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

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

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 Overview

• Status: Completed
• Conditions: HIV Infections; Infection, Human Immunodeficiency Virus
• Intervention / Treatment: Drug: GSK2838232; Drug: Cobicistat

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2C4
      • GSK Investigational Site
  • Quebec
    • Montreal, Quebec, Canada, H2L 4P9
      • GSK Investigational Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35226
      • GSK Investigational Site
  • California
    • Bakersfield, California, United States, 93301
      • GSK Investigational Site
    • Los Angeles, California, United States, 90069
      • GSK Investigational Site
    • Los Angeles, California, United States, 90027
      • GSK Investigational Site
  • Florida
    • Fort Pierce, Florida, United States, 34982
      • GSK Investigational Site
    • Miami, Florida, United States, 33133
      • GSK Investigational Site
    • Orlando, Florida, United States, 32803
      • GSK Investigational Site
  • Massachusetts
    • Springfield, Massachusetts, United States, 01107
      • GSK Investigational Site
  • Michigan
    • Berkley, Michigan, United States, 48072
      • GSK Investigational Site
  • New Jersey
    • Newark, New Jersey, United States, 07102
      • GSK Investigational Site
  • Texas
    • Dallas, Texas, United States, 75246
      • GSK Investigational Site
    • Longview, Texas, United States, 75602
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	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.
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.	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.
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.	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.
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.	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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.	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).	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	Pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Day 10

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	Baseline (Day 1), Days 10 and 11
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.	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.	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	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.	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.	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.	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.	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.	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.	Pre-dose on Days 8, 9 and 10

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

General 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. 2020 Aug 22;71(5):1255-1262. doi: 10.1093/cid/ciz938.

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 17, 2017
• Primary Completion (ACTUAL): April 23, 2018
• Study Completion (ACTUAL): April 23, 2018

Study Registration Dates

• First Submitted: January 12, 2017
• First Submitted That Met QC Criteria: February 3, 2017
• First Posted (ESTIMATE): February 8, 2017

Study Record Updates

• Last Update Posted (ACTUAL): March 11, 2020
• Last Update Submitted That Met QC Criteria: March 2, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; RNA Virus Infections; Virus Diseases; Blood-Borne Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immune System Diseases; Disease Attributes; Slow Virus Diseases; HIV Infections; Infections; Communicable Diseases; Acquired Immunodeficiency Syndrome; Immunologic Deficiency Syndromes; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Cobicistat; GSK-2838232
• Other Study ID Numbers: 200911

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
• IPD Sharing Time Frame: IPD is available via the Clinical Study Data Request site (click on the link provided below)
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No