GSK2838232 is a novel HIV-1 maturation inhibitor (MI) that is being developed for the treatment of HIV-1 infection in combination with other antiretroviral therapy (ART). This study will be a 10-day monotherapy, open-label, adaptive, dose ranging, repeat-dose study. This study will be conducted in two Parts (Part A and Part B) consisting single daily doses of GSK2838232 and Cobicistat from Day 1 to Day 10. This proof of concept open-label study will be aimed to characterize the acute antiviral activity, pharmacokinetics (PK), the relationship between PK and antiviral activity, and safety of GSK2838232/cobi administered across a range of doses over 10 days in HIV-1 infected patients. A cohort of 10 subjects will be studied in Part I followed by interim (go/no-go) analysis of Part A data. On completion of an interim analysis of part A data, further cohorts of 8 subjects will then be studied in Part B in a parallel design in two or more cohorts (depending upon the data obtained in Part A). Approximately 34 HIV-1 infected treatment-naive subjects will be enrolled during the study. Subjects in both parts will have a screening visit within 30 days prior to first dose and a follow-up visit 7-14 days after the last dose. Maximum duration of study participation will be approximately 6 Weeks.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
33
GSK2838232 capsules will be supplied as swedish orange, unmarked capsule (50 mg), and white, unmarked capsules (10 mg) in high-density polyethylene bottles.
Cobicistat tablets 150 mg will be supplied as an orange, round, biconvex, film-coated tablet in bulk containers for individualized dosing.
GSK Investigational Site
Birmingham, Alabama, United States
GSK Investigational Site
Bakersfield, California, United States
GSK Investigational Site
Los Angeles, California, United States
GSK Investigational Site
Los Angeles, California, United States
GSK Investigational Site
Ft. Pierce, Florida, United States
GSK Investigational Site
Miami, Florida, United States
GSK Investigational Site
Orlando, Florida, United States
GSK Investigational Site
Springfield, Massachusetts, United States
GSK Investigational Site
Berkley, Michigan, United States
GSK Investigational Site
Newark, New Jersey, United States
...and 4 more locations
Maximum Decline From Baseline in Plasma HIV-1 Ribonucleic Acid (RNA)
Plasma samples were collected for quantitative analysis of plasma HIV-1 RNA. An HIV-1 RNA polymerase chain reaction (PCR) assay with a lower limit of detection (LLOD) of 50 copies/milliliter (ultrasensitive assay) was used for post-baseline assessments. Baseline value was the value at latest pre-dose assessment. The maximum decline was determined using change from Baseline in plasma HIV-RNA values at each time point. The analysis was performed on Intent To Treat (ITT) Population which comprised of all participants who met study criteria and were enrolled into the study with documented evidence of having received at least 1 dose of treatment and at least one post-Baseline HIV-1 RNA measurement.
Time frame: Baseline (Day 1) to Day 21
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; is a congenital anomaly/birth defect; other important medical events; is associated with liver injury and impaired liver function. Safety Population comprised of all participants who received at least one dose of study treatment.
Time frame: Up to Day 22
Number of Participants With Clinical Chemistry Abnormalities of Potential Clinical Importance
Blood samples were collected for the assessment of clinical chemistry parameters. The clinical concern range for the parameters were: carbon dioxide/bicarbonate (low: \<18 millimoles per liter \[mmol/L\] and high: \>32 mmol/L); urea (high: \>9 mmol/L); creatinine (high: change from Baseline \>44.2 micromoles per liter \[µmol/L\]), glucose (low: \<3 and high: \>9 mmol/L); potassium (low: \<3 and high: \>5.5 mmol/L); troponin I (high: \>=0.01 micrograms per liter \[µg/L\]) and sodium (low: \<130 mmol/L and high: \>150 mmol/L). Data for any visit post-Baseline is reported.
Time frame: Up to Day 22
Number of Participants With Hematology Parameter Abnormalities of Potential Clinical Importance
Blood samples were collected for the assessment of hematology parameters. The clinical concern range for the parameters were: hematocrit (high: \>0.54 proportion of red blood cells in blood); hemoglobin (high: \>180 grams per liter \[g/L\]), lymphocytes (low: \<0.8x10\^9 cells/L); neutrophil count (low: \<1.5x10\^9 cells/L); platelet count (low: \<100x10\^9 cells/L and high: \>550x10\^9 cells/L); white blood cells (low: \<3x10\^9 cells/L and high: \>20x10\^9cells/L). Data for any visit post-Baseline is reported.
