GSK2983559 First Time in Human Study

NCT03358407 | Terminated Phase 1 Results

• 2 other identifiers: 2050212017-002664-40
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 1

Brief Summary

This study is the first administration of GSK2983559, a selective receptor interacting protein 2 (RIP2) kinase inhibitor, to humans. This will be randomized, double-blinded (sponsor open) and two part study (A and B). Part A of the study is single ascending dose crossover design with two separate cohorts (1 and 2). In Part A, 9 single dose levels will be explored. In Cohort 1, 10 healthy subjects will randomized to receive single oral doses of either GSK2983559 or placebo in a ratio of 4:1 in 5 way cross-over design with 5 treatment periods. In Cohort 2, 8 healthy subjects will be randomized to receive single oral doses of either GSK2983559 or placebo in a ratio of 3:1 in 4 way cross-overs design with 4 treatment periods. In Cohort 2 there will be an additional period (period 5-open label) for assessing GSK2983559 under fed conditions. There will be 48 hours wash-out period between each dose escalation period. Part B is repeat ascending dose sequential group design. It will contain 4 Cohorts of and dosing will be done sequential dosing. Subjects in Part B will receive once daily (QD) dose or twice daily dose (will be decided based upon the pharmacokinetic, safety and tolerability observed in Part A). There will 58 subjects involved in this study. Total duration of Part A will be approximately for 11 Weeks and Part B will be approximately for 15 Weeks.

Conditions

Inflammatory Bowel Diseases

Keywords

Inflammatory Bowel disease; Pro-drug; Double-blinded; Crossover

Outcome Measures

Primary Outcomes (24)

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

  An adverse event was 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 was defined as any untoward medical occurrence that, at any dose may result in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgement.

  Up to 7 weeks

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

  An adverse event was 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 was defined as any untoward medical occurrence that, at any dose may result in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment. Non-SAEs and SAEs were planned to be collected.

  Up to 11 weeks

• Part A: Number of Participants With Worst Case Hematology Parameters of Potential Clinical Importance (PCI)

  Hematology parameters included hematocrit, hemoglobin, lymphocytes, platelet counts, total neutrophils and white blood cells (WBCs) count. PCI ranges were: hematocrit (high: \>0.54 proportion of red blood cells in blood and low: change from baseline\<0.0075); hemoglobin (high: \>180 grams per liter \[g/L\] and low: change from baseline\<25 g/L); lymphocytes (low: \<0.8 Giga cells/L); platelet count (low: \<100 Giga cells/L and high: \>550 Giga cells/L); neutrophil count (low: \<1.5 Giga cells/L); white blood cell count (low: \<3 Giga cells/L and high: \>20 Giga cells/L). Participants were counted in the worst-case category that their value changed to (low, within range or no change, or high) unless there was no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became within range, were recorded in the 'To within Range or No Change' category. Only those hematology parameters with PCI values have been presented.

  Up to 7 weeks

• Part B: Number of Participants With Worst Case Hematology Parameters of PCI

  Hematology parameters included hematocrit, hemoglobin, lymphocytes, platelet counts, total neutrophils and WBC count. PCI ranges were: hematocrit (high: \>0.54 proportion of red blood cells in blood and low: change from baseline\<0.0075); hemoglobin (high: \>180 grams per liter \[g/L\] and low: change from baseline\<25 g/L); lymphocytes (low: \<0.8 Giga cells/L); platelet count (low: \<100 Giga cells/L and high: \>550 Giga cells/L); neutrophil count (low: \<1.5 Giga cells/L); white blood cell count (low: \<3 Giga cells/L and high: \>20 Giga cells/L). Participants were counted in the worst-case category that their value changed to (low, within range or no change, or high) unless there was no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became within range, were recorded in the 'To within Range or No Change' category. Participants with worst case hematology parameters of PCI were planned to be collected.

  Up to 11 weeks

• Part A: Number of Participants With Worst Case Clinical Chemistry Parameters of PCI

  Clinical chemistry parameters included alanine amino transferase (ALT), albumin, alkaline phosphatase (ALP), aspartate amino transferase (AST), calcium, creatinine, glucose, potassium, sodium and total bilirubin (T.bil). PCI ranges were: ALT, AST, ALP (high): \>=2\*Upper limit of Normal(ULN) units per liter(U/L), albumin(low): 30 g/L, calcium: \<2(low) or \>2.75 millimoles per liter (mmol/L)(high), creatinine (high): increase from Baseline \>44.2 micromoles per liter(µmol/L), glucose: \<3(low) or \>9 mmol/L(high), potassium: \<3(low) or \>5.5 mmol/L(high), sodium: \<130(low) or \>150 mmol/L(high) and T.bil(high): \>=1.5\*ULN (µmol/L). Participants were counted in the worst case category that their value changes to (low, or within range or no change, or high), unless there is no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became within range, were recorded in the 'To within Range or No Change' category.

