Human Immunodeficiency Virus Infections
Conditions
Keywords
Human Immunodeficiency Virus Infections
Brief summary
The purpose of this study was to compare the safety and tolerability of the to-be-marketed lopinavir/ritonavir (LPV/r) tablet formulation with the marketed soft gel capsule (SGC) formulation and to compare the safety, tolerability, and antiviral activity of once daily (QD) and twice daily (BID) dosing of the LPV/r tablet formulation in combination with select nucleoside reverse transcriptase inhibitors (NRTIs) in patients who have not previously received antiretroviral treatment.
Interventions
DRUGlopinavir/ritonavir (LPV/r) (tablet or capsule) with nucleoside reverse transcriptase inhibitors (NRTIs)
LPV/r 800/200 mg once daily (QD) tablet + emtricitabine (FTC) 200 mg QD + tenofovir disoproxil fumarate (TDF) 300 mg QD
Sponsors
Abbott
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Subjects were human immunodeficiency virus type 1 (HIV-1) positive, antiretroviral naïve adults at least 18 years of age with \< 7 days of prior antiretroviral therapy. * Subjects had plasma HIV-1 ribonucleic acid (RNA) levels \>= 1,000 copies/mL at screening and were not acutely ill. * Female subjects were nonpregnant and nonlactating.
Exclusion criteria
* Subjects were excluded if screening laboratory analyses showed any of the following abnormal laboratory results: * Presence of hepatitis B surface antigen (HBsAg) * Hemoglobin \<= 8.0 g/dL * Absolute neutrophil count \<= 750 cells/microliter * Platelet count \<= 50,000 per mL * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>= 3.0 x Upper Limit of Normal (ULN) * Calculated creatinine clearance \< 50 mL/min
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percentage of Subjects With Adverse Events of Diarrhea During the First 8 Weeks | Week 8 |
| Percentage of Subjects With Plasma Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) Levels < 50 Copies/mL at Week 48 | Week 48 |
Secondary
| Measure | Time frame |
|---|---|
| Percentage of Subjects With Plasma Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) Levels < 50 Copies/mL at Week 96 | Week 96 (End of Study) |
| Mean Change From Baseline to Week 96 in CD4+ T Cell Counts | Week 96 (End of Study) |
Countries
Australia, Belgium, Canada, Czechia, France, Germany, Greece, Ireland, Italy, Netherlands, Poland, Puerto Rico, Russia, Singapore, Spain, Switzerland, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
Subjects were enrolled at 131 sites in 19 countries.
Pre-assignment details
Of the 672 subjects randomized, 8 discontinued from the study prior to receiving study drug due to withdrawal of consent (3), acute illness (2), lost to follow-up (1), other (1), and required prohibited medication (1).
Participants by arm
| Arm | Count |
|---|---|
| LPV/r 800/200 mg QD Tablet lopinavir/ritonavir 800/200 mg once daily (QD) tablet | 167 |
| LPV/r 800/200 mg QD SGC (Through Week 8) lopinavir/ritonavir 800/200 mg once daily (QD) soft gel capsule (SGC) | 166 |
| LPV/r 400/100 mg BID Tablet lopinavir/ritonavir 400/100 mg twice daily (BID) tablet | 166 |
| LPV/r 400/100 mg BID SGC (Through Week 8) lopinavir/ritonavir 400/100 mg twice daily (BID) soft gel capsule (SGC) | 165 |
| Total | 664 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Study Start Through 48 Weeks | Adverse Event | 16 | 0 | 10 | 0 |
| Study Start Through 48 Weeks | Death | 2 | 0 | 1 | 0 |
| Study Start Through 48 Weeks | Lost to Follow-up | 8 | 0 | 14 | 0 |
| Study Start Through 48 Weeks | Noncompliance | 3 | 0 | 8 | 0 |
| Study Start Through 48 Weeks | Relocated, Needed to take twice daily | 8 | 0 | 7 | 0 |
| Study Start Through 48 Weeks | Virologic failure | 2 | 0 | 4 | 0 |
| Study Start Through 48 Weeks | Withdrawal by Subject | 10 | 0 | 11 | 0 |
| Study Start Through 8 Weeks | Adverse Event | 1 | 2 | 3 | 1 |
| Study Start Through 8 Weeks | Death | 1 | 0 | 0 | 0 |
| Study Start Through 8 Weeks | Lost to Follow-up | 1 | 2 | 3 | 2 |
| Study Start Through 8 Weeks | Noncompliance | 0 | 0 | 2 | 2 |
| Study Start Through 8 Weeks | Withdrawal by Subject | 1 | 1 | 3 | 0 |
| Study Start Through 96 Weeks | Adverse Event | 20 | 0 | 16 | 0 |
| Study Start Through 96 Weeks | Death | 2 | 0 | 2 | 0 |
| Study Start Through 96 Weeks | Lost to Follow-up | 19 | 0 | 18 | 0 |
| Study Start Through 96 Weeks | Noncompliance | 6 | 0 | 11 | 0 |
| Study Start Through 96 Weeks | Relocated, Needed to take twice daily | 10 | 0 | 9 | 0 |
| Study Start Through 96 Weeks | Virologic failure | 5 | 0 | 8 | 0 |
| Study Start Through 96 Weeks | Withdrawal by Subject | 15 | 0 | 13 | 0 |
Baseline characteristics
| Characteristic | LPV/r 800/200 mg QD Tablet | LPV/r 800/200 mg QD SGC (Through Week 8) | LPV/r 400/100 mg BID Tablet | LPV/r 400/100 mg BID SGC (Through Week 8) | Total |
|---|---|---|---|---|---|
| Age Continuous | 38.7 years STANDARD_DEVIATION 9.8 | 38.2 years STANDARD_DEVIATION 9.63 | 38.3 years STANDARD_DEVIATION 9.69 | 39.5 years STANDARD_DEVIATION 10.31 | 38.7 years STANDARD_DEVIATION 9.85 |
