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Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of GSK2831781 After an Intravenous (IV) Dose in Healthy Japanese and Caucasian Subjects, and a Subcutaneous (SC) Dose in Healthy Caucasian Subjects

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ClinicalTrials.gov Identifier: NCT03965533
Recruitment Status : Completed
First Posted : May 29, 2019
Results First Posted : November 18, 2020
Last Update Posted : November 18, 2020
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Tracking Information
First Submitted Date  ICMJE May 24, 2019
First Posted Date  ICMJE May 29, 2019
Results First Submitted Date  ICMJE October 23, 2020
Results First Posted Date  ICMJE November 18, 2020
Last Update Posted Date November 18, 2020
Actual Study Start Date  ICMJE June 10, 2019
Actual Primary Completion Date December 10, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 23, 2020)
  • Part A: Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs) [ Time Frame: Up to Day 112 ]
    An adverse event (AE) is any untoward medical occurrence in a clinical study 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; 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 as judged by physician. Number of participants who had SAEs and non-SAEs are presented.
  • Part B: Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs) [ Time Frame: Up to Day 112 ]
    An AE is any untoward medical occurrence in a clinical study 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; 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 as judged by physician. Number of participants who had SAEs and non-SAEs are presented.
  • Part A: Number of Participants With Vital Signs of Potential Clinical Importance [ Time Frame: Up to Day 112 ]
    Vital signs were measured in a semi-supine position after five minutes of rest and included temperature, systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate. The clinical concern range for the parameters were: SBP (low: <85 millimeters of mercury [mmHg] and high: >160 mmHg), DBP (low: <45 mmHg and high: >100 mmHg), heart rate (low: <40 beats per minute [bpm] and high: >110 bpm) and temperature (low: <35 degrees celsius [°C] and high: >=37.5 °C). Number of participants with any vital sign value of potential clinical importance is reported.
  • Part B: Number of Participants With Vital Signs of Potential Clinical Importance [ Time Frame: Up to Day 112 ]
    Vital signs were measured in a semi-supine position after five minutes of rest and included temperature, SBP, DBP and heart rate. The clinical concern range for the parameters were: SBP (low: <85 mmHg and high: >160 mmHg), DBP (low: <45 mmHg and high: >100 mmHg), heart rate (low: <40 bpm and high: >110 bpm) and temperature (low: <35 °C and high: >=37.5 °C). Number of participants with any vital sign value of potential clinical importance is reported.
  • Part A: Number of Participants With Any Hematology Parameter of Potential Clinical Importance [ Time Frame: Up to Day 112 ]
    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 and low: change from Baseline <0.075 proportion of red cells in blood); hemoglobin (high: >180 grams per liter [g/L] and low: change from Baseline <25 g/L), lymphocytes (low: <0.8 Giga cells per liter [Giga cells/L]); neutrophil count (low: <1.5 Giga cells/L); eosinophil count (high: >1 Giga cells/L); platelet count (low: <100 Giga cells/L and high: >550 Giga cells/L) and white blood cells count (low: <3 Giga cells/L and high: >20 Giga cells/L). Number of participants with any hematology parameter value of potential clinical importance is reported.
  • Part B: Number of Participants With Any Hematology Parameter of Potential Clinical Importance [ Time Frame: Up to Day 112 ]
    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 and low: change from Baseline <0.075 proportion of red cells in blood); hemoglobin (high: >180 g/L and low: change from Baseline <25 g/L), lymphocytes (low: <0.8 Giga cells/L); neutrophil count (low: <1.5 Giga cells/L); eosinophil count (high: >1 Giga cells/L); platelet count (low: <100 Giga cells/L and high: >550 Giga cells/L) and white blood cells count (low: <3 Giga cells/L and high: >20 Giga cells/L). Number of participants with any hematology parameter value of potential clinical importance is reported.