  Up to 7 weeks

• Part B: Number of Participants With Worst Case Clinical Chemistry Parameters of PCI

  Clinical chemistry parameters included ALT, albumin, alkaline phosphatase, AST, calcium, creatinine, glucose, potassium, sodium and total bilirubin. PCI ranges were ALT(high): \>=2\*ULN U/L, albumin(low): 30 g/L, alkaline phosphatase(high): \>=2\*ULN U/L, AST(high): \>=2\*ULN U/L, calcium: \<2(low) or \>2.75 mmol/L (high), creatinine (high): increase from Baseline \>44.25 µmol/L, glucose: \<3(low) or \>9 mmol/L(high), potassium: \<3(low) or \>5.5 mmol/L(high), sodium: \<130(low) or \>150 mmol/L(high) and total bilirubin(high): \>=1.5\*ULN (µmol/L). Participants with worst case clinical chemistry parameters of PCI were planned to be collected.

  Up to 11 weeks

• Part A: Number of Participants With Worst Case Any Increase in Urinalysis Results Post-Baseline Relative to Baseline by Dipstick Method

  Urine samples were collected to assess glucose, ketones, occult blood and protein by dipstick method. The dipstick test gave results in a semi-quantitative manner, and results for urinalysis parameters glucose, ketones, occult blood and protein were categorized as 'any increase from Baseline', which imply any increase in their concentrations in the urine sample. Baseline was defined as latest predose (Day 1) assessment with a non-missing value.

  Up to 7 weeks

• Part B: Number of Participants With Worst Case Any Increase in Urinalysis Results Post-Baseline Relative to Baseline by Dipstick Method

  Urine analysis included assessment of glucose, ketones, occult blood and protein by dipstick method. The dipstick test gives results in a semi-quantitative manner. Baseline was defined as latest predose (Day 1) assessment with a non-missing value. Participants with worst case any increase in urinalysis results post-Baseline relative to Baseline were planned to be collected.

  Up to 11 weeks

• Part A: Number of Participants With Abnormal Electrocardiogram (ECG) Findings

  12-lead ECGs were obtained using an ECG machine. Only those participants who had any abnormal ECG findings are presented. Abnormal ECG findings were categorized as clinically significant (CS) and not clinically significant (NCS) abnormal ECG findings. 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.

  1.5, 2, 2.5, 3, 4, 5, 8, 12, 24 and 48 hours post-dose

• Part B: Number of Participants With Abnormal ECG Findings

  12-lead ECGs were planned to be obtained using an ECG machine. Abnormal ECG findings were categorized as CS and NCS abnormal ECG findings. CS 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. Participants with any abnormal ECG findings were planned to be evaluated.

  Up to 11 weeks

• Part A: Number of Participants With Worst Case Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP) Values of PCI

  DBP and SBP were measured in semi-supine position after 5 minutes rest. PCI ranges included DBP: \<45 millimeters of mercury (mmHg) (lower) and \>100 mmHg (higher) and SBP: \<85 mmHg (lower) and \>160 mmHg (higher). Participants were counted in the worst case category that their value changes to (low, or within range or no change, or high), unless there is no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became within range, were recorded in the 'To within Range or No Change' category.

  Up to 7 weeks

• Part B: Number of Participants With Worst Case DBP and SBP Values of PCI

  DBP and SBP were measured in semi-supine position after 5 minutes rest. PCI ranges included DBP: \<45 mmHg (lower) and \>100 mmHg (higher) and SBP: \<85 mmHg (lower) and \>160 mmHg (higher). Participants were counted in the worst case category that their value changes to (low, or within range or no change, or high), unless there is no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became within range, were recorded in the 'To within Range or No Change' category. Participants with worst case DBP and SBP values of PCI were planned to be evaluated.

  Up to 11 weeks

• Part A: Number of Participants With Worst Case Respiration Rate Values of PCI

  Respiration rate was measured in semi-supine position after 5 minutes rest. PCI ranges included \<=8 breaths per minute (lower) and \>=20 breaths per minute (higher). Participants were counted in the worst case category that their value changes to (low, or within range or no change, or high), unless there is no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became within range, were recorded in the 'To within Range or No Change' category.

