Back to resultsFirst-time-in-Human (FTIH) Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single (in Both Fed and Fasted States) or Repeat Doses of GSK3358699
Primary Purpose
Arthritis, Rheumatoid
Status
Terminated
Phase
Phase 1
Locations
United Kingdom
Study Type
Interventional
Intervention
Placebo
GSK3358699
GM-CSF
LPS
Cantharidin
Sponsored by
About this trial
This is an interventional treatment trial for Arthritis, Rheumatoid
Eligibility Criteria
Inclusion Criteria: - Subjects enrolled into the study, where they will be administered LPS or GM-CSF challenge, must be 18 to 55 years of age inclusive, at the time of signing the informed consent. Subjects enrolled into the study where they will not be administered LPS or GM-CSF challenge must be 18 to 65 years of age inclusive, at the time of signing the informed consent. - Subjects must be overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. - Body weight must be > = 50 kilogram (kg) and body mass index (BMI) within the range 18.5-35.0 kg per square meter (kg/m^2) (inclusive). - Male subjects agreeing to use contraceptive methods during the treatment Period and for at least 91 days, after the last dose of study treatment and refrain from donating sperm during this Period. - Capable of giving informed consent. Exclusion Criteria: - Current or chronic history of pancreatitis, diabetes mellitus or impaired glucose tolerance, gastrointestinal disease, liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones), anaphylaxis, and /or anaphylactoid (resembling anaphylaxis) reactions [Sampson et al 2006], cardiac disease including clinically significant ventricular arrhythmias or long QT syndrome, renal disease where clinically significant (minor abnormalities may be permitted base on discussion between investigator and medical monitor), respiratory disease or conditions including but not limited to asthma, chronic obstructive pulmonary disease (COPD), and bronchiectasis and any current respiratory infection (childhood asthma is not an exclusion criterion), sensitivity or severe allergic responses to any of the challenge agents or cantharidin, or components thereof or a history of drug or other allergy that, in the opinion of the Investigator or GlaxoSmithKline (GSK) Medical Monitor, contraindicates their participation; frequent vasovagal syncope, surgery requiring general anaesthetic or significant trauma in 3 months leading to study enrolment, relevant skin conditions (e.g. recent history of eczema or recurrent eczema, keloid, skin allergies, psoriasis, atopic dermatitis, and vitiligo) which in the opinion of the investigator could pose safety issues or cause interference with study procedures, sepsis, coagulation disorders, peripheral edema, lymphangitis, lymphedema, pleural or pericardial effusion, hemorrhage (eg sub-arachnoid) or hemophilia or a related bleeding disorder. - History of malignancies e.g. recurrent basal cell carcinoma, hematological malignancy. - For subjects receiving cantharidin: Presence on either forearm of tattoos, naevi, hypertrophic scars, keloids, hyper- or hypo- pigmentation that may, in the opinion of the Investigator, interfere with study assessments. Subjects with very fair skin, very dark skin, excessive hair or any skin abnormalities that may, in the opinion of the Investigator, interfere with study assessments. - Family history of premature cardiovascular disease or long QT syndrome. - QT interval with Fridericia's correction (QTcF) > 450 millisecond (msec), based on averaged QTcF values of triplicate ECGs obtained over a brief recording period. - Unable or unwilling to refrain from taking prescription or non-prescription drugs (including vitamins and dietary or herbal supplements) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) before the start of study treatment until completion of the follow-up visit. Paracetamol, at a dose of <= 2 grams per day was permitted for use anytime during the study. Other concomitant medications will be considered on case by case basis. - The subjects have participated in a clinical trial and received an investigational product within the following time period prior to the first dosing day in the study: 30 days; 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer) or currently in a study of an investigational device. - Exposure to more than four new chemical entities within 12 months prior to the first dosing day. - Previous exposure to intravenous lipopolysaccharide (LPS) in a clinical research setting. - Alanine transaminase (ALT) >1.5x upper limit of normal (ULN) at screening. - Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) at screening. - Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment. - A positive pre-study drug/alcohol screen at screening. - A positive test for human immunodeficiency virus (HIV) antibody at screening. - Persistent clinically significant abnormal C-reactive protein (CRP) levels at screening - Persistent clinically significant abnormal white cell count (WCC) levels at screening (if clinically significant abnormality is detected, WCC can be retested as clinically indicated) - Platelets < 150 x 10^9 per liter (L) at screening. - Fasted Triglycerides >3.4 millimole per liter (mmol/L) at screening. - Fasted Total cholesterol >7.7 mmol/L at screening. - Random glucose > = 11.1 mmol/L at screening. - Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 3 months prior to screening. - History of regular alcohol consumption within 6 months of the study defined as: an average weekly intake of >14 units. One unit is equivalent to 8 gram of alcohol: a half-pint (approximately 240 milliliter [mL]) of beer, 1 glass (125 mL) of wine or 1 (25 mL). - Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period. - Unable to comply with precautions to minimize phototoxicity risk.
