Acquired Immunodeficiency Syndrome, HIV Infections
Conditions
Keywords
HIV-1, HIV, Treatment Naïve, Treatment Experienced
Brief summary
This study is to evaluate the safety and tolerability of cobicistat-boosted darunavir plus two fully active nucleoside analogue reverse transcriptase inhibitors in HIV 1 infected, antiretroviral treatment-naive and treatment-experienced adults with no darunavir (DRV) resistance-associated mutations. After the Week 48 Visit, participants will be given the option to participate in an open-label rollover phase to receive cobicistat and attend visits every 12 weeks until it becomes commercially available, or until Gilead Sciences elects to terminate development of cobicistat.
Interventions
DRUGCOBI
150 mg tablet administered orally with food once daily
DRUGDRV
800 mg (2 x 400 mg tablets) administered orally with food once daily
DRUGNRTIs
Participants will receive 2 nucleoside analogue reverse transcriptase inhibitors (NRTIs) selected by the investigator after resistance testing at screening and administered according to prescribing information. NRTIs may include emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF), zidovudine+FTC/TDF, abacavir (ABC)+TDF, ABC+FTC/TDF, ABC+lamivudine (3TC), or didanosine (DDI)+FTC.
Sponsors
Janssen Research & Development, LLC
Gilead Sciences
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
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 that does not interfere with the assessments and the completion of the trial * Treatment Naive: No prior use of any approved or investigational antiretroviral drug for any length of time OR * Treatment Experienced: Stable antiretroviral regimen for at least 12 weeks prior to screening * Plasma HIV-1 RNA levels ≥ 1000 copies/mL at Screening * Screening genotype report shows full sensitivity to two nucleoside analogue reverse transcriptase inhibitors (NRTIs) and no darunavir resistance-associated mutations * Normal electrocardiogram (ECG) * Hepatic transaminases ≤ 2.5 × upper limit of normal (ULN) * Total bilirubin ≤ 1.5 mg/dL * Adequate hematologic function * Serum amylase ≤ 2 × ULN and serum lipase ≤ 3 × ULN * Adequate renal function: Estimated glomerular filtration rate ≥ 80 mL/min * Females of childbearing potential must agree to utilize protocol-recommended methods of contraception, or be nonheterosexually active, practice sexual abstinence or have a vasectomized partner from Screening throughout the duration of the study period and for 30 days following the last dose of study drug. * Male subjects must agree to utilize protocol-recommended methods of contraception during heterosexual intercourse from the Screening visit, throughout the duration of the study and for 30 days following discontinuation of investigational medicinal product or be nonheterosexually active, practice sexual abstinence, or be vasectomized.
Exclusion criteria
* Previous or current use of darunavir * A new AIDS-defining condition diagnosed within the 30 days prior to Screening * Females who are breastfeeding * Positive serum pregnancy test (if female of childbearing potential) * Proven or suspected acute hepatitis in the 30 days prior to study entry * Subjects receiving drug treatment for hepatitis C virus (HCV), or subjects who are anticipated to receive treatment for HCV during the course of the study * Have a history of ongoing active liver disease or experiencing decompensated cirrhosis irrespective of liver enzyme levels * Have an implanted defibrillator or pacemaker * Current alcohol or substance use that may interfere with subject study compliance * A history of malignancy within the past 5 years or ongoing malignancy other than cutaneous Kaposi's sarcoma * Active, serious infections requiring parenteral antibiotic or antifungal therapy within 30 days prior to Baseline * Participation in any other clinical trial * Any other clinical condition or prior therapy that would make the subject unsuitable for the study or unable to comply with the dosing requirements. * Subjects receiving ongoing therapy with any of the medications, including drugs not to be used with cobicistat, darunavir, or investigator selected NRTIs; or subjects with any known allergies to cobicistat tablets, darunavir tablets or contraindications for the 2 NRTIs as part of the regimen.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percentage of Participants With Onset of Any Treatment-emergent Grade 3 or 4 Adverse Event Between Baseline and Week 24 | Up to 24 weeks |
Secondary
| Measure | Time frame |
|---|---|
| Percentage of Participants Achieving HIV-1 RNA < 50 Copies/mL at Week 48 (Snapshot Analysis) | Week 48 |
| Change From Baseline in CD4+ Cell Count at Week 24 | Baseline; Week 24 |
| Percentage of Participants Achieving HIV-1 RNA < 50 Copies/mL at Week 24 (Snapshot Analysis) | Week 24 |
| Percentage of Participants Experiencing Any Treatment-emergent Adverse Event and Any Treatment-emergent Adverse Event Leading to Discontinuation of Study Drug Through Week 24 | Up to 24 weeks |
| Percentage of Participants Experiencing Any Treatment-emergent Adverse Event and Any Treatment-emergent Adverse Event Leading to Discontinuation of Study Drug Through Week 48 | Up to 48 weeks |
| 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 a total of 56 study sites in the United States. The first participant was screened on 22 September 2011. The last study visit occurred on 30 October 2015.
