 |
| CD4 Cell Count | 700 cells/µL STANDARD_DEVIATION 372.5 | 583 cells/µL STANDARD_DEVIATION 275.9 | 571 cells/µL STANDARD_DEVIATION 245.2 | 562 cells/µL STANDARD_DEVIATION 260.8 |
| CD4 Cell Count Category < 200 cells/µL | 1 participants | 7 participants | 1 participants | 5 participants |
| CD4 Cell Count Category ≥ 200 to < 350 cells/µL | 3 participants | 25 participants | 7 participants | 15 participants |
| CD4 Cell Count Category ≥ 350 cells/µL | 17 participants | 124 participants | 38 participants | 69 participants |
| HIV-1 RNA Category < 50 copies/mL | 19 participants | 152 participants | 46 participants | 87 participants |
| HIV-1 RNA Category ≥ 50 copies/mL | 2 participants | 4 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Asian | 0 participants | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Black | 12 participants | 73 participants | 26 participants | 35 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 2 participants | 21 participants | 7 participants | 12 participants |
| Race/Ethnicity, Customized Native Hawaiian or Pacific Islander | 0 participants | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 19 participants | 135 participants | 39 participants | 77 participants |
| Race/Ethnicity, Customized Not Permitted | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Other | 0 participants | 3 participants | 3 participants | 0 participants |
| Race/Ethnicity, Customized White | 9 participants | 77 participants | 17 participants | 51 participants |
| Region of Enrollment Canada | 0 participants | 12 participants | 3 participants | 9 participants |
| Region of Enrollment United States | 21 participants | 144 participants | 43 participants | 80 participants |
| Sex: Female, Male Female | 8 Participants | 42 Participants | 18 Participants | 16 Participants |
| Sex: Female, Male Male | 13 Participants | 114 Participants | 28 Participants | 73 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 13 / 21 | 56 / 89 | 28 / 46 | 104 / 144 |
| serious Total, serious adverse events | 1 / 21 | 9 / 89 | 1 / 46 | 20 / 144 |
Outcome results
Primary
Percentage of Participants in Each Treatment Arm in Cohort 2 With HIV-1 RNA < 50 Copies/mL at Week 24
The percentage of participants achieving HIV-1 RNA \< 50 copies/mL at Week 24 was analyzed using the snapshot algorithm, 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 (FAS) in Cohort 2, included all participants who (1) were randomized to Cohort 2 and (2) received at least 1 dose of study drug during the open-label Phase.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 2: E/C/F/TAF+DRV | Percentage of Participants in Each Treatment Arm in Cohort 2 With HIV-1 RNA < 50 Copies/mL at Week 24 | 96.6 percentage of participants |
| Cohort 2: Stay on Baseline Regimen (SBR) | Percentage of Participants in Each Treatment Arm in Cohort 2 With HIV-1 RNA < 50 Copies/mL at Week 24 | 91.3 percentage of participants |
p-value: 0.2395.001% CI: [-3.4, 17.4]Fisher Exact
Secondary
Change From Baseline in CD4+ Cell Count at Week 24
Time frame: Baseline; Week 24
Population: Full Analysis Set (FAS) included participants who (1) were randomized into Cohort 2 and (2) had received at least one dose of study drug during the OL phase of the study. Participants with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 2: E/C/F/TAF+DRV | Change From Baseline in CD4+ Cell Count at Week 24 | 23 cells/μL | Standard Deviation 155.2 |
| Cohort 2: Stay on Baseline Regimen (SBR) | Change From Baseline in CD4+ Cell Count at Week 24 | 12 cells/μL | Standard Deviation 100.9 |
Secondary
Change From Baseline in CD4+ Cell Count at Week 48
Time frame: Baseline; Week 48
Population: Full Analysis Set (FAS) included participants who (1) were randomized into Cohort 2 and (2) had received at least one dose of study drug during the OL phase of the study. Participants with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 2: E/C/F/TAF+DRV | Change From Baseline in CD4+ Cell Count at Week 48 | 5 cells/μL | Standard Deviation 162.6 |
| Cohort 2: Stay on Baseline Regimen (SBR) | Change From Baseline in CD4+ Cell Count at Week 48 | 41 cells/μL | Standard Deviation 104.2 |
Secondary
Percentage of Participants in Each Treatment Arm in Cohort 2 With HIV-1 RNA < 50 Copies/mL at Week 48
The percentage of participants achieving HIV-1 RNA \< 50 copies/mL at Week 48 was analyzed using the snapshot algorithm, 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 included participants who (1) were randomized into Cohort 2 and (2) had received at least one dose of study drug during the OL phase of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 2: E/C/F/TAF+DRV | Percentage of Participants in Each Treatment Arm in Cohort 2 With HIV-1 RNA < 50 Copies/mL at Week 48 | 94.4 percentage of participants |
| Cohort 2: Stay on Baseline Regimen (SBR) | Percentage of Participants in Each Treatment Arm in Cohort 2 With HIV-1 RNA < 50 Copies/mL at Week 48 | 76.1 percentage of participants |
p-value: 0.00495.001% CI: [3.5, 33]Fisher Exact