A Safety Study of GSK3039294 in Healthy Volunteers and Patients With Systemic Amyloidosis

Triplicate ECG was measured in semi-supine position after 5 minutes (min) rest. A single 12-lead ECG was measured by using ECG machine that automatically measured PR, QRS, QT, and Fridericia's formula (QTcF) intervals. Baseline is defined as the latest available assessment pre the first dose of study drug within each period in Part A. Change from Baseline was calculated as any visit post Baseline value minus Baseline value.

Time frame: Baseline (pre-dose) and 15, 30 minutes, 1, 2, 4, 6, 8, 12, 24, 48 and 72 hours post-dose

Population: Safety Population

Systolic BP and diastolic BP were measured in semi-supine position after 5 min rest for the participants at indicated time points. Baseline is defined as the latest available assessment pre the first dose of study drug within each period in Part A. Change from Baseline was calculated as any visit post Baseline value minus Baseline value.

Time frame: Baseline (pre-dose) and 15, 30 minutes, 1, 2, 4, 6, 8, 12, 24, 48 and 72 hours post-dose

Population: Safety population.

Triplicate ECG was measured in semi-supine position after 5 min rest. A single 12-lead ECG was measured by using ECG machine that automatically measures the heart rate. Baseline is defined as the latest available assessment pre the first dose of study drug within each period in Part A. Change from Baseline was calculated as any visit post Baseline value minus Baseline value.

Time frame: Baseline (pre-dose) and 15, 30 minutes, 1, 2, 4, 6, 8, 12, 24, 48 and 72 hours post-dose

Population: Safety population.

Pulse rate was measured in semi-supine position after 5 minutes rest for the participants at indicated time points. Baseline is defined as the latest available assessment pre the first dose of study drug within each period in Part A. Change from Baseline was calculated as any visit post Baseline value minus Baseline value.

Time frame: Baseline (pre-dose) and 15, 30 minutes, 1, 2, 4, 6, 8, 12, 24, 48 and 72 hours post-dose

Population: Safety population.

Temperature was measured in semi-supine position after 5 min rest for the participants at indicated time points. Baseline is defined as the latest available assessment pre the first dose of study drug within each period in Part A. Change from Baseline was calculated as any visit post Baseline value minus Baseline value.

Time frame: Baseline (pre-dose) and 15, 30 minutes, 1, 2, 4, 6, 8, 12, 24, 48 and 72 hours post-dose

Population: Safety population.

Urine samples were collected and urinalysis included analysis of specific gravity, potential of hydrogen (pH), glucose, protein, blood, ketones by dipstick. The dipstick test gives results in a semi-quantitative manner.

Time frame: Day 1

Population: Safety population

An AE is any untoward medical occurrence in a participants or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE is defined as any untoward medical occurrence that, at any dose: results in death, is life-threatening, requires inpatient hospitalization clinical chemor prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect and other important medical events judged by the investigator that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention. Safety population consist of all participants who received at least one dose of the study medication.

Time frame: Up to Day 14

Population: Safety population.

PCI ranges for the clinical chemistry parameters were as follows : albumin (low: \<0.86 gram \[g\] per liter \[L\]), calcium (low: \<0.91 millimole \[mmol\]/L and high: \>1.06 mmol/L), glucose (low: \<0.71 mmol/L and high: \>1.41 mmol/L), magnesium (low: \<0.63 mmol/L and high: \>1.03 mmol/L), phosphorous (low: \<0.80 mmol/L and high: \>1.14 mmol/L), potassium (low: \<0.86 mmol/L and high: \>1.10 mmol/L), sodium (low: \<0.96 mmol/L and high: \>1.03 mmol/L), and total carbon dioxide (CO2) (low: \<0.86 mmol/L and high: \>1.14 mmol/L).

Time frame: Day 1

Population: Safety population.

