Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of GSK3915393 in Healthy Participants and to Evaluate the Interaction Between GSK3915393 and Grapefruit Juice and Itraconazole

NCT04604795 | Completed Phase 1 Results

• 1 other identifier: 213585
• Study Type: interventional
• Target: 65
• Locations: 1 country
• Sites: 1

Brief Summary

This is a 3-part first time into human study (FTIH) study for GSK3915393. Parts A and B of the study will evaluate the safety, tolerability and pharmacokinetics (PK) of single ascending and repeat oral doses of GSK3915393 in healthy adult participants. Part C will evaluate the impact of co-administration of GSK3915393 with grapefruit juice and itraconazole on the PK of GSK3915393.

Conditions

Celiac Disease; Coeliac Disease

Keywords

Celiac disease; Itraconazole; Grape fruit juice; GSK3915393; Healthy Participants; Pharmacokinetics; First time into human

Outcome Measures

Primary Outcomes (33)

• Part A: Number of Participants With All Non-serious Adverse Events (AEs) and Serious AEs (SAEs) Following Administration of Oral Dose

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. SAE is defined as any serious adverse event that, at any dose which results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, other situations as per investigator's medical or scientific judgment.

  Up to 70 days

• Part A: Number of Participants With Treatment-related AEs Following Administration of Oral Dose

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. Number of participants with treatment related AEs were presented.

  Up to 70 days

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

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. SAE is defined as any serious adverse event that, at any dose which results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, other situations as per investigator's medical or scientific judgment.

  Up to 28 days

• Part B: Number of Participants With Treatment-related AEs

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. Number of participants with treatment related AEs are presented.

  Up to 28 days

• Part A: Number of Participants With Worst Case Chemistry Results by Potential Clinical Importance (PCI) Criteria Post-Baseline Relative to Baseline Following Administration of Oral Dose

  Blood samples were collected for analysis of chemistry parameters. PCI ranges were \>=2\*Upper limit of normal (ULN) units per liter (U/L)(Alanine Aminotransferase \[ALT\]), \>=2\*ULN (U/L) (Aspartate Aminotransferase (\[AST\]), \>=2\*ULN (Alkaline Phosphatase \[ALP\]) (U/L), \>=1.5\*ULN (micromoles per liter) (bilirubin), \<2 or \>2.75 millimoles/liter (L) (mmol/L)(calcium), \<3 or \>11 mmol/L (glucose), \<3 or \>5.5 mmol/L (potassium), \<130 or \>150 mmol/L (sodium),\<50 or \>85 grams/liter (protein). Participants were counted in worst case category that their value changes to (low, within \[w/in\] range or no change \[NC\], or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (e.g., High to High), or whose value became within range, are recorded in 'To within Range No Change' category. Participants were counted twice if participant had values that changed 'To Low' and 'To High', so percentages may not add to 100 percentage (%).

  Up to 70 days

• Part A: Number of Participants With Worst Case Chemistry Results-creatinine by PCI Criteria Post-Baseline Relative to Baseline Following Administration of Oral Dose

  Blood samples were collected for analysis of creatinine. Participants were counted under increase of PCI if they had change from Baseline \> 44.2 micromoles per Liter for any post Baseline assessment. Participants who did not meet this PCI criteria are counted as within (w/in) range.

  Up to 70 days

• Part A: Number of Participants With Worst Case Chemistry Results-urea by PCI Criteria Post-Baseline Relative to Baseline Following Administration of Oral Dose

  Blood samples were collected for analysis of chemistry parameters. PCI range for Urea: High \>10.5 mmol/L. Participants were counted in worst case category that their value changes to (within \[w/in\] range or no change \[NC\], or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (e.g., High to High), or whose value became within range, are recorded in 'To within Range No Change' category.