Time frame: Up to Day 22
Number of Participants With Liver Function Laboratory Abnormalities of Potential Clinical Importance
Blood samples were collected for the assessment of liver function parameters. The clinical concern range for liver function parameters were: albumin (low: \<30 g/L), total protein (low: \<15 and high: \>15 g/L), alanine aminotransferase (high: \>=2 times upper limit of normal \[ULN\]); aspartate aminotransferase (high: \>=2 times ULN); alkaline phosphatase (high: \>=2 times ULN); total bilirubin (high: \>=1.5 times ULN); direct bilirubin (high: \>0.3 times ULN).
Time frame: Up to Day 22
Number of Participants With Abnormal Urine Parameters
Urine samples were collected for the assessment of following urine parameters by dipstick method: pH, glucose, protein, blood and ketones. The number of participants with abnormal urine parameters is presented.
Time frame: Up to Day 22
Number of Participants With Abnormal Electrocardiogram (ECG) Findings
Triplicate 12-lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, and corrected QT (QTc) intervals. Number of participants with abnormal ECG findings at worst-case post Baseline is presented.
Time frame: Up to Day 22
Number of Participants With Vital Signs Data Outside Clinical Concern Range
Vital signs were measured in a semi-supine position after 5 minutes rest and included temperature, systolic and diastolic blood pressure and pulse rate. The clinical concern range for vital signs were: systolic blood pressure (SBP) (low: \<85 and high: \>160 millimeters of mercury \[mmHg\]) and diastolic blood pressure (DBP) (low: \<45 and high: \>100 mmHg). Number of participants with vital signs data outside clinical concern range is presented.
Time frame: Day 1 (pre-dose)
Number of Participants Who Were Administered Concomitant Medications
Concomitant medications (prescription and non-prescription) were administered only as medically necessary during the study. Number of participants who received any concomitant medications is presented.
Time frame: Up to Day 22
Area Under the Plasma Concentration Time Curve From Zero (Pre-dose) to 24 Hours (AUC[0 to 24]) for GSK2838232 on Day 1
Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232. The analysis was performed on Pharmacokinetic Population which comprised of participants who received GSK2838232 and underwent plasma pharmacokinetic sampling during the study.
Time frame: Pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Day 1
Maximum Observed Concentration (Cmax) for GSK2838232 on Day 1
Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232.
Time frame: Pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Day 1
Time to Maximum Observed Concentration (Tmax) for GSK2838232 on Day 1
Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232.
Time frame: Pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Day 1
Absorption Lag Time (Tlag) for GSK2838232 on Day 1
Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232.
Time frame: Pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Day 1
Concentration of GSK2838232 at 24 Hours Post-dose on Day 1
Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232.
Time frame: 24 hours post-dose on Day 1
Area Under the Concentration-time Curve Over the Dosing Interval (AUC [0 to Tau]) for GSK2838232 on Day 10
Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232.
Time frame: Pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Day 10
Pre-dose Concentration (C0) of GSK2838232 on Day 10
Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232.
Time frame: Pre dose on Day 10
Concentration at End of Dosing Interval (Ctau) for GSK2838232 on Day 10
Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232.
Time frame: 24 hours post-dose on Day 10
Cmax for GSK2838232 on Day 10
Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232.
Time frame: Pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Day 10
Apparent Oral Clearance of GSK2838232 Following Administration on Day 10
Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232.
Time frame: Pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Day 10
Terminal Elimination Half-life (T1/2) of GSK2838232 Following Administration on Day 10
Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232.
Time frame: Pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Day 10
Tmax for GSK2838232 Following Administration on Day 10
Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232.
Time frame: Pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Day 10
Change From Baseline to Day 11 in log10 Plasma HIV-1 RNA Relative to Day 10 AUC (0 to Tau)
Plasma samples were collected for quantitative analysis of HIV-1 RNA. Change from Baseline is the value at indicated time point minus Baseline value. Statistical analysis for relationship between pharmacokinetic parameters (AUC) and pharmacodynamic measures (Change from Baseline in plasma HIV-1 RNA) was explored using a frequentist three parameter Emax non-linear model. The model parameters estimated included: maximum response (Emax), pharmacokinetic parameter value that attains 50% of the maximal effect (ED50) and residual variability (s2e). Pharmacokinetic/Pharmacodynamic Population comprised of participants who met criteria for Per-Protocol (all participants who met study criteria and are enrolled into the study with documented evidence of having received all doses and all post-baseline HIV-1 RNA measurement, with exceptions of those who have at least one major protocol deviation) and Pharmacokinetic Population analysis sets and who underwent pharmacodynamic sampling during study.
Time frame: Baseline (Day 1), Days 10 and 11
Change From Baseline to Day 11 in log10 Plasma HIV-1 RNA Relative to Day 10 Cmax
Plasma samples were collected for quantitative analysis of HIV-1 RNA. Change from Baseline is the value at indicated time point minus Baseline value. Statistical analysis for the relationship between pharmacokinetic parameters (Cmax) and pharmacodynamic measures (change from Baseline in log10 plasma HIV-1 RNA) was explored using a frequentist three parameter Emax non-linear model. The model parameters estimated included: maximum response (Emax), pharmacokinetic parameter value that attains the 50% of the maximal effect (ED50) and s2e.