PCI ranges for the hematology parameters were as follows: white blood cell (WBC) count (low: \<0.67 10\^9 cells/L and high: \>1.82 10\^9 cells/L), neutrophil count (low: \<0.83 10\^9 cells/L), hemoglobin (high: \>1.03 g/L in male, \>1.13 g/L in female), hemocrit (high: \>1.02 proportion of red blood cell \[RBC\] in blood for male, \>1.17 proportion of RBC in blood for female), platelet count (low: \<0.67 10\^9 cells/L and high: 1.57 10\^9 cells/L), and lymphocytes (low: \<0.81 10\^9 cells/L).

Time frame: Day 1

Population: Safety population

Triplicate ECG was measured in semi-supine position after 5 minutes rest. A single 12-lead ECG was measured by using ECG machine that automatically measured PR, QRS, QT, and QTcF intervals. Baseline is defined as the latest available assessment pre the first dose of study drug in Part B. Change from Baseline was calculated as any visit post Baseline value minus Baseline value.

Time frame: Cohort 3: Baseline (pre-dose), Day 1 (1 hour), Days 2, 3, 4, 5, 6, 7 (pre-dose and 1 hour), 8 and 21; Cohort 4: Up to Day 35

Population: Safety population. Data was not collected as study was terminated, due to safety reasons during conduct of Part B (end of Cohort 3) whereas Cohort 4a and 4b were not recruited in Part B.

Triplicate ECG was measured in semi-supine position after 5 min rest. A single 12-lead ECG was measured by using ECG machine that automatically measures heart rate. Baseline is defined as the latest available assessment pre the first dose of study drug within each period in Part B. Change from Baseline was calculated as any visit post Baseline value minus Baseline value.

Time frame: Cohort 3: Baseline (pre-dose), Day 1 (1 hour), Days 2, 3, 4, 5, 6, 7 (pre-dose and 1 hour), 8 and 21; Cohort 4: Up to Day 35

Population: Safety population. Data was not collected as study was terminated, due to safety reasons during conduct of Part B (end of Cohort 3) whereas Cohort 4a and 4b were not recruited in Part B.

The cardiac monitoring was measured by using an appropriate nonimplantable recording device which is acceptable to the participants. This was evaluated the arrhythmic background of eligible cardiac amyloidosis participants such that false positive attribution of arrhythmias to GSK3039294 during repeat dosing was minimized.

Time frame: Cohort 3: Up to Day 8

Population: Safety population.

Urine samples were collected and urinalysis included analysis of specific gravity, pH, glucose, protein, blood, ketones by dipstick. The dipstick test gives results in a semi-quantitative manner.

Time frame: Cohort 3 and 4: Up to Day 3

Population: Safety population. Data was not collected as study was terminated, due to safety reasons during conduct of Part B (end of Cohort 3) whereas Cohort 4a and 4b were not recruited in Part B.

An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A 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, results in persistent disability/incapacity, is a congenital anomaly/birth defect and other important medical events judged by the investigator that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention.

Time frame: Cohort 3: Up to Day 21; Cohort 4: Up to Day 35

Population: Safety population. Data was not collected as study was terminated, due to safety reasons during conduct of Part B (end of Cohort 3) whereas Cohort 4a and 4b were not recruited in Part B.

PCI ranges for the clinical chemistry parameters were as follows: albumin (low: \<0.86 g/L), calcium (low: \<0.91 mmol/L and high: \>1.06 mmol/L), glucose (low: \<0.71 mmol/L and high: \>1.41 mmol/L), magnesium (low: \<0.63 mmol/L and high: \>1.03 mmol/L), phosphorous (low: \<0.80 mmol/L and high: \>1.14 mmol/L), potassium (low: \<0.86 mmol/L and high: \>1.10 mmol/L), sodium (low: \<0.96 mmol/L and high: \>1.03 mmol/L), and total CO2 (low: \<0.86 mmol/L and high: \>1.14 mmol/L).

Time frame: Cohort 3 and 4: Up to Day 3

Population: Safety population. Data was not collected as study was terminated, due to safety reasons during conduct of Part B (end of Cohort 3) whereas Cohort 4a and 4b were not recruited in Part B.