  Up to 70 days

• Part A: Number of Participants With Worst Case Hematology Results by PCI Criteria Post-Baseline Relative to Baseline Following Administration of Oral Dose

  Blood samples were collected for analysis of hematology parameters. PCI ranges were \>1\*10\^9 cell per liter (cells/L) (eosinophils), \<0.2 or \>0.54 proportion of red blood cells in blood (hematocrit), \<80 or \>180 grams per liter(g/L) (hemoglobin), \<3 or \>20 x10\^9 cells/L (leukocytes), \<0.8\*10\^9 cells/L (lymphocytes), \<1.5 or \>16\*10\^9 cells/L (neutrophils) and \<100 or \>550\*10\^9 cells/L (platelets). Participants were counted in worst case category that their value changes to (low, within range or no change or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (for example \[e.g.\], High to High), or whose value became within range, were recorded in "To within Range or No Change" category. Participants were counted twice if participant has values that changed 'To Low' \& 'To High', so the percentages may not add to 100%.

  Up to 70 days

• Part A: Number of Participants With Worst Case Vital Sign Results by PCI Criteria Post-Baseline Relative to Baseline Following Administration of Oral Dose

  Vital signs included diastolic blood pressure (DBP), systolic blood pressure (SBP), pulse rate (PR), body temperature, respiratory rate (RR) and were measured after resting for at least 5 minutes in semi-supine position. PCI ranges were, SBP (millimeters of mercury\[mmHg\]): \<85 (low) or \>160 (high), DBP (mmHg): \<45 (low) or \>100 (high), heart rate (beats per minute): \<40 (low) or \>110 (high), respiration rate (breaths per minute):\<=8 (low) or \>20 (high) and body temperature (degrees Celsius) \<=35.5 (low) or \>38.0 (high). Participants were counted in worst case category that their value changes to (low, within range or no change, or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (e.g., High to High), or whose value became within range, are recorded in 'To W/in Range No Change' category. Participants were counted twice if participant had values that changed 'To Low' and 'To High', so percentages may not add to 100%.

  Up to 70 days

• Part A: Number of Participants With Worst Case Post-Baseline Abnormal Electrocardiogram (ECG) Findings Following Administration of Oral Dose

  Twelve lead ECG was obtained using an ECG machine that automatically calculated the heart rate and measured QTc, PR, QRS intervals. Abnormal findings were categorized as clinically significant and not clinically significant. 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. Data for number of participants with worst case post-Baseline abnormal ECG findings have been presented.

  Up to 70 days

• Part A: Number of Participants With Abnormal Physical Examination Findings Following Administration of Oral Dose

  A full physical examination was performed which included, at a minimum, assessments of the Skin, Cardiovascular, Respiratory, Gastrointestinal and Neurological systems.

  Up to 70 days

• Part B: Number of Participants With Worst Case Chemistry Results by PCI Criteria Post-Baseline Relative to Baseline Following Administration of Repeat Oral Dose of GSK3915393

  Blood samples were collected for analysis of chemistry parameters. PCI ranges were \>=2\*ULN (U/L)(ALT), \>=2\*ULN (U/L) (AST), \>=2\*ULN (ALP) (U/L), \>=1.5\*ULN (micromoles per liter) (bilirubin), \<2 or \>2.75 millimoles/liter (L) (mmol/L)(calcium), \<3 or \>11 mmol/L (glucose), \<3 or \>5.5 mmol/L (potassium), \<130 or \>150 mmol/L (sodium),\<50 or \>85 grams/liter (protein). Participants were counted in worst case category that their value changes to (low, within \[w/in\] range or no change \[NC\], or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (e.g., High to High), or whose value became within range, are recorded in 'To within Range No Change' category. Participants were counted twice if participant had values that changed 'To Low' and 'To High', so percentages may not add to 100 percentage (%).

  Up to 28 days

• Part B: Number of Participants With Worst Case Chemistry Results-urea by PCI Criteria Post-Baseline Relative to Baseline Following Administration of Repeat Oral Dose of GSK3915393

  Blood samples were collected for analysis of chemistry parameters. PCI range for Urea: High \>10.5 mmol/L. Participants were counted in worst case category that their value changes to (within \[w/in\] range or NC, or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (e.g., High to High), or whose value became within range, are recorded in 'To within Range No Change' category.