Sites / Locations
- GSK Investigational Site
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm 6
Arm 7
Arm 8
Arm Type
Experimental
Experimental
Placebo Comparator
Placebo Comparator
Experimental
Experimental
Experimental
Placebo Comparator
Arm Label
GSK3358699, Part A, Cohort 1
GSK3358699, Part A, Cohort 2
Placebo, Part A, Cohort 1
Placebo, Part A, Cohort 2
Part B, GSK3358699 under Fasted followed by Fed conditions
Part B, GSK3358699 under Fed followed by Fasted conditions
GSK3358699, Part C
Placebo, Part C
Arm Description
Part A will comprise of 4 TPs. The subjects in this cohort will receive GSK3358699, as single escalation dose, during TP (1 to 3) with planned escalated doses as 1 mg, 10 mg and 35 mg. Dose of 1 mg will be given as solution and doses of 10 mg and 35 mg, will be given as a capsule. Each TP will be of 1 day and separated by a washout Period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 1 will receive GSK3358699 at a dose level already given in TP 1-3, and will then receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram post administration of GSK3358699. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge. LPS dose will be based on data of study 207654 (NCT03306589).
Part A will comprise of 4 TPs. The subjects in this cohort will receive GSK3358699, as single escalation dose during TP (1 to 3) with planned escalated doses as 3 mg, 20 mg and 45 mg. Dose of 3 mg will be given as solution and that of 20 and 45 mg, as capsule. Each TP will be of 1 day and separated by a washout Period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 2 will receive GSK3358699 at a dose level already given in TP 1-3, and will then receive 60 microgram per meter^2 of in vivo GM CSF challenge as an intravenous infusion during TP 4, post administration of GSK3358699. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge GM-CSF infusion. GM-CSF dose will be based on data of study 207654 (NCT03306589).
Part A will comprise of 4 TPs. The subjects in this cohort will receive matching Placebo solution to the study drug GSK3358699 solution for 1 mg and a matching placebo capsule to the study drug GSK3358699, 10 mg and 35 mg capsule, during TP (1 to 3). Each TP will be of 1 day and separated by a washout Period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 1 will receive Placebo at a dose level already given in TP 1-3, and will then receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram post administration of Placebo. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge. LPS dose will be based on data of study 207654 (NCT03306589).
Part A will comprise of 4 TPs. The subjects in this cohort will receive matching Placebo solution to the study drug GSK3358699 solution for 3 mg and a matching placebo capsule to the study drug GSK3358699, for 20 and 45 mg capsule, during TP (1 to 3). Each TP will be of 1 day and separated by a washout Period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 2 will receive Placebo at a dose level already given in TP 1-3, and will then receive 60 microgram per meter^2 of in vivo GM CSF challenge as an intravenous infusion during TP 4, post administration of Placebo. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge GM-CSF infusion. GM-CSF dose will be based on data of study 207654 (NCT03306589).