  Up to 7 weeks

• Part B: Number of Participants With Worst Case Respiration Rate Values of PCI

  Respiration rate was measured in semi-supine position after 5 minutes rest. PCI ranges included \<=8 breaths per minute (lower) and \>=20 breaths per minute (higher). Participants were counted in the worst case category that their value changes to (low, or within range or no change, or high), unless there is no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became within range, were recorded in the 'To within Range or No Change' category. Participants with worst case respiratory rate values of PCI were planned to be evaluated.

  Up to 11 weeks

• Part A: Number of Participants With Worst Case Heart Rate Values of PCI

  Heart rate was measured in semi-supine position after 5 minutes rest. PCI ranges included \<40 beats per minute (lower) and \>110 beats per minute (higher). Participants were counted in the worst case category that their value changes to (low, or within range or no change, or high), unless there is no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became within range, were recorded in the 'To within Range or No Change' category.

  Up to 7 weeks

• Part B: Number of Participants With Worst Case Heart Rate Values of PCI

  Heart rate was measured in semi-supine position after 5 minutes rest. PCI ranges included \<40 beats per minute (lower) and \>110 beats per minute (higher). Participants were counted in the worst case category that their value changes to (low, or within range or no change, or high), unless there is no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became within range, were recorded in the 'To within Range or No Change' category. Participants with worst case heart rate values of PCI were planned to be evaluated.

  Up to 11 weeks

• Part A: Number of Participants With Worst Case Body Temperature Values of PCI

  Body temperature was measured in semi-supine position after 5 minutes rest. PCI ranges included \<=35.5 degrees Celsius (lower) and \>=37.8 degrees Celsius (higher). Participants were counted in the worst case category that their value changes to (low, or within range or no change, or high), unless there is no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became within range, were recorded in the 'To within Range or No Change' category.

  Up to 7 weeks

• Part B: Number of Participants With Worst Case Body Temperature Values of PCI

  Body temperature was measured in semi-supine position after 5 minutes rest. PCI ranges included \<=35.5 degrees Celsius (lower) and \>=37.8 degrees Celsius (higher). Participants were counted in the worst case category that their value changes to (low, or within range or no change, or high), unless there is no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became within range, were recorded in the 'To within Range or No Change' category. Participants with worst case body temperature values of PCI were planned to be evaluated.

  Up to 11 weeks

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

  Physical examinations included assessment of the skin, cardiovascular, respiratory, and gastrointestinal systems. This analysis was not planned and data was not collected and not captured in the database.

  Up to 7 weeks

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

  Physical examinations included assessment of the skin, cardiovascular, respiratory, and gastrointestinal systems. Data was not collected and not captured in the database.

  Up to 11 weeks

• Part A: Change From Baseline in Activated Partial Thromboplastin Time and Prothrombin Time at Indicated Time Points

  Blood samples were collected to evaluate activated partial thromboplastin time (APTT) and prothrombin time (PT) at indicated time points. Baseline was defined as latest pre-dose (Day 1) assessment with a non-missing value. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

  Baseline (Day 1, Pre-dose), 24 and 48 hours post-dose

• Part B: Change From Baseline in Activated Partial Thromboplastin Time and Prothrombin Time at Indicated Time Points

  Blood samples were planned to be collected to evaluate PTT and PT at indicated time points. Baseline was defined as latest pre-dose (Day 1) assessment with a non-missing value. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

  Baseline and Up to 11 weeks

• Part A: Change From Baseline in International Normalized Ratio at Indicated Time Points

  Blood samples were collected to evaluate international normalized ratio at indicated time points. Baseline was defined as latest pre-dose (Day 1) assessment with a non-missing value. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

  Baseline (Day 1, Pre-dose), 24 and 48 hours

• Part B: Change From Baseline in International Normalized Ratio at Indicated Time Points

  Blood samples were planned to be collected to evaluate international normalized ratio at indicated time points. Baseline was defined as latest pre-dose (Day 1) assessment with a non-missing value. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

  Baseline and Up to 11 weeks

Secondary Outcomes (62)

• Part A (Cohort 1): Area Under Plasma Concentration-time Curve (AUC) From Zero Hours to Time of Last Quantifiable Concentration (AUC[0-t]) for GSK2983559

  Pre-dose and at 15 and 30 minutes; 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

• Part A (Cohort 2): AUC(0-t) for GSK2983559

  Pre-dose and at 15 and 30 minutes; 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

• Part A (Cohort 1): AUC(0-t) for GSK2668176 (Active Moiety of GSK2983559)

  Pre-dose and at 15 and 30 minutes; 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

• Part A (Cohort 2): AUC(0-t) for GSK2668176 (Active Moiety of GSK2983559)

  Pre-dose and at 15 and 30 minutes; 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

• Part A (Cohort 1): AUC From Time Zero to Infinity (AUC[0-inf]) for GSK2983559

  Pre-dose and at 15 and 30 minutes; 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

Study Arms (4)

Part A: Cohort 1

EXPERIMENTAL

Cohort 1 will be 5-way crossover with 5 treatment periods. Subjects will be randomized in the ratio 4:1 to receive either single dose of GSK2983559 or placebo.