  Up to 28 days

• Part B: Number of Participants With Worst Case Chemistry Results-creatinine by PCI Criteria Post-Baseline Relative to Baseline Following Administration of Repeat Oral Dose

  Blood samples were collected for analysis of creatinine. Participants were counted under increase of PCI if they had change from Baseline \> 44.2 micromoles per Liter for any post Baseline assessment. Participants who did not meet this PCI criteria are counted as w/in range. Participants whose laboratory value became within range, were recorded in 'To within Range' category.

  Up to 28 days

• Part B: Number of Participants With Worst Case Hematology Results by PCI Criteria Post-Baseline Relative to Baseline Following Repeat Oral Dose of GSK3915393

  Blood samples were collected for analysis of hematology parameters. PCI ranges were 1\*10\^9 cell per liter (cells/L) (eosinophils), \<0.2 or \>0.54 proportion of red blood cells in blood (hematocrit), \<80 or \>180 grams per liter(g/L) (hemoglobin), \<3 or \>20 x10\^9 cells/L (leukocytes), \<0.8\*10\^9 cells/L (lymphocytes), \<1.5 or \>16\*10\^9 cells/L (neutrophils) and \<100 or \>550\*10\^9 cells/L (platelets). Participants were counted in worst case category that their value changes to (low, within range or no change or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (for example \[e.g.\], High to High), or whose value became within range, were recorded in "To within Range or No Change" category. Participants were counted twice if participant has values that changed 'To Low' \& 'To High', so the percentages may not add to 100%.

  Up to 28 days

• Part B: Number of Participants With Worst Case Vital Sign Results by PCI Criteria Post-Baseline Relative to Baseline Following Repeat Oral Dose of GSK3915393

  Vital signs included DBP, SBP, PR, body temperature, RR and were measured after resting for at least 5 minutes in semi-supine position. PCI ranges were, SBP (mmHg): \<85 (low) or \>160 (high), DBP (mmHg): \<45 (low) or \>100 (high), heart rate (beats per minute): \<40 (low) or \>110 (high), respiration rate (breaths per minute):\<=8 (low) or \>20 (high) and body temperature (degrees Celsius) \<=35.5 (low) or \>38.0 (high). Participants were counted in worst case category that their value changes to (low, within range or no change, or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (e.g., High to High), or whose value became within range, are recorded in 'To W/in Range No Change' category. Participants were counted twice if participant had values that changed 'To Low' and 'To High', so percentages may not add to 100%.

  Up to 28 days

• Part B: Number of Participants With Worst Case Post-Baseline Abnormal ECG Findings Following Repeat Oral Dose of GSK3915393

  Twelve lead ECG was obtained using an ECG machine that automatically calculated the heart rate and measured QTc, PR, QRS intervals. Abnormal findings were categorized as clinically significant and not clinically significant. 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. Data for number of participants with worst case post-Baseline abnormal ECG findings have been presented.

  Up to 28 days

• Part B: Number of Participants With Abnormal Physical Examination Findings Following Administration of Repeat Oral Dose of GSK3915393

  A full physical examination was performed which included, at a minimum, assessments of the Skin, Cardiovascular, Respiratory, Gastrointestinal and Neurological systems.

  Up to 28 days

• Part C: Maximum Observed Plasma Drug Concentration (Cmax) Following IV Dose of GSK3915393

  Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3915393.

  Pre-dose and at 20, 40 minutes, 1, 1 hour 5 minutes, 1 hour 10 minutes, 1 hours 20 minutes, 1 hour 40 minutes, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, and 10 hours post-dose

• Part C: Cmax of GSK3915393 Following IV Dose of GSK3915393+ITZ

  Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3915393.

