HIV-1
Conditions
Keywords
HIV-1. Treatment Naive, HIV Infections, treatment naive
Brief summary
This is a 96 week study to determine if UK- 453,061 in combination with Truvada is as efficacious, safe and tolerable as efavirenz in combination with Truvada in HIV-1 infected patients who have not been previously treated with antiretroviral drugs.
Interventions
DRUGUK-453, 061
UK-453,061 500 mg tablets PO QD + Tenofovir DF 300 mg/Emtricitabine 200 mg tablets PO QD.
DRUGEFV +TVA
Efavirenz 600 mg tablets PO QD + Tenofovir DF 300 mg/Emtricitabine 200 tablets mg PO QD.
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female at least 18 years of age available for a follow-up period of at least 96 weeks. * HIV 1 RNA viral load of greater then 1,000 copies/mL * Negative urine pregnancy test.
Exclusion criteria
* Suspected or documented active, untreated HIV-1 related opportunist infection or other condition requiring acute therapy at the time of randomization. * Subjects with acute Hepatitis B and/or C within 30 days of randomization. * Absolute CD4 count \<200 cells/mm3.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Less Than 50 Copies Per Milliliter (Copies/mL) of Human Immunodeficiency Virus Type 1 Ribonucleic Acid (HIV-1 RNA) at Week 48 | Week 48 | Plasma HIV-1 RNA level was determined by validated Roche Amplicor HIV-1 Monitor standard assay. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Less Than 400 Copies/mL of HIV-1 RNA at Week 24, 48 and 96 | Week 24, 48, 96 | Plasma HIV-1 RNA level was determined by validated Roche Amplicor HIV-1 Monitor standard assay. |
| Change From Baseline in Log 10 Transformed HIV-1 RNA Levels at Week 24, 48 and 96 | Baseline, Week 24, 48, 96 | For the log 10 scale, all the HIV-1 RNA levels were log 10 transformed prior to the average calculations. Baseline value was calculated as the average of all the measurements collected prior to and including Day 1 pre-dose. |
| Time-Averaged Difference (TAD) in Log 10 Transformed HIV-1 RNA Levels at Week 24, 48 and 96 | Baseline up to Week 24, 48, 96 | TAD was calculated as area under the curve of HIV-1 RNA levels (log10 copies/mL) from baseline to the time point of interest divided by time period in weeks minus baseline HIV-1 RNA level (log10 copies/mL). Baseline value was calculated as the average of all the measurements collected prior to and including Day 1 pre-dose. |
| Percentage of Participants With Response as Determined Using the Time-to Loss of Virologic Response (TLOVR50) Algorithm at Week 24, 48 and 96 | Week 24, 48, 96 | TLOVR50 response is compliment to TLOVR50 failure. TLOVR50 failure based on observed HIV-1 RNA levels and failure events (death; permanent discontinuation of drug; lost to follow-up; met treatment failure \[TF\] criteria). TF: an increase to at least 3 times baseline plasma HIV-1 RNA level at Week 2 or thereafter; failure to achieve HIV-1 RNA level \<50 copies/mL at Week 24; starting at Week 2, an increase in HIV-1 RNA level to detectable levels (\>50 copies/mL). TF criteria's defined above were confirmed by second measurement at least 14 days after first. In 'TLOVR50', '50' denotes the lower limit of quantification (LLOQ) of assay (which is 50 copies/mL). Baseline value was calculated as the average of all the measurements collected prior to and including Day 1 pre-dose. |
| Change From Baseline in Cluster of Differentiation (CD4+) Absolute Cell Count at Week 24, 48 and 96 | Baseline, Week 24, 48, 96 | Baseline value was calculated as the average of all the measurements collected prior to and including Day 1 pre-dose. |
| Change From Baseline in Cluster of Differentiation (CD4+) Percentage Cell Count at Week 24, 48 and 96 | Baseline, Week 24, 48, 96 | Baseline value was calculated as the average of all the measurements collected prior to and including Day 1 pre-dose. |
| Number of Participants With NRTI and NNRTI Resistance-Associated Mutations (RAMs) at Time of Treatment Failure Through Week 24, 48 and 96 | Day 1 (pre-dose) through Week 24, 48, 96 | Phenotypic resistance and genotypic resistance was assessed for all participants at Day 1 predose, and was evaluated for nucleotide reverse transcriptase inhibitors (NRTIs), and non-NRTIs (NNRTIs) resistance-associated mutations at time of treatment failure using Monogram GenoSeq and/or PhenoSenseGT assays. This was then repeated for all participants with HIV-1 viral load more than 500 copies/mL at treatment failure, up to Week 96. |
| Percentage of Participants With Less Than 50 Copies/mL of HIV-1 RNA at Week 24 and 96 | Week 24, 96 | Plasma HIV-1 RNA level was determined by validated Roche Amplicor HIV-1 Monitor standard assay. |
| Population Pharmacokinetic (PK) of Lersivirine | Week 2, 4, 8, 12, 16, 24, 32, 40, 48 | Data for this outcome measure are not reported here because the analysis population includes participants who were not enrolled in this study. ClinicalTrials.gov is designed for reporting results from only those participants who were enrolled in the study and described in the participant flow and baseline characteristics modules. |