Drug: GSK2983559; Drug: Placebo

Part A: Cohort 2 fasting

EXPERIMENTAL

Cohort 2 will be 4-way crossover design with one additional period of open-label. Subjects will be randomized in the ratio 3:1 to receive either single dose of GSK2983559 or placebo in fasted conditions

Drug: GSK2983559; Drug: Placebo

Part A: Cohort 2 fed

EXPERIMENTAL

In Cohort 2, treatment period 5 will be open-label period. This open-label period is to determine food effect and subjects will receive GSK2983559 under fed conditions.

Drug: GSK2983559

Part B

EXPERIMENTAL

Part B is repeat ascending dose sequential period. There will four cohorts (3-6) of 10 healthy subjects. In each cohort subjects will be randomized to receive GSK2983559 or placebo in ratio 4:1. Subjects will receive GSK2983559 or placebo QD and twice daily dose will be decided based upon the pharmacokinetic, safety and tolerability observed in Part A.

Drug: GSK2983559; Drug: Placebo

Interventions

GSK2983559 DRUG

GSK2983559 will be available as oral capsules with dose strength of 2-45 milligram (mg), 100 and 114 mg.

Part A: Cohort 1; Part A: Cohort 2 fasting; Part A: Cohort 2 fed; Part B

Placebo DRUG

Placebo oral capsules matching GSK2983559 will be available for subjects.

Part A: Cohort 1; Part A: Cohort 2 fasting; Part B

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male and female subjects between 18 and 65 years of age inclusive, at the time of signing the informed consent.
• Volunteers who are overtly healthy as determined by medical evaluation including medical and psychiatric history, physical examination, neurological examination, clinical laboratory tests and cardiac monitoring.
• Body weight \>= 50 kg (kilogram) and body mass index (BMI) within the range 19-32 kilogram per meter square (kg/m\^2) .
• A male subject must agree to use a highly effective contraception during the treatment period and for at least 5 half-lives plus an additional 90 days after the last dose of study treatment and refrain from donating sperm during this period.
• A female subject is eligible to participate if she is not pregnant, not breastfeeding, and is not a woman of childbearing potential (WOCBP)
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
• Participants must agree to avoid prolonged Ultraviolet (UV) exposure to natural sunlight without required Ultraviolet A (UVA)/ Ultraviolet B (UVB) protection or tanning beds for the duration of the study.

You may not qualify if:

• History or presence of/significant history of or current cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological 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.
• History or current evidence of febrile seizures, epilepsy, convulsions, significant head injury, or other significant neurologic conditions.
• History of clinically significant psychiatric disorders as judged by the investigator.
• Any history of suicidal behavior within the past 6 months or any history of attempted suicide in a subject's lifetime.
• ALT \>1.5x upper limit of normal (ULN).
• Bilirubin \>1.5xULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
• 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 QTc \> 450 millisecond (msec)
• Intended use of over-the-counter or prescription medication including herbal medications within 7 days prior to dosing
• Live or attenuated vaccine(s) within 30 days of randomization, or plans to receive such vaccines during the study or plans to receive a vaccine within 30 days + 5 half-lives of the last dose of study medication.
• Regular alcohol consumption within 6 months prior to the study defined as: An average weekly intake of \>21 units for males or \>14 units for females. One unit is equivalent to 8 g of alcohol: a half pint (approximately 240 milliliter \[mL\]) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
• Current use or history of regular tobacco- or nicotine-containing products within 6 months prior to screening. Subject must have urinary cotinine levels indicative of non-smoking status at screening visit.
• Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day.
• Current enrollment or past participation within the last 30 days before signing of consent in this or any other clinical study involving an investigational study treatment or any other type of medical research.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Cambridge, Cambridgeshire, CB2 2GG, United Kingdom

Location

MeSH Terms

Conditions

Inflammatory Bowel Diseases

Condition Hierarchy (Ancestors)

Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal 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: November 27, 2017
• First Posted: November 30, 2017
• Study Start: January 11, 2018
• Primary Completion: February 19, 2019
• Study Completion: February 19, 2019
• Last Updated: November 27, 2020
• Results First Posted: June 22, 2020

Record last verified: 2020-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD is available via the Clinical Study Data Request site (copy the URL below to your browser)
• 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)