  Pre-dose and at 20, 40 minutes, 1, 1 hour 5 minutes, 1 hour 10 minutes, 1 hours 20 minutes, 1 hour 40 minutes, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24, 36, 48, and 60 hours post-dose

• Part C: Cmax Following Oral Dose of GSK3915393 in Combination With Water, GFJ and ITZ

  Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3915393. For Part C: GSK3915393 20 mg+ Water and Part C: GSK3915393 20 mg+ GFJ, concentrations after 24 hours post-dose were expected to be non-quantifiable. Cmax was derived based on collected assessments (up to 24 hours for Part C: GSK3915393 20 mg+ Water and Part C: GSK3915393 20 mg+ GFJ, up to 60 hours for Part C: GSK3915393 20 mg+ ITZ). Only the quantifiable concentration time points were to be considered for assessment of pharmacokinetic parameters.

  Pre-dose and at 20, 40 minutes, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 24, 36, 48 and 60 hours post-dose

• Part C: Time to Maximum Observed Plasma Drug Concentration (Tmax) Following IV Dose of GSK3915393

  Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3915393.

  Pre-dose and at 20, 40 minutes, 1, 1 hour 5 minutes, 1 hour 10 minutes, 1 hours 20 minutes, 1 hour 40 minutes, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, and 10 hours post-dose

• Part C: Tmax of GSK3915393 Following IV Dose of GSK3915393+ITZ

  Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3915393.

  Pre-dose and at 20, 40 minutes, 1, 1 hour 5 minutes, 1 hour 10 minutes, 1 hours 20 minutes, 1 hour 40 minutes, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24, 36, 48, and 60 hours post-dose

• Part C: Tmax of GSK3915393 Following Oral Dose of GSK3915393 in Combination With Water, GFJ and ITZ

  Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3915393. For Part C: GSK3915393 20 mg+ Water and Part C: GSK3915393 20 mg+ GFJ, concentrations after 24 hours post-dose were expected to be non-quantifiable. Tmax was derived based on collected assessments (up to 24 hours for Part C: GSK3915393 20 mg+ Water and Part C: GSK3915393 20 mg+ GFJ, up to 60 hours for Part C: GSK3915393 20 mg+ ITZ). Only the quantifiable concentration time points were to be considered for assessment of pharmacokinetic parameters.

  Pre-dose and at 20, 40 minutes, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 24, 36, 48 and 60 hours post-dose

• Part C: Area Under Curve up to the Last Measurable Concentration (AUCLST[0-10]) Following IV Dose of GSK3915393

  Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3915393.

  Pre-dose and at 20, 40 minutes, 1, 1 hour 5 minutes, 1 hour 10 minutes, 1 hours 20 minutes, 1 hour 40 minutes, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, and 10 hours post-dose

• Part C: AUCLST(0-24) of GSK3915393 Following IV Dose of GSK3915393+ITZ

  Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3915393.

  Pre-dose and at 20, 40 minutes, 1, 1 hour 5 minutes, 1 hour 10 minutes, 1 hours 20 minutes, 1 hour 40 minutes, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, and 24 hours post-dose

• Part C: AUCLST(0-24) of GSK3915393 Following Oral Dose of GSK3915393 in Combination With Water, GFJ and ITZ

  Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3915393.

  Pre-dose and at 20, 40 minutes, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14 and 24 hours post-dose

• Part C: AUC From Time Zero to Infinity (AUC[0-inf]) Following IV Dose of GSK3915393

  Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3915393.

  Pre-dose and at 20, 40 minutes, 1, 1 hour 5 minutes, 1 hour 10 minutes, 1 hours 20 minutes, 1 hour 40 minutes, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, and 10 hours post-dose

• Part C: AUC(0-inf) of GSK3915393 Following IV Dose of GSK3915393+ITZ

  Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3915393.