| Lersivirine Success Percentage With Reference to Median Minimum Observed Plasma Concentration (Cmin) | Week 2, 4, 8, 12, 16, 24, 32, 40, 48 | Simple quartile exposure analysis of success rate (viral load \<50 copies/mL) versus median Cmin assesses the exposure response relationship. Percentage of participants with HIV-1 RNA level \<50 copies/mL at median Cmin quartile were planned to be reported. |
| Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24]) of Lersivirine | 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 24 hours (hrs) post-dose on Week 4 | AUC (0-24)= Area under the plasma concentration versus time curve from time zero (pre-dose) to 24 hours post-dose (0-24). Only participants from Lersivirine treatment arms were planned to be analyzed for Pharmacokinetic (PK) sub-study. |
| Maximum Observed Plasma Concentration (Cmax) of Lersivirine | 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 24 hrs post-dose on Week 4 | — |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Lersivirine | 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 24 hrs post-dose on Week 4 | — |
| Plasma Concentration of Lersivirine at 24 Hour | 24 hrs post-dose on Week 4 | The observed plasma concentration at 24 hours post-dose (C 24h). |
| Number of Participants With Laboratory Test Abnormalities | Baseline up to Week 96 or early termination | Laboratory analysis included hematology, blood chemistry, serum and urine pregnancy test, hepatitis testing and urinalysis. Laboratory values that met the criteria of the Division of Acquired Immuno Deficiency Syndrome (DAIDS) grade 1 (mild, symptoms causing no or minimal interference with usual social and functional activities) or greater were considered as abnormal. |
Countries
Argentina, Australia, Canada, Italy, Mexico, Poland, South Africa, Switzerland, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Lersivirine 500 mg Two lersivirine 250 milligram (mg) tablets (equivalent to lersivirine 500 mg), a placebo tablet matched to lersivirine and a placebo tablet matched to efavirenz orally once daily along with tenofovir disoproxil fumarate (DF) 300 mg tablet and emtricitabine 200 mg tablet orally once daily, in the evening up to 96 weeks. Participants enrolled in pharmacokinetic (PK) substudy switched to lersivirine morning dosing regimen, received 2 Lersivirine 250 mg tablets, a placebo tablet matched to lersivirine orally once daily in the morning for 7 days prior to Week 4, and in the morning and evening on 1 day following Week 4. A placebo tablet matched to efavirenz, tenofovir DF 300 mg tablet and emtricitabine 200 mg tablet were continued in the evening in PK substudy. Evening dosing was continued for the remainder of the study up to Week 96. | 65 |
| Lersivirine 750 mg Three Lersivirine 250 mg tablets (equivalent to lersivirine 750 mg) and a placebo tablet matched to efavirenz orally once daily along with tenofovir DF 300 mg and emtricitabine 200 mg tablet orally once daily, in the evening up to 96 weeks. Participants enrolled in PK substudy switched to morning dosing regimen, received 3 Lersivirine 250 mg tablets orally once daily in the morning for 7 days prior to Week 4, and in the morning and evening on 1 day following Week 4. A placebo tablet matched to efavirenz, tenofovir DF 300 mg tablet and emtricitabine 200 mg tablet were continued in the evening in PK substudy. Evening dosing was continued for the remainder of the study up to Week 96. | 65 |
| Efavirenz 600 mg Three placebo tablets matched to lersivirine, efavirenz 600 mg tablet orally once daily along with tenofovir DF 300 mg and emtricitabine 200 mg tablet orally once daily, in the evening up to 96 weeks. Participants enrolled in PK substudy switched to morning dosing regimen, received 3 placebo tablets matched to lersivirine and efavirenz 600 mg tablet orally once daily in the morning for 7 days prior to Week 4, and in the morning and evening on 1 day following Week 4. Efavirenz 600 mg tablet, tenofovir DF 300 mg tablet and emtricitabine 200 mg tablet were continued in the evening in PK substudy. Evening dosing was continued for the remainder of the study up to Week 96. | 63 |
| Total | 193 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 6 | 6 | 6 |
| Overall Study | Death | 0 | 1 | 0 |
| Overall Study | Lack of Efficacy | 5 | 7 | 4 |
| Overall Study | Lost to Follow-up | 2 | 3 | 0 |
| Overall Study | Other | 0 | 1 | 0 |
| Overall Study | Pregnancy | 1 | 0 | 1 |
| Overall Study | Randomized but not Treated | 1 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 3 | 3 |
Baseline characteristics
| Characteristic | Lersivirine 500 mg | Lersivirine 750 mg | Efavirenz 600 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 36.5 years STANDARD_DEVIATION 8 | 35.7 years STANDARD_DEVIATION 8.2 | 36.3 years STANDARD_DEVIATION 8.7 | 36.2 years STANDARD_DEVIATION 8.2 |
| Sex: Female, Male Female | 16 Participants | 19 Participants | 17 Participants | 52 Participants |
| Sex: Female, Male Male | 49 Participants | 46 Participants | 46 Participants | 141 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 | 51 / 65 | 58 / 65 | 59 / 63 |
| serious Total, serious adverse events | 6 / 65 | 7 / 65 | 6 / 63 |
Outcome results
Primary
Percentage of Participants With Less Than 50 Copies Per Milliliter (Copies/mL) of Human Immunodeficiency Virus Type 1 Ribonucleic Acid (HIV-1 RNA) at Week 48
Plasma HIV-1 RNA level was determined by validated Roche Amplicor HIV-1 Monitor standard assay.
