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GSK2248761

Phase 2

Infection, Human Immunodeficiency Virus | Small molecule | Other |GSK plc|Last Updated: Nov 29, 2018

Success Probability
Approval Probability 71%
TA Base Rate26%
Adjusted LOA41%
ML RiskLOW_RISK
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Market & Valuation
rNPV $3.2B
Market Size $9.4B
Revenue Basis $1.6B
Competitors 6
Premium
Trial Design
RandomizedDouble-BlindCONTROLLEDBiomarker
Total Trials2
Total Enrollment22
FDA Designations
No designations recorded
Clinical Trials (2)
NCT IDTitlePhaseStatusEnrollmentVelocityDesignStartCompletionLast UpdatedSitesCountries
NCT00945282Safety and Tolerability Study to Evaluate Lower Dose of GSK2248761 in Antiretroviral Treatment-Naive HIV-1 Infected Adults.PHASE2 COMPLETED 8Oct 20, 2009Nov 28, 2009Nov 29, 20181 Argentina
NCT01138072A Drug Interaction Study Between Simvastatin, Atorvastatin, Rosuvastatin, and GSK2248761 in Healthy Subjects.PHASE1 COMPLETED 14Jun 1, 2010Aug 1, 2010Nov 5, 20101 United States
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Study Endpoints
Primary Endpoints
Number of Participants With Serious Adverse Events (SAEs) and Adverse Events (AEs)
Up to 38 days

An AE is defined as any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An 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, or is a congenital anomaly/birth defect, or is an important medical events that jeopardize the participants or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition, or a drug-induced liver injury.

Change From Baseline in Hematology Paramaters- Basophils, Eosinophils, Lymphocytes, Monocytes, White Blood Cell Count
Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)

The data for hematology parameters for Basophils, eosinophils, lymphocytes, monocytes, and white blood cell count from the change from baseline was reported. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. Baseline (pre-dose \[Screening, Day -1 or Day 1\]) was defined as last available scheduled assessment prior to time of the first dose unless it is specified otherwise.

Change From Baseline in Hematology Paramaters- Hemoglobin
Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)

The data for hematology parameter hemoglobin from the change from baseline was reported. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. Baseline (pre-dose \[Screening, Day -1 or Day 1\]) was defined as last available scheduled assessment prior to time of the first dose unless it is specified otherwise.

Change From Baseline in Hematology Paramaters- Platelet Count
Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)

The data for hematology parameter platelet count, for the change from baseline was reported. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. Baseline (pre-dose \[Screening, Day -1 or Day 1\]) was defined as last available scheduled assessment prior to time of the first dose unless it is specified otherwise.

Change From Baseline in Hematology Paramaters- Red Blood Cell Count
Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)

The data for hematology parameter red blood cell count, for the change from baseline was reported. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. Baseline (pre-dose \[Screening, Day -1 or Day 1\]) was defined as last available scheduled assessment prior to time of the first dose unless it is specified otherwise.

Change From Baseline in Hematology Parameters- Total Neutrophil
Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)

The data for hematology parameter total neutrophil count, for the change from baseline was reported. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. Baseline (pre-dose \[Screening, Day -1 or Day 1\]) was defined as last available scheduled assessment prior to time of the first dose unless it is specified otherwise.

Change From Baseline in Hematology Paramaters- Mean Corpuscle Hemoglobin (MCH)
Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)

The data for hematology parameter MCH, the change from baseline was reported. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. Baseline (pre-dose \[Screening, Day -1 or Day 1\]) was defined as last available scheduled assessment prior to time of the first dose unless it is specified otherwise.

Change From Baseline in Hematology Paramaters- Mean Corpuscle Volume (MCV)
Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)

The change from baseline data for hematology parameter MCV, was reported. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. Baseline (pre-dose \[Screening, Day -1 or Day 1\]) was defined as last available scheduled assessment prior to time of the first dose unless it is specified otherwise.

Change From Baseline in Hematology Paramaters- Hematocrit
Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)

The data for hematology parameter Hematocrit, the change from baseline was reported. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. Baseline (pre-dose \[Screening, Day -1 or Day 1\]) was defined as last available scheduled assessment prior to time of the first dose unless it is specified otherwise.

Change From Baseline in Hematology Paramaters-Mean Corpuscle Hemoglobin Concentration
Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)

The data for hematology parameter Mean Corpuscle Hemoglobin concentration, the change from baseline was reported. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. Baseline (pre-dose \[Screening, Day -1 or Day 1\]) was defined as last available scheduled assessment prior to time of the first dose unless it is specified otherwise.

