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Safety and Efficacy Study of GSK2838232 in Human Immunodeficiency Virus (HIV)-1 Infected Adults

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ClinicalTrials.gov Identifier: NCT03045861
Recruitment Status : Completed
First Posted : February 8, 2017
Results First Posted : May 29, 2019
Last Update Posted : March 11, 2020
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Tracking Information
First Submitted Date  ICMJE January 12, 2017
First Posted Date  ICMJE February 8, 2017
Results First Submitted Date  ICMJE April 1, 2019
Results First Posted Date  ICMJE May 29, 2019
Last Update Posted Date March 11, 2020
Actual Study Start Date  ICMJE March 17, 2017
Actual Primary Completion Date April 23, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 9, 2019)
  • Maximum Decline From Baseline in Plasma HIV-1 Ribonucleic Acid (RNA) [ Time Frame: Baseline (Day 1) to Day 21 ]
    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.
  • Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to Day 22 ]
    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.
  • Number of Participants With Clinical Chemistry Abnormalities of Potential Clinical Importance [ Time Frame: Up to Day 22 ]
    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.
  • Number of Participants With Hematology Parameter Abnormalities of Potential Clinical Importance [ Time Frame: Up to Day 22 ]
    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.
  • Number of Participants With Liver Function Laboratory Abnormalities of Potential Clinical Importance [ Time Frame: Up to Day 22 ]
    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).
  • Number of Participants With Abnormal Urine Parameters [ Time Frame: Up to Day 22 ]
    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.
  • Number of Participants With Abnormal Electrocardiogram (ECG) Findings [ Time Frame: Up to Day 22 ]
    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.
  • Number of Participants With Vital Signs Data Outside Clinical Concern Range [ Time Frame: Day 1 (pre-dose) ]
    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.
  • Number of Participants Who Were Administered Concomitant Medications [ Time Frame: Up to Day 22 ]
    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.
  • Area Under the Plasma Concentration Time Curve From Zero (Pre-dose) to 24 Hours (AUC[0 to 24]) for GSK2838232 on Day 1 [ Time Frame: Pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose 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.
  • Maximum Observed Concentration (Cmax) for GSK2838232 on Day 1 [ Time Frame: Pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Day 1 ]
    Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232.
  • Time to Maximum Observed Concentration (Tmax) for GSK2838232 on Day 1 [ Time Frame: Pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Day 1 ]
    Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232.
  • Absorption Lag Time (Tlag) for GSK2838232 on Day 1 [ Time Frame: Pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Day 1 ]
    Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232.
  • Concentration of GSK2838232 at 24 Hours Post-dose on Day 1 [ Time Frame: 24 hours post-dose on Day 1 ]
    Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232.
  • Area Under the Concentration-time Curve Over the Dosing Interval (AUC [0 to Tau]) for GSK2838232 on Day 10 [ Time Frame: Pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Day 10 ]
    Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232.
  • Pre-dose Concentration (C0) of GSK2838232 on Day 10 [ Time Frame: Pre dose on Day 10 ]
    Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232.
  • Concentration at End of Dosing Interval (Ctau) for GSK2838232 on Day 10 [ Time Frame: 24 hours post-dose on Day 10 ]
    Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232.
  • Cmax for GSK2838232 on Day 10 [ Time Frame: Pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Day 10 ]
    Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232.
  • Apparent Oral Clearance of GSK2838232 Following Administration on Day 10 [ Time Frame: Pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Day 10 ]
    Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232.
  • Terminal Elimination Half-life (T1/2) of GSK2838232 Following Administration on Day 10 [ Time Frame: Pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Day 10 ]
    Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232.
  • Tmax for GSK2838232 Following Administration on Day 10 [ Time Frame: Pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Day 10 ]
    Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232.
Original Primary Outcome Measures  ICMJE
 (submitted: February 3, 2017)
  • Maximum decline from Baseline (Day 1) in plasma HIV-1 ribonucleic acid (RNA) [ Time Frame: Baseline (Day 1) and up to Day 11 ]
    Blood samples for the measurement of HIV-1 RNA levels will be obtained for HIV-1 RNA analysis.