Time frame: Week 48
Population: ITT population included all randomized participants who received at least 1 dose of study medication. Participants who had been discontinued from the study, were lost to follow-up, or had missing HIV-1 RNA level data at a visit were considered to have HIV-1 RNA levels \>=50 copies/mL and were referred to as non-completer = failure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lersivirine 500 mg | Percentage of Participants With Less Than 50 Copies Per Milliliter (Copies/mL) of Human Immunodeficiency Virus Type 1 Ribonucleic Acid (HIV-1 RNA) at Week 48 | 78.5 percentage of participants |
| Lersivirine 750 mg | Percentage of Participants With Less Than 50 Copies Per Milliliter (Copies/mL) of Human Immunodeficiency Virus Type 1 Ribonucleic Acid (HIV-1 RNA) at Week 48 | 78.5 percentage of participants |
| Efavirenz 600 mg | Percentage of Participants With Less Than 50 Copies Per Milliliter (Copies/mL) of Human Immunodeficiency Virus Type 1 Ribonucleic Acid (HIV-1 RNA) at Week 48 | 85.7 percentage of participants |
Secondary
Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24]) of Lersivirine
AUC (0-24)= Area under the plasma concentration versus time curve from time zero (pre-dose) to 24 hours post-dose (0-24). Only participants from Lersivirine treatment arms were planned to be analyzed for Pharmacokinetic (PK) sub-study.
Time frame: 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 24 hours (hrs) post-dose on Week 4
Population: Pharmacokinetic sub-study analysis set (PKSSAS) included all randomized Lersivirine participants who consented to participate in the PK sub-study, received the study medication on the day of the PK sub-study and had sufficient PK data for analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Lersivirine 500 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24]) of Lersivirine | 6002 nanogram*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 30 |
| Lersivirine 750 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24]) of Lersivirine | 8677 nanogram*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 21 |
Secondary
Change From Baseline in Cluster of Differentiation (CD4+) Absolute Cell Count at Week 24, 48 and 96
Baseline value was calculated as the average of all the measurements collected prior to and including Day 1 pre-dose.
Time frame: Baseline, Week 24, 48, 96
Population: ITT population included all randomized participants who received at least 1 dose of study medication. LOCF method was used to impute missing values. No or zero change from baseline was imputed for participants with missing baseline or no CD4+ count available on treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lersivirine 500 mg | Change From Baseline in Cluster of Differentiation (CD4+) Absolute Cell Count at Week 24, 48 and 96 | Baseline | 349 cells per microliter (cells/mcL) | Standard Deviation 120 |
| Lersivirine 500 mg | Change From Baseline in Cluster of Differentiation (CD4+) Absolute Cell Count at Week 24, 48 and 96 | Change at Week 24 | 146 cells per microliter (cells/mcL) | Standard Deviation 164 |
| Lersivirine 500 mg | Change From Baseline in Cluster of Differentiation (CD4+) Absolute Cell Count at Week 24, 48 and 96 | Change at Week 48 | 191 cells per microliter (cells/mcL) | Standard Deviation 206 |
| Lersivirine 500 mg | Change From Baseline in Cluster of Differentiation (CD4+) Absolute Cell Count at Week 24, 48 and 96 | Change at Week 96 | 215 cells per microliter (cells/mcL) | Standard Deviation 194 |
| Lersivirine 750 mg | Change From Baseline in Cluster of Differentiation (CD4+) Absolute Cell Count at Week 24, 48 and 96 | Change at Week 96 | 231 cells per microliter (cells/mcL) | Standard Deviation 187 |
| Lersivirine 750 mg | Change From Baseline in Cluster of Differentiation (CD4+) Absolute Cell Count at Week 24, 48 and 96 | Baseline | 352 cells per microliter (cells/mcL) | Standard Deviation 154 |
| Lersivirine 750 mg | Change From Baseline in Cluster of Differentiation (CD4+) Absolute Cell Count at Week 24, 48 and 96 | Change at Week 48 | 195 cells per microliter (cells/mcL) | Standard Deviation 130 |
| Lersivirine 750 mg | Change From Baseline in Cluster of Differentiation (CD4+) Absolute Cell Count at Week 24, 48 and 96 | Change at Week 24 | 167 cells per microliter (cells/mcL) | Standard Deviation 127 |
| Efavirenz 600 mg | Change From Baseline in Cluster of Differentiation (CD4+) Absolute Cell Count at Week 24, 48 and 96 | Change at Week 96 | 221 cells per microliter (cells/mcL) | Standard Deviation 144 |
| Efavirenz 600 mg | Change From Baseline in Cluster of Differentiation (CD4+) Absolute Cell Count at Week 24, 48 and 96 | Change at Week 24 | 139 cells per microliter (cells/mcL) | Standard Deviation 104 |
| Efavirenz 600 mg | Change From Baseline in Cluster of Differentiation (CD4+) Absolute Cell Count at Week 24, 48 and 96 | Change at Week 48 | 188 cells per microliter (cells/mcL) | Standard Deviation 117 |
| Efavirenz 600 mg | Change From Baseline in Cluster of Differentiation (CD4+) Absolute Cell Count at Week 24, 48 and 96 | Baseline | 319 cells per microliter (cells/mcL) | Standard Deviation 80 |
Secondary
Change From Baseline in Cluster of Differentiation (CD4+) Percentage Cell Count at Week 24, 48 and 96
Baseline value was calculated as the average of all the measurements collected prior to and including Day 1 pre-dose.