PCI ranges for the hematology parameters were as follows: WBC count (low: \<0.67 10\^9 cells/L and high: \>1.82 10\^9 cells/L), neutrophil count (low: \<0.83 10\^9 cells/L), hemoglobin (high: \>1.03 g/L in male, \>1.13 g/L in female), hemocrit (high: \>1.02 proportion of RBC in blood for male, \>1.17 proportion of RBC in blood for female), platelet count (low: \<0.67 10\^9 cells/L and high: 1.57 10\^9 cells/L), and lymphocytes (low: \<0.81 10\^9 cells/L).

Time frame: Cohort 3 and 4: Up to Day 3

Population: Safety population. Data was not collected as study was terminated, due to safety reasons during conduct of Part B (end of Cohort 3) whereas Cohort 4a and 4b were not recruited in Part B.

Triplicate ECG was planned to be measured in semi-supine position after 5 minutes rest. A single 12-lead ECG was measured by using ECG machine that automatically measured PR, QRS, QT, and QTcF intervals. Baseline is defined as the latest available assessment pre the first dose of study drug within each period in Part C. Change from Baseline was calculated as any visit post Baseline value minus Baseline value. This analysis was planned but not performed for Part C as the study was terminated early during Part B.

Time frame: Up to Day 35

Population: Safety Population. Data was not collected as study was terminated due to safety reasons during conduct of Part B (end of Cohort 3) whereas Part C was not initiated.

The cardiac monitoring was planned to be measured by using an appropriate nonimplantable recording device which is acceptable to the participants. This was evaluated the arrhythmic background of eligible cardiac amyloidosis participants such that false positive attribution of arrhythmias to GSK3039294 during repeat dosing was minimized. This analysis was planned but not performed for Part C as the study was terminated early during Part B.

Time frame: Up to Day 35

Population: Safety Population. Data was not collected as study was terminated due to safety reasons during conduct of Part B (end of Cohort 3) whereas Part C was not initiated.

Vital signs included systolic and diastolic BP, pulse rate, heart rate and temperature. This analysis was planned but not performed for Part C as the study was terminated early during Part B.

Time frame: Up to Day 35

Population: Safety Population. Data was not collected as study was terminated due to safety reasons during conduct of Part B (end of Cohort 3) whereas Part C was not initiated.

An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A 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, results in persistent disability/incapacity, is a congenital anomaly/birth defect and other important medical events judged by the investigator that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention. This analysis was planned but not performed for Part C as the study was terminated early during Part B.

Time frame: Up to Day 63

Population: Safety Population. Data was not collected as study was terminated due to safety reasons during conduct of Part B (end of Cohort 3) whereas Part C was not initiated.

PCI parameters for the clinical chemistry that were planned for analysis are as follows: albumin, calcium, glucose, magnesium, phosphorous , potassium , sodium , and total CO2. This analysis was planned but not performed for Part C as the study was terminated early during Part B.

Time frame: Up to Day 63

Population: Safety Population. Data was not collected as study was terminated due to safety reasons during conduct of Part B (end of Cohort 3) whereas Part C was not initiated.

Hematology parameters that were planned for analysis were as follows: WBC count , neutrophil count , hemoglobin , hemocrit , platelet count , and lymphocytes. This analysis was planned but not performed for Part C as the study was terminated early during Part B.

Time frame: Up to Day 63

Population: Safety Population. Data was not collected as study was terminated due to safety reasons during conduct of Part B (end of Cohort 3) whereas Part C was not initiated.

Urine samples were planned to be collected and urinalysis included analysis of specific gravity, pH, glucose, protein, blood, ketones by dipstick. This analysis was planned but not performed for Part C as the study was terminated early during Part B.

Time frame: Up to Day 63

Population: Safety Population. Data was not collected as study was terminated due to safety reasons during conduct of Part B (end of Cohort 3) whereas Part C was not initiated.

Blood samples were collected at specified time points for GSK3039294 and GSK2315698. AUC(0-inf) was determined using standard non-compartmental methods. Pharmacokinetic (PK) population consists of all participants administered at least one dose of study medication and who had at least one PK sample taken and analyzed.