  • Number of subjects with any adverse event (AE) and any serious adverse event (SAE) [ Time Frame: Up to 3 Weeks ]
    An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, other situations judged by physician, is associated with liver injury and impaired liver function.
  • Safety as assessed by concurrent medications during the treatment period [ Time Frame: Up to 3 Weeks ]
    Concurrent medications (permitted as per study protocol) received during the treatment period will be documented in case report forms.
  • Number of subjects with abnormal hematology laboratory tests [ Time Frame: Up to 3 Weeks ]
    Hematology values will be assessed.
  • Number of subjects with abnormal clinical chemistry laboratory tests [ Time Frame: Up to 3 Weeks ]
    Clinical chemistry values will be assessed.
  • Number of subjects with abnormal routine urinalysis laboratory tests [ Time Frame: Up to 3 Weeks ]
    Routine urinalysis parameters will be assessed.
  • Number of subjects with abnormal electrocardiogram (ECG) findings [ Time Frame: Up to 3 Weeks ]
    Triplicate 12-lead ECGs will be obtained at indicated time point during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QT corrected (QTc) intervals. On Day 1, ECGs (x2) will be performed pre dose , and then 1, 1.5, 2, 3, 4 and 6 hours post dose. On Days 4, 5 and 8, ECGs will be obtained prior to morning dosing and at 2, 4 and 6 hours post dose. On Day 10, ECGs (x2) will be performed pre dose, and then 1, 1.5, 2, 3, 4 and 6 hours post dose. On Day 11, an ECG will be obtained prior to the 24-hour PK sample.
  • Systolic and diastolic blood pressure (BP) as a measure of safety [ Time Frame: Up to 3 Weeks ]
    Systolic and diastolic BP will be measured in semi-supine position after 5 minutes rest. Three readings of blood pressure will be taken of which first reading will be rejected. Second and third readings will be averaged to give the measurement. Systolic and diastolic BP will be obtained at Screening (x1) and Day 1 pre dose (x2); on Day 1 at 2 hours post-morning dose and on Days 4, 5 and 8 pre dose; on Day 10 at pre dose and 2 hours post-morning dose, and at Follow-up.
  • Pulse rate as a measure of safety [ Time Frame: Up to 3 Weeks ]
    Pulse rate will be measured in semi-supine position after 5 minutes rest. Three readings of pulse rate will be taken of which first reading will be rejected. Second and third readings will be averaged to give the measurement. Pulse rate will be obtained at Screening (x1) and Day 1 pre dose (x2); on Day 1 at 2 hours post-morning dose and on Days 4, 5 and 8 pre dose; on Day 10 at pre dose and 2 hours post-morning dose, and at Follow-up.
  • Body temperature as a measure of safety [ Time Frame: Up to 3 Weeks ]
    Body temperature will be measured in semi-supine position after 5 minutes rest. Body temperature will be obtained at Screening (x1) and Day 1 pre dose (x2).
  • Area under the plasma concentration-time curve (AUC) from time zero (Pre-dose) to over 24 hours time (AUC[0-24]) of GSK2838232 following dose administration on Day 1 [ Time Frame: PK samples will be taken at pre dose and post dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours on Day 1 ]
    2 milliliter (mL) of blood samples will be collected at indicated time points for PK analysis.
  • Maximum observed plasma concentration (Cmax) and concentration at 24 hours post dose (C24) of GSK2838232 on Day 1 [ Time Frame: PK samples will be taken at pre dose and post dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours on Day 1. ]
    Cmax is defined as the maximum observed plasma concentration. 2 mL of blood samples will be collected at indicated time points for PK analysis.
  • Time to maximum observed concentration (Tmax) of GSK2838232 on Day 1 [ Time Frame: PK samples will be taken at pre dose and post dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours on Day 1 ]
    2 mL of blood samples will be collected at indicated time points for PK analysis.