Change From Baseline in Clinical Chemistry Paramaters- Albumin and Total Protein
Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)

The data for clinical chemistry parameters Albumin and total protein, the change from baseline was reported. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. Baseline (pre-dose \[Screening, Day -1 or Day 1\]) was defined as last available scheduled assessment prior to time of the first dose unless it is specified otherwise.

Change From Baseline in Clinical Chemistry Parameters- Blood Urea Nitrogen, Triglycerides, Glucose, Creatinine, Calcium, Cholesterol, Total Bilirubin, and Direct Bilirubin.
Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)

The data for clinical chemistry parameters- Blood urea nitrogen, triglycerides, glucose, creatinine, calcium, cholesterol, total bilirubin, and direct bilirubin. The change from baseline was reported. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. Baseline (pre-dose \[Screening, Day -1 or Day 1\]) was defined as last available scheduled assessment prior to time of the first dose unless it is specified otherwise.

Change From Baseline in Clinical Chemistry Paramaters- Alkaline Phosphatase, Alanine Amino Transferase, Aspartate Amino Transferase
Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)

The data for clinical chemistry paramaters- alkaline phosphatase, alanine amino transferase, aspartate amino transferase, the change from baseline was reported. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. Baseline (pre-dose \[Screening, Day -1 or Day 1\]) was defined as last available scheduled assessment prior to time of the first dose unless it is specified otherwise.

Change From Baseline in Clinical Chemistry Paramaters-sodium, Potassium and Carbondioxide or Bicarbonate
Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)

The data for clinical chemistry parameters- sodium, potassium and carbon dioxide or bicarbonate, the change from baseline was reported. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. Baseline (pre-dose \[Screening, Day -1 or Day 1\]) was defined as last available scheduled assessment prior to time of the first dose unless it is specified otherwise.

Change From Baseline in Clinical Chemistry Paramaters- Phosphorus
Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)

The data for clinical chemistry paramaters- phosphorous, the change from baseline was reported. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. Baseline (pre-dose \[Screening, Day -1 or Day 1\]) was defined as last available scheduled assessment prior to time of the first dose unless it is specified otherwise.

Change From Baseline in Clinical Chemistry Paramaters- Uric Acid
Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)

The data for clinical chemistry parameters Uric acid, the change from baseline was reported. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. Baseline (pre-dose \[Screening, Day -1 or Day 1\]) was defined as last available scheduled assessment prior to time of the first dose unless it is specified otherwise.

Change From Baseline in Clinical Chemistry Paramaters- Thyroxine, Free
Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)

The data for clinical chemistry parameters Thyroxine, free the change from baseline was reported. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. Baseline (pre-dose \[Screening, Day -1 or Day 1\]) was defined as last available scheduled assessment prior to time of the first dose unless it is specified otherwise.

Change From Baseline in Clinical Chemistry Paramaters- Thyroxine Total, Thyroxine Binding Globulin, Total T3.
Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)

The data for clinical chemistry parameters Thyroxine total, thyroxine binding globulin, Total T3 the change from baseline was reported. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. Baseline (pre-dose \[Screening, Day -1 or Day 1\]) was defined as last available scheduled assessment prior to time of the first dose unless it is specified otherwise.

Number of Participants With Abnormal Electrocardiogram (ECG) Findings
Day 1, Day 4, Day 7, Day 8 and follow-up

Triplicate 12-lead ECGs were collected at different timepoints, after participants were supine for 5 minutes, during the study using an ECG machine that automatically calculated the heart rate (HR) and measures PR, QRS, QT, and QTc intervals. The three consecutive determinations were collected 5 plus or minus 2 minutes apart and all three tracings were recorded. The participants with abnormal values categorized as abnormal clinically significant (CS) and not clinically significant (NCS) were reported.

Change From Baseline in Vital Signs-systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
Baseline (pre-dose at Day -1 or Day 1) and Day 1, 4, 7 , Day 8 and Follow-up (Day 14)

Vital sign measurements for SBP and DBP after sitting for 5 minutes were measured. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. Baseline (pre-dose \[Screening, Day -1 or Day 1\]) was defined as last available scheduled assessment prior to time of the first dose unless it is specified otherwise.

Change From Baseline in HR
Baseline (pre-dose at Day -1 or Day 1) and Day 1 (4-hour), Day 4 (Pre-dose and 4 hour), Day 7 (pre-dose and 4-hour), Day 8 and follow up (Day 14)

Vital sign measurements for HR after sitting for 5 minutes were measured. The average mean values were measured. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. Baseline (pre-dose \[Screening, Day -1 or Day 1\]) was defined as last available scheduled assessment prior to time of the first dose unless it is specified otherwise.