  • Part A: Number of Participants With Any Clinical Chemistry Parameter of Potential Clinical Importance [ Time Frame: Up to Day 112 ]
    Blood samples were collected for the assessment of clinical chemistry parameters. The clinical concern range for the parameters were: 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); blood urea nitrogen (high: >10.5 millimoles per liter [mmol/L]); calcium (low: <2 mmol/L and high: >2.75 mmol/L); creatinine (high: change from Baseline >26 micromoles per liter); estimated glomerular filtration rate (low: <60 milliliter per minute per 1.73 squared meter); glucose (low: <3 mmol/L and high: >9 mmol/L); potassium (low: <3 mmol/L and high: >5.5 mmol/L); sodium (low: <130 mmol/L and high: >150 mmol/L) and total protein (low: <50 g/L and high: >85 g/L). Number of participants with any clinical chemistry parameter value of potential clinical importance is reported.
  • Part B: Number of Participants With Any Clinical Chemistry Parameter of Potential Clinical Importance [ Time Frame: Up to Day 112 ]
    Blood samples were collected for the assessment of clinical chemistry parameters. The clinical concern range for the parameters were: alanine aminotransferase (high: >=2 times ULN); aspartate aminotransferase (high: >=2 times ULN); alkaline phosphatase (high: >=2 times ULN); total bilirubin (high: >=1.5 times ULN); blood urea nitrogen (high: >10.5 mmol/L]); calcium (low: <2 mmol/L and high: >2.75 mmol/L); creatinine (high: change from Baseline >26 micromoles per liter); estimated glomerular filtration rate (low: <60 milliliter per minute per 1.73 squared meter); glucose (low: <3 mmol/L and high: >9 mmol/L); potassium (low: <3 mmol/L and high: >5.5 mmol/L); sodium (low: <130 mmol/L and high: >150 mmol/L) and total protein (low: <50 g/L and high: >85 g/L). Number of participants with any clinical chemistry parameter value of potential clinical importance is reported.
  • Part A: Number of Participants With Any Urinalysis Parameter of Potential Clinical Importance (PCI) [ Time Frame: Up to Day 112 ]
    Urine samples were analyzed for bilirubin (Bil.),glucose (Gl.),ketones (Keto),leukocytes (leuko),nitrite (Nit.),occult blood (OB) and protein (Pro.) by dipstick method. Urine red blood cells (RBC) and white blood cells (WBC) were assessed by microscopy. Urine potential of hydrogen (pH) and specific gravity (Sp.Gr.) were also analyzed. The dipstick results are read as Trace,1+,2+ indicating proportional concentrations. pH is measured on a numeric scale of 0 to 14 (pH 7: neutral, pH <7: acidic and pH >7: basic). Urine Sp. Gr. is a measure of the concentration of solutes in the urine and indicated as ratio of urine density to water density. The clinical concern range for these parameters were: Bil., Gl., Leuko, OB and Pro. (high: >1+),Keto (high: >2+),Nit. (high: positive),pH (low: <4.6 and high: >8),Sp.Gr. (low: <1.001 and high: >1.035),RBC (high: >3 cells/high power field [hpf]) and WBC (high: >5 cells/hpf). Number of participants with any urinalysis parameter value of PCI is reported.
  • Part B: Number of Participants With Any Urinalysis Parameter of Potential Clinical Importance [ Time Frame: Up to Day 112 ]
    Urine samples were analyzed for Bil., Gl., Keto, leuko, Nit., OB and Pro. by dipstick method. Urine RBC and WBC were assessed by microscopy. Urine pH and Sp.Gr. were also analyzed. The dipstick results are read as Trace, 1+, 2+ indicating proportional concentrations. pH is measured on a numeric scale of 0 to 14 (pH 7: neutral, pH <7: acidic and pH >7: basic). Urine Sp. Gr. is a measure of the concentration of solutes in the urine and indicated as ratio of urine density to water density. The clinical concern range for these parameters were: Bil., Gl., Leuko, OB and Pro. (high: >1+), Keto (high: >2+), Nit. (high: positive), pH (low: <4.6 and high: >8), Sp.Gr. (low: <1.001 and high: >1.035), RBC (high: >3 cells/hpf) and WBC (high: >5 cells/hpf). Number of participants with any urinalysis parameter value of PCI is reported.