Time frame: Baseline, Week 24, 48, 96
Population: ITT population included all randomized participants who received at least 1 dose of study medication. LOCF method was used to impute missing values. No or zero change from baseline was imputed for participants with missing baseline or no CD4+ count available on treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lersivirine 500 mg | Change From Baseline in Cluster of Differentiation (CD4+) Percentage Cell Count at Week 24, 48 and 96 | Baseline | 19.9 percentage of total lymphocytes | Standard Deviation 6.6 |
| Lersivirine 500 mg | Change From Baseline in Cluster of Differentiation (CD4+) Percentage Cell Count at Week 24, 48 and 96 | Change at Week 24 | 6.0 percentage of total lymphocytes | Standard Deviation 4.1 |
| Lersivirine 500 mg | Change From Baseline in Cluster of Differentiation (CD4+) Percentage Cell Count at Week 24, 48 and 96 | Change at Week 48 | 8.3 percentage of total lymphocytes | Standard Deviation 5 |
| Lersivirine 500 mg | Change From Baseline in Cluster of Differentiation (CD4+) Percentage Cell Count at Week 24, 48 and 96 | Change at Week 96 | 10.1 percentage of total lymphocytes | Standard Deviation 6.4 |
| Lersivirine 750 mg | Change From Baseline in Cluster of Differentiation (CD4+) Percentage Cell Count at Week 24, 48 and 96 | Change at Week 96 | 12.1 percentage of total lymphocytes | Standard Deviation 6.5 |
| Lersivirine 750 mg | Change From Baseline in Cluster of Differentiation (CD4+) Percentage Cell Count at Week 24, 48 and 96 | Baseline | 20.0 percentage of total lymphocytes | Standard Deviation 6.7 |
| Lersivirine 750 mg | Change From Baseline in Cluster of Differentiation (CD4+) Percentage Cell Count at Week 24, 48 and 96 | Change at Week 48 | 9.9 percentage of total lymphocytes | Standard Deviation 4.3 |
| Lersivirine 750 mg | Change From Baseline in Cluster of Differentiation (CD4+) Percentage Cell Count at Week 24, 48 and 96 | Change at Week 24 | 7.5 percentage of total lymphocytes | Standard Deviation 3.7 |
| Efavirenz 600 mg | Change From Baseline in Cluster of Differentiation (CD4+) Percentage Cell Count at Week 24, 48 and 96 | Change at Week 96 | 11.1 percentage of total lymphocytes | Standard Deviation 6 |
| Efavirenz 600 mg | Change From Baseline in Cluster of Differentiation (CD4+) Percentage Cell Count at Week 24, 48 and 96 | Change at Week 24 | 7.3 percentage of total lymphocytes | Standard Deviation 4.7 |
| Efavirenz 600 mg | Change From Baseline in Cluster of Differentiation (CD4+) Percentage Cell Count at Week 24, 48 and 96 | Change at Week 48 | 8.7 percentage of total lymphocytes | Standard Deviation 4.9 |
| Efavirenz 600 mg | Change From Baseline in Cluster of Differentiation (CD4+) Percentage Cell Count at Week 24, 48 and 96 | Baseline | 19.5 percentage of total lymphocytes | Standard Deviation 5.4 |
Secondary
Change From Baseline in Log 10 Transformed HIV-1 RNA Levels at Week 24, 48 and 96
For the log 10 scale, all the HIV-1 RNA levels were log 10 transformed prior to the average calculations. Baseline value was calculated as the average of all the measurements collected prior to and including Day 1 pre-dose.