Pre-assignment details
397 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Treatment-Naive Treatment-naive participants received DRV (800 mg; 2 × 400 mg tablets) + COBI (1 × 150 mg tablet) once daily + two NRTIs (per prescribing information) for 48 weeks, and may have continued their regimen in the open-label rollover phase. | 295 |
| Treatment-Experienced Treatment-experienced participants received DRV (800 mg; 2 × 400 mg tablets) + COBI (1 × 150 mg tablet) once daily + two NRTIs (per prescribing information) for 48 weeks, and may have continued their regimen in the open-label rollover phase. | 18 |
| Total | 313 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Main Study | Adverse Event | 9 | 0 |
| Main Study | Enrolled but not treated | 1 | 0 |
| Main Study | Investigator's Discretion | 1 | 1 |
| Main Study | Lost to Follow-up | 13 | 2 |
| Main Study | Pregnancy | 1 | 0 |
| Main Study | Protocol Violation | 1 | 0 |
| Main Study | Subject Non-Compliance | 3 | 0 |
| Main Study | Withdrew Consent | 7 | 1 |
| Open-Label Rollover Phase | Adverse Event | 3 | 0 |
| Open-Label Rollover Phase | Investigator's Discretion | 3 | 1 |
| Open-Label Rollover Phase | Lack of Efficacy | 2 | 0 |
| Open-Label Rollover Phase | Lost to Follow-up | 26 | 3 |
| Open-Label Rollover Phase | Pregnancy | 1 | 0 |
| Open-Label Rollover Phase | Subject Non-Compliance | 1 | 1 |
| Open-Label Rollover Phase | Withdrew Consent | 11 | 1 |
Baseline characteristics
| Characteristic | Treatment-Experienced | Treatment-Naive | Total |
|---|---|---|---|
| Age, Continuous | 45 years STANDARD_DEVIATION 10.9 | 36 years STANDARD_DEVIATION 10.3 | 36 years STANDARD_DEVIATION 10.6 |
| Background Antiretroviral Regimen ABC/3TC | 0 participants | 1 participants | 1 participants |
| Background Antiretroviral Regimen ABC+FTC/TDF | 1 participants | 1 participants | 2 participants |
| Background Antiretroviral Regimen ABC+TDF | 1 participants | 2 participants | 3 participants |
| Background Antiretroviral Regimen AZT+FTC/TDF | 5 participants | 0 participants | 5 participants |
| Background Antiretroviral Regimen DDI+FTC | 1 participants | 0 participants | 1 participants |
| Background Antiretroviral Regimen FTC/TDF | 10 participants | 291 participants | 301 participants |
| CD4 Count (cells/mm^3) | 197.8 cells/mm^3 STANDARD_DEVIATION 214.3 | 378.2 cells/mm^3 STANDARD_DEVIATION 199.94 | 367.8 cells/mm^3 STANDARD_DEVIATION 204.79 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 64 Participants | 68 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 231 Participants | 245 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Gender Female | 5 Participants | 29 Participants | 34 Participants |
| Gender Male | 13 Participants | 266 Participants | 279 Participants |
| HIV-1 RNA (log10 copies/mL) | 4.8 log10 copies/mL STANDARD_DEVIATION 1.04 | 4.8 log10 copies/mL STANDARD_DEVIATION 0.76 | 4.8 log10 copies/mL STANDARD_DEVIATION 0.78 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants | 4 participants | 4 participants |
| Race/Ethnicity, Customized Asian | 0 participants | 4 participants | 4 participants |
| Race/Ethnicity, Customized Black or African Heritage | 7 participants | 101 participants | 108 participants |
| Race/Ethnicity, Customized Native Hawaiian or Pacific Islander | 0 participants | 2 participants | 2 participants |
| Race/Ethnicity, Customized Other | 0 participants | 8 participants | 8 participants |
| Race/Ethnicity, Customized White | 11 participants | 176 participants | 187 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 261 / 295 | 16 / 18 |
| serious Total, serious adverse events | 45 / 295 | 5 / 18 |
Outcome results
Primary
Percentage of Participants With Onset of Any Treatment-emergent Grade 3 or 4 Adverse Event Between Baseline and Week 24
Time frame: Up to 24 weeks
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment-Naive | Percentage of Participants With Onset of Any Treatment-emergent Grade 3 or 4 Adverse Event Between Baseline and Week 24 | 5.4 percentage of participants |
| Treatment-Experienced | Percentage of Participants With Onset of Any Treatment-emergent Grade 3 or 4 Adverse Event Between Baseline and Week 24 | 11.1 percentage of participants |
Secondary
Change From Baseline in CD4+ Cell Count at Week 24
Time frame: Baseline; Week 24
Population: Full Analysis Set; the Missing = Excluded method was used, where participants with missing data were excluded from the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment-Naive | Change From Baseline in CD4+ Cell Count at Week 24 | 145 cells/μL | Standard Deviation 131.6 |