Time frame: Pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24 and 48 hours post-dose

Population: PK population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Blood samples were collected at specified time points for GSK3039294 and GSK2315698. AUC(0-t) was determined using standard non-compartmental methods.

Time frame: Pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24 and 48 hours post-dose

Population: PK population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Blood samples were collected at specified time points for GSK3039294 and GSK2315698. AUC(0-inf)/D was determined using standard non-compartmental methods.

Time frame: Pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24 and 48 hours post-dose

Population: PK population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Blood samples were collected at specified time points for GSK3039294 and GSK2315698. AUC(0-t)/D was determined using standard non-compartmental methods.

Time frame: Pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24 and 48 hours post-dose

Population: PK population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Blood samples were collected at specified time points for GSK3039294 and GSK2315698. Cmax/D was determined using standard non-compartmental methods.

Time frame: Pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24 and 48 hours post-dose

Population: PK population. Data could not be calculated because only one participant was analyzed. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). NA indicates that data could not be calculated because only one participant was analyzed.

Blood samples were collected at specified time points for GSK3039294 and GSK2315698. Cmax was determined using standard non-compartmental methods.

Time frame: Pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24 and 48 hours post-dose

Population: PK population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). NA indicates that data could not be calculated because only one participant was analyzed.

Blood samples were collected at specified time points for GSK3039294 and GSK2315698. t1/2 was determined using standard non-compartmental methods.

Time frame: Pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24 and 48 hours post-dose

Population: PK population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Blood samples were collected at specified time points for GSK3039294 and GSK2315698. tmax was determined using standard non-compartmental methods.

Time frame: Pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24 and 48 hours post-dose

Population: PK population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Blood samples were collected at specified time points for GSK3039294 and GSK2315698. AUC(0-6) was determined using standard non-compartmental methods.

Time frame: Cohort 3- Day 4 and 5: pre-dose, and 0.5, 1, 2, 3, 4, and 6 hours post-dose; Cohort 4: Day 4 (pre-dose), Day 5 (pre-dose and 0.5, 1, 2, 3, 4, and 6 hours post-dose)

Population: PK population. Data was not collected as study was terminated, due to safety reasons during conduct of Part B (end of Cohort 3) whereas Cohort 4a and 4b were not recruited in Part B. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Blood samples were collected at specified time points for GSK3039294 and GSK2315698. AUC(0-inf)/D was determined using standard non-compartmental methods.

Time frame: Cohort 3- Day 4 and 5: pre-dose, and 0.5, 1, 2, 3, 4, and 6 hours post-dose; Cohort 4: Day 4 (pre-dose), Day 5 (pre-dose and 0.5, 1, 2, 3, 4, and 6 hours post-dose)

Population: PK population. Data was not collected for Cohort 4a and 4b as study was terminated due to safety reasons during conduct of Part B (end of Cohort 3). Data was not calculated for Cohort 3 as the concentration-time data does not provide an accurate representation of the terminal elimination phase for the drug. Hence, AUC(\[0-inf\]/D) was not derived.

Blood samples were collected at specified time points for GSK3039294 and GSK2315698. AUC(0-inf) was determined using standard non-compartmental methods.

Time frame: Cohort 3- Day 4 and 5: pre-dose, and 0.5, 1, 2, 3, 4, and 6 hours post-dose; Cohort 4: Day 4 (pre-dose), Day 5 (pre-dose and 0.5, 1, 2, 3, 4, and 6 hours post-dose)

Population: PK population. Data was not collected for Cohort 4a and 4b as study was terminated due to safety reasons during conduct of Part B (end of Cohort 3). Data was not calculated for Cohort 3 as the concentration-time data does not provide an accurate representation of the terminal elimination phase for the drug. Hence, AUC (0-inf) was not derived.

Blood samples were collected at specified time points for GSK3039294 and GSK2315698. AUC(0-t)/D was determined using standard non-compartmental methods.