Time frame: Baseline, Week 24, 48, 96
Population: ITT population. Participant discontinued before a visit of interest: value imputed as zero; not discontinued but observation is missing: Last observation carried forward (LOCF) imputation used; missing baseline or no HIV-1 RNA level assessment: value imputed as zero.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lersivirine 500 mg | Change From Baseline in Log 10 Transformed HIV-1 RNA Levels at Week 24, 48 and 96 | Change at Week 48 | -2.36 log 10 copies/mL | Standard Deviation 1.26 |
| Lersivirine 500 mg | Change From Baseline in Log 10 Transformed HIV-1 RNA Levels at Week 24, 48 and 96 | Baseline | 4.62 log 10 copies/mL | Standard Deviation 0.61 |
| Lersivirine 500 mg | Change From Baseline in Log 10 Transformed HIV-1 RNA Levels at Week 24, 48 and 96 | Change at Week 96 | -2.19 log 10 copies/mL | Standard Deviation 1.38 |
| Lersivirine 500 mg | Change From Baseline in Log 10 Transformed HIV-1 RNA Levels at Week 24, 48 and 96 | Change at Week 24 | -2.44 log 10 copies/mL | Standard Deviation 1.19 |
| Lersivirine 750 mg | Change From Baseline in Log 10 Transformed HIV-1 RNA Levels at Week 24, 48 and 96 | Change at Week 48 | -2.34 log 10 copies/mL | Standard Deviation 1.33 |
| Lersivirine 750 mg | Change From Baseline in Log 10 Transformed HIV-1 RNA Levels at Week 24, 48 and 96 | Change at Week 24 | -2.63 log 10 copies/mL | Standard Deviation 1.11 |
| Lersivirine 750 mg | Change From Baseline in Log 10 Transformed HIV-1 RNA Levels at Week 24, 48 and 96 | Baseline | 4.69 log 10 copies/mL | Standard Deviation 0.66 |
| Lersivirine 750 mg | Change From Baseline in Log 10 Transformed HIV-1 RNA Levels at Week 24, 48 and 96 | Change at Week 96 | -1.98 log 10 copies/mL | Standard Deviation 1.48 |
| Efavirenz 600 mg | Change From Baseline in Log 10 Transformed HIV-1 RNA Levels at Week 24, 48 and 96 | Change at Week 24 | -2.68 log 10 copies/mL | Standard Deviation 1.05 |
| Efavirenz 600 mg | Change From Baseline in Log 10 Transformed HIV-1 RNA Levels at Week 24, 48 and 96 | Baseline | 4.66 log 10 copies/mL | Standard Deviation 0.62 |
| Efavirenz 600 mg | Change From Baseline in Log 10 Transformed HIV-1 RNA Levels at Week 24, 48 and 96 | Change at Week 96 | -2.27 log 10 copies/mL | Standard Deviation 1.34 |
| Efavirenz 600 mg | Change From Baseline in Log 10 Transformed HIV-1 RNA Levels at Week 24, 48 and 96 | Change at Week 48 | -2.52 log 10 copies/mL | Standard Deviation 1.17 |
Secondary
Lersivirine Success Percentage With Reference to Median Minimum Observed Plasma Concentration (Cmin)
Simple quartile exposure analysis of success rate (viral load \<50 copies/mL) versus median Cmin assesses the exposure response relationship. Percentage of participants with HIV-1 RNA level \<50 copies/mL at median Cmin quartile were planned to be reported.
Time frame: Week 2, 4, 8, 12, 16, 24, 32, 40, 48
Population: Due to the sparsity of the data, it was deemed that the interpretation of the pharmacokinetic/pharmacodynamic (PK/PD) results would be questionable, thus data was not analyzed.
Secondary
Maximum Observed Plasma Concentration (Cmax) of Lersivirine
Time frame: 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 24 hrs post-dose on Week 4
Population: PKSSAS included all randomized Lersivirine participants who consented to participate in the PK sub-study, received the study medication on the day of the PK sub-study and had sufficient PK data for analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Lersivirine 500 mg | Maximum Observed Plasma Concentration (Cmax) of Lersivirine | 1056 ng/mL | Geometric Coefficient of Variation 41 |
| Lersivirine 750 mg | Maximum Observed Plasma Concentration (Cmax) of Lersivirine | 1354 ng/mL | Geometric Coefficient of Variation 31 |
Secondary
Number of Participants With Laboratory Test Abnormalities
Laboratory analysis included hematology, blood chemistry, serum and urine pregnancy test, hepatitis testing and urinalysis. Laboratory values that met the criteria of the Division of Acquired Immuno Deficiency Syndrome (DAIDS) grade 1 (mild, symptoms causing no or minimal interference with usual social and functional activities) or greater were considered as abnormal.