  Pre-dose and at 20, 40 minutes, 1, 1 hour 5 minutes, 1 hour 10 minutes, 1 hours 20 minutes, 1 hour 40 minutes, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24, 36, 48, and 60 hours post-dose

• Part C: AUC(0-inf) of GSK3915393 Following Oral Dose of GSK3915393 in Combination With Water, GFJ and ITZ

  Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3915393. For Part C: GSK3915393 20 mg+ Water and Part C: GSK3915393 20 mg+ GFJ, concentrations after 24 hours post-dose were expected to be non-quantifiable. AUC(0-inf) was derived based on collected assessments (up to 24 hours for Part C: GSK3915393 20 mg+ Water and Part C: GSK3915393 20 mg+ GFJ, up to 60 hours for Part C: GSK3915393 20 mg+ ITZ). Only the quantifiable concentration time points were to be considered for assessment of pharmacokinetic parameters.

  Pre-dose and at 20, 40 minutes, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 24, 36, 48 and 60 hours post-dose

• Part C: Apparent Terminal Half-life (t1/2) of GSK3915393 Following IV Dose of GSK3915393

  Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3915393.

  Pre-dose and at 20, 40 minutes, 1, 1 hour 5 minutes, 1 hour 10 minutes, 1 hours 20 minutes, 1 hour 40 minutes, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, and 10 hours post-dose

• Part C: t1/2 of GSK3915393 Following IV Dose of GSK3915393+ITZ

  Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3915393.

  Pre-dose and at 20, 40 minutes, 1, 1 hour 5 minutes, 1 hour 10 minutes, 1 hours 20 minutes, 1 hour 40 minutes, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24, 36, 48, and 60 hours post-dose

• Part C: t1/2 of GSK3915393 Following Oral Dose of GSK3915393 in Combination With Water, GFJ and ITZ

  Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3915393. For Part C: GSK3915393 20 mg+ Water and Part C: GSK3915393 20 mg+ GFJ, concentrations after 24 hours post-dose were expected to be non-quantifiable. t1/2 was derived based on collected assessments (up to 24 hours for Part C: GSK3915393 20 mg+ Water and Part C: GSK3915393 20 mg+ GFJ, up to 60 hours for Part C: GSK3915393 20 mg+ ITZ). Only the quantifiable concentration time points were to be considered for assessment of pharmacokinetic parameters.

  Pre-dose and at 20, 40 minutes, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 24, 36, 48 and 60 hours post-dose

Secondary Outcomes (51)

• Part A: Cmax Following Single Oral Dose of GSK3915393

  Pre-dose and at 20, 40 minutes, 1, 1.5, 2, 3, 4, 6, 10, 12, 14, 24 and 36 hours post-dose

• Part A: Cmax Following Single IV Dose of GSK3915393

  Pre-dose and at 20, 40 minutes, 1, 1 hour 5 minutes, 1 hour 10 minutes, 1 hours 20 minutes, 1 hour 40 minutes, 2, 2.5, 3, 3.5, 4, 5 and 6 hours post-dose

• Part A: Tmax Following Single Oral Dose of GSK3915393

  Pre-dose and at 20, 40 minutes, 1, 1.5, 2, 3, 4, 6, 10, 12, 14, 24 and 36 hours post-dose

• Part A: Tmax Following IV Dose of GSK3915393

  Pre-dose and at 20, 40 minutes, 1, 1 hour 5 minutes, 1 hour 10 minutes, 1 hours 20 minutes, 1 hour 40 minutes, 2, 2.5, 3, 3.5, 4, 5 and 6 hours post-dose

• Part A: AUCLST(0-24) Following Single Oral Dose of GSK3915393

  Pre-dose and at 20, 40 minutes, 1, 1.5, 2, 3, 4, 6, 10, 12, 14, and 24 hours post-dose

Study Arms (12)

Part A:GSK3915393 DLs 1,3,4,intravenous (IV) microdose and placebo (Sequence A)

EXPERIMENTAL

In Part A, participants will receive dose levels (DLs) 1, 3, 4, IV microdose of GSK3915393, and placebo in a pre-determined sequence (Sequence A). There will be a washout period of at least 7 days between each dose. Oral dose levels will be determined based on safety, tolerability and PK data.