The subjects in this arm will receive single oral dose of GSK3358699, at a dose level evaluated in Part A, under fasted condition in TP1 followed by fed condition in TP2. This cohort intended to evaluate the effect of food.
The subjects in this arm will receive single oral dose of GSK3358699, at a dose level evaluated in Part A, under fed condition in TP1 followed by fasted condition in TP2. This cohort intended to evaluate the effect of food.
The dose level for the first cohort in Part C will be decided following completion of Part A of the study for GSK3358699. The subjects in this arm will constitute 3 cohorts each (cohort 4 to 6), where the subjects will receive GSK3358699, as one repeat dose treatment once daily for 14-consecutive days. Subjects will have control blisters induced on the forearm (0.2% cantharidin) on Day -10. On the Day 14 of each cohort, each subject will receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram or an intravenous infusion of GM-CSF, in vivo as 60 microgram per meter^2. The administration of LPS or GM CSF will be followed by blister induction on forearm (0.2 % cantharidin).
The subjects in this cohort will receive a matching placebo to GSK3358699, Part C, as a single oral dose once daily for 14 consecutive days. The subjects in this arm will constitute 3 cohorts each (cohort 4 to 6), where the subjects will receive placebo, as one repeat dose treatment once daily for 14-consecutive days. Subjects will have control blisters induced on the forearm (0.2% cantharidin) on Day -10. On the Day 14 of each cohort, each subject will receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram or an intravenous infusion of GM-CSF, in vivo as 60 microgram per meter^2. The administration of LPS or GM CSF will be followed by blister induction on forearm (0.2 % cantharidin).
Outcomes
Primary Outcome Measures
Part A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, important medical events that may jeopardize the participant or require medical or surgical intervention to prevent one of the outcomes listed before. Safety Population consisted of all randomized participants who took at least 1 dose of study treatment.
Part B: Number of Participants With AEs and SAEs
An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, important medical events that may jeopardize the participant or require medical or surgical intervention to prevent one of the outcomes listed before.
Part C: Number of Participants With AEs and SAEs
An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, important medical events that may jeopardize the participant or require medical or surgical intervention to prevent one of the outcomes listed before.
Part A: Number of Participants With Worst Case Chemistry Results by Potential Clinical Importance (PCI) Criteria Post-Baseline Relative to Baseline
Blood samples were collected for analysis of clinical chemistry parameters. PCI ranges were <30 grams per liter (g/L) (albumin), <2 or >2.75 millimoles/L (mmol/L) (calcium), >1.3* upper limit of normal (ULN) mmol/L (creatinine), <3 or >9 mmol/L (glucose), <3 or >5.5 mmol/L (potassium), and <130 or >150 mmol/L (sodium). 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, were recorded in To within Range or No Change (NC) category. Participants were counted twice if participant had values that changed To Low and To High, so the percentages may not add to 100%.
Part A: Number of Participants With Worst Case Chemistry Results Relative to Normal Range Post-Baseline Relative to Baseline
Clinical chemistry parameters assessed were alanine aminotransferase(ALT)(<10 or >50 international units per liter[IU/L]),alkaline phosphatase(ALP)(<40 or >129 IU/L),aspartate aminotransferase(AST)(<0 or >37 IU/L),cholesterol(<2.3 or >4.9 mmol/L),direct bilirubin(DB)(<0 or >5 micromoles[mcmol]/L),high density lipoprotein (DL)(<0.9 or >1.5 mmol/L),C-reactive protein(CRP)(<0.0 or >5.0mg/liter),low DL(<0 or >3.0 mmol/L), total bilirubin (<0 or >20 mcmol/L),total protein(<63 or >83 grams/L),triglycerides(<0 or >2.3 mmol/L) and blood urea nitrogen(BUN)(<4.76 or >23.24 mg/deciliter).Participants were counted in worst case category that their value changes to (low, normal or high), unless there is NC in their category.Participants whose laboratory value category was unchanged(e.g.,High to High) or whose value became normal, are recorded in "To Normal or NC" category.Participants were counted twice if participant had values that changed To Low and To High, so percentages may not add to 100%.