Time frame: Baseline up to Week 96 or early termination
Population: Safety analysis set included all randomized participants who received at least 1 dose of study medication. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lersivirine 500 mg | Number of Participants With Laboratory Test Abnormalities | 59 participants |
| Lersivirine 750 mg | Number of Participants With Laboratory Test Abnormalities | 58 participants |
| Efavirenz 600 mg | Number of Participants With Laboratory Test Abnormalities | 57 participants |
Secondary
Number of Participants With NRTI and NNRTI Resistance-Associated Mutations (RAMs) at Time of Treatment Failure Through Week 24, 48 and 96
Phenotypic resistance and genotypic resistance was assessed for all participants at Day 1 predose, and was evaluated for nucleotide reverse transcriptase inhibitors (NRTIs), and non-NRTIs (NNRTIs) resistance-associated mutations at time of treatment failure using Monogram GenoSeq and/or PhenoSenseGT assays. This was then repeated for all participants with HIV-1 viral load more than 500 copies/mL at treatment failure, up to Week 96.
Time frame: Day 1 (pre-dose) through Week 24, 48, 96
Population: Virology analysis set (TLOVR50 failures) included all participants who meet the TLOVR50 failure definition. Here 'N' (number of participants analyzed) signifies participants evaluable for this measure and 'n' signifies participants evaluable for this measure at specified time point for each group, respectively.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lersivirine 500 mg | Number of Participants With NRTI and NNRTI Resistance-Associated Mutations (RAMs) at Time of Treatment Failure Through Week 24, 48 and 96 | Week 48 (n=4, 3, 3) | 3 participants |
| Lersivirine 500 mg | Number of Participants With NRTI and NNRTI Resistance-Associated Mutations (RAMs) at Time of Treatment Failure Through Week 24, 48 and 96 | Week 24 (n=3, 4, 2) | 3 participants |
| Lersivirine 500 mg | Number of Participants With NRTI and NNRTI Resistance-Associated Mutations (RAMs) at Time of Treatment Failure Through Week 24, 48 and 96 | Week 96 (n= 5, 8, 6) | 3 participants |
| Lersivirine 750 mg | Number of Participants With NRTI and NNRTI Resistance-Associated Mutations (RAMs) at Time of Treatment Failure Through Week 24, 48 and 96 | Week 48 (n=4, 3, 3) | 1 participants |
| Lersivirine 750 mg | Number of Participants With NRTI and NNRTI Resistance-Associated Mutations (RAMs) at Time of Treatment Failure Through Week 24, 48 and 96 | Week 24 (n=3, 4, 2) | 0 participants |
| Lersivirine 750 mg | Number of Participants With NRTI and NNRTI Resistance-Associated Mutations (RAMs) at Time of Treatment Failure Through Week 24, 48 and 96 | Week 96 (n= 5, 8, 6) | 1 participants |
| Efavirenz 600 mg | Number of Participants With NRTI and NNRTI Resistance-Associated Mutations (RAMs) at Time of Treatment Failure Through Week 24, 48 and 96 | Week 24 (n=3, 4, 2) | 1 participants |
| Efavirenz 600 mg | Number of Participants With NRTI and NNRTI Resistance-Associated Mutations (RAMs) at Time of Treatment Failure Through Week 24, 48 and 96 | Week 96 (n= 5, 8, 6) | 1 participants |
| Efavirenz 600 mg | Number of Participants With NRTI and NNRTI Resistance-Associated Mutations (RAMs) at Time of Treatment Failure Through Week 24, 48 and 96 | Week 48 (n=4, 3, 3) | 1 participants |
Secondary
Percentage of Participants With Less Than 400 Copies/mL of HIV-1 RNA at Week 24, 48 and 96
Plasma HIV-1 RNA level was determined by validated Roche Amplicor HIV-1 Monitor standard assay.
Time frame: Week 24, 48, 96
Population: ITT population included all randomized participants who received at least 1 dose of study medication. Participants who had been discontinued from the study, were lost to follow-up, or had missing HIV-1 RNA level data at a visit were considered to have HIV-1 RNA levels \>=400 copies/mL and were referred to as non-completer = failure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lersivirine 500 mg | Percentage of Participants With Less Than 400 Copies/mL of HIV-1 RNA at Week 24, 48 and 96 | Week 48 | 81.5 percentage of participants |
| Lersivirine 500 mg | Percentage of Participants With Less Than 400 Copies/mL of HIV-1 RNA at Week 24, 48 and 96 | Week 24 | 84.6 percentage of participants |
| Lersivirine 500 mg | Percentage of Participants With Less Than 400 Copies/mL of HIV-1 RNA at Week 24, 48 and 96 | Week 96 | 73.8 percentage of participants |
| Lersivirine 750 mg | Percentage of Participants With Less Than 400 Copies/mL of HIV-1 RNA at Week 24, 48 and 96 | Week 48 | 80.0 percentage of participants |
| Lersivirine 750 mg | Percentage of Participants With Less Than 400 Copies/mL of HIV-1 RNA at Week 24, 48 and 96 | Week 24 | 87.7 percentage of participants |
| Lersivirine 750 mg | Percentage of Participants With Less Than 400 Copies/mL of HIV-1 RNA at Week 24, 48 and 96 | Week 96 | 67.7 percentage of participants |
| Efavirenz 600 mg | Percentage of Participants With Less Than 400 Copies/mL of HIV-1 RNA at Week 24, 48 and 96 | Week 24 | 90.5 percentage of participants |
| Efavirenz 600 mg | Percentage of Participants With Less Than 400 Copies/mL of HIV-1 RNA at Week 24, 48 and 96 | Week 96 | 77.8 percentage of participants |
| Efavirenz 600 mg | Percentage of Participants With Less Than 400 Copies/mL of HIV-1 RNA at Week 24, 48 and 96 | Week 48 | 85.7 percentage of participants |
Secondary
Percentage of Participants With Less Than 50 Copies/mL of HIV-1 RNA at Week 24 and 96
Plasma HIV-1 RNA level was determined by validated Roche Amplicor HIV-1 Monitor standard assay.