Drug: GSK3915393 Capsules; Drug: GSK3915393 Solution for Infusion; Drug: Placebo capsules

Part A:GSK3915393 DLs 1,2,4,IV microdose and placebo (Sequence B)

EXPERIMENTAL

In Part A, participants will receive dose levels 1, 2, 4, IV microdose of GSK3915393 and placebo in a pre-determined sequence (Sequence B). There will be a washout period of at least 7 days between each dose. Oral dose levels will be determined based on safety, tolerability and PK data.

Drug: GSK3915393 Capsules; Drug: GSK3915393 Solution for Infusion; Drug: Placebo capsules

Part A:GSK3915393 DLs 1,2,3,IV microdose and placebo (Sequence C)

EXPERIMENTAL

In Part A, participants will receive dose levels 1, 2, 3, IV microdose of GSK3915393 and placebo in a pre-determined sequence (Sequence C). There will be a washout period of at least 7 days between each dose. Oral dose levels will be determined based on safety, tolerability and PK data.

Drug: GSK3915393 Capsules; Drug: GSK3915393 Solution for Infusion; Drug: Placebo capsules

Part A:GSK3915393 DLs 2,3,4,IV microdose and placebo (Sequence D)

EXPERIMENTAL

In Part A, participants will receive dose levels 2, 3, 4, IV microdose of GSK3915393 and placebo in a pre-determined sequence (Sequence D). There will be a washout period of at least 7 days between each dose. Oral dose levels will be determined based on safety, tolerability and PK data.

Drug: GSK3915393 Capsules; Drug: GSK3915393 Solution for Infusion; Drug: Placebo capsules

Part B: Cohort 1: Participants receiving GSK3915393 DL X

EXPERIMENTAL

Participants will receive GSK3915393 dose level X twice daily during Part B of the study. Dose levels will be determined based on safety, tolerability and PK data from Part A.

Drug: GSK3915393 Capsules

Part B: Cohort 1: Participants receiving placebo

PLACEBO COMPARATOR

Participants will receive placebo matching GSK3915393 dose level X during Part B of the study.

Drug: Placebo capsules

Part B: Cohort 2: Participants receiving GSK3915393 DL Y

EXPERIMENTAL

Participants will receive GSK3915393 dose level Y twice daily during Part B of the study. Dose levels will be determined based on safety, tolerability and PK data from Part A and Part B.

Drug: GSK3915393 Capsules

Part B: Cohort 2: Participants receiving placebo

PLACEBO COMPARATOR

Participants will receive placebo matching GSK3915393 dose level Y twice daily during Part B of the study

Drug: Placebo capsules

Part B: Cohort 3: Participants receiving GSK3915393 DL Z

EXPERIMENTAL

Participants will receive GSK3915393 dose level Z twice daily during Part B of the study. Dose levels will be determined based on safety, tolerability and PK data from Part A and Part B.

Drug: GSK3915393 Capsules

Part B: Cohort 3: Participants receiving placebo

PLACEBO COMPARATOR

Participants will receive placebo matching GSK3915393 dose level Z twice daily during Part B of the study.

Drug: Placebo capsules

Part C: GSK3915393 IV/GSK3915393 IV+ITZ/GSK3915393+water/GSK3915393+GFJ/GSK3915393+ITZ (Sequence A)

EXPERIMENTAL

Participants will receive GSK3915393 IV microdose in period 1 followed by combination of GSK3915393 IV microdose and itraconazole (ITZ) in period 2. Participants will then receive oral GSK3915393 plus water in period 3, oral GSK3915393 plus grape fruit juice (GFJ) in period 4 and oral GSK3915393 plus ITZ in period 5.

