A Phase 1, First Time in Human (FTIH) Study to Evaluate GSK3352589, a REarranged During Transfection (RET) Growth Factor Receptor Tyrosine Kinase Inhibitor, in Healthy Volunteers

NCT03154086 | Completed Phase 1 Results

• 1 other identifier: 207440
• Study Type: interventional
• Target: 68
• Locations: 1 country
• Sites: 1

Brief Summary

This FTIH study is designed to assess the safety, tolerability and pharmacokinetic (PK) of escalating single and repeat oral doses of GSK3352589 in normal healthy volunteers. This is a randomized, double-blind (sponsor unblinded), placebo controlled, dose escalation study that will have two parts; Part A and Part B.

Conditions

Irritable Bowel Syndrome

Keywords

REarranged during Transfection

Outcome Measures

Primary Outcomes (70)

• Part A: Number of Participants With Serious Adverse Events (SAEs) and Non-SAEs in Cohort 1

  An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. 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 or other situations as per medical or scientific judgment.

  Up to 64 days in Cohort 1

• Part A: Number of Participants With SAEs and Non-SAEs in Cohort 2

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. 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 or other situations as per medical or scientific judgment.

  Up to 30 days in Cohort 2

• Part A: Number of Participants With SAEs and Non-SAEs in Cohort 3

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. 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 or other situations as per medical or scientific judgment.

  Up to 30 days in Cohort 3

• Part B: Number of Participants With SAEs and Non-SAEs

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. 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 or other situations as per medical or scientific judgment.

  Up to 25 days

• Part A: Number of Participants With Abnormal Findings After Physical Examination in Cohort 1

  A complete physical examination will include, at a minimum, assessments of the skin, cardiovascular, respiratory, gastrointestinal and neurological systems. Brief symptom directed physical examination included, at a minimum, assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen). Number of participants with clinically significant abnormal physical examination findings have been presented.

  Up to 64 days in Cohort 1

• Part A: Number of Participants With Abnormal Findings After Physical Examination in Cohort 2

  A complete physical examination included, at a minimum, assessments of the skin, cardiovascular, respiratory, gastrointestinal and neurological systems. Brief symptom directed physical examination included, at a minimum, assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen). Number of participants with clinically significant abnormal physical examination findings have been presented.

  Up to 30 days in Cohort 2

• Part A: Number of Participants With Abnormal Findings After Physical Examination in Cohort 3

  A complete physical examination included, at a minimum, assessments of the skin, cardiovascular, respiratory, gastrointestinal and neurological systems. Brief symptom directed physical examination included, at a minimum, assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen). Number of participants with clinically significant abnormal physical examination findings have been presented.

  Up to 30 days in Cohort 3

• Part B: Number of Participants With Abnormal Findings After Physical Examination

  A complete physical examination included, at a minimum, assessments of the skin, cardiovascular, respiratory, gastrointestinal and neurological systems. Brief symptom directed physical examination included, at a minimum, assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen). Number of participants with clinically significant abnormal physical examination findings have been presented.

  Up to 25 days

• Part A: Number of Participants With Abnormal Electrocardiogram (ECG) Findings in Cohort 1 and Cohort 3

  Triplicate 12-lead ECGs were obtained at indicated time points during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QT corrected (QTc) intervals. 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. Baseline is defined as the last available, non-missing mean value of triplicate assessment prior to the first administration of study drug in Dosing Period 1 (or the first available Dosing Period if Dosing Period 1 is unavailable). The number of participants with abnormal clinically significant (CS) and not clinically significant (NCS) findings for ECG parameters have been presented.

  Baseline (Pre-dose on Day 1), Day 1 (1, 4, 12 Hours Post-dose), Day 2

• Part A: Number of Participants With Abnormal ECG Findings in Cohort 2

  Triplicate 12-lead ECGs were obtained at indicated time points during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. 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. Baseline is defined as the last available, non-missing mean value of triplicate assessment prior to the first administration of study drug in Dosing Period 1 (or the first available Dosing Period if Dosing Period 1 is unavailable). The number of participants with abnormal CS and NCS findings for ECG parameters have been presented.

  Baseline (Pre-dose on Day 1), Day 1 (1, 4, 12 Hours Post-dose), Day 2

• Part B: Number of Participants With Abnormal ECG Findings

  Triplicate 12-lead ECGs were obtained at indicated time points during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. 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. Baseline is defined as the last available, non-missing mean value of triplicate assessment prior to the first administration of study drug. The number of participants with abnormal CS and NCS findings for ECG parameters have been presented.