Time frame: Week 24, 96
Population: ITT population included all randomized participants who received at least 1 dose of study medication. Participants who had been discontinued from the study, were lost to follow-up, or had missing HIV-1 RNA level data at a visit were considered to have HIV-1 RNA levels \>=50 copies/mL and were referred to as non-completer = failure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lersivirine 500 mg | Percentage of Participants With Less Than 50 Copies/mL of HIV-1 RNA at Week 24 and 96 | Week 24 | 83.1 percentage of participants |
| Lersivirine 500 mg | Percentage of Participants With Less Than 50 Copies/mL of HIV-1 RNA at Week 24 and 96 | Week 96 | 70.8 percentage of participants |
| Lersivirine 750 mg | Percentage of Participants With Less Than 50 Copies/mL of HIV-1 RNA at Week 24 and 96 | Week 24 | 83.1 percentage of participants |
| Lersivirine 750 mg | Percentage of Participants With Less Than 50 Copies/mL of HIV-1 RNA at Week 24 and 96 | Week 96 | 67.7 percentage of participants |
| Efavirenz 600 mg | Percentage of Participants With Less Than 50 Copies/mL of HIV-1 RNA at Week 24 and 96 | Week 24 | 87.3 percentage of participants |
| Efavirenz 600 mg | Percentage of Participants With Less Than 50 Copies/mL of HIV-1 RNA at Week 24 and 96 | Week 96 | 77.8 percentage of participants |
Secondary
Percentage of Participants With Response as Determined Using the Time-to Loss of Virologic Response (TLOVR50) Algorithm at Week 24, 48 and 96
TLOVR50 response is compliment to TLOVR50 failure. TLOVR50 failure based on observed HIV-1 RNA levels and failure events (death; permanent discontinuation of drug; lost to follow-up; met treatment failure \[TF\] criteria). TF: an increase to at least 3 times baseline plasma HIV-1 RNA level at Week 2 or thereafter; failure to achieve HIV-1 RNA level \<50 copies/mL at Week 24; starting at Week 2, an increase in HIV-1 RNA level to detectable levels (\>50 copies/mL). TF criteria's defined above were confirmed by second measurement at least 14 days after first. In 'TLOVR50', '50' denotes the lower limit of quantification (LLOQ) of assay (which is 50 copies/mL). Baseline value was calculated as the average of all the measurements collected prior to and including Day 1 pre-dose.
Time frame: Week 24, 48, 96
Population: ITT population included all randomized participants who received at least 1 dose of study medication. Missing value was imputed per the TLOVR algorithm.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lersivirine 500 mg | Percentage of Participants With Response as Determined Using the Time-to Loss of Virologic Response (TLOVR50) Algorithm at Week 24, 48 and 96 | Week 48 | 78.5 percentage of participants |
| Lersivirine 500 mg | Percentage of Participants With Response as Determined Using the Time-to Loss of Virologic Response (TLOVR50) Algorithm at Week 24, 48 and 96 | Week 24 | 83.1 percentage of participants |
| Lersivirine 500 mg | Percentage of Participants With Response as Determined Using the Time-to Loss of Virologic Response (TLOVR50) Algorithm at Week 24, 48 and 96 | Week 96 | 67.7 percentage of participants |
| Lersivirine 750 mg | Percentage of Participants With Response as Determined Using the Time-to Loss of Virologic Response (TLOVR50) Algorithm at Week 24, 48 and 96 | Week 48 | 78.5 percentage of participants |
| Lersivirine 750 mg | Percentage of Participants With Response as Determined Using the Time-to Loss of Virologic Response (TLOVR50) Algorithm at Week 24, 48 and 96 | Week 24 | 83.1 percentage of participants |
| Lersivirine 750 mg | Percentage of Participants With Response as Determined Using the Time-to Loss of Virologic Response (TLOVR50) Algorithm at Week 24, 48 and 96 | Week 96 | 67.7 percentage of participants |
| Efavirenz 600 mg | Percentage of Participants With Response as Determined Using the Time-to Loss of Virologic Response (TLOVR50) Algorithm at Week 24, 48 and 96 | Week 24 | 87.3 percentage of participants |
| Efavirenz 600 mg | Percentage of Participants With Response as Determined Using the Time-to Loss of Virologic Response (TLOVR50) Algorithm at Week 24, 48 and 96 | Week 96 | 76.2 percentage of participants |
| Efavirenz 600 mg | Percentage of Participants With Response as Determined Using the Time-to Loss of Virologic Response (TLOVR50) Algorithm at Week 24, 48 and 96 | Week 48 | 85.7 percentage of participants |
Secondary
Plasma Concentration of Lersivirine at 24 Hour
The observed plasma concentration at 24 hours post-dose (C 24h).
