HIV, HIV Infections
Conditions
Keywords
HIV, HIV-1, Antiretroviral Treatment-Naive, treatment naive
Brief summary
The objective of this double-blinded, multicenter, randomized, active-controlled study is to evaluate the safety and efficacy of Stribild, a single-tablet regimen (STR) containing fixed doses of elvitegravir (EVG)/GS-9350 (cobicistat; COBI)/emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) versus efavirenz (EFV)/FTC/TDF (Atripla) in HIV-1 infected, antiretroviral treatment-naive adult participants. Stribild offers an alternative STR for patients who are not candidates for non-nucleoside reverse transcriptor (NNRTI)-based STRs. Participants will be randomized in a 2:1 ratio to receive Stribild or Atripla. Randomization will be stratified by HIV-1 RNA level (≤ 100,000 copies/mL or \> 100,000 copies/mL) at screening. After Week 48, participants will continue to take their blinded study drug and attend visits every 12 weeks until treatment assignments are unblinded (Week 60), at which point all participants will attend an Unblinding Visit and be given the option to participate in an open-label rollover extension (the extension is scheduled to be open until Stribild becomes commercially available, or until Gilead Sciences elects to terminate the study).
Interventions
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
* Plasma HIV-1 RNA levels ≥ 5,000 copies/mL * No prior use of any approved or experimental anti-HIV drug * Normal electrocardiogram (ECG) * Adequate renal function: estimated glomerular filtration rate ≥ 80 mL/min according to the Cockcroft-Gault formula * Hepatic transaminases ≤ 2.5 x upper limit of normal (ULN) * Total bilirubin ≤ 1.5 mg/dL, or normal direct bilirubin * Adequate hematologic function * Cluster determinant 4 (CD4) cell count \> 50 cells/µL * Serum amylase ≤ 1.5 x ULN * Normal thyroid-stimulating hormone * Negative serum pregnancy test (for females of childbearing potential only) * Males and females of childbearing potential must agree to utilize highly effective contraception methods from screening throughout the duration of study treatment and for 12 weeks following the last dose of study drugs * Life expectancy ≥ 1 year * Ability to understand and sign a written informed consent form
Exclusion criteria
* New acquired immunodeficiency syndrome (AIDS)-defining condition diagnosed within the 30 days prior to screening * Documented drug resistance to nucleoside reverse transcriptase inhibitors or nonnucleoside reverse transcriptase inhibitors or primary protease inhibitor resistance mutation(s) * Hepatitis B surface antigen positive * Hepatitis C antibody positive * Participants experiencing cirrhosis * Participants experiencing ascites * Participants experiencing encephalopathy * Females who are breastfeeding * Positive serum pregnancy test (for females of childbearing potential) * Vaccinated within 90 days of study dosing * History or family history of Long QT Syndrome or family history of sudden cardiac death or unexplained death in an otherwise healthy individual under the age of 30 * Presence or history of cardiovascular disease, cardiomyopathy, and/or cardiac conduction abnormalities * Prolonged QTcF interval at screening * PR interval ≥ 200 msec or ≤ 120 msec on ECG at screening * QRS ≥ 120 msec on ECG at screening * Implanted defibrillator or pacemaker * Participants receiving ongoing therapy with any disallowed medications * Current alcohol or substance use judged to potentially interfere with participant study compliance * History of or ongoing malignancy (including untreated carcinoma in situ) 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 * Participation in any other clinical trial without prior approval * Medications contraindicated for use with EFV, EVG, COBI, FTC, or TDF * Any known allergies to the excipients of Atripla or Stribild tablets * Any other clinical condition or prior therapy that would make the participant unsuitable for the study or unable to comply with the dosing requirements
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage of Participants With HIV-1 Ribonucleic Acid (RNA) Less Than 50 Copies/mL at Week 24 | Week 24 | The percentage of participants with plasma HIV-1 RNA \< 50 copies/mL at Week 24 was summarized. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage of Participants With HIV-1 RNA Less Than 50 Copies/mL at Week 48 | Week 48 | The percentage of participants with plasma HIV-1 RNA \< 50 copies/mL at Week 48 was summarized. |
| Change From Baseline in HIV-1 RNA (log_10 Copies/mL) | Baseline to Weeks 24 and 48 | Change = Week 24 or 48 value minus baseline value |
| Change From Baseline in Cluster Determinant 4 (CD4) Cell Count at Week 24 | Baseline to Week 24 | Change = Week 24 value minus baseline value |
| Change From Baseline in CD4 Cell Count at Week 48 | Baseline to Week 48 | Change = Week 48 value minus baseline value |
| The Percentage of Participants With Virologic Success at Weeks 24 and 48 Using FDA-Defined Snapshot Analysis and HIV-1 RNA Less Than 50 Copies/mL | Baseline to Weeks 24 and 48 | The percentage of participants with virologic success at Weeks 24 and 48 assessed using the FDA-defined snapshot analysis for an HIV-1 RNA cutoff of 50 copies/mL was summarized. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled in a total of 30 sites in the United States. The first participant was screened on 30 March 2009. Last participant visit: * Primary endpoint analysis (Week 24): November 2009 * Week 48 analysis: April 2010 * Week 96 analysis: March 2011 * End of study: September 2013
Pre-assignment details
126 participants were screened; 71 were randomized (48 to the Stribild group and 23 to the Atripla group). All randomized participants received at least 1 dose of study medication and comprised the safety and intent-to-treat (ITT) analysis sets. No site enrolled more than 7% of participants.