  Baseline (Pre-dose on Day 1), Day 1 (4 Hours Post-dose), Day 7 (Pre-dose, 4 Hours Post-dose), Day 14 (Pre-dose, 4 Hours Post-dose), Follow-up (Day 25)

• Part A: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) in Cohort 1 and Cohort 3

  Blood pressure of participants was measured at indicated time points in a supine position after 5 minutes rest. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug in Dosing Period 1 (or the first available Dosing Period if Dosing Period 1 is unavailable). Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Pre-dose on Day 1), Day 1 (1, 4, 12 Hours Post-dose), Day 2 and Day 3

• Part A: Change From Baseline in SBP and DBP in Cohort 2

  Blood pressure of participants was measured at indicated time points in a supine position after 5 minutes rest. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug in Dosing Period 1 (or the first available Dosing Period if Dosing Period 1 is unavailable). Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Pre-dose on Day 1), Day 1 (1, 4, 12 Hours Post-dose), Day 2 and Day 3

• Part B: Change From Baseline in SBP and DBP

  Blood pressure of participants was measured at indicated time points in a supine position after 5 minutes rest. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Pre-dose on Day 1), Day 1 (4 Hours Post-dose), Day 2, Day 3, Day 4, Day 5, Day 6, Day 7 (Pre-dose, 4 Hours Post-dose), Day 8, Day 9, Day 10, Day 11, Day 12, Day 13, Day 14 (Pre-dose, 4 Hours Post-dose), Day 15, Follow-up (Day 25)

• Part A: Change From Baseline in Pulse Rate in Cohort 1 and Cohort 3

  Pulse rate of participants was measured at indicated time points in a supine position after 5 minutes rest. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug in Dosing Period 1 (or the first available Dosing Period if Dosing Period 1 is unavailable). Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Pre-dose on Day 1), Day 1 (1, 4, 12 Hours Post-dose), Day 2 and Day 3

• Part A: Change From Baseline in Pulse Rate in Cohort 2

  Pulse rate of participants was measured at indicated time points in a supine position after 5 minutes rest. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug in Dosing Period 1 (or the first available Dosing Period if Dosing Period 1 is unavailable). Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Pre-dose on Day 1), Day 1 (1, 4, 12 Hours Post-dose), Day 2 and Day 3

• Part B: Change From Baseline in Pulse Rate

  Pulse rate of participants was measured at indicated time points in a supine position after 5 minutes rest. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Pre-dose on Day 1), Day 1 (4 Hours Post-dose), Day 2, Day 3, Day 4, Day 5, Day 6, Day 7 (Pre-dose, 4 Hours Post-dose), Day 8, Day 9, Day 10, Day 11, Day 12, Day 13, Day 14 (Pre-dose, 4 Hours Post-dose), Day 15, Follow-up (Day 25)

• Part A: Change From Baseline in Body Temperature in Cohort 1 and Cohort 3

  Body temperature of participants was measured at indicated time points in a supine position after 5 minutes rest. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug in Dosing Period 1 (or the first available Dosing Period if Dosing Period 1 is unavailable). Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Pre-dose on Day 1), Day 1 (1, 4, 12 Hours Post-dose), Day 2 and Day 3

• Part A: Change From Baseline in Body Temperature in Cohort 2

  Body temperature of participants was measured at indicated time points in a supine position after 5 minutes rest. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug in Dosing Period 1 (or the first available Dosing Period if Dosing Period 1 is unavailable). Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Pre-dose on Day 1), Day 1 (1, 4, 12 Hours Post-dose), Day 2 and Day 3

• Part B: Change From Baseline in Body Temperature

  Body temperature of participants was measured at indicated time points in a supine position after 5 minutes rest. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Pre-dose on Day 1), Day 1 (4 Hours Post-dose), Day 2, Day 3, Day 4, Day 5, Day 6, Day 7 (Pre-dose, 4 Hours Post-dose), Day 8, Day 9, Day 10, Day 11, Day 12, Day 13, Day 14 (Pre-dose, 4 Hours Post-dose), Day 15, Follow-up (Day 25)

• Part A: Number of Participants With Different Stool Types Assessed Using Bristol Stool Form Scale (BSFS) in Cohort 1

  The BSFS describes 7 types of stool as following; Type 1-Separate hard lumps (hard to pass), Type 2-Sausage-shaped but lumpy, Type 3-Like a sausage but cracks on surface, Type 4-Like a sausage or snake, smooth and soft, Type 5- Soft blobs with clear cut edges, Type-6 Fluffy pieces with ragged edges, a mushy stool, and Type 7-Watery, no solid pieces (entirely liquid). BSFS was used by the participants during the study to capture the quality of stool using a 7-point scale ranging from Type 1=separate hard lumps like nuts (difficult to pass) to 7= watery, no solid pieces (entirely liquid).