Change From Baseline Through Day 8 in Plasma HIV-1 RNA
Baseline (pre-dose Day 1) to Day 8

The quantitative analysis of plasma was done to evaluate the amount of HIV-1 RNA at Day 1,2,3,4,5,6,7, 8 and End of treatment visit. The quantification was done using a Polymerase chain reactor (PCR). The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. Baseline (pre-dose Day 1) was defined as last available scheduled assessment prior to time of the first dose unless it is specified otherwise.

Change From Baseline to Nadir in Plasma HIV-1 RNA
Baseline (pre-dose Day 1) to Day 8

The quantification of plasma HIV-1 RNA, was conducted for the change from baseline to on treatment nadir (maximum change) before starting HAART or Kaletra monotherapy on Day 8. The quantification was done using a PCR. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. Baseline (pre-dose Day 1\]) was defined as last available scheduled assessment prior to time of the first dose unless it is specified otherwise.

HIV-1 Rate of Decline by Treatment
Day 1 to Day 8

The rate of decrease in the viral load of HIV-1 virus in response to individual treatment was measured. The viral load data was assumed to have a log normal prior distribution and followed linear decline with non-informative conjugate prior densities. The rate of decline (slope of the day) for each treatment was measured using a PCR from Day 1 to Day 8. The slope has been reported as mean.

GSK2248761 Pharmacokinetic (PK) Parameters Following Dose Administration on Day 1: Area Under the Plasma Concentration Time Curve 0 to Infinite (AUC[0-∞]) and Area Under the Plasma Concentration Time Curve (AUC [0-24])
Day 1 (Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose)

AUC (0-24), measured the plasma concentration of GSK2248761 against time, from time zero (pre-dose) to 24 hrs post-dose AUC (0-24) and from time zero to extrapolated infinite time AUC (0-∞). Serial blood samples were collected on Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose on Day 1 and used for analysis.

GSK2248761 PK Parameters Following Dose Administration on Day 1: Maximum Observed Concentration (Cmax) and Concentration at 24 Hours Post Dose (C24)
Day 1 (Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours)

Cmax represents the maximum concentration of GSK2248761 in the plasma. C24 is defined as the measure of plasma drug concentration of GSK2248761, 24 hours post dose, determined on Day 1. Serial blood samples were collected on Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose on Day 1 and used for analysis.Data for dose normalized Cmax and C24 was reported.

GSK2248761 PK Parameters Following Dose Administration on Day 7: Predose Concentration (C0), Concentration at End of Dosing Interval (Cτ), Minimum Observed Concentration During One Dosing Interval (Cmin) and Cmax
Day 7 (Pre -dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose)

The C0 was defined as the concentration of drug in plasma, before dose administration on Day 7. Cτ, was defined as the concentration of drug in the plasma at the end of dosing interval. The Cmin was defined as the minimum concentration of the drug in plasma during one dosing interval on Day 7. Cmax represents the maximum concentration of GSK2248761 in the plasma on Day 7. Serial blood samples were collected on Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose on Day 7 and used for analysis.

GSK2248761 PK Parameters Following Dose Administration on Day 1: Time to Maximum Observed Concentration (Tmax), Terminal Half-life (t1/2), Absorption Lag Time (Tlag)
Day 1 (Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose)

Tmax is defined as the, time of maximum measured GSK2248761 concentration in the plasma, on Day 1. The t1/2 was defined as the time measured for plasma concentration to decrease by one half. The tlag was defined as the time taken for the drug GSK2248761, to appear in the systemic circulation following administration. Serial blood samples were collected on Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose on Day 1 and used for analysis.

GSK2248761 PK Parameters Following Dose Administration on Day 1: Apparent Clearance (CL/F)
Day 1 (Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose)

The Clearance factor was defined as the volume of plasma cleared of the drug GSK2248761, per unit time. Serial blood samples were collected on Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose on Day 1 and used for analysis.

GSK2248761 PK Parameters Following Dose Administration on Day 7: AUC(0-τ)
Day 7 (Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose)

AUC(0-τ) is the AUC to the end of dosing period. For Day 7, it is the AUC measured at the end of the dosing period at Day 7. Serial blood samples were collected on Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose on Day 7 and used for analysis.