Participants by arm
| Arm | Count |
|---|---|
| Stribild Stribild QD and placebo to match Atripla QHS were administered during the double-blind phase. Stribild QD was administered during the extension phase. | 48 |
| Atripla Atripla QHS and placebo to match Stribild QD were administered during the double blind phase. Stribild QD was administered during the extension phase. | 23 |
| Total | 71 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Extension Phase | Adverse Event | 2 | 2 |
| Extension Phase | Investigator's Discretion | 2 | 0 |
| Extension Phase | Lack of Efficacy | 1 | 0 |
| Extension Phase | Lost to Follow-up | 3 | 1 |
| Extension Phase | Withdrew Consent | 2 | 0 |
| Randomized Phase | Investigator's Discretion | 1 | 0 |
| Randomized Phase | Lost to Follow-up | 2 | 1 |
| Randomized Phase | Withdrew Consent | 0 | 1 |
Baseline characteristics
| Characteristic | Stribild | Atripla | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 48 Participants | 23 Participants | 71 Participants |
| Age, Continuous | 36 years STANDARD_DEVIATION 8.9 | 35 years STANDARD_DEVIATION 9.6 | 36 years STANDARD_DEVIATION 9.1 |
| Cluster Determinant 4 (CD4) Cell Count (/µL) 201 to ≤ 350 | 17 participants | 8 participants | 25 participants |
| Cluster Determinant 4 (CD4) Cell Count (/µL) 351 to ≤ 500 | 14 participants | 5 participants | 19 participants |
| Cluster Determinant 4 (CD4) Cell Count (/µL) ≤ 50 | 0 participants | 0 participants | 0 participants |
| Cluster Determinant 4 (CD4) Cell Count (/µL) > 500 | 10 participants | 10 participants | 20 participants |
| Cluster Determinant 4 (CD4) Cell Count (/µL) 51 to ≤ 200 | 7 participants | 0 participants | 7 participants |
| Hepatitis B Virus (HBV) Infection Status Negative | 48 participants | 23 participants | 71 participants |
| Hepatitis B Virus (HBV) Infection Status Positive | 0 participants | 0 participants | 0 participants |
| Hepatitis C Virus (HCV) Infection Status Negative | 48 participants | 23 participants | 71 participants |
| Hepatitis C Virus (HCV) Infection Status Positive | 0 participants | 0 participants | 0 participants |
| HIV-1 RNA Category (copies/mL) ≤ 100,000 | 37 participants | 18 participants | 55 participants |
| HIV-1 RNA Category (copies/mL) > 100,000 | 11 participants | 5 participants | 16 participants |
| HIV Disease Status AIDS | 3 participants | 1 participants | 4 participants |
| HIV Disease Status Asymptomatic | 40 participants | 22 participants | 62 participants |
| HIV Disease Status Symptomatic HIV Infections | 5 participants | 0 participants | 5 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Asian | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Black | 12 participants | 5 participants | 17 participants |
| Race/Ethnicity, Customized Other | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White | 33 participants | 18 participants | 51 participants |
| Region of Enrollment United States | 48 participants | 23 participants | 71 participants |
| Sex: Female, Male Female | 4 Participants | 2 Participants | 6 Participants |
| Sex: Female, Male Male | 44 Participants | 21 Participants | 65 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 39 / 48 | 20 / 23 | 57 / 62 |
| serious Total, serious adverse events | 2 / 48 | 1 / 23 | 9 / 62 |
Outcome results
Primary
The Percentage of Participants With HIV-1 Ribonucleic Acid (RNA) Less Than 50 Copies/mL at Week 24
The percentage of participants with plasma HIV-1 RNA \< 50 copies/mL at Week 24 was summarized.