  • Absorption lag time (Tlag) of GSK2838232 on Day 1 [ Time Frame: PK samples will be taken at pre dose and post dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours on Day 1 ]
    Absorption lag time is defined as the time taken for a drug to appear in the systemic circulation following administration. 2 mL of blood samples will be collected at indicated time points for PK analysis.
  • Area under the concentration-time curve over the dosing interval (AUC[0-tau]) of GSK2838232 on Day 10 [ Time Frame: PK samples will be taken at pre dose and post dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours on Day 1 and Day 10. Pre dose PK samples will be taken on Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14. ]
    AUC (0-tau) is defined as the area under the concentration-time curve over the dosing interval. 2 mL of blood samples will be collected at indicated time points for PK analysis.
  • Pre-dose Concentration (C0) of GSK2838232 on Day 10 [ Time Frame: PK samples will be taken at pre dose and post dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours on Day 1 and Day 10. Pre dose PK samples will be taken on Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14. ]
    C0 is defined as the pre-dose concentration. 2 mL of blood samples will be collected at indicated time points for PK analysis.
  • Concentration at the end of the dosing interval (Ctau) of GSK2838232 on Day 10 [ Time Frame: PK samples will be taken at pre dose and post dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours on Day 1 and Day 10. Pre dose PK samples will be taken on Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14. ]
    Ctau is defined as the concentration at the end of the dosing interval. 2 mL of blood samples will be collected at indicated time points for PK analysis.
  • Cmax of GSK2838232 on Day 10 [ Time Frame: PK samples will be taken at pre dose and post dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours on Day 1 and Day 10. Pre dose PK samples will be taken on Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14. ]
    Cmax is defined as the maximum observed plasma concentration. 2 mL of blood samples will be collected at indicated time points for PK analysis.
  • Tmax of GSK2838232 on Day 10 [ Time Frame: PK samples will be taken at pre dose and post dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours on Day 1 and Day 10. Pre dose PK samples will be taken on Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14. ]
    Tmax is defined as the time to the maximum observed plasma concentration. 2 mL of blood samples will be collected at indicated time points for PK analysis
  • Terminal half-life (t1/2) of GSK2838232 on Day 10 [ Time Frame: PK samples will be taken at pre dose and post dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours on Day 1 and Day 10. Pre dose PK samples will be taken on Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14. ]
    T1/2 of GSK2838232 is defined as the time required for the plasma concentration of GSK2838232 to reach half of its original concentration. 2 mL of blood samples will be collected at indicated time points for PK analysis.
  • Apparent oral clearance (CL/F) of GSK2838232 on Day 10 [ Time Frame: PK samples will be taken at pre dose and post dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours on Day 1 and Day 10. Pre dose PK samples will be taken on Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14. ]
    The CL/F is defined as the apparent total clearance of the drug from plasma after oral administration. 2 mL of blood samples will be collected at indicated time points for PK analysis
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 9, 2019)
  • Change From Baseline to Day 11 in log10 Plasma HIV-1 RNA Relative to Day 10 AUC (0 to Tau) [ Time Frame: Baseline (Day 1), Days 10 and 11 ]
    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.
  • Change From Baseline to Day 11 in log10 Plasma HIV-1 RNA Relative to Day 10 Cmax [ Time Frame: Baseline (Day 1), Days 10 and 11 ]
    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.
  • Change From Baseline to Day 11 in log10 Plasma HIV-1 RNA Relative to Day 10 Ctau [ Time Frame: Baseline (Day 1), Days 10 and 11 ]
    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.
  • Change From Baseline in Cluster of Differentiation 4+ (CD4+) Cell Count to Day 11 [ Time Frame: Baseline (Day 1) and 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.
  • Change From Baseline to Day 11 in CD4+ Count Relative to Day 10 AUC (0 to Tau) [ Time Frame: Baseline (Day 1), Days 10 and 11 ]
    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.