GSK2248761 PK Parameters Following Dose Administration on Day 7: Tmax
Day 7 (Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose)

Tmax is defined as the, time of maximum measured GSK2248761 concentration in the plasma, on Day 7. Serial blood samples were collected on Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose on Day 7 and used for analysis

GSK2248761 PK Parameters Following Dose Administration on Day 7: t1/2
Day 7 (Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose)

The t1/2 was defined as the time measured for plasma concentration to decrease by one half. Serial blood samples were collected on Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose on Day 7 and used for analysis

Change From Baseline in CD4+ and CD8+ T-lymphocyte Cell Count at Day1 and Day 8.
Baseline (Screening), Day 1 and Day 8

Whole venous blood samples were obtained from each participant for the analysis of lymphocyte subsets by flow cytometry (total lymphocyte counts, percentage, CD4+ cell counts, and CD8+ cell counts) at Screening, Day 1 and Day 8. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values (Day 1 and Day 8). Baseline was defined as Screening.

Plasma simvastatin and simvastatin acid Cmax, AUC(0-infinity) and AUC(0-t) following oral administration of a single dose of simvastatin 20mg alone and in combination with GSK2248761 200mg once daily.
18 days
Plasma atorvastatin Cmax, AUC(0-infinity) and AUC(0-t) following oral administration of a single dose of atorvastatin 20mg alone and in combination with GSK2248761 200mg once daily.
21 days
Plasma rosuvastatin Cmax, AUC(0-∞) and AUC(0-t) following oral administration of a single dose of rosuvastatin 10mg alone and in combination with GSK2248761 200mg once daily.
25 days
Secondary Endpoints
Percent Change From Baseline in CD4+ and CD8+ T-lymphocyte Cell Count at Day 1 and Day 8
Baseline (Screening), Day 1 and Day 8
Accumulation Ratio for AUC , Cmax, Cτ, and Time Invariance Ratio Following Repeat Administration
(Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose ) on Day 1 and Day 7
Change From Baseline in Reverse Transcriptase Sequences of HIV-1 at Day 8
Baseline (Screening) and Day 8
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Study Design & Arms
AllocationRANDOMIZED
MaskingDOUBLE
ModelPARALLEL
PurposeTREATMENT
Treatment Arms
ArmTypeDescription
Cohort 1EXPERIMENTALIn Cohort 1 subjects will receive either GSK2248761 30 mg or placebo once a day for 7 days. On Day 8 subjects will receive either Kaletra or HAART for 28 days. The doctor will choose the most appropriate medications for HAART.
Cohort 2EXPERIMENTALIn Cohort 2 subjects will receive either GSK2248761 in the range of 10 mg - 20 mg or 40 mg - 90 mg or placebo once a day for 7 days. On Day 8 subjects will receive either Kaletra or HAART for 28 days. The doctor will choose the most appropriate medications for HAART. The dose for Cohort 2 will be determined following evaluation of results from Cohort 1. Cohort 2 may not be done.
Treatment AEXPERIMENTALSimvastatin 20mg (single dose) Day 1
Treatment BEXPERIMENTALAtorvastain 20 mg (single dose) Day 3
Treatment CEXPERIMENTALRosuvastatin 10mg (single dose) Day 7
Treatment XEXPERIMENTALGSK2248761 200mg single dose Day 10-14, Day 16-17, Day 19-21, Day 23-24
Treatment DEXPERIMENTALGSK2248761 200mg + simvastatin 20 mg Day 15
Treatment EEXPERIMENTALGSK2248761 200mg + atorvastatin 20 mg Day 18
Treatment FEXPERIMENTALGSK2248761 200mg + rosuvastatin 20 mg Day 22
Interventions
NameTypeDescription
GSK2248761DRUGGSK2248761 30 mg capsule once a day for 7 days. GSK2248761 is an investigational (not approved by the FDA) HIV drug in the class of non-nucleoside reuptake inhibitor class.
Lopinavir/ritonavirDRUGLopinavir 400 mg and ritonovir 100 mg every 12 hours for 28 days. Lopinavir/ritonavir is approved by the FDA as an HIV medication in the protease inhibitor class. Kaletra is a trademark of Abbott Laboratories.
HAARTDRUGHighly Active Antiretroviral therapy of the doctor's choice.
PlaceboDRUGPlacebo is a capsule with no drug in it.
SimvastatinDRUG20 mg Simvastatin single dose
AtorvastatinDRUG20 mg atorvastatin single dose
RosuvastatinDRUG10 mg rosuvastatin single dose
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Eligibility Criteria
Age Range21 Years — 65 Years
SexALL
Healthy VolunteersNo
Study Sites1

Inclusion Criteria: * Male or Female, 21 to 65 years of age. * Female of non-childbearing potential defined as: being post-menopausal, defined as 12 months of spontaneous amenorrhea and having a serum FSH level \>40 MIU/ml at Screening OR have had a documented bilateral tubal ligation or hysterecto...

Countries:ArgentinaUnited States
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