Drug: GSK3915393 Capsules; Drug: GSK3915393 Solution for Infusion; Drug: Itraconazole; Other: Water; Other: Grape fruit juice

Part C: GSK3915393 IV/GSK3915393 IV+ITZ/GSK3915393+GFJ/GSK3915393+water/GSK3915393+ITZ (Sequence B)

EXPERIMENTAL

Participants will receive GSK3915393 IV microdose in period 1 followed by combination of GSK3915393 IV microdose and ITZ in period 2. Participants will then receive oral GSK3915393 plus GFJ in period 3, oral GSK3915393 plus water in period 4 and oral GSK3915393 plus ITZ in period 5.

Drug: GSK3915393 Capsules; Drug: GSK3915393 Solution for Infusion; Drug: Itraconazole; Other: Water; Other: Grape fruit juice

Interventions

GSK3915393 Capsules DRUG

GSK3915393 capsules will be given orally.

Part A:GSK3915393 DLs 1,2,3,IV microdose and placebo (Sequence C); Part A:GSK3915393 DLs 1,2,4,IV microdose and placebo (Sequence B); Part A:GSK3915393 DLs 1,3,4,intravenous (IV) microdose and placebo (Sequence A); Part A:GSK3915393 DLs 2,3,4,IV microdose and placebo (Sequence D); Part B: Cohort 1: Participants receiving GSK3915393 DL X; Part B: Cohort 2: Participants receiving GSK3915393 DL Y; Part B: Cohort 3: Participants receiving GSK3915393 DL Z; Part C: GSK3915393 IV/GSK3915393 IV+ITZ/GSK3915393+GFJ/GSK3915393+water/GSK3915393+ITZ (Sequence B); Part C: GSK3915393 IV/GSK3915393 IV+ITZ/GSK3915393+water/GSK3915393+GFJ/GSK3915393+ITZ (Sequence A)

GSK3915393 Solution for Infusion DRUG

GSK3915393 solution for infusion will be administered intravenously.

Part A:GSK3915393 DLs 1,2,3,IV microdose and placebo (Sequence C); Part A:GSK3915393 DLs 1,2,4,IV microdose and placebo (Sequence B); Part A:GSK3915393 DLs 1,3,4,intravenous (IV) microdose and placebo (Sequence A); Part A:GSK3915393 DLs 2,3,4,IV microdose and placebo (Sequence D); Part C: GSK3915393 IV/GSK3915393 IV+ITZ/GSK3915393+GFJ/GSK3915393+water/GSK3915393+ITZ (Sequence B); Part C: GSK3915393 IV/GSK3915393 IV+ITZ/GSK3915393+water/GSK3915393+GFJ/GSK3915393+ITZ (Sequence A)

Placebo capsules DRUG

Placebo matching GSK3915393 capsules will be given orally.

Part A:GSK3915393 DLs 1,2,3,IV microdose and placebo (Sequence C); Part A:GSK3915393 DLs 1,2,4,IV microdose and placebo (Sequence B); Part A:GSK3915393 DLs 1,3,4,intravenous (IV) microdose and placebo (Sequence A); Part A:GSK3915393 DLs 2,3,4,IV microdose and placebo (Sequence D); Part B: Cohort 1: Participants receiving placebo; Part B: Cohort 2: Participants receiving placebo; Part B: Cohort 3: Participants receiving placebo

Itraconazole DRUG

Participants will be administered with GSK3915393 along with ITZ orally

Part C: GSK3915393 IV/GSK3915393 IV+ITZ/GSK3915393+GFJ/GSK3915393+water/GSK3915393+ITZ (Sequence B); Part C: GSK3915393 IV/GSK3915393 IV+ITZ/GSK3915393+water/GSK3915393+GFJ/GSK3915393+ITZ (Sequence A)

Water OTHER

Participants will be administered with GSK3915393 along with water orally

Part C: GSK3915393 IV/GSK3915393 IV+ITZ/GSK3915393+GFJ/GSK3915393+water/GSK3915393+ITZ (Sequence B); Part C: GSK3915393 IV/GSK3915393 IV+ITZ/GSK3915393+water/GSK3915393+GFJ/GSK3915393+ITZ (Sequence A)