  • Change From Baseline to Day 11 in CD4+ Count Relative to Day 10 Cmax [ Time Frame: Baseline (Day 1), Days 10 and 11 ]
    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
  • Change From Baseline to Day 11 in CD4+ Count Relative to Day 10 Ctau [ Time Frame: Baseline (Day 1), Days 10 and 11 ]
    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.
  • Number of Participants With Emergent Drug Resistance Mutations [ Time Frame: Up to Day 11 ]
    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.
  • Accumulation Ratio for GSK2838232 [ 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 ]
    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.
  • Dose Proportionality of GSK2838232 [ 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 ]
    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.
  • Pre-morning Dose Concentrations (C0) on Day 2 Through 11 [ Time Frame: Pre-dose on Days 2, 3, 4, 5, 8, 9, 10 and 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.
  • Steady State Assessment of Plasma Pre-dose Concentrations by Treatment [ Time Frame: Pre-dose on Days 8, 9 and 10 ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 3, 2017)
  • Relationship of GSK2838232 PK parameter AUC(0-tau) (Day 10) with respect to change from baseline in HIV-1 RNA (Day 11) [ Time Frame: Up to 3 weeks ]
    Relationships between various PK parameters and PD measures will be explored using various models.
  • Relationship of GSK2838232 PK parameters Cmax (Day 10) with respect to change from baseline in HIV-1 RNA (Day 11) [ Time Frame: Up to 3 weeks ]
    Relationships between various PK parameters and PD measures will be explored using various models.
  • Relationship of GSK2838232 PK parameter Ctau (Day 10) with respect to change from baseline in HIV-1 RNA (Day 11) [ Time Frame: Up to 3 weeks ]
    Relationships between various PK parameters and PD measures will be explored using various models)
  • Change from baseline in cluster of differentiation 4+ (CD4+) cell count [ Time Frame: Up to Day 11 ]
    Change from Baseline in CD4+ cell count will be calculated as the Day 11 value minus the Baseline value.
  • Relationship of GSK2838232 PK parameter Cmax (Day 10) with respect to change from baseline in CD4+ cell count [ Time Frame: PD: Baseline (Day 1) and Day 11; PK: pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post- am dose on Day 1 and Day 10; pre dose on the mornings of Days 3, 4, 5, 8 and 9 and a single sample on Days 12 and 14. ]
    Relationships between various PK parameters and PD measures will be explored using various models.
  • Relationship of GSK2838232 PK parameter Ctau (Day 10) with respect to change from baseline in CD4+ cell count [ Time Frame: PD: Baseline (Day 1) and Day 11; PK: pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post- am dose on Day 1 and Day 10; pre dose on the mornings of Days 3, 4, 5, 8 and 9 and a single sample on Days 12 and 14. ]
    Relationships between various PK parameters and PD measures will be explored using various models.
  • Number of participants with the emergence of drug resistance mutations [ Time Frame: Baseline (Day 1) and Day 11 ]
    The number of participants with the emergence (from Baseline) of drug resistance mutations at Day 11 was measured
  • GSK2838232 Day 10 AUC(0-tau) compared to Day 1 AUC(0-24) to estimate accumulation ratio (R) [ Time Frame: PK samples will be taken pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-am dose on Day 1 and Day 10. Pre dose PK samples will be taken on the mornings of Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14. ]
    Comparisons of Day 10 with Day 1 PK for each dose will be used for the accumulation ratio (R) evaluation.
  • GSK2838232 Day 10 Cmax and Ctau compared to Day 1 Cmax and C24 to estimate accumulation ratio (R), respectively [ Time Frame: PK samples will be taken pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-am dose on Day 1 and Day 10. Pre dose PK samples will be taken on the mornings of Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14. ]
    Comparisons of Day 10 with Day 1 PK for each dose will be used for the accumulation ratio (R) evaluation.
  • Pre-morning dose concentrations (C0) of GSK2838232 from Day 2 to Day 11 [ Time Frame: Pre dose on Days 1, 3, 4, 5, 8, 9 and 10 ]
    2 mL of blood samples will be collected at indicated time points for PK analysis.