  Up to 64 days in Cohort 1

• Part A: Number of Participants With Different Stool Types Assessed Using BSFS in Cohort 2

  The BSFS describes 7 types of stool as following; Type 1-Separate hard lumps (hard to pass), Type 2-Sausage-shaped but lumpy, Type 3-Like a sausage but cracks on surface, Type 4-Like a sausage or snake, smooth and soft, Type 5- Soft blobs with clear cut edges, Type-6 Fluffy pieces with ragged edges, a mushy stool, and Type 7-Watery, no solid pieces (entirely liquid). BSFS was used by the participants during the study to capture the quality of stool using a 7-point scale ranging from Type 1=separate hard lumps like nuts (difficult to pass) to 7= watery, no solid pieces (entirely liquid).

  Up to 30 days in Cohort 2

• Part A: Number of Participants With Different Stool Types Assessed Using BSFS in Cohort 3

  The BSFS describes 7 types of stool as following; Type 1-Separate hard lumps (hard to pass), Type 2-Sausage-shaped but lumpy, Type 3-Like a sausage but cracks on surface, Type 4-Like a sausage or snake, smooth and soft, Type 5- Soft blobs with clear cut edges, Type-6 Fluffy pieces with ragged edges, a mushy stool, and Type 7-Watery, no solid pieces (entirely liquid). BSFS was used by the participants during the study to capture the quality of stool using a 7-point scale ranging from Type 1=separate hard lumps like nuts (difficult to pass) to 7= watery, no solid pieces (entirely liquid).

  Up to 30 days in Cohort 3

• Part B: Average BSFS at Indicated Time Points

  The BSFS describes 7 types of stool as following; Type 1-Separate hard lumps (hard to pass), Type 2-Sausage-shaped but lumpy, Type 3-Like a sausage but cracks on surface, Type 4-Like a sausage or snake, smooth and soft, Type 5- Soft blobs with clear cut edges, Type-6 Fluffy pieces with ragged edges, a mushy stool, and Type 7-Watery, no solid pieces (entirely liquid). BSFS was used by the participants during the study to capture the quality of stool using a 7-point scale ranging from Type 1=separate hard lumps like nuts (difficult to pass) to 7= watery, no solid pieces (entirely liquid).

  Day -1, Days 1-3, Days 4-7, Days 1-7, Days 8-14

• Part A: Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets, Leukocytes in Cohort 1 and Cohort 3

  Blood samples were collected for analysis of hematology parameters including Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets, and Leukocytes. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug in Dosing Period 1 (or the first available Dosing Period if Dosing Period 1 is unavailable). Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Day -1) and Day 3

• Part A: Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets, Leukocytes in Cohort 2

  Blood samples were collected for analysis of hematology parameters including Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets, and Leukocytes. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug in Dosing Period 1 (or the first available Dosing Period if Dosing Period 1 is unavailable). Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Day -1) and Day 3

• Part B: Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets, Leukocytes

  Blood samples were collected for analysis of hematology parameters including Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets, and Leukocytes. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Day -2), Day 7, Day 15 and Follow-up (Day 25)

• Part A: Change From Baseline in Erythrocytes in Cohort 1 and 3

  Blood samples were collected for analysis of hematology parameters including Erythrocytes. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug in Dosing Period 1 (or the first available Dosing Period if Dosing Period 1 is unavailable). Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Day -1) and Day 3

• Part A: Change From Baseline in Erythrocytes in Cohort 2

  Blood samples were collected for analysis of hematology parameters including Erythrocytes. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug in Dosing Period 1 (or the first available Dosing Period if Dosing Period 1 is unavailable). Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Day -1) and Day 3

• Part B: Change From Baseline in Erythrocytes

  Blood samples were collected for analysis of hematology parameters including Erythrocytes. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Day -2), Day 7, Day 15 and Follow-up (Day 25)

• Part A: Change From Baseline in Hemoglobin in Cohort 1 and 3

  Blood samples were collected for analysis of hematology parameters including hemoglobin. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug in Dosing Period 1 (or the first available Dosing Period if Dosing Period 1 is unavailable). Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Day -1) and Day 3