Part B: Number of Participants With Worst Case Chemistry Results by PCI Criteria Post-Baseline Relative to Baseline
Blood samples were planned to be collected to analyze the chemistry parameters.
Part B: Number of Participants With Worst Case Chemistry Results Relative to Normal Range Post-Baseline Relative to Baseline
Blood samples were planned to be collected to analyze the chemistry parameters.
Part C: Number of Participants With Worst Case Chemistry Results by PCI Criteria Post-Baseline Relative to Baseline
Blood samples were collected for analysis of chemistry parameters. PCI ranges were <30 g/L (albumin), <2 or >2.75 mmol/L (calcium), >1.3* ULN mmol/L (creatinine), <3 or >9 mmol/L (glucose), <3 or >5.5 mmol/L (potassium), and <130 or >150 mmol/L (sodium). 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, were recorded in To within Range or No Change category. Participants were counted twice if participant had values that changed To Low and To High, so the percentages may not add to 100%.
Part C: Number of Participants With Worst Case Chemistry Results Relative to Normal Range Post-Baseline Relative to Baseline
Clinical chemistry parameters assessed were ALT (<10 or >50 IU/L), ALP (<40 or >129 IU/L), AST (<0 or >37 IU/L), cholesterol (<2.3 or >4.9 mmol/L), DB (<0 or >5 mcmol/L), high DL (<0.9 or >1.5 mmol/L), CRP (<0.0 or >5.0 mg/liter), low DL (<0 or >3.0 mmol/L), total bilirubin (<0 or >20 mcmol/L), total protein (<63 or >83 grams/L), triglycerides (<0 or >2.3 mmol/L) and BUN (<4.76 or >23.24 mg/deciliter). Participants were counted in worst case category that their value changes to (low, normal or high), unless there is NC in their category. Participants whose laboratory value category was unchanged (e.g., High to High) or whose value became normal, are recorded in "To Normal or NC" category. Participants were counted twice if participant had values that changed To Low and To High, so percentages may not add to 100%.
Part A: Number of Participants With Worst Case Hematology Results by PCI Criteria Post-Baseline Relative to Baseline
Blood samples collected for analysis of hematology parameters. PCI ranges were >0.54 proportion of red blood cells in blood (hematocrit), >180 grams/liter (hemoglobin), <0.8 *10^9 cells/L (lymphocyte count), <1.5 *10^9 cells/L (total absolute neutrophil count [ANC]), <100 or >550 *10^9 cells/L (platelet count), and <3 or >20*10^9 cells/L (white blood cell [WBC] count). 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, were recorded in To within Range or No Change category. Participants were counted twice if the participant had values that changed To Low and To High, so the percentages may not add to 100%.
Part A: Number of Participants With Worst Case Hematology Results Relative to Normal Range Post-Baseline Relative to Baseline
Hematology parameters assessed were activated partial thromboplastin time (APTT) (<25 or >37 seconds), basophil count (<0.0 or >0.1*10^9 cells/L), eosinophil count (<0.0 or >0.4*10^9 cells/L), fibrinogen (<1.5 or >4.0 g/L), mean corpuscle hemoglobin (MCH) (<26.0 or >33.5 picogram), mean corpuscle volume (MCV) (<80 or >99 femtoliter), monocyte count (<0.2 or >1.0*10^9 cells/L), prothrombin time (PT) (<10 or >12 seconds), red blood cell (RBC) count (<4.4 or >5.8*10^12 cells/L) and reticulocyte count (<0.38 or >2.64 percentage of reticulocytes). Participants were counted in worst case category that their value changes to (low, normal or high), unless there is NC in their category. Participants whose laboratory value category was unchanged (e.g., High to High) or whose value became normal, are recorded in "To Normal or NC" category. Participants were counted twice if participant had values that changed To Low and To High, so percentages may not add to 100%.