  • Day 1 AUC(0-24) and at different doses levels (20, 50, 100 and 200 milligram [mg]) for the assessment of dose proportionality [ Time Frame: PK samples will be taken at pre dose and post dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours on Day 1 and Day 10. Pre dose PK samples will be taken on Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14. ]
    Dose proportionality of plasma GSK2838232 PK parameters from Day 1 and Day 10 will be assessed using a power model for all doses (20, 50, 100 and 200 mg)
  • Day 10 AUC(0-tau) at different doses levels (20, 50, 100 and 200 milligram [mg]) for the assessment of dose proportionality [ Time Frame: PK samples will be taken at pre dose and post dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours on Day 1 and Day 10. Pre dose PK samples will be taken on Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14. ]
    Dose proportionality of plasma GSK2838232 PK parameters from Day 1 and Day 10 will be assessed using a power model for all doses (20, 50, 100 and 200 mg).
  • Day 1 and Day 10 Cmax [ Time Frame: PK samples will be taken at pre dose and post dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours on Day 1 and Day 10. Pre dose PK samples will be taken on Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14. ]
    Dose proportionality of plasma GSK2838232 PK parameters from Day 1 and Day 10 will be assessed using a power model if multiple dose levels are assessed.
  • Day 1 C24 [ Time Frame: PK samples will be taken at pre dose and post dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours on Day 1 and Day 10. Pre dose PK samples will be taken on Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14. ]
    Dose proportionality of plasma GSK2838232 PK parameters from Day 1 and Day 10 will be assessed using a power model if multiple dose levels are assessed.
  • Day 10 Ctau [ Time Frame: PK samples will be taken at pre dose and post dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours on Day 1 and Day 10. Pre dose PK samples will be taken on Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14. ]
    Dose proportionality of plasma GSK2838232 PK parameters from Day 1 and Day 10 will be assessed using a power model if multiple dose levels are assessed.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Efficacy Study of GSK2838232 in Human Immunodeficiency Virus (HIV)-1 Infected Adults
Official Title  ICMJE A Phase 2a, Multicenter, Randomized, Adaptive, Open-label, Dose Ranging Study to Evaluate the Antiviral Effect, Safety, Tolerability and Pharmacokinetics of Cobicistat-boosted GSK2838232 Monotherapy Over 10 Days in HIV-1 Infected Treatment-naive Adults
Brief Summary 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Infection, Human Immunodeficiency Virus
  • HIV Infections
Intervention  ICMJE
  • Drug: GSK2838232
    GSK2838232 capsules will be supplied as swedish orange, unmarked capsule (50 mg), and white, unmarked capsules (10 mg) in high-density polyethylene bottles.
  • Drug: Cobicistat
    Cobicistat tablets 150 mg will be supplied as an orange, round, biconvex, film-coated tablet in bulk containers for individualized dosing.
Study Arms  ICMJE
  • Experimental: Cohort 1-GSK2838232 100 mg + Cobicistat 150 mg in Part A
    During Part A (Cohort 1), subjects will receive a single dose of GSK2838232 100 mg and Cobicistat 150 mg once daily each morning with a light breakfast meal and 240 mL of water from Day 1 to Day 10. Subjects will be followed up to Day 22.
    Interventions:
    • Drug: GSK2838232
    • Drug: Cobicistat
  • Experimental: Cohort 2-GSK2838232 200 mg + Cobicistat 150 mg in Part B
    During Part B (Cohort 2), subjects will receive a single dose of GSK2838232 200 mg and Cobicistat 150 mg once daily each morning with a light breakfast meal and 240 mL of water from Day 1 to Day 10. Subjects will be followed up to Day 22.
    Interventions:
    • Drug: GSK2838232
    • Drug: Cobicistat
  • Experimental: Cohort 3-GSK2838232 50 mg + Cobicistat 150 mg in Part B
    During Part B (Cohort 3), subjects will receive a single dose of GSK2838232 50 mg and Cobicistat 150 mg once daily each morning with a light breakfast meal and 240 mL of water from Day 1 to Day 10. Subjects will be followed up to Day 22.