Time frame: Cohort 3- Day 4 and 5: pre-dose, and 0.5, 1, 2, 3, 4, and 6 hours post-dose; Cohort 4: Day 4 (pre-dose), Day 5 (pre-dose and 0.5, 1, 2, 3, 4, and 6 hours post-dose)

Population: PK population. Data was not collected as study was terminated, due to safety reasons during conduct of Part B (end of Cohort 3) whereas Cohort 4a and 4b were not recruited in Part B. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Blood samples were collected at specified time points for GSK3039294 and GSK2315698. AUC(0-t) was determined using standard non-compartmental methods.

Time frame: Cohort 3- Day 4 and 5: pre-dose, and 0.5, 1, 2, 3, 4, and 6 hours post-dose; Cohort 4: Day 4 (pre-dose), Day 5 (pre-dose and 0.5, 1, 2, 3, 4, and 6 hours post-dose)

Population: PK population. Data was not collected as study was terminated, due to safety reasons during conduct of Part B (end of Cohort 3) whereas Cohort 4a and 4b were not recruited in Part B. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Blood samples were collected at specified time points for GSK3039294 and GSK2315698. Cmax/D was determined using standard non-compartmental methods. NA indicates that, data could not be calculated because only one participant was analyzed.

Time frame: Cohort 3- Day 4 and 5: pre-dose, and 0.5, 1, 2, 3, 4, and 6 hours post-dose; Cohort 4: Day 4 (pre-dose), Day 5 (pre-dose and 0.5, 1, 2, 3, 4, and 6 hours post-dose)

Population: PK population. Data was not collected as study was terminated, due to safety reasons during conduct of Part B (end of Cohort 3) whereas Cohort 4a and 4b were not recruited in Part B. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Blood samples were collected at specified time points for GSK3039294 and GSK2315698. Cmax was determined using standard non-compartmental methods. NA indicates data could not be calculated because only one participant was analyzed.

Time frame: Cohort 3- Day 4 and 5: pre-dose, and 0.5, 1, 2, 3, 4, and 6 hours post-dose; Cohort 4: Day 4 (pre-dose), Day 5 (pre-dose and 0.5, 1, 2, 3, 4, and 6 hours post-dose)

Population: PK population. Data was not collected as study was terminated, due to safety reasons during conduct of Part B (end of Cohort 3) whereas Cohort 4a and 4b were not recruited in Part B. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Blood samples were collected at specified time points for GSK3039294. Pharmacodynamic (PD) population consist of all participants who received at least one dose of study medication and who also had a baseline measurement and at least one post-treatment PD measure.

Time frame: Cohort 3:Days1(pre-dose, 2hour post-dose),2(pre-dose),4(pre-dose),5(pre-dose, 30min,1,2,3,4,6 hours post-dose),7(pre-dose)and 21post-dose;Cohort4:Days1(pre-dose, 2 hour post-dose),2(pre-dose),4(pre-dose), 5(pre-dose, and 2 hours post-dose) and 35post-dose

Population: PD population. Data was not collected as study was terminated, due to safety reasons during conduct of Part B (end of Cohort 3) whereas Cohort 4a and 4b were not recruited in Part B. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Blood samples were collected at specified time points for GSK3039294 and GSK2315698. t1/2 was determined using standard non-compartmental methods.

Time frame: Cohort 3- Day 4 and 5: pre-dose, and 0.5, 1, 2, 3, 4, and 6 hours post-dose; Cohort 4: Day 4 (pre-dose), Day 5 (pre-dose and 0.5, 1, 2, 3, 4, and 6 hours post-dose)

Population: PK population. Data was not collected for Cohort 4a and 4b as study was terminated due to safety reasons during conduct of Part B (end of Cohort 3). Data was not calculated for Cohort 3 as the concentration-time data does not provide an accurate representation of the terminal elimination phase for the drug. Hence, t1/2 was not derived.

Blood samples were collected at specified time points for GSK3039294 and GSK2315698. tmax was determined using standard non-compartmental methods.