Time frame: 24 hrs post-dose on Week 4
Population: PKSSAS included all randomized Lersivirine participants who further consented to participate in the PK sub-study, received the study medication on the day of the PK sub-study and had sufficient PK data for analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Lersivirine 500 mg | Plasma Concentration of Lersivirine at 24 Hour | 49.56 ng/mL | Geometric Coefficient of Variation 73 |
| Lersivirine 750 mg | Plasma Concentration of Lersivirine at 24 Hour | 57.70 ng/mL | Geometric Coefficient of Variation 34 |
Secondary
Population Pharmacokinetic (PK) of Lersivirine
Data for this outcome measure are not reported here because the analysis population includes participants who were not enrolled in this study. ClinicalTrials.gov is designed for reporting results from only those participants who were enrolled in the study and described in the participant flow and baseline characteristics modules.
Time frame: Week 2, 4, 8, 12, 16, 24, 32, 40, 48
Secondary
Time-Averaged Difference (TAD) in Log 10 Transformed HIV-1 RNA Levels at Week 24, 48 and 96
TAD was calculated as area under the curve of HIV-1 RNA levels (log10 copies/mL) from baseline to the time point of interest divided by time period in weeks minus baseline HIV-1 RNA level (log10 copies/mL). Baseline value was calculated as the average of all the measurements collected prior to and including Day 1 pre-dose.
Time frame: Baseline up to Week 24, 48, 96
Population: ITT population. Participant discontinued before a visit of interest: value imputed as zero; not discontinued but observation was missing: value calculated to the last non-missing timepoint; not discontinued and missing values between baseline and visit: ignore missing values; missing baseline or no HIV-1 RNA level assessment: value imputed as zero.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lersivirine 500 mg | Time-Averaged Difference (TAD) in Log 10 Transformed HIV-1 RNA Levels at Week 24, 48 and 96 | Week 48 | -2.23 log10 copies/mL | Standard Deviation 1.17 |
| Lersivirine 500 mg | Time-Averaged Difference (TAD) in Log 10 Transformed HIV-1 RNA Levels at Week 24, 48 and 96 | Week 24 | -2.17 log10 copies/mL | Standard Deviation 0.99 |
| Lersivirine 500 mg | Time-Averaged Difference (TAD) in Log 10 Transformed HIV-1 RNA Levels at Week 24, 48 and 96 | Week 96 | -2.16 log10 copies/mL | Standard Deviation 1.33 |
| Lersivirine 750 mg | Time-Averaged Difference (TAD) in Log 10 Transformed HIV-1 RNA Levels at Week 24, 48 and 96 | Week 48 | -2.24 log10 copies/mL | Standard Deviation 1.19 |
| Lersivirine 750 mg | Time-Averaged Difference (TAD) in Log 10 Transformed HIV-1 RNA Levels at Week 24, 48 and 96 | Week 24 | -2.30 log10 copies/mL | Standard Deviation 0.94 |
| Lersivirine 750 mg | Time-Averaged Difference (TAD) in Log 10 Transformed HIV-1 RNA Levels at Week 24, 48 and 96 | Week 96 | -1.92 log10 copies/mL | Standard Deviation 1.43 |
| Efavirenz 600 mg | Time-Averaged Difference (TAD) in Log 10 Transformed HIV-1 RNA Levels at Week 24, 48 and 96 | Week 24 | -2.40 log10 copies/mL | Standard Deviation 0.89 |
| Efavirenz 600 mg | Time-Averaged Difference (TAD) in Log 10 Transformed HIV-1 RNA Levels at Week 24, 48 and 96 | Week 96 | -2.21 log10 copies/mL | Standard Deviation 1.29 |
| Efavirenz 600 mg | Time-Averaged Difference (TAD) in Log 10 Transformed HIV-1 RNA Levels at Week 24, 48 and 96 | Week 48 | -2.39 log10 copies/mL | Standard Deviation 1.09 |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Lersivirine
Time frame: 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 24 hrs post-dose on Week 4
Population: PKSSAS included all randomized Lersivirine participants who consented to participate in the PK sub-study, received the study medication on the day of the PK sub-study and had sufficient PK data for analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lersivirine 500 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Lersivirine | 1.00 hr |
| Lersivirine 750 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Lersivirine | 2.00 hr |