| CD4+ T Cell Count | 209.9 cells/mm3 STANDARD_DEVIATION 125.1 | 222.6 cells/mm3 STANDARD_DEVIATION 127.37 | 226.4 cells/mm3 STANDARD_DEVIATION 136.64 | 202.9 cells/mm3 STANDARD_DEVIATION 139.57 | 215.5 cells/mm3 STANDARD_DEVIATION 132.34 |
| Plasma HIV-1 RNA Level | 4.92 log10 copies/mL STANDARD_DEVIATION 0.64 | 4.94 log10 copies/mL STANDARD_DEVIATION 0.67 | 5.04 log10 copies/mL STANDARD_DEVIATION 0.68 | 5.06 log10 copies/mL STANDARD_DEVIATION 0.64 | 4.99 log10 copies/mL STANDARD_DEVIATION 0.66 |
| Sex: Female, Male Female | 36 Participants | 31 Participants | 39 Participants | 38 Participants | 144 Participants |
| Sex: Female, Male Male | 131 Participants | 135 Participants | 127 Participants | 127 Participants | 520 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 292 / 333 | 287 / 331 |
| serious Total, serious adverse events | 37 / 333 | 50 / 331 |
Outcome results
Primary
Percentage of Subjects With Adverse Events of Diarrhea During the First 8 Weeks
Time frame: Week 8
Population: All randomized subjects who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LPV/r 800/200 mg QD Tablet | Percentage of Subjects With Adverse Events of Diarrhea During the First 8 Weeks | 49.1 Percentage of Subjects |
| LPV/r 800/200 mg QD SGC (Through Week 8) | Percentage of Subjects With Adverse Events of Diarrhea During the First 8 Weeks | 54.8 Percentage of Subjects |
| LPV/r 400/100 mg BID Tablet | Percentage of Subjects With Adverse Events of Diarrhea During the First 8 Weeks | 44.6 Percentage of Subjects |
| LPV/r 400/100 mg BID SGC (Through Week 8) | Percentage of Subjects With Adverse Events of Diarrhea During the First 8 Weeks | 49.7 Percentage of Subjects |
Comparison: Cochran-Mantel-Haenszel (CMH) test stratified by dosing regimen was used to assess the null hypothesis of no difference between the tablet and soft gel capsule (SGC). Sample size was 600 subjects (150 each in the 4 groups). Based on a projected 48% reporting treatment-emergent diarrhea in the QD arm and 32% in the BID arm within the SGC group, with a 12% reduction in the corresponding tablet groups, this sample size provided 80% power to determine a difference between the tablet and SGC.p-value: >0.1Cochran-Mantel-Haenszel
Primary
Percentage of Subjects With Plasma Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) Levels < 50 Copies/mL at Week 48
Time frame: Week 48
Population: Intent-to-treat noncompleters considered failures (ITT, NC=F); all randomized subjects who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LPV/r 800/200 mg QD Tablet | Percentage of Subjects With Plasma Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) Levels < 50 Copies/mL at Week 48 | 77.2 Percentage of Subjects |
| LPV/r 400/100 mg BID Tablet | Percentage of Subjects With Plasma Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) Levels < 50 Copies/mL at Week 48 | 75.8 Percentage of Subjects |
Comparison: The null hypothesis was that the response rate for the once daily (QD) regimen was more than 12% lower than the response rate for the twice daily (BID) regimen. The planned sample size of 600 subjects (300 subjects in each of the QD and BID treatment regimens) provided over 90% power to reject the null hypothesis, i.e., to determine noninferiority based on the 12% margin.p-value: 0.71595% CI: [-5.1, 7.8]normal approx. to the binomial distr.
Secondary
Mean Change From Baseline to Week 96 in CD4+ T Cell Counts
Time frame: Week 96 (End of Study)
Population: All randomized subjects who received at least 1 dose of study drug and who had CD4+ T cell counts available at both the Baseline Visit and Week 96.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LPV/r 800/200 mg QD Tablet | Mean Change From Baseline to Week 96 in CD4+ T Cell Counts | 238.4 cells/microliter | Standard Error 10.02 |
| LPV/r 400/100 mg BID Tablet | Mean Change From Baseline to Week 96 in CD4+ T Cell Counts | 254.0 cells/microliter | Standard Error 10 |
p-value: 0.269ANOVA
Secondary
Percentage of Subjects With Plasma Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) Levels < 50 Copies/mL at Week 96
Time frame: Week 96 (End of Study)
Population: Intent-to-treat noncompleters considered failures (ITT, NC=F); all randomized subjects who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LPV/r 800/200 mg QD Tablet | Percentage of Subjects With Plasma Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) Levels < 50 Copies/mL at Week 96 | 64.9 Percentage of Subjects |
| LPV/r 400/100 mg BID Tablet | Percentage of Subjects With Plasma Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) Levels < 50 Copies/mL at Week 96 | 69.2 Percentage of Subjects |
Comparison: The null hypothesis was that the response rate for the once daily (QD) regimen was more than 12% lower than the response rate for the twice daily (BID) regimen. The planned sample size of 600 subjects (300 subjects in each of the QD and BID treatment regimens) provided over 90% power to reject the null hypothesis, i.e., to determine noninferiority based on the 12% margin.p-value: 0.24995% CI: [-11.5, 2.8]normal approx. to the binomial distr.