Time frame: Cohort 3- Day 4 and 5: pre-dose, and 0.5, 1, 2, 3, 4, and 6 hours post-dose; Cohort 4: Day 4 (pre-dose), Day 5 (pre-dose and 0.5, 1, 2, 3, 4, and 6 hours post-dose)

Population: PK population. Data was not collected as study was terminated, due to safety reasons during conduct of Part B (end of Cohort 3) whereas Cohort 4a and 4b were not recruited in Part B. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

This analysis was planned but not performed for Part C as the study was terminated early during Part B.

Time frame: Day 1 (pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 hours post-dose); Day 2 to 20 (pre-dose); Day 21 (pre-dose, and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose; Week 4 and 5

Population: PK population. Data was not collected as study was terminated due to safety reasons during conduct of Part B (end of Cohort 3) whereas Part C was not initiated.

This analysis was planned but not performed for Part C as the study was terminated early during Part B.

Time frame: Day 1 (pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 hours post-dose); Day 2 to 20 (pre-dose); Day 21 (pre-dose, and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose; Week 4 and 5

Population: PK population. Data was not collected as study was terminated due to safety reasons during conduct of Part B (end of Cohort 3) whereas Part C was not initiated.

This analysis was planned but not performed for Part C as the study was terminated early during Part B.

Time frame: Day 1 (pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 hours post-dose); Day 2 to 20 (pre-dose); Day 21 (pre-dose, and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose; Week 4 and 5

Population: PK population. Data was not collected as study was terminated due to safety reasons during conduct of Part B (end of Cohort 3) whereas Part C was not initiated.

This analysis was planned but not performed for Part C as the study was terminated early during Part B.

Time frame: Day 1 (pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 hours post-dose); Day 2 to 20 (pre-dose); Day 21 (pre-dose, and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose; Week 4 and 5

Population: PK population. Data was not collected as study was terminated due to safety reasons during conduct of Part B (end of Cohort 3) whereas Part C was not initiated.

This analysis was planned but not performed for Part C as the study was terminated early during Part B.

Time frame: Day 1 (pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 hours post-dose); Day 2 to 20 (pre-dose); Day 21 (pre-dose, and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose; Week 4 and 5

Population: PK population. Data was not collected as study was terminated due to safety reasons during conduct of Part B (end of Cohort 3) whereas Part C was not initiated.

This analysis was planned but not performed for Part C as the study was terminated early during Part B.

Time frame: Day 1 (pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 hours post-dose); Day 2 to 20 (pre-dose); Day 21 (pre-dose, and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose; Week 4 and 5

Population: PK population. Data was not collected as study was terminated due to safety reasons during conduct of Part B (end of Cohort 3) whereas Part C was not initiated.

This analysis was planned but not performed for Part C as the study was terminated early during Part B.

Time frame: Day 1 (pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 hours post-dose); Day 2 to 20 (pre-dose); Day 21 (pre-dose, and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose; Week 4 and 5

Population: PK population. Data was not collected as study was terminated due to safety reasons during conduct of Part B (end of Cohort 3) whereas Part C was not initiated.

This analysis was planned but not performed for Part C as the study was terminated early during Part B.

Time frame: Day 1 (pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 hours post-dose); Day 2 to 20 (pre-dose); Day 21 (pre-dose, and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose; Week 4 and 5

Population: PK population. Data was not collected as study was terminated due to safety reasons during conduct of Part B (end of Cohort 3) whereas Part C was not initiated.

This analysis was planned but not performed for Part C as the study was terminated early during Part B.

Time frame: Day 1 (pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 hours post-dose); Day 2 to 20 (pre-dose); Day 21 (pre-dose, and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose; Week 4 and 5

Population: PK population. Data was not collected as study was terminated due to safety reasons during conduct of Part B (end of Cohort 3) whereas Part C was not initiated.

This analysis was planned but not performed for Part C as the study was terminated early during Part B.

Time frame: Day 1 (pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 hours post-dose); Day 2 to 20 (pre-dose); Day 21 (pre-dose, and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose; Week 4 and 5

Population: PK population. Data was not collected as study was terminated due to safety reasons during conduct of Part B (end of Cohort 3) whereas Part C was not initiated.