| Treatment-Experienced | Change From Baseline in CD4+ Cell Count at Week 24 | 99 cells/μL | Standard Deviation 161.9 |
Secondary
Change From Baseline in CD4+ Cell Count at Week 48
Time frame: Baseline; Week 48
Population: Full Analysis Set; the Missing = Excluded method was used, where participants with missing data were excluded from the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment-Naive | Change From Baseline in CD4+ Cell Count at Week 48 | 194 cells/µL | Standard Deviation 152.1 |
| Treatment-Experienced | Change From Baseline in CD4+ Cell Count at Week 48 | 121 cells/µL | Standard Deviation 157 |
Secondary
Percentage of Participants Achieving HIV-1 RNA < 50 Copies/mL at Week 24 (Snapshot Analysis)
Time frame: Week 24
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment-Naive | Percentage of Participants Achieving HIV-1 RNA < 50 Copies/mL at Week 24 (Snapshot Analysis) | 83.7 percentage of participants |
| Treatment-Experienced | Percentage of Participants Achieving HIV-1 RNA < 50 Copies/mL at Week 24 (Snapshot Analysis) | 61.1 percentage of participants |
Secondary
Percentage of Participants Achieving HIV-1 RNA < 50 Copies/mL at Week 48 (Snapshot Analysis)
Time frame: Week 48
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment-Naive | Percentage of Participants Achieving HIV-1 RNA < 50 Copies/mL at Week 48 (Snapshot Analysis) | 82.7 percentage of participants |
| Treatment-Experienced | Percentage of Participants Achieving HIV-1 RNA < 50 Copies/mL at Week 48 (Snapshot Analysis) | 50.0 percentage of participants |
Secondary
Percentage of Participants Experiencing Any Treatment-emergent Adverse Event and Any Treatment-emergent Adverse Event Leading to Discontinuation of Study Drug Through Week 24
Time frame: Up to 24 weeks
Population: Full Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment-Naive | Percentage of Participants Experiencing Any Treatment-emergent Adverse Event and Any Treatment-emergent Adverse Event Leading to Discontinuation of Study Drug Through Week 24 | Any treatment-emergent adverse event (TEAE) | 88.1 percentage of participants |
| Treatment-Naive | Percentage of Participants Experiencing Any Treatment-emergent Adverse Event and Any Treatment-emergent Adverse Event Leading to Discontinuation of Study Drug Through Week 24 | Any TEAE that led to study drug discontinuation | 5.1 percentage of participants |
| Treatment-Experienced | Percentage of Participants Experiencing Any Treatment-emergent Adverse Event and Any Treatment-emergent Adverse Event Leading to Discontinuation of Study Drug Through Week 24 | Any treatment-emergent adverse event (TEAE) | 83.3 percentage of participants |
| Treatment-Experienced | Percentage of Participants Experiencing Any Treatment-emergent Adverse Event and Any Treatment-emergent Adverse Event Leading to Discontinuation of Study Drug Through Week 24 | Any TEAE that led to study drug discontinuation | 0 percentage of participants |
Secondary
Percentage of Participants Experiencing Any Treatment-emergent Adverse Event and Any Treatment-emergent Adverse Event Leading to Discontinuation of Study Drug Through Week 48
Time frame: Up to 48 weeks
Population: Full Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment-Naive | Percentage of Participants Experiencing Any Treatment-emergent Adverse Event and Any Treatment-emergent Adverse Event Leading to Discontinuation of Study Drug Through Week 48 | Any treatment-emergent adverse event (TEAE) | 91.5 percentage of participants |
| Treatment-Naive | Percentage of Participants Experiencing Any Treatment-emergent Adverse Event and Any Treatment-emergent Adverse Event Leading to Discontinuation of Study Drug Through Week 48 | Any TEAE that led to study drug discontinuation | 5.4 percentage of participants |
| Treatment-Experienced | Percentage of Participants Experiencing Any Treatment-emergent Adverse Event and Any Treatment-emergent Adverse Event Leading to Discontinuation of Study Drug Through Week 48 | Any treatment-emergent adverse event (TEAE) | 88.9 percentage of participants |
| Treatment-Experienced | Percentage of Participants Experiencing Any Treatment-emergent Adverse Event and Any Treatment-emergent Adverse Event Leading to Discontinuation of Study Drug Through Week 48 | Any TEAE that led to study drug discontinuation | 0 percentage of participants |