Grape fruit juice OTHER

Participants will be administered with GSK3915393 along with GFJ orally

Part C: GSK3915393 IV/GSK3915393 IV+ITZ/GSK3915393+GFJ/GSK3915393+water/GSK3915393+ITZ (Sequence B); Part C: GSK3915393 IV/GSK3915393 IV+ITZ/GSK3915393+water/GSK3915393+GFJ/GSK3915393+ITZ (Sequence A)

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Between 18 and 50 years of age inclusive, at the time of signing the informed consent.
• Healthy participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring.
• Negative coronavirus disease of 2019 (COVID-19) test on admission.
• Body weight \>=40 kilograms (kg) and body mass index (BMI) within the range 18.5-29.9 kilograms per square meter (kg/m\^2) (inclusive).
• Capable of giving signed informed consent.

You may not qualify if:

• History or current evidence of cardiovascular, respiratory, hepatic, renal, gastrointestinal (Irritable bowel syndrome \[IBS\], Gastroesophageal reflux disease \[GERD\], nausea, vomiting or dysphagia), endocrine, hematological, neurological, or psychiatric disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study treatment; or interfering with the interpretation of data.
• Current evidence of active infection.
• Participants with signs/symptoms suggestive of COVID-19 (i.e. fever, cough, etc) within the past 14 days prior to screening and admission to clinical unit.
• Participants with known COVID-19 positive contacts in the past 14 days prior to screening and admission to clinical unit.
• Any history of suicidal behavior within the past 6 months or any history of attempted suicide in a participant's lifetime.
• Alanine transaminase (ALT) \>1.5 times upper limit of normal (ULN).
• Bilirubin \>1.5 times ULN (isolated bilirubin \>1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35 percent).
• 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 gastrointestinal (GI) surgery (with exception of appendectomy).
• Average QT interval corrected using Fridericia's formula (QTcF) \>450 milliseconds (msec) at screening.
• Any clinically relevant abnormality on the screening medical assessment, laboratory examination, or electrocardiogram.
• History of QTc prolongation, symptomatic cardiac arrhythmias or cardiac arrest.
• For Part C only, history of liver toxicity resulting from drug administration.
• For Part C only, history of intolerance to itraconazole.
• History of sensitivity to any of the study medication, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GlaxoSmithKline Medical Monitor, contraindicates their participation.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

London, NW10 7EW, United Kingdom

Location

MeSH Terms

Conditions

Celiac Disease

Interventions

Itraconazole; Water

Condition Hierarchy (Ancestors)

Malabsorption Syndromes; Intestinal Diseases; Gastrointestinal Diseases; Digestive System Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Piperazines; Hydroxides; Alkalies; Inorganic Chemicals; Anions; Ions; Electrolytes; Oxides; Oxygen Compounds

Limitations and Caveats

Cardiac telemetry traces were examined after the study had completed. For all the participants with an adverse event of ventricular tachycardia reported following repeat dosing of 160 mg QD (part B), the tracings revealed narrow QRS complex beats that "march" through the presumed wide complex beats at a fixed rate, identical to the heart rate prior to and immediately following the event. These findings support a diagnosis of artifact and are not consistent with ventricular tachycardia.

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
• Masking Details: Parts A and B will be double blind and Part C will be open label.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This is a 3-part study. Parts A and C will have a 5 period crossover design Part B will be conducted as a parallel group dose escalation study.

Study Record Dates

• First Submitted: October 6, 2020
• First Posted: October 27, 2020
• Study Start: November 4, 2020
• Primary Completion: June 29, 2021
• Study Completion: June 29, 2021
• Last Updated: May 9, 2023
• Results First Posted: May 9, 2023

Record last verified: 2022-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints, key secondary endpoints and safety data of the study.
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

GB (1)