Time frame: Baseline (Day 1), Days 10 and 11
Change From Baseline to Day 11 in log10 Plasma HIV-1 RNA Relative to Day 10 Ctau
Plasma samples were collected for quantitative analysis of HIV-1 RNA. Change from Baseline is the value at indicated time point minus Baseline value. Statistical analysis for the relationship between pharmacokinetic parameters (Ctau) and pharmacodynamic measures (change from Baseline in log10 plasma HIV-1 RNA) was explored using a frequentist three parameter Emax non-linear model. The model parameters estimated included: maximum response (Emax), pharmacokinetic parameter value that attains the 50% of the maximal effect (ED50) and s2e.
Time frame: Baseline (Day 1), Days 10 and 11
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Change From Baseline in Cluster of Differentiation 4+ (CD4+) Cell Count to Day 11
CD4+ cell counts were assessed by flow cytometry. Baseline value is the latest pre-dose assessment value. Change from Baseline is calculated as the post-dose visit value minus Baseline value.
Time frame: Baseline (Day 1) and Day 11
Change From Baseline to Day 11 in CD4+ Count Relative to Day 10 AUC (0 to Tau)
The relationship between pharmacokinetic parameters (AUC) and pharmacodynamic measures (change from Baseline CD4+ cell count) was explored using a frequentist linear model. The model parameters estimated included slope and intercept. The estimate (slope) along with 95% confidence interval is presented.
Time frame: Baseline (Day 1), Days 10 and 11
Change From Baseline to Day 11 in CD4+ Count Relative to Day 10 Cmax
The relationship between pharmacokinetic parameters (Cmax) and pharmacodynamic measures (change from Baseline CD4+ cell count) was explored using a frequentist linear model. The model parameters estimated included slope and intercept. The estimate (slope) along with 95% confidence interval is presented
Time frame: Baseline (Day 1), Days 10 and 11
Change From Baseline to Day 11 in CD4+ Count Relative to Day 10 Ctau
The relationship between pharmacokinetic parameters (Ctau) and pharmacodynamic measures (change from Baseline CD4+ cell count) was explored using a frequentist linear model. The model parameters estimated included slope and intercept. The estimate (slope) along with 95% confidence interval is presented.
Time frame: Baseline (Day 1), Days 10 and 11
Number of Participants With Emergent Drug Resistance Mutations
Plasma samples were collected to evaluate treatment-emergent genotypic mutations in Gag, reverse transcriptase (RT) and protease (PR) and to assess phenotypic resistance to GSK2838232 and RT and PR drugs. Number of participants with treatment emergent RT/PR mutations, reduced susceptibility to nucleoside/nucleotide reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), or protease inhibitor (PI), treatment emergent maturation inhibitor A364A/V and GSK2838232 phenotypic resistance is presented.
Time frame: Up to Day 11
Accumulation Ratio for GSK2838232
Serial blood samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232. The accumulation ratios were calculated as R\_AUC=AUC(0-tau) Day 10/AUC(0-24) Day 1; R\_Cmax=Cmax Day 10/Cmax Day 1 and R\_Ctau=Ctau Day 10/C24 Day 1.
Time frame: pre dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Days 1 and 10; pre-dose on Days 3, 4, 5, 8 and 9; Days 12 and 14
Dose Proportionality of GSK2838232
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232. Dose proportionality was assessed using a fixed effects power model. Estimated slope and 90% confidence interval is presented.
Time frame: pre dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Days 1 and 10
Pre-morning Dose Concentrations (C0) on Day 2 Through 11
Blood samples were collected for pharmacokinetic analysis of GSK2838232. The pre-morning dose concentrations for Days 2 to 11 is presented. One participant from GSK2838232 100 mg arm was dosed with GSK2838232 50 mg on Days 1 and 2; hence, pharmacokinetic parameters for that participant were summarized with GSK2838232 50 mg for Days 1 and 2 and with GSK2838232 100 mg for Days 3 to 10.
Time frame: Pre-dose on Days 2, 3, 4, 5, 8, 9, 10 and 11
Steady State Assessment of Plasma Pre-dose Concentrations by Treatment
A linear mixed model using Day, treatment and Day by treatment as fixed effects and participant as a random effect on the log-transformed pre-dose values was performed to evaluate if steady state was achieved using the Helmert transformation approach. The comparison was done as Day 8 versus the average of Days 9 and 10 values. The ratio of geometric least square mean for Day 8 versus average of Days 9 and 10 values is presented along with 95% confidence interval.
Time frame: Pre-dose on Days 8, 9 and 10