Human Immunodeficiency Virus Infections
Conditions
Brief summary
The purpose of this study was to compare the safety, tolerability, and antiviral activity of once-daily (QD) and twice-daily (BID) dosing of the lopinavir/ritonavir (LPV/r) tablet formulation in combination with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) in antiretroviral-experienced human immunodeficiency virus type 1 infected subjects with detectable viral load while receiving their current antiretroviral therapy.
Interventions
DRUGlopinavir/ritonavir (LPV/r) tablet with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
LPV/r 800/200 mg once-daily (QD) tablet
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
No
Inclusion criteria
* Subjects were human immunodeficiency virus type 1 (HIV-1) positive, antiretroviral-experienced adults at least 18 years of age currently receiving an antiretroviral regimen which had not changed for at least 12 weeks. * Subjects had plasma HIV-1 ribonucleic acid (RNA) levels \> 1,000 copies/mL at screening and were not acutely ill. * Subject was currently failing his/her antiretroviral regimen with the most recent 2 consecutive prestudy plasma HIV-1 RNA levels \> 400 copies/mL with the most recent being \> 1000 copies/mL, and in the investigator's opinion, should change therapy * Female subjects were nonpregnant and nonlactating.
Exclusion criteria
* Subjects were excluded if screening laboratory analyses showed hemoglobin \<= 8.0 grams per deciliter. * Subjects were excluded if screening laboratory analyses showed absolute neutrophil count \<= 750 cells/microliter. * Subjects were excluded if screening laboratory analyses showed platelet count \<= 50,000 per cubic millimeter. * Subjects were excluded if screening laboratory analyses showed alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>= 5.0 x upper limit of normal (ULN).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Responding at Week 48 Based on the Food and Drug Administration (FDA) Time to Loss of Virologic Response (TLOVR) Algorithm | Week 48 (End of Study) | A participant was classified as a responder at the first of 2 consecutive human immunodeficiency virus type 1 (HIV-1) ribonucleic acid (RNA) levels \<50 copies/mL. The participant continued to be a responder until 2 consecutive values \>=50 copies/mL were reached, until the final value if that value was \>=50 copies/mL, or until discontinuation or death. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Plasma Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) Levels < 50 Copies/Milliliter (mL) at Week 48 | Week 48 (End of Study) | — |
| Mean Change From Baseline to Week 48 in Cluster of Differentiation 4 Single-Positive Thymocyte (CD4+ T) Cell Counts | Week 48 (End of Study) | — |
| Virologic Response (HIV-1 RNA <50 Copies/mL) at Week 48 for Participants With 0-2 Protease Inhibitor Substitutions at Baseline Associated With Reduced Response to Lopinavir/Ritonavir | Week 48 (End of Study) | Substitutions considered in the analysis were L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V as defined in the proposed United States Package Insert. |
| Percentage of Participants With New Primary Protease Mutations at Week 48 | Week 48 (End of Study) | Emergence of new primary protease inhibitor mutations (i.e., mutations at codons 30, 32, 48, 50, 82, 84, and 90 that were not present at baseline). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| LPV/r 800/200 mg QD Tablet lopinavir/ritonavir 800/200 mg once daily (QD) tablet | 300 |
| LPV/r 400/100 mg BID Tablet lopinavir/ritonavir 400/100 mg twice daily (BID) tablet | 299 |
| Total | 599 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 14 | 21 |
| Overall Study | Death | 2 | 3 |
| Overall Study | Lost to Follow-up | 20 | 17 |
| Overall Study | Noncompliance | 12 | 11 |
| Overall Study | Unable to Continue Participation | 2 | 2 |
| Overall Study | Virologic failure | 11 | 8 |
| Overall Study | Withdrawal by Subject | 5 | 7 |
Baseline characteristics
| Characteristic | LPV/r 400/100 mg BID Tablet | Total | LPV/r 800/200 mg QD Tablet |
|---|---|---|---|
| Age Continuous | 40.8 years STANDARD_DEVIATION 8.63 | 40.6 years STANDARD_DEVIATION 8.92 | 40.4 years STANDARD_DEVIATION 9.22 |
| Cluster of Differentiation 4 Single-Positive Thymocyte (CD4+ T) Cell Count | 268.3 cells/microliter STANDARD_DEVIATION 183.55 | 253.9 cells/microliter STANDARD_DEVIATION 171.98 | 239.3 cells/microliter STANDARD_DEVIATION 158.39 |
| Plasma Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) Level | 4.26 log10 copies/milliliter (mL) STANDARD_DEVIATION 0.809 | 4.26 log10 copies/milliliter (mL) STANDARD_DEVIATION 0.817 | 4.26 log10 copies/milliliter (mL) STANDARD_DEVIATION 0.826 |
| Received Prior Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) Did Not Receive Prior NNRTI | 58 participants | 94 participants | 36 participants |
| Received Prior Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) Received Prior NNRTI | 241 participants | 505 participants | 264 participants |
| Received Prior Nucleoside/nucleotide Reverse Transcriptase Inhibitor (NRTI) Did Not Receive Prior NRTI | 2 participants | 3 participants | 1 participants |
| Received Prior Nucleoside/nucleotide Reverse Transcriptase Inhibitor (NRTI) Received Prior NRTI | 297 participants | 596 participants | 299 participants |
| Received Prior Protease Inhibitor (PI) Did Not Receive Prior PI | 163 participants | 323 participants | 160 participants |
| Received Prior Protease Inhibitor (PI) Received Prior PI | 136 participants | 276 participants | 140 participants |
| Sex: Female, Male Female | 103 Participants | 206 Participants | 103 Participants |
| Sex: Female, Male Male | 196 Participants | 393 Participants | 197 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 201 / 300 | 180 / 299 |
| serious Total, serious adverse events | 27 / 300 | 37 / 299 |
Outcome results
Primary
Percentage of Participants Responding at Week 48 Based on the Food and Drug Administration (FDA) Time to Loss of Virologic Response (TLOVR) Algorithm
A participant was classified as a responder at the first of 2 consecutive human immunodeficiency virus type 1 (HIV-1) ribonucleic acid (RNA) levels \<50 copies/mL. The participant continued to be a responder until 2 consecutive values \>=50 copies/mL were reached, until the final value if that value was \>=50 copies/mL, or until discontinuation or death.