• Part A: Change From Baseline in Hemoglobin in Cohort 2

  Blood samples were collected for analysis of hematology parameters including hemoglobin. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug in Dosing Period 1 (or the first available Dosing Period if Dosing Period 1 is unavailable). Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Day -1) and Day 3

• Part B: Change From Baseline in Hemoglobin

  Blood samples were collected for analysis of hematology parameters including hemoglobin. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Day -2), Day 7, Day 15 and Follow-up (Day 25)

• Part A: Change From Baseline in Erythrocyte Mean Corpuscular Volume (MCV) in Cohort 1 and Cohort 3

  Blood samples were collected for analysis of hematology parameters including Erythrocyte MCV. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug in Dosing Period 1 (or the first available Dosing Period if Dosing Period 1 is unavailable). Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Day -1) and Day 3

• Part A: Change From Baseline in Erythrocyte MCV in Cohort 2

  Blood samples were collected for analysis of hematology parameters including Erythrocyte MCV. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug in Dosing Period 1 (or the first available Dosing Period if Dosing Period 1 is unavailable). Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Day -1) and Day 3

• Part B: Change From Baseline in Erythrocyte MCV

  Blood samples were collected for analysis of hematology parameters including Erythrocyte MCV. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Day -2), Day 7, Day 15 and Follow-up (Day 25)

• Part A: Change From Baseline in Erythorocyte Mean Corpuscular Hemoglobin (MCH) in Cohort 1 and 3

  Blood samples were collected for analysis of hematology parameters including Erythorocyte MCH. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug in Dosing Period 1 (or the first available Dosing Period if Dosing Period 1 is unavailable). Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Day -1) and Day 3

• Part A: Change From Baseline in Erythrocyte MCH in Cohort 2

  Blood samples were collected for analysis of hematology parameters including Erythorocyte MCH. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug in Dosing Period 1 (or the first available Dosing Period if Dosing Period 1 is unavailable). Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Day -1) and Day 3

• Part B: Change From Baseline in Erythrocyte MCH

  Blood samples were collected for analysis of hematology parameters including Erythorocyte MCH. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Day -2), Day 7, Day 15 and Follow-up (Day 25)

• Part A: Change From Baseline in Hematocrit in Cohort 1 and 3

  Blood samples were collected for analysis of hematology parameters including Hematocrit. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug in Dosing Period 1 (or the first available Dosing Period if Dosing Period 1 is unavailable). Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Day -1) and Day 3

• Part A: Change From Baseline in Hematocrit in Cohort 2

  Blood samples were collected for analysis of hematology parameters including Hematocrit. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug in Dosing Period 1 (or the first available Dosing Period if Dosing Period 1 is unavailable). Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Day -1) and Day 3

• Part B: Change From Baseline in Hematocrit

  Blood samples were collected for analysis of hematology parameters including Hematocrit. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Day -2), Day 7, Day 15 and Follow-up (Day 25)

• Part A: Change From Baseline in Alanine Aminotransferase (ALT),Aspartate Aminotransferase (AST), Alkaline Phosphatase (Alk Phos) in Cohort 1 and 3

  Blood samples were collected for analysis of clinical chemistry parameters including ALT, AST and Alk Phos. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug in Dosing Period 1 (or the first available Dosing Period if Dosing Period 1 is unavailable). Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Day -1) and Day 3

• Part A: Change From Baseline in ALT, AST and Alk Phos in Cohort 2

  Blood samples were collected for analysis of clinical chemistry parameters including ALT, AST and Alk Phos. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug in Dosing Period 1 (or the first available Dosing Period if Dosing Period 1 is unavailable). Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Day -1) and Day 3

• Part B: Change From Baseline in ALT, AST and Alk Phos

  Blood samples were collected for analysis of hematology parameters including ALT, AST and Alk Phos. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Day -2), Day 7, Day 15 and Follow-up (Day 25)

• Part A: Change From Baseline in Bilirubin, Creatinine, Direct Bilirubin in Cohort 1 and 3

  Blood samples were collected for analysis of clinical chemistry parameters including bilirubin, creatinine, direct bilirubin. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug in Dosing Period 1 (or the first available Dosing Period if Dosing Period 1 is unavailable). Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Day -1) and Day 3

• Part A: Change From Baseline in Bilirubin, Creatinine, Direct Bilirubin in Cohort 2