Time frame: Week 24
Population: ITT analysis set (all participants who were randomized into the study and received at least 1 dose of study drug). The missing = failure (M = F) analysis 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 Ribonucleic Acid (RNA) Less Than 50 Copies/mL at Week 24 | 89.6 percentage of participants |
| Atripla | The Percentage of Participants With HIV-1 Ribonucleic Acid (RNA) Less Than 50 Copies/mL at Week 24 | 87.0 percentage of participants |
Comparison: The null hypothesis was that the response rate (proportion of participants with HIV-1 RNA \< 50 copies/mL at Week 24) in the Stribild group was at least 12% worse than the response rate in Atripla group; the alternative hypothesis was that the response rate in the Stribild group was less than 12% worse than that in the Atripla group.95% CI: [-14.5, 20.1]
Secondary
Change From Baseline in CD4 Cell Count at Week 48
Change = Week 48 value minus baseline value
Time frame: Baseline to Week 48
Population: ITT analysis set; M = E analysis (all missing data were excluded from the analysis).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stribild | Change From Baseline in CD4 Cell Count at Week 48 | 240 cells/µL | Standard Deviation 172.8 |
| Atripla | Change From Baseline in CD4 Cell Count at Week 48 | 166 cells/µL | Standard Deviation 158.5 |
Secondary
Change From Baseline in Cluster Determinant 4 (CD4) Cell Count at Week 24
Change = Week 24 value minus baseline value
Time frame: Baseline to Week 24
Population: ITT analysis set. M = E analysis (all missing data were excluded from the analysis).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stribild | Change From Baseline in Cluster Determinant 4 (CD4) Cell Count at Week 24 | 161 cells/µL | Standard Deviation 141.1 |
| Atripla | Change From Baseline in Cluster Determinant 4 (CD4) Cell Count at Week 24 | 117 cells/µL | Standard Deviation 143.7 |
Secondary
Change From Baseline in HIV-1 RNA (log_10 Copies/mL)
Change = Week 24 or 48 value minus baseline value
Time frame: Baseline to Weeks 24 and 48
Population: ITT analysis set; The missing = excluded (M = E) analysis method was used in which all missing data were excluded from the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stribild | Change From Baseline in HIV-1 RNA (log_10 Copies/mL) | Baseline to Week 24 | -2.87 log_10 copies/mL | Standard Deviation 0.578 |
| Stribild | Change From Baseline in HIV-1 RNA (log_10 Copies/mL) | Baseline to Week 48 | -2.89 log_10 copies/mL | Standard Deviation 0.57 |
| Atripla | Change From Baseline in HIV-1 RNA (log_10 Copies/mL) | Baseline to Week 24 | -2.88 log_10 copies/mL | Standard Deviation 0.586 |
| Atripla | Change From Baseline in HIV-1 RNA (log_10 Copies/mL) | Baseline to Week 48 | -2.71 log_10 copies/mL | Standard Deviation 0.933 |
Secondary
The Percentage of Participants With HIV-1 RNA Less Than 50 Copies/mL at Week 48
The percentage of participants with plasma HIV-1 RNA \< 50 copies/mL at Week 48 was summarized.
Time frame: Week 48
Population: ITT analysis set; M = F analysis (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 Less Than 50 Copies/mL at Week 48 | 89.6 percentage of participants |
| Atripla | The Percentage of Participants With HIV-1 RNA Less Than 50 Copies/mL at Week 48 | 87.0 percentage of participants |
Secondary
The Percentage of Participants With Virologic Success at Weeks 24 and 48 Using FDA-Defined Snapshot Analysis and HIV-1 RNA Less Than 50 Copies/mL
The percentage of participants with virologic success at Weeks 24 and 48 assessed using the FDA-defined snapshot analysis for an HIV-1 RNA cutoff of 50 copies/mL was summarized.
Time frame: Baseline to Weeks 24 and 48
Population: ITT analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Stribild | The Percentage of Participants With Virologic Success at Weeks 24 and 48 Using FDA-Defined Snapshot Analysis and HIV-1 RNA Less Than 50 Copies/mL | Virologic Success at Week 24 | 89.6 percentage of participants |
| Stribild | The Percentage of Participants With Virologic Success at Weeks 24 and 48 Using FDA-Defined Snapshot Analysis and HIV-1 RNA Less Than 50 Copies/mL | Virologic Success at Week 48 | 91.7 percentage of participants |
| Atripla | The Percentage of Participants With Virologic Success at Weeks 24 and 48 Using FDA-Defined Snapshot Analysis and HIV-1 RNA Less Than 50 Copies/mL | Virologic Success at Week 24 | 87.0 percentage of participants |
| Atripla | The Percentage of Participants With Virologic Success at Weeks 24 and 48 Using FDA-Defined Snapshot Analysis and HIV-1 RNA Less Than 50 Copies/mL | Virologic Success at Week 48 | 82.6 percentage of participants |