    Interventions:
    • Drug: GSK2838232
    • Drug: Cobicistat
  • Experimental: Cohort 4-GSK2838232 20 mg + Cobicistat 150 mg in Part B
    During Part B (Cohort 4), subjects will receive a single dose of GSK2838232 20 mg and Cobicistat 150 mg once daily each morning with a light breakfast meal and 240 mL of water from Day 1 to Day 10. Subjects will be followed up to Day 22.
    Interventions:
    • Drug: GSK2838232
    • Drug: Cobicistat
Publications * DeJesus E, Harward S, Jewell RC, Johnson M, Dumont E, Wilches V, Halliday F, Talarico CL, Jeffrey J, Gan J, Xu J, Felizarta F, Scribner A, Ramgopal M, Benson P, Johns BA. A Phase IIa Study Evaluating Safety, Pharmacokinetics, and Antiviral Activity of GSK2838232, a Novel, Second-generation Maturation Inhibitor, in Participants With Human Immunodeficiency Virus Type 1 Infection. Clin Infect Dis. 2019 Nov 26. pii: ciz938. doi: 10.1093/cid/ciz938. [Epub ahead of print]

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 10, 2018)
33
Original Estimated Enrollment  ICMJE
 (submitted: February 3, 2017)
40
Actual Study Completion Date  ICMJE April 23, 2018
Actual Primary Completion Date April 23, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Between 18 and 55 years of age inclusive, at the time of signing the informed consent.
  • Healthy (other than HIV infection) male or female as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring, defined as no other chronic medical conditions and taking no chronic medications.
  • A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included only if the investigator in consultation with the medical monitor agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
  • A creatinine clearance >80 mL/minute as determined by Cockcroft-Gault equation creatinine clearance CLcr (mL/minute) = (140 - age) x weight (Wt) divided by (72 x serum creatinine [Scr]) (times 0.85 if female) where age is in years, Wt is in kilogram (kg), and Scr is in units of mg/decilitre (dL).
  • Confirmed HIV positive; CD4+ cell count >=350 cells/millimetre (mm)^3 and plasma HIV-1 RNA >=5000 copies/mL at screening.
  • No current and no prior ART.
  • Body weight >=50 kg (110 pound [lbs.]) for men and >=45 kg (99 lbs) for women and body mass index (BMI) within the range 18.5-31.0 kg/meter^2 (inclusive)
  • A female subject of reproductive or non-reproductive potential is eligible to participate if she is not pregnant (as confirmed by a negative serum or urine human chorionic gonadotrophin (hCG) test at screening and prior to first dose), not lactating, and at least one of the following conditions applies: females of reproductive potential may only be enrolled if they are using two forms of complementary contraception, which must include one barrier method. They will be counselled on safer sex practices; there is no definitive drug-drug interaction (DDI) information with GSK2838232 and an interaction with oral contraceptives is possible, so other (barrier, inter-uterine device etc.) methods of contraception will be required; fertile females, who have an established, long-term lifestyle of sexual abstinence, or only same sex partners, require no other means of birth control. Pre-menopausal females with one of the following: documented tubal ligation; documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion; hysterectomy; documented bilateral oophorectomy; postmenopausal defined as 12 months of spontaneous amenorrhea in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause. Females on hormone replacement therapy (HRT) must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment.
  • Male subjects with female partners of child bearing potential must comply with the following contraception requirements from the time of first dose of study medication until one week after the last dose of study medication; vasectomy with documentation of azoospermia; male condom plus partner use of one of the contraceptive options as: Contraceptive sub dermal implant including a <1 percent rate of failure per year; intrauterine device or intrauterine system including a <1 percent rate of failure per year; oral contraceptive, either combined or progestogen alone or injectable progestogen; contraceptive vaginal ring; percutaneous contraceptive patches. These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.
  • Capable of giving signed informed consent.