  Blood samples were collected for analysis of clinical chemistry parameters including bilirubin, creatinine, and direct bilirubin. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug in Dosing Period 1 (or the first available Dosing Period if Dosing Period 1 is unavailable). Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Day -1) and Day 3

• Part B: Change From Baseline in Bilirubin, Creatinine, Direct Bilirubin

  Blood samples were collected for analysis of hematology parameters including bilirubin, creatinine, and direct bilirubin. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Day -2), Day 7, Day 15 and Follow-up (Day 25)

• Part A: Change From Baseline in Calcium, Glucose, Potassium, Sodium, Urea in Cohort 1 and 3

  Blood samples were collected for analysis of clinical chemistry parameters including Calcium, Glucose, Potassium, Sodium, Urea. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug in Dosing Period 1 (or the first available Dosing Period if Dosing Period 1 is unavailable). Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Day -1) and Day 3

• Part A: Change From Baseline in Calcium, Glucose, Potassium, Sodium, Urea in Cohort 2

  Blood samples were collected for analysis of clinical chemistry parameters including Calcium, Glucose, Potassium, Sodium, Urea. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug in Dosing Period 1 (or the first available Dosing Period if Dosing Period 1 is unavailable). Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Day -1) and Day 3

• Part B: Change From Baseline in Calcium, Glucose, Potassium, Sodium, Urea

  Blood samples were collected for analysis of hematology parameters including Calcium, Glucose, Potassium, Sodium, Urea. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Day -2), Day 7, Day 15 and Follow-up (Day 25)

• Part A: Change From Baseline in Albumin and Total Protein in Cohort 1 and 3

  Blood samples were collected for analysis of clinical chemistry parameters including albumin, and total protein. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug in Dosing Period 1 (or the first available Dosing Period if Dosing Period 1 is unavailable). Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Day -1) and Day 3

• Part A: Change From Baseline in Albumin and Total Protein in Cohort 2

  Blood samples were collected for analysis of clinical chemistry parameters including albumin and total protein. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug in Dosing Period 1 (or the first available Dosing Period if Dosing Period 1 is unavailable). Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Day -1) and Day 3

• Part B: Change From Baseline in Albumin, Total Protein

  Blood samples were collected for analysis of hematology parameters including albumin and total protein. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Day -2), Day 7, Day 15 and Follow-up (Day 25)

• Part A: Number of Participants With Abnormal Findings for Urine Parameters in Cohort 1 and Cohort 3

  Urine samples were collected from participants for analysis of specific gravity of urine. Urine parameters including bilirubin, glucose, ketones, leukocyte esterase, nitrite, occult blood, potential of hydrogen (pH), protein, specific gravity and Urobilinogen were analyzed by dipstick method. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug in Dosing Period 1 (or the first available Dosing Period if Dosing Period 1 is unavailable).

  Baseline (Day-1) and Day 3

• Part A: Number of Participants With Abnormal Findings for Urine Parameters in Cohort 2

  Urine samples were collected from participants for analysis of specific gravity of urine. Urine parameters including bilirubin, glucose, ketones, leukocyte esterase, nitrite, occult blood, potential of hydrogen (pH), protein, specific gravity and Urobilinogen were analyzed by dipstick method. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug in Dosing Period 1 (or the first available Dosing Period if Dosing Period 1 is unavailable).

  Baseline (Day -1) and Day 3

• Part B: Number of Participants With Abnormal Findings for Urine Parameters

  Blood samples were collected for analysis of hematology parameters including Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets, Leukocytes. Baseline is defined as the last available, non-missing assessment prior to the first administration of study drug. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

  Baseline (Day -2), Day 7, Day 15 and Follow-up (Day 25)

• Part A: Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Non-zero Concentration (AUC [0-t]) Following Single Dose Administration of GSK3352589

  Blood samples were collected from participants for pharmacokinetic analysis including AUC (0-t) following administration of GSK3352589. Pharmacokinetic analysis of GSK3352589 in Part A was conducted by non-compartmental methods. The PK Parameter population comprised of all randomized participants who received at least one dose of active treatment and who had GSK3352589 Pharmacokinetic parameter estimates from any portion of the study.

  Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 16, 24, 36, 48 Hours Post-dose

• Part A: Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC [0-infinity]) Following Single Dose Administration of GSK3352589

  Blood samples were collected from participants for pharmacokinetic analysis including AUC (0-infinity) following administration of GSK3352589. Pharmacokinetic analysis of GSK3352589 in Part A was conducted by non-compartmental methods.

  Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 16, 24, 36, 48 Hours Post-dose

• Part A: Maximum Observed Plasma Concentration (Cmax) Following Single Dose Administration of GSK3352589

  Blood samples were collected from participants for pharmacokinetic analysis including Cmax following administration of GSK3352589. Pharmacokinetic analysis of GSK3352589 in Part A was conducted by non-compartmental methods.

  Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 16, 24, 36, 48 Hours Post-dose

• Part A: Time to Reach Cmax (Tmax) Following Single Dose Administration of GSK3352589

  Blood samples were collected from participants for pharmacokinetic analysis including Tmax following administration of GSK3352589. Pharmacokinetic analysis of GSK3352589 in Part A was conducted by non-compartmental methods.

  Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 16, 24, 36, 48 Hours Post-dose

• Part A: Terminal Elimination Half-life (t1/2) Following Single Dose Administration of GSK3352589

  Blood samples were collected from participants for pharmacokinetic analysis including t1/2 following administration of GSK3352589. Pharmacokinetic analysis of GSK3352589 in Part A was conducted by non-compartmental methods.

  Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 16, 24, 36, 48 Hours Post-dose

• Part A: Cmax Following Single Dose Administration of GSK3352589-Food Effect

  Blood samples were collected from participants for pharmacokinetic analysis following administration of GSK3352589 in fasted and fed condition to assess the effect of food on pharmacokinetics of GSK3352589. Pharmacokinetic analysis of GSK3352589 in Part A was conducted by non-compartmental methods.

  Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 16, 24, 36, 48 Hours Post-dose

• Part A: AUC (0-t) Following Single Dose Administration of GSK3352589- Food Effect

  Blood samples were collected from participants for pharmacokinetic analysis including AUC (0-t) following administration of GSK3352589 in fasted and fed condition to assess the effect of food on pharmacokinetics of GSK3352589. Pharmacokinetic analysis of GSK3352589 in Part A was conducted by non-compartmental methods.

  Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 16, 24, 36, 48 Hours Post-dose

• Part A: AUC (0-infinity) Following Single Dose Administration of GSK3352589- Food Effect

  Blood samples were collected from participants for pharmacokinetic analysis including AUC (0-infinity) following administration of GSK3352589 in fasted and fed condition to assess the effect of food on pharmacokinetics of GSK3352589. Pharmacokinetic analysis of GSK3352589 in Part A was conducted by non-compartmental methods.

  Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 16, 24, 36, 48 Hours Post-dose

• Part B: AUC (0-t) Following Repeat Dose Administration of GSK3352589

  Blood samples were collected from participants for pharmacokinetic analysis including AUC (0-t) following administration of GSK3352589. Pharmacokinetic analysis of GSK3352589 in Part B was conducted by non-compartmental methods.

  Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 10, 11, 12, 14, 16, 24 Hours Post-dose on Day 1; Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 10, 11, 12, 14, 16, 24 Hours Post-dose on Day 14

• Part B: Area Under the Concentration-time Curve From Time Zero (Pre-dose) to 24 Hours Post-dose (AUC [0-24]) Following Repeat Dose Administration of GSK3352589

  Blood samples were collected from participants for pharmacokinetic analysis including AUC (0-24) following administration of GSK3352589. Pharmacokinetic analysis of GSK3352589 in Part B was conducted by non-compartmental methods.

  Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 10, 11, 12, 14, 16, 24 Hours Post-dose on Day 1; Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 10, 11, 12, 14, 16, 24 Hours Post-dose on Day 14

• Part B: Area Under the Concentration-time Curve Over the Dosing Interval (AUC [0-tau]) Following Repeat Dose Administration of GSK3352589

  Blood samples were collected from participants for pharmacokinetic analysis including AUC (0-tau) following administration of GSK3352589. Pharmacokinetic analysis of GSK3352589 in Part B was conducted by non-compartmental methods.

  Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 10, 11, 12, 14, 16, 24 Hours Post-dose on Day 1; Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 10, 11, 12, 14, 16, 24 Hours Post-dose on Day 14

• Part B: Cmax Following Repeat Dose Administration of GSK3352589

  Blood samples were collected from participants for pharmacokinetic analysis including Cmax following administration of GSK3352589. Pharmacokinetic analysis of GSK3352589 in Part B was conducted by non-compartmental methods.

  Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 10, 11, 12, 14, 16, 24 Hours Post-dose on Day 1; Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 10, 11, 12, 14, 16, 24 Hours Post-dose on Day 14

• Part B: Tmax Following Repeat Dose Administration of GSK3352589

  Blood samples were collected from participants for pharmacokinetic analysis including Tmax following administration of GSK3352589. Pharmacokinetic analysis of GSK3352589 in Part B was conducted by non-compartmental methods.

  Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 10, 11, 12, 14, 16, 24 Hours Post-dose on Day 1; Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 10, 11, 12, 14, 16, 24 Hours Post-dose on Day 14

Study Arms (11)

Part A: Cohort 1: Placebo/GSK3352589 5mg/15mg/50mg

EXPERIMENTAL

Subjects will receive single oral dose of placebo tablet in Period 1 followed by GSK3352589 5 milligrams (mg) tablet in Period 2 followed by GSK3352589 15 mg tablet in Period 3 followed by GSK3352589 50 mg tablet in Period 4 of Cohort 1 in Part A of the study. Subjects will return for their next scheduled dosing period approximately 14 days (wash out period) after administration of the study drug during the prior dosing period.

Drug: GSK3352589; Drug: Matching Placebo

Part A:Cohort 1:GSK3352589 2mg/ Placebo/GSK3352589 15mg/50mg

EXPERIMENTAL

Subjects will receive single oral dose of GSK3352589 2 mg tablet in Period 1 followed by Placebo tablet in Period 2 followed by GSK3352589 15 mg tablet in Period 3 followed by GSK3352589 50 mg tablet in Period 4 of Cohort 1 in Part A of the study. Subjects will return for their next scheduled dosing period approximately 14 days (wash out period) after administration of the study drug during the prior dosing period.

Drug: GSK3352589; Drug: Matching Placebo

Part A:Cohort 1: GSK3352589 2mg/5mg/Placebo/GSK3352589 50mg

EXPERIMENTAL

Subjects will receive single oral dose of GSK3352589 2 mg tablet in Period 1 followed by GSK3352589 5 mg tablet in Period 2 followed by Placebo tablet in Period 3 followed by GSK3352589 50 mg tablet in Period 4 of Cohort 1 in Part A of the study. Subjects will return for their next scheduled dosing period approximately 14 days (wash out period) after administration of the study drug during the prior dosing period.

Drug: GSK3352589; Drug: Matching Placebo

Part A:Cohort 1: GSK3352589 2mg/5mg/15mg/Placebo

EXPERIMENTAL

Subjects will receive single oral dose of GSK3352589 2 mg tablet in Period 1 followed by GSK3352589 5 mg tablet in Period 2 followed by GSK3352589 15 mg tablet in Period 3 followed by Placebo tablet in Period 4 of Cohort 1 in Part A of the study. Subjects will return for their next scheduled dosing period approximately 14 days (wash out period) after administration of the study drug during the prior dosing period.

Drug: GSK3352589; Drug: Matching Placebo

Part A:Cohort 2: GSK3352589 25mg Fasted/GSK3352589 25mg Fed

EXPERIMENTAL

Subjects will receive single oral dose of GSK3352589 25 mg tablet in Period 1 (fasted state) and Period 2 (fed state). Subjects will return for their next scheduled dosing Period approximately 14 days (wash out period) after administration of the study drug during the prior dosing period.

Drug: GSK3352589

Part A: Cohort 2: Placebo Fasted/Placebo Fed

EXPERIMENTAL

Subjects will receive single oral dose of placebo tablet matching GSK3352589 25 mg in Period 1 (fasted state) and Period 2 (fed state). Subjects will return for their next scheduled dosing period approximately 14 days (wash out period) after administration of the study drug during the prior dosing period.

Drug: Matching Placebo

Part A:Cohort 3: GSK3352589 150 mg/Placebo

EXPERIMENTAL

Subjects will receive single oral dose of GSK3352589 150 mg tablet in Period 1 followed by placebo tablet matching GSK3352589 150 mg in Period 2 in Cohort 3 of Part A. Subjects will return for their next scheduled dosing period approximately 14 days (wash out period) after administration of the study drug during the prior dosing period.

Drug: GSK3352589; Drug: Matching Placebo

Part A:Cohort 3: Placebo/GSK3352589 400 mg

EXPERIMENTAL

Subjects will receive single oral dose of placebo tablet matching GSK3352589 400 mg in Period 1 followed by single oral dose of GSK3352589 400 mg tablet in Period 2 in Cohort 3 of Part A. Subjects will return for their next scheduled dosing period approximately 14 days (wash out period) after administration of the study drug during the prior dosing period.