Time frame: Week 48 (End of Study)
Population: Intention to treat analysis of all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LPV/r 800/200 mg QD Tablet | Percentage of Participants Responding at Week 48 Based on the Food and Drug Administration (FDA) Time to Loss of Virologic Response (TLOVR) Algorithm | 55.3 Percentage of Participants |
| LPV/r 400/100 mg BID Tablet | Percentage of Participants Responding at Week 48 Based on the Food and Drug Administration (FDA) Time to Loss of Virologic Response (TLOVR) Algorithm | 51.8 Percentage of Participants |
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 participants (300 participants in each of the QD and BID treatment regimens) provided 83% power (with a type I error rate of 0.05) to reject the null hypothesis, i.e., to determine noninferiority based on the 12% margin.p-value: 0.41395% CI: [-4.5, 11.5]normal approx. to binomial distribution
Secondary
Mean Change From Baseline to Week 48 in Cluster of Differentiation 4 Single-Positive Thymocyte (CD4+ T) Cell Counts
Time frame: Week 48 (End of Study)
Population: All randomized participants who received at least 1 dose of study drug and who had CD4+ T cell counts at both the Baseline Visit and Week 48.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LPV/r 800/200 mg QD Tablet | Mean Change From Baseline to Week 48 in Cluster of Differentiation 4 Single-Positive Thymocyte (CD4+ T) Cell Counts | 135.3 cells/microliter | Standard Error 9.03 |
| LPV/r 400/100 mg BID Tablet | Mean Change From Baseline to Week 48 in Cluster of Differentiation 4 Single-Positive Thymocyte (CD4+ T) Cell Counts | 121.5 cells/microliter | Standard Error 9.08 |
p-value: 0.281ANOVA
Secondary
Percentage of Participants With New Primary Protease Mutations at Week 48
Emergence of new primary protease inhibitor mutations (i.e., mutations at codons 30, 32, 48, 50, 82, 84, and 90 that were not present at baseline).
Time frame: Week 48 (End of Study)
Population: All randomized participants who received at least 1 dose of study drug and had post baseline genotypic resistance assay results.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LPV/r 800/200 mg QD Tablet | Percentage of Participants With New Primary Protease Mutations at Week 48 | 8.0 Percentage of Participants |
| LPV/r 400/100 mg BID Tablet | Percentage of Participants With New Primary Protease Mutations at Week 48 | 15.6 Percentage of Participants |
p-value: 0.222Fisher Exact
Secondary
Percentage of Participants With Plasma Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) Levels < 50 Copies/Milliliter (mL) at Week 48
Time frame: Week 48 (End of Study)
Population: Observed data analysis using all available Week 48 data from all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LPV/r 800/200 mg QD Tablet | Percentage of Participants With Plasma Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) Levels < 50 Copies/Milliliter (mL) at Week 48 | 76.0 Percentage of Participants |
| LPV/r 400/100 mg BID Tablet | Percentage of Participants With Plasma Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) Levels < 50 Copies/Milliliter (mL) at Week 48 | 72.2 Percentage of Participants |
p-value: 0.38995% CI: [-4.3, 11.9]normal approx. to binomial distribution
Secondary
Virologic Response (HIV-1 RNA <50 Copies/mL) at Week 48 for Participants With 0-2 Protease Inhibitor Substitutions at Baseline Associated With Reduced Response to Lopinavir/Ritonavir
Substitutions considered in the analysis were L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V as defined in the proposed United States Package Insert.
Time frame: Week 48 (End of Study)
Population: Dropouts-as-censored: participants were responders if they had HIV-1 RNA \<50 copies/mL at Week 48. Participants who discontinued (d/c'd) while suppressed or w/o post baseline (BL) levels were excluded. Those d/c'd \<Day 85 were excluded unless they had \>=1 post BL level \& didn't achieve a decrease \>=1.0 log10 copies/mL, then they were nonresponders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LPV/r 800/200 mg QD Tablet | Virologic Response (HIV-1 RNA <50 Copies/mL) at Week 48 for Participants With 0-2 Protease Inhibitor Substitutions at Baseline Associated With Reduced Response to Lopinavir/Ritonavir | 65.5 Percentage of Participants |
| LPV/r 400/100 mg BID Tablet | Virologic Response (HIV-1 RNA <50 Copies/mL) at Week 48 for Participants With 0-2 Protease Inhibitor Substitutions at Baseline Associated With Reduced Response to Lopinavir/Ritonavir | 61.6 Percentage of Participants |