Part B: Number of Participants With Worst Case Hematology Results by PCI Criteria Post-Baseline Relative to Baseline
Blood samples were planned to be collected to analyze hematology parameters.
Part B: Number of Participants With Worst Case Hematology Results Relative to Normal Range Post-Baseline Relative to Baseline
Blood samples were planned to be collected to analyze hematology parameters.
Part C: Number of Participants With Worst Case Hematology Results by PCI Criteria Post-Baseline Relative to Baseline
Blood samples were collected for analysis of hematology parameters. PCI ranges were >0.54 proportion of red blood cells in blood (hematocrit), >180 grams/liter (hemoglobin), <0.8*10^9 cells/L (lymphocyte count), <1.5*10^9 cells/L (total ANC), <100 or >550*10^9 cells/L (platelet count), and <3 or >20*10^9 cells/L (WBC count). 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, were recorded in To within Range or No Change category. Participants were counted twice if the participant had values that changed To Low and To High, so the percentages may not add to 100%.
Part C: Number of Participants With Worst Case Hematology Results Relative to Normal Range Post-Baseline Relative to Baseline
Hematology parameters assessed were APTT (<25 or >37 seconds), basophil count (<0.0 or >0.1*10^9 cells/L), eosinophil count (<0.0 or >0.4*10^9 cells/L), fibrinogen (<1.5 or >4.0 g/L), MCH (<26.0 or >33.5 picogram), MCV (<80 or >99 femtoliter), monocyte count (<0.2 or >1.0*10^9 cells/L), PT (<10 or >12 seconds), RBC count (<4.4 or >5.8*10^12 cells/L) and reticulocyte count (<0.38 or >2.64 percentage of reticulocytes). Participants were counted in worst case category that their value changes to (low, normal or high), unless there is NC in their category. Participants whose laboratory value category was unchanged (e.g., High to High) or whose value became normal, are recorded in "To Normal or NC" category. Participants were counted twice if participant had values that changed To Low and To High, so percentages may not add to 100%.
Part A: Number of Participants With Abnormal Urinalysis Parameters
Urine samples were collected from participants for analyzing the following urine parameters: potential of hydrogen (pH) and glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocytes levels by dipstick. Urine samples showing any abnormality were sent for microscopic examination to detect the presence of RBC, WBC, cellular casts, granular casts, hyaline casts, and were counted as cells per high-power field (cells/HPF). Number of participants with abnormal urinalysis result by microscopic examination have been presented.
Part B: Number of Participants With Abnormal Urinalysis Parameters
Urine samples were planned to be collected to analyze urine parameters.
Part C: Number of Participants With Abnormal Urinalysis Parameters
Urine samples were collected from participants for analyzing the following urine parameters: pH and glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocytes levels by dipstick. Urine samples showing any abnormality were sent for microscopic examination to detect the presence of RBC, WBC, cellular casts, granular casts, hyaline casts, and were counted as cells/HPF. Number of participants with abnormal urinalysis result by microscopic examination have been presented.
Part A: Number of Participants With Worst Case Vital Sign Results by PCI Criteria Post-Baseline Relative to Baseline
Vital signs included systolic blood pressure(SBP), diastolic blood pressure(DBP), heart rate, respiratory rate and body temperature and were measured in a semi-supine position after 5 minutes rest. 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): <11(low) or >20(high) and body temperature (degrees Celsius) <35.5 (low) or >38.0 (high). Participants were counted in the 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 vital signs 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 were counted twice if the participant had values that changed "To Low" and "To High", so the percentages may not add to 100%.
Part B: Number of Participants With Worst Case Vital Sign Results by PCI Criteria Post-Baseline Relative to Baseline
Vital signs were planned to be measured in a semi-supine position after 5 minutes of rest.
Part C: Number of Participants With Worst Case Vital Sign Results by PCI Criteria Post-Baseline Relative to Baseline
Vital signs included SBP, DBP, heart rate, respiratory rate and body temperature and were measured in a semi-supine position after 5 minutes rest. 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): <11 (low) or >20 (high) and body temperature (degrees Celsius) <35.5 (low) or >38.0 (high). Participants were counted in the 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 vital signs 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 were counted twice if the participant had values that changed "To Low" and "To High", so the percentages may not add to 100%.
Part A: Number of Participants With Worst Case Post-Baseline Abnormal Electrocardiogram (ECG) Findings
Twelve lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, and QT interval corrected using the Fridericia's formula (QTcF) intervals. Abnormal findings were categorized as clinically significant (CS) and not clinically significant (NCS). 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.
Part B: Number of Participants With Worst Case Post-Baseline Abnormal ECG Findings
Twelve lead ECGs were planned to be performed to measure PR interval, QRS duration, QT interval and QTcF.
Part C: Number of Participants With Worst Case Post-Baseline Abnormal ECG Findings
Twelve lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, and QTcF 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.
Secondary Outcome Measures
Part A: Plasma Concentrations of GSK3358699
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. Pharmacokinetic (PK) parameters were calculated using standard non-compartmental analysis. PK Population consisted of all participants in the Safety Population who received an active dose and for whom a PK sample was obtained and analyzed.
Part B: Plasma Concentrations of GSK3358699
Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3358699.
Part C: Plasma Concentrations of GSK3358699
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Part A: Area Under the Plasma Concentration Curve From Time Zero to Last Time of Quantifiable Concentration (AUC[0-t]) of GSK3358699
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Part B: AUC(0-t) of GSK3358699
Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3358699.
Part C: AUC(0-t) of GSK3358699
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Part A: Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUC[0-infinity]) of GSK3358699
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Part B: AUC(0-infinity) of GSK3358699
Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3358699.
Part C: AUC(0-infinity) of GSK3358699
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Part A: Area Under the Plasma Concentration Curve From Time Zero to 24 Hours (AUC[0-24]) of GSK3358699
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Part B: AUC(0-24) of GSK3358699
Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3358699.
Part C: AUC(0-24) of GSK3358699
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Part A: Maximum Plasma Concentration (Cmax) of GSK3358699
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Part B: Cmax of GSK3358699
Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3358699.
Part C: Cmax of GSK3358699
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Part A: Time to Cmax (Tmax) of GSK3358699
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Part B: Tmax of GSK3358699
Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3358699.
Part C: Tmax of GSK3358699
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Part A: Apparent Terminal Phase Half-life (t1/2) of GSK3358699
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Part B: t1/2 of GSK3358699
Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3358699.
Part C: t1/2 of GSK3358699
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Part A: Plasma Concentrations of GSK3206944
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Part B: Plasma Concentrations of GSK3206944
Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3206944. GSK3206944 is a metabolite of GSK3358699.
Part C: Plasma Concentrations of GSK3206944
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Part A: AUC(0-t) of GSK3206944
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Part B: AUC(0-t) of GSK3206944
Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3206944. GSK3206944 is a metabolite of GSK3358699.
Part C: AUC(0-t) of GSK3206944
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Part A: AUC(0-infinity) of GSK3206944
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Part B: AUC(0-infinity) of GSK3206944
Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3206944. GSK3206944 is a metabolite of GSK3358699.
Part C: AUC(0-infinity) of GSK3206944
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Part A: AUC(0-24) of GSK3206944
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Part B: AUC(0-24) of GSK3206944
Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3206944. GSK3206944 is a metabolite of GSK3358699.
Part C: AUC(0-24) of GSK3206944
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Part A: Cmax of GSK3206944
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Part B: Cmax of GSK3206944
Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3206944. GSK3206944 is a metabolite of GSK3358699.
Part C: Cmax of GSK3206944
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Part A: Tmax of GSK3206944
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Part B: Tmax of GSK3206944
Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3206944. GSK3206944 is a metabolite of GSK3358699.
Part C: Tmax of GSK3206944
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Part A: t1/2 of GSK3206944
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Part B: t1/2 of GSK3206944
Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3206944. GSK3206944 is a metabolite of GSK3358699.