Drug: GSK3352589; Drug: Matching Placebo

Part A:Cohort 3: GSK3352589 150mg/GSK3352589 400mg

EXPERIMENTAL

Subjects will receive single oral dose of GSK3352589 150 mg tablet in Period 1 followed by GSK3352589 400 mg tablet in Period 2 in Cohort 3 of Part A. Subjects will return for their next scheduled dosing period approximately 14 days (wash out period) after administration of the study drug during the prior dosing period.

Drug: GSK3352589

Part B: GSK3352589

EXPERIMENTAL

Subjects will receive repeat oral doses of GSK3352589 of 5 mg, 15 mg, 50 mg, 100 mg or 200 mg twice daily administered for 14 days.

Drug: GSK3352589

Part B: Placebo

PLACEBO COMPARATOR

Subjects will receive repeat oral doses of placebo twice a day tablet administered for 14 days.

Drug: Matching Placebo

Interventions

GSK3352589 DRUG

It will be available in the dose of 1, 5, 25 and 100 mg tablet for oral administration.

Part A: Cohort 1: Placebo/GSK3352589 5mg/15mg/50mg; Part A:Cohort 1: GSK3352589 2mg/5mg/15mg/Placebo; Part A:Cohort 1: GSK3352589 2mg/5mg/Placebo/GSK3352589 50mg; Part A:Cohort 1:GSK3352589 2mg/ Placebo/GSK3352589 15mg/50mg; Part A:Cohort 2: GSK3352589 25mg Fasted/GSK3352589 25mg Fed; Part A:Cohort 3: GSK3352589 150 mg/Placebo; Part A:Cohort 3: GSK3352589 150mg/GSK3352589 400mg; Part A:Cohort 3: Placebo/GSK3352589 400 mg; Part B: GSK3352589

Matching Placebo DRUG

It will be available across all strengths to match active drug in the form of tablet for oral administration.

Part A: Cohort 1: Placebo/GSK3352589 5mg/15mg/50mg; Part A: Cohort 2: Placebo Fasted/Placebo Fed; Part A:Cohort 1: GSK3352589 2mg/5mg/15mg/Placebo; Part A:Cohort 1: GSK3352589 2mg/5mg/Placebo/GSK3352589 50mg; Part A:Cohort 1:GSK3352589 2mg/ Placebo/GSK3352589 15mg/50mg; Part A:Cohort 3: GSK3352589 150 mg/Placebo; Part A:Cohort 3: Placebo/GSK3352589 400 mg; Part B: Placebo

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Between 18 and 55 years of age inclusive, at the time of signing the informed consent.
• Healthy as determined by the investigator based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. - History of regular bowel habits
• Male or Female of non-childbearing potential.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions.

You may not qualify if:

• ALT and bilirubin \>1.5 x upper limit of normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
• Previous Diagnosis of IBS
• Estimated Glomerular Filtration Rate \<60 millilter per minute per 1.73 square meter (mL/min/1.73m\^2)
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
• History of Gastroesophageal reflux disease (GERD), dyspepsia, Gastrointestinal (GI) bleeding, diverticulitis, diverticular stricture or other intestinal strictures, GI surgery that could affect motility
• Unwillingness or inability to follow the procedures outlined in the protocol

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Adelaide, South Australia, 5000, Australia

Location

Related Publications (1)

• Reedy BA, O'Connor-Semmes R, Hacquoil K, Gorycki P, Verticelli A, Molga A. First-in-Human Study for a Selective Rearranged During Transfection Tyrosine Kinase Inhibitor, GSK3352589, to Investigate the Safety, Tolerability, and Pharmacokinetics in Healthy Volunteers. Clin Pharmacol Drug Dev. 2021 Apr;10(4):334-345. doi: 10.1002/cpdd.911. Epub 2021 Feb 19.

  PMID: 33606922 DERIVED

MeSH Terms

Conditions

Irritable Bowel Syndrome; Multiple Endocrine Neoplasia Type 2a

Interventions

GSK3352589

Condition Hierarchy (Ancestors)

Colonic Diseases, Functional; Colonic Diseases; Intestinal Diseases; Gastrointestinal Diseases; Digestive System Diseases; Multiple Endocrine Neoplasia; Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Neoplasms, Multiple Primary; Neoplastic Syndromes, Hereditary; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Endocrine System Diseases

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 12, 2017
• First Posted: May 15, 2017
• Study Start: May 17, 2017
• Primary Completion: March 5, 2018
• Study Completion: March 5, 2018
• Last Updated: August 9, 2019
• Results First Posted: August 9, 2019

Record last verified: 2019-06

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1)