  • Part A: Number of Participants With Abnormal Electrocardiogram (ECG) Findings [ Time Frame: Up to Day 112 ]
    Twelve-lead ECGs were recorded with the participants in a semi-supine position, after 5 minutes of rest using an ECG machine that automatically calculated heart rate and measured PR, QRS, QT and corrected QT (QTc) intervals. Number of participants with worst-case clinically significant and not clinically significant abnormal ECG findings have been presented. Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition.
  • Part B: Number of Participants With Abnormal Electrocardiogram (ECG) Findings [ Time Frame: Up to Day 112 ]
    Twelve-lead ECGs were recorded with the participants in a semi-supine position, after 5 minutes of rest using an ECG machine that automatically calculated heart rate and measured PR, QRS, QT and QTc intervals. Number of participants with worst-case clinically significant and not clinically significant abnormal ECG findings have been presented. Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition.
  • Part A: Number of Participants With Injection Site Reaction [ Time Frame: Up to 24 hours (Day 1) ]
    Local tolerability as measured by injection site reaction example; bruise at the site of injection and/or itching, pain, blistering or skin damage. Number of participants with any injection site reaction are presented.
  • Part B: Number of Participants With Injection Site Reaction [ Time Frame: Up to Day 8 ]
    Local tolerability as measured by injection site reaction example; bruise at the site of injection and/or itching, pain, blistering or skin damage. Number of participants with any injection site reaction are presented.
Original Primary Outcome Measures  ICMJE
 (submitted: May 24, 2019)
  • Number of subjects with adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: Up to 113 days ]
    An AE is any untoward medical occurrence in a clinical study subject, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is defined as any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization or is a congenital abnormality/birth defect.
  • Number of subjects with abnormal vital signs [ Time Frame: Up to 113 days ]
    Vital signs will be measured in a semi-supine position after 5 minutes rest and will include temperature, systolic, diastolic blood pressure and pulse rate.
  • Number of subjects with abnormal hematology parameters [ Time Frame: Up to 113 days ]
    Blood samples will be collected to measure hematological parameters such as platelet count, red blood cell (RBC) count, hemoglobin, hematocrit, Mean Corpuscular Volume (MCV), Mean Corpuscular Hemoglobin (MCH), percentage of reticulocytes, neutrophils, lymphocytes, monocytes, eosinophils and basophils.
  • Number of subjects with abnormal clinical chemistry parameters [ Time Frame: Up to 113 days ]
    Blood samples will be collected to measure clinical chemistry parameters such as blood urea nitrogen (BUN), creatinine, estimated glomerular filtration rate (eGFR), glucose (non-fasting), potassium, sodium, calcium, Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Alkaline phosphatase, Total and direct bilirubin and total protein.
  • Number of subjects with abnormal urinalysis [ Time Frame: Up to 113 days ]
    Urine samples will be collected to measure specific gravity, potential of hydrogen (pH), glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase by dipstick method and microscopic examination (if blood or protein is abnormal).
  • Number of subjects with abnormal electrocardiogram (ECG) values [ Time Frame: Up to 113 days ]
    Single 12-lead ECG will be obtained in a semi-supine position, after 5 minutes rest using an automated ECG machine and PR, QRS, QT, and corrected QT (QTc) intervals will be measured.
  • Number of subjects with infusion site reaction in Part A [ Time Frame: Pre-dose and 2, 6, 12 and 24 hours post dose ]
    Local tolerability will be assessed in subjects post GSK2831781 Dose-1 IV infusion at indicated time points.
  • Number of subjects with injection site reaction in Part B [ Time Frame: Pre-dose and 2, 4, 6, 12 and 24 hours and at Days 2, 4 and 8 post dose ]
    Local tolerability will be assessed in subjects post GSK2831781 Dose-2 SC injection at indicated time points.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 23, 2020)
  • Part A: Area Under the Plasma Drug Concentration Versus Time Curve From Time Zero to Time of Last Quantifiable Concentration (AUC[0 to t]) of GSK2831781 Following IV Dose [ Time Frame: Day 1 (Pre-dose and 1, 2, 6, 12, 24 hours post-dose); Days 3, 4, 8, 15, 22, 29, 43, 57, 71, 85 and 112 ]
    Blood samples were collected at indicated time points for pharmacokinetic analysis. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
  • Part A: Maximum Observed Plasma Concentration (Cmax) of GSK2831781 Following IV Dose [ Time Frame: Day 1 (Pre-dose and 1, 2, 6, 12, 24 hours post-dose); Days 3, 4, 8, 15, 22, 29, 43, 57, 71, 85 and 112 ]
    Blood samples were collected at indicated time points for pharmacokinetic analysis. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
  • Part A: Time to Maximum Observed Plasma Concentration (Tmax) of GSK2831781 Following IV Dose [ Time Frame: Day 1 (Pre-dose and 1, 2, 6, 12, 24 hours post-dose); Days 3, 4, 8, 15, 22, 29, 43, 57, 71, 85 and 112 ]
    Blood samples were collected at indicated time points for pharmacokinetic analysis. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
  • Part B: AUC(0 to t) of GSK2831781 Following SC Dose [ Time Frame: Day 1 (Pre-dose); Days 2, 3, 4, 6, 8, 11, 15, 18, 22, 29, 43, 57, 71, 85 and 112 ]
    Blood samples were collected at indicated time points for pharmacokinetic analysis. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
  • Part B: Cmax of GSK2831781 Following SC Dose [ Time Frame: Day 1 (Pre-dose); Days 2, 3, 4, 6, 8, 11, 15, 18, 22, 29, 43, 57, 71, 85 and 112 ]
    Blood samples were collected at indicated time points for pharmacokinetic analysis. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
  • Part B: Tmax of GSK2831781 Following SC Dose [ Time Frame: Day 1 (Pre-dose); Days 2, 3, 4, 6, 8, 11, 15, 18, 22, 29, 43, 57, 71, 85 and 112 ]
    Blood samples were collected at indicated time points for pharmacokinetic analysis. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
  • Part A and Part B: Bioavailability (F) of GSK2831781 Following IV Dosing at 450 mg (Caucasian and Japanese Participants) or SC Dosing at 150 mg and 450 mg (Caucasian Participants) [ Time Frame: Part A (IV): Day 1 (Pre-dose and 1, 2, 6, 12, 24 hours post-dose); Days 3, 4, 8, 15, 22, 29, 43, 57, 71, 85 and 112; Part B (SC): Day 1 (Pre-dose); Days 2, 3, 4, 6, 8, 11, 15, 18, 22, 29, 43, 57, 71, 85 and 112 ]
    Blood samples were collected at indicated time points for pharmacokinetic analysis in Part A (IV dose) and Part B (SC doses). Bioavailability of GSK2831781 was estimated by fitting a population pharmacokinetic model to all available data (Part A and Part B) of GSK2831781 concentrations in plasma and total soluble lymphocyte activation gene-3 (LAG3) concentrations in serum and was expressed as a percentage.
  • Degradation Rate of LAG3 Positive T Cells (Kout) Derived From Statistical Analysis of the Relationship Between LAG3 Positive T Cell Levels in Blood and GSK2831781 Concentrations in Plasma (Part A and Part B) [ Time Frame: Up to Day 112 ]
    Blood samples were collected to measure LAG3 positive T cell levels. Plasma samples were collected to measure concentrations of GSK2831781 in plasma. The relationship between the pharmacodynamic measure (LAG3 positive T cell levels in blood) and plasma concentrations of GSK2831781 was described by an indirect response (Emax type) pharmacokinetic/pharmacodynamic (PK/PD) model. Kout was calculated by fitting the PK/PD model to all available data (Part A and Part B) of GSK2831781 concentrations in plasma and LAG3 positive T cells in blood. The model parameter; Kout is presented.
  • Baseline of LAG3 Positive T Cell Count (CELL0) Derived From Statistical Analysis of the Relationship Between LAG3 Positive T Cell Levels in Blood and GSK2831781 Concentrations in Plasma (Part A and B) [ Time Frame: Up to Day 112 ]
    Blood samples were collected to measure LAG3 positive T cell levels. Plasma samples were collected to measure concentrations of GSK2831781 in plasma. The relationship between the pharmacodynamic measure (LAG3 positive T cell levels in blood) and plasma concentrations of GSK2831781 was described by an indirect response (Emax type) PK/PD model. CELL0 was calculated by fitting the PK/PD model to all available data (Part A and Part B) of GSK2831781 concentrations in plasma and LAG3 positive T cells in blood. The model parameter; CELL0 is presented.
  • Concentration of Free GSK2831781 at Which Half Maximum Effect on Kout is Achieved (EC50) Derived From Statistical Analysis of the Relationship Between LAG3 Positive T Cell Levels in Blood and GSK2831781 Concentrations in Plasma (Part A and B) [ Time Frame: Up to Day 112 ]
    Blood samples were collected to measure LAG3 positive T cell levels. Plasma samples were collected to measure concentrations of GSK2831781 in plasma. The relationship between the pharmacodynamic measure (LAG3 positive T cell levels in blood) and plasma concentrations of GSK2831781 was described by an indirect response (Emax type) PK/PD model. EC50 was calculated by fitting the PK/PD model to all available data (Part A and Part B) of GSK2831781 concentrations in plasma and LAG3 positive T cells in blood. As there was a limited dose range, to allow for a successful model conversion, EC50 was fixed to the EC50 value estimated from a previous study. The model parameter; EC50 is presented.
  • Maximum Effect of Change in Kout (Emax) Derived From Statistical Analysis of the Relationship Between LAG3 Positive T Cell Levels in Blood and GSK2831781 Concentrations in Plasma (Part A and B) [ Time Frame: Up to Day 112 ]
    Blood samples were collected to measure LAG3 positive T cell levels. Plasma samples were collected to measure concentrations of GSK2831781 in plasma. The relationship between the pharmacodynamic measure (LAG3 positive T cell levels in blood) and plasma concentrations of GSK2831781 was described by an indirect response (Emax type) PK/PD model. Emax, a unitless parameter that describes the maximum change in Kout at infinite GSK2831781 concentration, was calculated by fitting the PK/PD model to all available data (Part A and Part B) of GSK2831781 concentrations in plasma and LAG3 positive T cells in blood. The model parameter; Emax is presented.
  • Hill Coefficient (GAM) Derived From Statistical Analysis of the Relationship Between LAG3 Positive T Cell Levels in Blood and GSK2831781 Concentrations in Plasma (Part A and B) [ Time Frame: Up to Day 112 ]
    Blood samples were collected to measure LAG3 positive T cell levels. Plasma samples were collected to measure concentrations of GSK2831781 in plasma. The relationship between the pharmacodynamic measure (LAG3 positive T cell levels in blood) and plasma concentrations of GSK2831781 was described by an indirect response (Emax type) PK/PD model. The Hill coefficient GAM, a unitless parameter defining the steepness of the concentration-effect curve, was calculated by fitting the PK/PD model to all available data (Part A and Part B) of GSK2831781 concentrations in plasma and LAG3 positive T cells in blood. The model parameter; GAM is presented.
  • Part A: Number of Participants With Confirmed Positive Post-Baseline Anti-drug Antibody Result [ Time Frame: Up to Day 112 ]
    Serum samples were analyzed for the presence of anti-GSK2831781 antibodies using a validated immunoassay. The assay involved screening, confirmation and titration steps. If serum samples tested positive in the screening assay, they were considered 'potentially positive' and were further analyzed for the specificity using the confirmation assay. Samples that confirmed positive in the confirmation assay were reported as 'confirmed positive'. Number of participants with confirmed positive post-Baseline ADA result are presented.
  • Part B: Number of Participants With Confirmed Positive Post-Baseline Anti-drug Antibody Result [ Time Frame: Up to Day 112 ]
    Serum samples were analyzed for the presence of anti-GSK2831781 antibodies using a validated immunoassay. The assay involved screening, confirmation and titration steps. If serum samples tested positive in the screening assay, they were considered 'potentially positive' and were further analyzed for the specificity using the confirmation assay. Samples that confirmed positive in the confirmation assay were reported as 'confirmed positive'. Number of participants with confirmed positive post-Baseline ADA result are presented.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 24, 2019)
  • Area under the concentration-time curve from time 0 to t [AUC(0-t)] of GSK2831781 in Part A [ Time Frame: Pre-dose, 1, 2, 6, 12, 24 hours on Day 1; Days 3, 4, 8, 15, 22, 29, 43, 57, 71, 85 and 112 post dose ]
    Blood samples for PK analysis will be collected at the indicated time points.
  • Maximum observed plasma concentration (Cmax) of GSK2831781 in Part A [ Time Frame: Pre-dose, 1, 2, 6, 12, 24 hours on Day 1; Days 3, 4, 8, 15, 22, 29, 43, 57, 71, 85 and 112 post dose ]
    Blood samples for PK analysis will be collected at the indicated time points.
  • Time of occurrence of Cmax (tmax) of GSK2831781 in Part A [ Time Frame: Pre-dose, 1, 2, 6, 12, 24 hours on Day 1; Days 3, 4, 8, 15, 22, 29, 43, 57, 71, 85 and 112 post dose ]
    Blood samples for PK analysis will be collected at the indicated time points.
  • AUC(0-t) of GSK2831781 in Part B [ Time Frame: Pre-dose and on Days 2, 3, 4, 6, 8, 11, 15, 18, 22, 29, 43, 57, 71, 85 and 112 post dose ]
    Blood samples for PK analysis will be collected at the indicated time points.
  • Cmax of GSK2831781 in Part B [ Time Frame: Pre-dose and on Days 2, 3, 4, 6, 8, 11, 15, 18, 22, 29, 43, 57, 71, 85 and 112 post dose ]
    Blood samples for PK analysis will be collected at the indicated time points.
  • Tmax of GSK2831781 in Part B [ Time Frame: Pre-dose and on Days 2, 3, 4, 6, 8, 11, 15, 18, 22, 29, 43, 57, 71, 85 and 112 post dose ]
    Blood samples for PK analysis will be collected at the indicated time points.
  • Bioavailability (F) of GSK2831781 in Part B [ Time Frame: Pre-dose and on Days 2, 3, 4, 6, 8, 11, 15, 18, 22, 29, 43, 57, 71, 85 and 112 post dose ]
    Blood samples for PK analysis will be collected at the indicated time points.
  • PK/PD relationship between plasma PK of GSK2831781 and LAG3+ T cells in blood over time [ Time Frame: Up to 113 days ]
    A population PK/PD analysis will be performed based on the safety population. This will investigate PK, Soluble LAG3 (sLAG3) and cell depletion data.
  • Anti-drug antibodies (ADAs) to GSK2831781 over time [ Time Frame: Up to 113 days ]
    Serum samples will be collected from all subjects to evaluate the presence of ADA using a tiered approach.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of GSK2831781 After an Intravenous (IV) Dose in Healthy Japanese and Caucasian Subjects, and a Subcutaneous (SC) Dose in Healthy Caucasian Subjects
Official Title  ICMJE A Randomised, Double-blind, Placebo-controlled Phase I Study of the Safety and Tolerability, Pharmacokinetics, and Pharmacodynamics of a Single Intravenous Dose of GSK2831781 in Healthy Japanese and Caucasian Participants, and a Single Subcutaneous Dose of GSK2831781 in Healthy Caucasian Participants
Brief Summary This is a double-blind, placebo-controlled, randomized, parallel group, two-part study where single IV doses of GSK2831781 will be administered to healthy Japanese and Caucasian subjects in part A and SC doses will be administered to healthy Caucasian subjects in part B. GSK2831781 is a humanized, antibody-dependent cell cytotoxicity (ADCC) enhanced depleting monoclonal antibody that is specific to the lymphocyte activation gene-3 (LAG3) protein. LAG3 is a transmembrane receptor, which is upregulated on T cells following activation. The objective of the study is to assess the safety, tolerability, PK, PD and immunogenicity post administration of GSK2831781 in healthy subjects. The duration of the study is approximately 147 days for each subject enrolled. Approximately 36 subjects will be enrolled in the study, 16 subjects in Part A and 20 subjects in Part B.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Healthy Volunteers
Intervention  ICMJE
  • Drug: GSK2831781
    GSK2831781 will be available as Dose-1 and Dose-2 as IV infusion or SC injection. Subjects will receive GSK2831781 Dose-1 IV diluted in 0.9% saline or GSK2831781 SC as multiples of Dose-2 SC.
  • Drug: Placebo
    Placebo will be 0.9% saline solution which will be administered in subjects as IV infusion or SC injection.
Study Arms  ICMJE
  • Placebo Comparator: Part A: Placebo IV- Caucasian Participants
    Caucasian male participants were administered a single IV infusion of 0.9% weight by volume (w/v) saline placebo.
    Intervention: Drug: Placebo
  • Experimental: Part A: GSK2831781 450 mg IV- Caucasian Participants
    Caucasian male participants were administered a single IV infusion of GSK2831781 at a dose of 450 milligram (mg), diluted in 0.9% w/v saline.
    Intervention: Drug: GSK2831781
  • Placebo Comparator: Part A: Placebo IV- Japanese Participants
    Japanese male participants were administered a single IV infusion of 0.9% w/v saline placebo.
    Intervention: Drug: Placebo
  • Experimental: Part A: GSK2831781 450 mg IV- Japanese Participants
    Japanese male participants were administered a single IV infusion of GSK2831781 at a dose of 450 mg, diluted in 0.9% w/v saline.
    Intervention: Drug: GSK2831781
  • Placebo Comparator: Part B: Placebo SC
    Caucasian male participants were administered three SC injections of 0.9% w/v saline placebo.
    Intervention: Drug: Placebo
  • Experimental: Part B: GSK2831781 150 mg SC
    Caucasian male participants were administered a single SC injection of a unit dose strength of 150 mg per milliliter (mL) of GSK2831781, diluted in 0.9% w/v saline. Participants also received 2 dummy injections of 0.9% w/v saline placebo SC to maintain the blinding.
    Intervention: Drug: GSK2831781
  • Experimental: Part B: GSK2831781 450 mg SC
    Caucasian male participants were administered three SC injections of a unit dose strength of 150 mg per mL of GSK2831781 to achieve a dose of 450 mg.
    Intervention: Drug: GSK2831781
Publications * Not Provided

*   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: May 24, 2019)
36
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE December 10, 2019
Actual Primary Completion Date December 10, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Subjects who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and 12-lead ECGs. A subject with a clinical abnormality or laboratory parameter(s) outside the reference range for the population being studied that is not specifically listed in the inclusion or exclusion criteria may be included if the Investigator (in consultation with the Medical Monitor if required) agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures or interpretation.
  • Between 18 and 65 years of age inclusive, at the time of signing the informed consent.
  • Body weight >=40 kilogram (kg) and body mass index (BMI) <=30 kilogram per meter square (kg/m^2).
  • Male.
  • Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
  • Japanese ancestry, defined as having been born in Japan, being descendants of four ethnic Japanese grandparents and two ethnic Japanese parents, holding a Japanese passport or identity papers, and being able to speak Japanese. Subjects should have lived outside Japan for less than 10 years at the time of screening.
  • Caucasian ancestry, defined as Caucasian descent as evidenced by appearance and verbal confirmation of familial heritage (a subject has 2 Caucasian parents and 4 Caucasian grandparents).

Exclusion Criteria:

  • History or presence of a disease that in the opinion of the investigator constitutes a risk when taking the study intervention or interfering with study assessment or interpretation of the data.
  • A medical history of severe allergic reaction, angioedema, anaphylaxis, clinically significant drug hypersensitivity reaction, or autoimmune or immunodeficiency disorder.
  • An active infection or a history of serious infections as follows:

    1. Use of antimicrobials (antibacterials, antivirals, antifungals or antiparasitic agents) for an infection within 30 days before first dose. Topical treatments may be allowed at the Medical Monitor's discretion.
    2. A history of opportunistic infections.
    3. Recurrent or chronic infection, or other active infection, that in the opinion of the Investigator might cause this study to be detrimental to the subject.
    4. Symptomatic herpes zoster within 3 months prior to screening.
    5. History of tuberculosis (TB) (active or latent) irrespective of treatment status.
    6. A positive diagnostic TB test at screening (defined as a positive QuantiFERON test). In cases where the QuantiFERON test is indeterminate, the subject may have the test repeated once and if their second test is negative they will be eligible. In the event a second test is also indeterminate, the investigator has the option to undertake purified protein derivative (PPD) testing. If the PPD reaction is <5 millimeter (mm) at 48 to 72 hours, then the subject is eligible. If the reaction is >=5 mm, or PPD testing is not undertaken, the subject is not eligible.
  • Any planned major surgical procedure during the study.
  • A history of malignant neoplasm within the last 10 years, except for fully treated nonmetastatic basal or squamous cell cancers of the skin (within 3 years) that shows no evidence of recurrence.
  • Use of prescription or non-prescription drugs (including recreational drugs and herbal medications) within 7 days or 5 half-lives (whichever is longer) prior to dosing, unless in the opinion of the investigator, the medication will not interfere with the study or compromise subject safety. Paracetamol (acetaminophen) at doses of <=4 grams per day, and occasional use of non-steroidal anti-inflammatory drugs (NSAIDs) at licensed doses, are permitted.
  • Received live vaccination within 4 weeks of Day 1, or plan to receive a live vaccination during the study until follow-up.
  • Previous exposure to GSK2831781, or hypersensitivity to any excipients in the clinical formulation of GSK2831781.
  • Treatment with biologic agents (such as monoclonal antibodies) within 3 months or 5 half-lives (whichever is longer) prior to dosing.
  • Participation in a clinical trial and has received an investigational medicinal product (IMP) within the following time period prior to screening in the current study: 3 months, 5 half-lives, or twice the duration of the biological effect of the IMP (whichever is longer).
  • Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day.
  • Participation in the study would result in loss of blood or blood products in excess of 500 milliliter (mL) within 3 months.
  • Neutrophil or lymphocyte counts below the normal range.
  • eGFR by Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) calculation <=90 milliliter per minute per 1.73 meter square (mL/min/1.73m^2) at screening.
  • ALT >2x upper limit of normal (ULN) and bilirubin >1.5x ULN (isolated bilirubin >1.5x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) at screening.
  • Other clinically significant abnormalities of laboratory assessments, as judged by the Investigator and/or GSK Medical Monitor, that could affect the safety of the subject, or the interpretation of the data from the study.
  • Presence of hepatitis B surface antigen (HBsAg) or Hepatitis B core antibody (HBcAb), or positive hepatitis C antibody result at screening (Subjects with positive Hepatitis C antibody due to prior resolved disease can be enrolled only if a confirmatory negative Hepatitis C ribonucleic acid [RNA] test is obtained).
  • Positive serology for human immunodeficiency virus (HIV) at screening.
  • Positive pre-study drug/alcohol screen.
  • QTc >450 millisecond (msec), based on the mean of triplicate ECGs. The QTc is the QT interval corrected for heart rate according to Fridericia's formula (QTcF; preferred method), or another method, machine or overread.
  • History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >21 units. One unit is equivalent to 8 grams (g) of alcohol: a halfpint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
  • Unstable lifestyle factors, to the extent that in the opinion of the investigator they would interfere with the ability of a subject to complete the study.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Gender Based Eligibility: Yes
Gender Eligibility Description: Male subjects will be included in the study
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03965533
Other Study ID Numbers  ICMJE 207823
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 will be made available within 6 months of publishing the results of the primary endpoints of the study.
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: http://clinicalstudydatarequest.com
Responsible Party GlaxoSmithKline
Study Sponsor  ICMJE GlaxoSmithKline
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: GSK Clinical Trials GlaxoSmithKline
PRS Account GlaxoSmithKline
Verification Date September 2020

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