Exclusion Criteria:

  • Alanine aminotransferase (ALT) and bilirubin (BIL) >1.5 x upper limit of normal (ULN), isolated BIL >1.5xULN is acceptable if BIL is fractionated and direct BIL <35 percent.
  • Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones); hepatitis B virus (HBV) and/or hepatitis C virus (HCV) positive.
  • Subjects who have any other chronic medical condition, including cardiovascular (CV), respiratory, neurologic, psychiatric, renal, gastrointestinal (GI), oncologic, rheumatologic, or dermatologic.
  • Medical history of cardiac arrhythmias or cardiac disease or a family or personal history of long QT syndrome.
  • Unable to refrain from the use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GSK medical monitor the medication will not interfere with the study procedures or compromise subject safety.
  • History of regular alcohol consumption within 6 months of the study defined as: an average weekly intake of >14 drinks for males or >7 drinks for females. One drink is equivalent to 12 grams (g) of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.
  • Smoking is an exclusion criteria for this study. Subject having urinary cotinine levels indicative of smoking at screening.
  • Chronic marijuana or use of other elicit medications (cocaine, heroin) is an exclusion criteria.
  • History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates their participation.
  • Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment.
  • Screening or Baseline cardiac troponin I greater than the 99 percent cutoff (>0.045 nanogram [ng]/mL by the Dimension Vista cardiac troponin [CTN] I assay).
  • A positive pre-study drug/alcohol screen.
  • Prior history of receiving an HIV maturation inhibitor
  • Where participation in the study would result in donation of blood or blood products in excess of 500 mL within 56 days.
  • The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
  • Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
  • Treatment with radiation therapy or cytotoxic chemotherapeutic agents within 30 days of study drug administration or anticipated need for such treatment within the study.
  • Treatment with immunomodulating agents (such as systemic corticosteroids, interleukins, interferons) or any agent with known anti-HIV activity (such as hydroxyurea or foscarnet) within 30 days of study drug administration.
  • An active Center for Disease Control and Prevention (CDC) category C disease except cutaneous Kaposi's sarcoma not requiring systemic therapy during the trial.
  • Treatment with any vaccine within 30 days prior to receiving study medication.
  • Exclusion criteria for 24-hour screening holter: any symptomatic arrhythmia (except isolated extra systoles); sustained cardiac arrhythmias (such as atrial fibrillation, flutter or supraventricular tachycardia [>=10 seconds]); non-sustained or sustained ventricular tachycardia (defined as >=3 consecutive ventricular ectopic beats); any conduction abnormality including but not specific to left or complete bundle branch block, atrioventricular (AV) block, high grade or complete heart block Wolff-Parkinson-White (WPW) syndrome etc.; sinus pauses >3 seconds.
  • Exclusion criteria for screening ECG (a single repeat is allowed for eligibility determination): heart rate <45 and >100 beats per minute (bpm) for males, and <50 and >100 bpm for females; PR Interval <120 and >220 milliseconds (msec); QRS duration <70 and >120 msec; corrected QT (QTc) interval >450 msec; Evidence of previous myocardial infarction (Does not include ST segment changes associated with repolarization); any conduction abnormality (including but not specific to left or right complete bundle branch block, AV block [2nd degree or higher], WPW syndrome); sinus pauses >3 seconds; any significant arrhythmia which, in the opinion of the principal investigator or GSK medical monitor, will interfere with the safety for the individual subject; non-sustained or sustained ventricular tachycardia (>=3 consecutive ventricular ectopic beats).
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years to 55 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03045861
Other Study ID Numbers  ICMJE 200911
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (CSR)
Time Frame: IPD is available via the Clinical Study Data Request site (click on the link provided below)
Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
URL: https://clinicalstudydatarequest.com/Posting.aspx?ID=20281
Responsible Party GlaxoSmithKline
Study Sponsor  ICMJE GlaxoSmithKline
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: GSK Clinical Trials GlaxoSmithKline
PRS Account GlaxoSmithKline
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP