Healthy Volunteers
Conditions
Keywords
Japanese, Caucasian, pharmacokinetics, pharmacodynamics, GSK2831781, lymphocyte activation gene-3
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.
Interventions
DRUGGSK2831781
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.
DRUGPlacebo
Placebo will be 0.9% saline solution which will be administered in subjects as IV infusion or SC injection.
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
18 Years to 65 Years
Healthy volunteers
Yes
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part B: Number of Participants With Injection Site Reaction | 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. |
| Part A: Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs) | 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) | 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 | 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 | 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 | 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 | 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 | 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 | 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) | 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 | 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 | 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 | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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 | 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 | 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 | 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 | 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 | 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) | 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) | 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) | 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) | 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) | 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) | 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 | 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 | 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. |
Countries
United Kingdom
Participant flow
Recruitment details
This was a double-blind, placebo-controlled, randomized, parallel group, two-part study to evaluate safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of intravenous (IV) dose of GSK2831781 in healthy Japanese and Caucasian participants (Part A) and subcutaneous (SC) dose of GSK2831781 in healthy Caucasian participants (Part B).
Pre-assignment details
A total of 30 participants were screened and 16 participants were enrolled in Part A (14 were screen failures). A total of 41 participants were screened and 20 participants were enrolled in Part B (21 were screen failures). Placebo arms across similar dosing strategies were combined in Part B.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 2 |
| 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. | 6 |
| Part A: Placebo IV- Japanese Participants Japanese male participants were administered a single IV infusion of 0.9% w/v saline placebo. | 2 |
| 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. | 6 |
| Part B: Placebo SC Caucasian male participants were administered three SC injections of 0.9% w/v saline placebo. | 4 |
| Part B: GSK2831781 150 mg SC Arm Description: 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. | 8 |
| 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. | 8 |
| Total | 36 |
Baseline characteristics
| Characteristic | Total | Part A: GSK2831781 450 mg IV- Caucasian Participants | Part A: Placebo IV- Japanese Participants | Part A: GSK2831781 450 mg IV- Japanese Participants | Part B: Placebo SC | Part B: GSK2831781 150 mg SC | Part A: Placebo IV- Caucasian Participants | Part B: GSK2831781 450 mg SC |
|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 36 Participants | 6 Participants | 2 Participants | 6 Participants | 4 Participants | 8 Participants | 2 Participants | 8 Participants |
| Race/Ethnicity, Customized Asian-Japanese H/East Asian H/South East Asian H | 8 Participants | 0 Participants | 2 Participants | 6 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White-White/Caucasian/European Heritage (H) | 28 Participants | 6 Participants | 0 Participants | 0 Participants | 4 Participants | 8 Participants | 2 Participants | 8 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 36 Participants | 6 Participants | 2 Participants | 6 Participants | 4 Participants | 8 Participants | 2 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 6 | 0 / 2 | 0 / 6 | 0 / 4 | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 2 / 2 | 5 / 6 | 0 / 2 | 4 / 6 | 4 / 4 | 6 / 8 | 4 / 8 |
| serious Total, serious adverse events | 0 / 2 | 0 / 6 | 0 / 2 | 0 / 6 | 0 / 4 | 1 / 8 | 0 / 8 |
Outcome results
Primary
Part A: Number of Participants With Abnormal Electrocardiogram (ECG) Findings
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.
Time frame: Up to Day 112
Population: Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: Placebo IV- Caucasian Participants | Part A: Number of Participants With Abnormal Electrocardiogram (ECG) Findings | Abnormal-not Clinically significant | 1 Participants |
| Part A: Placebo IV- Caucasian Participants | Part A: Number of Participants With Abnormal Electrocardiogram (ECG) Findings | Abnormal-Clinically significant | 0 Participants |
| Part A: GSK2831781 450 mg IV- Caucasian Participants | Part A: Number of Participants With Abnormal Electrocardiogram (ECG) Findings | Abnormal-Clinically significant | 0 Participants |
| Part A: GSK2831781 450 mg IV- Caucasian Participants | Part A: Number of Participants With Abnormal Electrocardiogram (ECG) Findings | Abnormal-not Clinically significant | 0 Participants |
| Part A: Placebo IV- Japanese Participants | Part A: Number of Participants With Abnormal Electrocardiogram (ECG) Findings | Abnormal-not Clinically significant | 0 Participants |
| Part A: Placebo IV- Japanese Participants | Part A: Number of Participants With Abnormal Electrocardiogram (ECG) Findings | Abnormal-Clinically significant | 0 Participants |
| Part A: GSK2831781 450 mg IV- Japanese Participants | Part A: Number of Participants With Abnormal Electrocardiogram (ECG) Findings | Abnormal-not Clinically significant | 0 Participants |
| Part A: GSK2831781 450 mg IV- Japanese Participants | Part A: Number of Participants With Abnormal Electrocardiogram (ECG) Findings | Abnormal-Clinically significant | 0 Participants |
Primary
Part A: Number of Participants With Any Clinical Chemistry Parameter of Potential Clinical Importance
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.
Time frame: Up to Day 112
Population: Safety Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Placebo IV- Caucasian Participants | Part A: Number of Participants With Any Clinical Chemistry Parameter of Potential Clinical Importance | 0 Participants |
| Part A: GSK2831781 450 mg IV- Caucasian Participants | Part A: Number of Participants With Any Clinical Chemistry Parameter of Potential Clinical Importance | 0 Participants |
| Part A: Placebo IV- Japanese Participants | Part A: Number of Participants With Any Clinical Chemistry Parameter of Potential Clinical Importance | 0 Participants |
| Part A: GSK2831781 450 mg IV- Japanese Participants | Part A: Number of Participants With Any Clinical Chemistry Parameter of Potential Clinical Importance | 1 Participants |
Primary
Part A: Number of Participants With Any Hematology Parameter 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 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.
Time frame: Up to Day 112
Population: Safety Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Placebo IV- Caucasian Participants | Part A: Number of Participants With Any Hematology Parameter of Potential Clinical Importance | 0 Participants |
| Part A: GSK2831781 450 mg IV- Caucasian Participants | Part A: Number of Participants With Any Hematology Parameter of Potential Clinical Importance | 1 Participants |
| Part A: Placebo IV- Japanese Participants | Part A: Number of Participants With Any Hematology Parameter of Potential Clinical Importance | 0 Participants |
| Part A: GSK2831781 450 mg IV- Japanese Participants | Part A: Number of Participants With Any Hematology Parameter of Potential Clinical Importance | 2 Participants |
Primary
Part A: Number of Participants With Any Urinalysis Parameter of Potential Clinical Importance (PCI)
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.
Time frame: Up to Day 112
Population: Safety Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Placebo IV- Caucasian Participants | Part A: Number of Participants With Any Urinalysis Parameter of Potential Clinical Importance (PCI) | 2 Participants |
| Part A: GSK2831781 450 mg IV- Caucasian Participants | Part A: Number of Participants With Any Urinalysis Parameter of Potential Clinical Importance (PCI) | 0 Participants |
| Part A: Placebo IV- Japanese Participants | Part A: Number of Participants With Any Urinalysis Parameter of Potential Clinical Importance (PCI) | 0 Participants |
| Part A: GSK2831781 450 mg IV- Japanese Participants | Part A: Number of Participants With Any Urinalysis Parameter of Potential Clinical Importance (PCI) | 1 Participants |
Primary
Part A: Number of Participants With Injection Site Reaction
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.
Time frame: Up to 24 hours (Day 1)
Population: Safety Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Placebo IV- Caucasian Participants | Part A: Number of Participants With Injection Site Reaction | 0 Participants |
| Part A: GSK2831781 450 mg IV- Caucasian Participants | Part A: Number of Participants With Injection Site Reaction | 0 Participants |
| Part A: Placebo IV- Japanese Participants | Part A: Number of Participants With Injection Site Reaction | 0 Participants |
| Part A: GSK2831781 450 mg IV- Japanese Participants | Part A: Number of Participants With Injection Site Reaction | 2 Participants |
Primary
Part A: Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs)
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.
Time frame: Up to Day 112
Population: Safety Population comprised of all randomized (all participants who were randomized into the study and received a randomization number) participants who received study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: Placebo IV- Caucasian Participants | Part A: Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs) | Non-SAEs | 2 Participants |
| Part A: Placebo IV- Caucasian Participants | Part A: Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs) | SAEs | 0 Participants |
| Part A: GSK2831781 450 mg IV- Caucasian Participants | Part A: Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs) | SAEs | 0 Participants |
| Part A: GSK2831781 450 mg IV- Caucasian Participants | Part A: Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs) | Non-SAEs | 5 Participants |
| Part A: Placebo IV- Japanese Participants | Part A: Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs) | Non-SAEs | 0 Participants |
| Part A: Placebo IV- Japanese Participants | Part A: Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs) | SAEs | 0 Participants |
| Part A: GSK2831781 450 mg IV- Japanese Participants | Part A: Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs) | Non-SAEs | 4 Participants |
| Part A: GSK2831781 450 mg IV- Japanese Participants | Part A: Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs) | SAEs | 0 Participants |
Primary
Part A: Number of Participants With Vital Signs of Potential Clinical Importance
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.
Time frame: Up to Day 112
Population: Safety Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Placebo IV- Caucasian Participants | Part A: Number of Participants With Vital Signs of Potential Clinical Importance | 0 Participants |
| Part A: GSK2831781 450 mg IV- Caucasian Participants | Part A: Number of Participants With Vital Signs of Potential Clinical Importance | 1 Participants |
| Part A: Placebo IV- Japanese Participants | Part A: Number of Participants With Vital Signs of Potential Clinical Importance | 0 Participants |
| Part A: GSK2831781 450 mg IV- Japanese Participants | Part A: Number of Participants With Vital Signs of Potential Clinical Importance | 0 Participants |
Primary
Part B: Number of Participants With Abnormal Electrocardiogram (ECG) Findings
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.
Time frame: Up to Day 112
Population: Safety Population. Placebo arms across similar dosing strategies were combined in Part B.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: Placebo IV- Caucasian Participants | Part B: Number of Participants With Abnormal Electrocardiogram (ECG) Findings | Abnormal-not Clinically significant | 0 Participants |
| Part A: Placebo IV- Caucasian Participants | Part B: Number of Participants With Abnormal Electrocardiogram (ECG) Findings | Abnormal-Clinically significant | 0 Participants |
| Part A: GSK2831781 450 mg IV- Caucasian Participants | Part B: Number of Participants With Abnormal Electrocardiogram (ECG) Findings | Abnormal-not Clinically significant | 1 Participants |
| Part A: GSK2831781 450 mg IV- Caucasian Participants | Part B: Number of Participants With Abnormal Electrocardiogram (ECG) Findings | Abnormal-Clinically significant | 0 Participants |
| Part A: Placebo IV- Japanese Participants | Part B: Number of Participants With Abnormal Electrocardiogram (ECG) Findings | Abnormal-not Clinically significant | 0 Participants |
| Part A: Placebo IV- Japanese Participants | Part B: Number of Participants With Abnormal Electrocardiogram (ECG) Findings | Abnormal-Clinically significant | 0 Participants |
Primary
Part B: Number of Participants With Any Clinical Chemistry Parameter of Potential Clinical Importance
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.
Time frame: Up to Day 112
Population: Safety Population. Placebo arms across similar dosing strategies were combined in Part B.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Placebo IV- Caucasian Participants | Part B: Number of Participants With Any Clinical Chemistry Parameter of Potential Clinical Importance | 0 Participants |
| Part A: GSK2831781 450 mg IV- Caucasian Participants | Part B: Number of Participants With Any Clinical Chemistry Parameter of Potential Clinical Importance | 0 Participants |
| Part A: Placebo IV- Japanese Participants | Part B: Number of Participants With Any Clinical Chemistry Parameter of Potential Clinical Importance | 1 Participants |
Primary
Part B: Number of Participants With Any Hematology Parameter 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 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.
Time frame: Up to Day 112
Population: Safety Population. Placebo arms across similar dosing strategies were combined in Part B.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Placebo IV- Caucasian Participants | Part B: Number of Participants With Any Hematology Parameter of Potential Clinical Importance | 0 Participants |
| Part A: GSK2831781 450 mg IV- Caucasian Participants | Part B: Number of Participants With Any Hematology Parameter of Potential Clinical Importance | 0 Participants |
| Part A: Placebo IV- Japanese Participants | Part B: Number of Participants With Any Hematology Parameter of Potential Clinical Importance | 1 Participants |
Primary
Part B: Number of Participants With Any Urinalysis Parameter of Potential Clinical Importance
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.
Time frame: Up to Day 112
Population: Safety Population. Placebo arms across similar dosing strategies were combined in Part B.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Placebo IV- Caucasian Participants | Part B: Number of Participants With Any Urinalysis Parameter of Potential Clinical Importance | 1 Participants |
| Part A: GSK2831781 450 mg IV- Caucasian Participants | Part B: Number of Participants With Any Urinalysis Parameter of Potential Clinical Importance | 0 Participants |
| Part A: Placebo IV- Japanese Participants | Part B: Number of Participants With Any Urinalysis Parameter of Potential Clinical Importance | 0 Participants |
Primary
Part B: Number of Participants With Injection Site Reaction
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.
Time frame: Up to Day 8
Population: Safety Population. Placebo arms across similar dosing strategies were combined in Part B.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Placebo IV- Caucasian Participants | Part B: Number of Participants With Injection Site Reaction | 0 Participants |
| Part A: GSK2831781 450 mg IV- Caucasian Participants | Part B: Number of Participants With Injection Site Reaction | 0 Participants |
| Part A: Placebo IV- Japanese Participants | Part B: Number of Participants With Injection Site Reaction | 0 Participants |
Primary
Part B: Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs)
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.
Time frame: Up to Day 112
Population: Safety Population. Placebo arms across similar dosing strategies were combined in Part B.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: Placebo IV- Caucasian Participants | Part B: Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs) | Non-SAEs | 4 Participants |
| Part A: Placebo IV- Caucasian Participants | Part B: Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs) | SAEs | 0 Participants |
| Part A: GSK2831781 450 mg IV- Caucasian Participants | Part B: Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs) | Non-SAEs | 6 Participants |
| Part A: GSK2831781 450 mg IV- Caucasian Participants | Part B: Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs) | SAEs | 1 Participants |
| Part A: Placebo IV- Japanese Participants | Part B: Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs) | Non-SAEs | 4 Participants |
| Part A: Placebo IV- Japanese Participants | Part B: Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs) | SAEs | 0 Participants |
Primary
Part B: Number of Participants With Vital Signs of Potential Clinical Importance
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.
Time frame: Up to Day 112
Population: Safety Population. Placebo arms across similar dosing strategies were combined in Part B.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Placebo IV- Caucasian Participants | Part B: Number of Participants With Vital Signs of Potential Clinical Importance | 1 Participants |
| Part A: GSK2831781 450 mg IV- Caucasian Participants | Part B: Number of Participants With Vital Signs of Potential Clinical Importance | 0 Participants |
| Part A: Placebo IV- Japanese Participants | Part B: Number of Participants With Vital Signs of Potential Clinical Importance | 1 Participants |
Secondary
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)
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.
Time frame: Up to Day 112
Population: Pharmacokinetic Population. Given the limited dose range (150 mg-450 mg) in each part, a population PK/PD analysis of combined data from Part A and Part B was more appropriate. Hence, this outcome measure was estimated on combined data from Part A and Part B.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Part A: Placebo IV- Caucasian Participants | 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) | 1.15 Cells per microliter |
Secondary
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)
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.
Time frame: Up to Day 112
Population: Pharmacokinetic Population. Given the limited dose range (150 mg-450 mg) in each part, a population PK/PD analysis of combined data from Part A and Part B was more appropriate. This outcome measure was fixed to the EC50 value estimated from a previous study.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Part A: Placebo IV- Caucasian Participants | 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) | 9509 Nanograms per milliliter |
Secondary
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)
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.
Time frame: Up to Day 112
Population: Pharmacokinetic Population. Given the limited dose range (150 mg-450 mg) in each part, a population PK/PD analysis of combined data from Part A and Part B was more appropriate. Hence, this outcome measure was estimated on combined data from Part A and Part B.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Part A: Placebo IV- Caucasian Participants | 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) | 0.0256 Per hour |
Secondary
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)
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.
Time frame: Up to Day 112
Population: Pharmacokinetic Population. Given the limited dose range (150 mg-450 mg) in each part, a population PK/PD analysis of combined data from Part A and Part B was more appropriate. Hence, this outcome measure was estimated on combined data from Part A and Part B.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Part A: Placebo IV- Caucasian Participants | 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) | 0.0942 Unitless |
Secondary
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)
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.
Time frame: Up to Day 112
Population: Pharmacokinetic Population. Given the limited dose range (150 mg-450 mg) in each part, a population PK/PD analysis of combined data from Part A and Part B was more appropriate. Hence, this outcome measure was estimated on combined data from Part A and Part B.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Part A: Placebo IV- Caucasian Participants | 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) | 2.35 Unitless |
Secondary
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)
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.
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
Population: Pharmacokinetic Population. Given the non-linearity in pharmacokinetics, a population pharmacokinetic analysis of pooled data from Part A and Part B was more appropriate. Hence, this outcome measure was estimated on pooled data from Part A and Part B.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Placebo IV- Caucasian Participants | 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) | 76.5 Percentage Bioavailability |
Secondary
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
Blood samples were collected at indicated time points for pharmacokinetic analysis. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
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
Population: Pharmacokinetic Population comprised of all safety participants for whom a pharmacokinetic sample was obtained and analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo IV- Caucasian Participants | 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 | 44261.755 Hours*micrograms per milliliter | Geometric Coefficient of Variation 23.8009 |
| Part A: GSK2831781 450 mg IV- Caucasian Participants | 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 | 49650.933 Hours*micrograms per milliliter | Geometric Coefficient of Variation 19.6053 |
Secondary
Part A: Maximum Observed Plasma Concentration (Cmax) of GSK2831781 Following IV Dose
Blood samples were collected at indicated time points for pharmacokinetic analysis. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
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
Population: Pharmacokinetic Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo IV- Caucasian Participants | Part A: Maximum Observed Plasma Concentration (Cmax) of GSK2831781 Following IV Dose | 137.61 Micrograms per milliliter | Geometric Coefficient of Variation 22.449 |
| Part A: GSK2831781 450 mg IV- Caucasian Participants | Part A: Maximum Observed Plasma Concentration (Cmax) of GSK2831781 Following IV Dose | 166.20 Micrograms per milliliter | Geometric Coefficient of Variation 20.428 |
Secondary
Part A: Number of Participants With Confirmed Positive Post-Baseline Anti-drug Antibody Result
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.
Time frame: Up to Day 112
Population: Safety Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Placebo IV- Caucasian Participants | Part A: Number of Participants With Confirmed Positive Post-Baseline Anti-drug Antibody Result | 0 Participants |
| Part A: GSK2831781 450 mg IV- Caucasian Participants | Part A: Number of Participants With Confirmed Positive Post-Baseline Anti-drug Antibody Result | 0 Participants |
| Part A: Placebo IV- Japanese Participants | Part A: Number of Participants With Confirmed Positive Post-Baseline Anti-drug Antibody Result | 0 Participants |
| Part A: GSK2831781 450 mg IV- Japanese Participants | Part A: Number of Participants With Confirmed Positive Post-Baseline Anti-drug Antibody Result | 0 Participants |
Secondary
Part A: Time to Maximum Observed Plasma Concentration (Tmax) of GSK2831781 Following IV Dose
Blood samples were collected at indicated time points for pharmacokinetic analysis. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
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
Population: Pharmacokinetic Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Placebo IV- Caucasian Participants | Part A: Time to Maximum Observed Plasma Concentration (Tmax) of GSK2831781 Following IV Dose | 1.980 Hours |
| Part A: GSK2831781 450 mg IV- Caucasian Participants | Part A: Time to Maximum Observed Plasma Concentration (Tmax) of GSK2831781 Following IV Dose | 1.990 Hours |
Secondary
Part B: AUC(0 to t) of GSK2831781 Following SC Dose
Blood samples were collected at indicated time points for pharmacokinetic analysis. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Time frame: Day 1 (Pre-dose); Days 2, 3, 4, 6, 8, 11, 15, 18, 22, 29, 43, 57, 71, 85 and 112
Population: Pharmacokinetic Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo IV- Caucasian Participants | Part B: AUC(0 to t) of GSK2831781 Following SC Dose | 6633.227 Hours*micrograms per milliliter | Geometric Coefficient of Variation 26.6369 |
| Part A: GSK2831781 450 mg IV- Caucasian Participants | Part B: AUC(0 to t) of GSK2831781 Following SC Dose | 24269.036 Hours*micrograms per milliliter | Geometric Coefficient of Variation 40.4247 |
Secondary
Part B: Cmax of GSK2831781 Following SC Dose
Blood samples were collected at indicated time points for pharmacokinetic analysis. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Time frame: Day 1 (Pre-dose); Days 2, 3, 4, 6, 8, 11, 15, 18, 22, 29, 43, 57, 71, 85 and 112
Population: Pharmacokinetic Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo IV- Caucasian Participants | Part B: Cmax of GSK2831781 Following SC Dose | 14.61 Micrograms per milliliter | Geometric Coefficient of Variation 30.229 |
| Part A: GSK2831781 450 mg IV- Caucasian Participants | Part B: Cmax of GSK2831781 Following SC Dose | 41.13 Micrograms per milliliter | Geometric Coefficient of Variation 34.252 |
Secondary
Part B: Number of Participants With Confirmed Positive Post-Baseline Anti-drug Antibody Result
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.
Time frame: Up to Day 112
Population: Safety Population. Placebo arms across similar dosing strategies were combined in Part B.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Placebo IV- Caucasian Participants | Part B: Number of Participants With Confirmed Positive Post-Baseline Anti-drug Antibody Result | 0 Participants |
| Part A: GSK2831781 450 mg IV- Caucasian Participants | Part B: Number of Participants With Confirmed Positive Post-Baseline Anti-drug Antibody Result | 0 Participants |
| Part A: Placebo IV- Japanese Participants | Part B: Number of Participants With Confirmed Positive Post-Baseline Anti-drug Antibody Result | 0 Participants |
Secondary
Part B: Tmax of GSK2831781 Following SC Dose
Blood samples were collected at indicated time points for pharmacokinetic analysis. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Time frame: Day 1 (Pre-dose); Days 2, 3, 4, 6, 8, 11, 15, 18, 22, 29, 43, 57, 71, 85 and 112
Population: Pharmacokinetic Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Placebo IV- Caucasian Participants | Part B: Tmax of GSK2831781 Following SC Dose | 95.750 Hours |
| Part A: GSK2831781 450 mg IV- Caucasian Participants | Part B: Tmax of GSK2831781 Following SC Dose | 120.270 Hours |