Part C: t1/2 of GSK3206944
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Part A: Monocyte Intracellular Concentration of GSK3206944
Blood samples were collected into sodium heparin tubes for the isolation of monocytes and for measurement of GSK3206944 concentrations in monocytes. GSK3206944 is a metabolite of GSK3358699.
Part B: Monocyte Intracellular Concentration of GSK3206944
Blood samples were planned to be collected into sodium heparin tubes for the isolation of monocytes and for measurement of GSK3206944 concentrations in monocytes. GSK3206944 is a metabolite of GSK3358699.
Part C: Monocyte Intracellular Concentration of GSK3206944
Blood samples were collected into sodium heparin tubes for the isolation of monocytes and for measurement of GSK3206944 concentrations in monocytes. GSK3206944 is a metabolite of GSK3358699.
Part A: Absolute Values of Monocyte Chemotactic Protein (MCP)-1, Interleukin (IL)6, Tumor Necrosis Factor (TNF) Alpha in Blood After Ex-vivo Lipopolysaccharide (LPS) Activation
Whole blood samples of 1 milliliter (mL) were collected in TruCulture tubes, containing LPS and incubated for 24 hours, post which the inflammatory mediators (MCP-1, IL-6 and TNF alpha) were analyzed.
Part B: Absolute Values of MCP-1, IL6, TNF Alpha in Blood After Ex-vivo LPS Activation
Whole blood samples were planned to be collected in TruCulture tubes, containing LPS and incubated for 24 hours, post which the inflammatory mediators (MCP-1, IL6 and TNF alpha) were planned to be analyzed.
Part C: Absolute Values of MCP-1, IL6, TNF Alpha in Blood After Ex-vivo LPS Activation
Whole blood samples of 1 mL were collected in TruCulture tubes, containing LPS and incubated for 24 hours, post which the inflammatory mediators (MCP-1, IL-6 and TNF alpha) were analyzed.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03426995
Brief Title
First-time-in-Human (FTIH) Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single (in Both Fed and Fasted States) or Repeat Doses of GSK3358699
Official Title
A Randomised, Double-blind (Sponsor Open), Placebo-controlled, Three Part Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single (in Both Fed and Fasted States) or Repeat Doses of GSK3358699 in Healthy Male Participants
Study Type
Interventional
2. Study Status
Record Verification Date
October 2020
Overall Recruitment Status
Terminated
Why Stopped
The trial was terminated for strategic reasons following the emergence of new data.
Study Start Date
March 13, 2018 (Actual)
Primary Completion Date
May 2, 2019 (Actual)
Study Completion Date
May 2, 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
GlaxoSmithKline
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
This FTIH study, intends to identify the doses of GSK3358699, which are well tolerated by the subjects whilst delivering a robust pharmacodynamic (PD) response. This study will evaluate the safety, tolerability, pharmacokinetic (PK) and PD profile of single (in both fed and fasted states) and multiple ascending doses of GSK3358699 in healthy male subjects within a pre-defined and controlled pharmacodynamic and pharmacokinetic range for each cohort. It also intends to understand the effect of GSK3358699 on systemic markers of inflammation following low dose in vivo lipopolysaccharide (LPS) or Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) challenge and local inflammation in cantharidin-induced blisters. The study has been carefully designed to explore the in vivo biology of the target and the potential for the study drug to become a transformative medicine for subjects in multiple immuno-inflammatory disease indications.
Detailed Description
Subjects who are enrolled in the dose escalation treatment Periods of Part A may choose to only take part in the dose escalation treatment Periods 1-3, or may choose to also take part in the challenge Treatment Period (Period 4). If a subject chooses to participate in the dose escalation treatment Periods 1-3 only, or does not (at screening) meet the eligibility criteria specific to challenges (treatment Period 4), a new subject will be recruited for treatment Period 4 only and will be regarded as a replacement subject. The study will be conducted in three Parts. Total duration for participation will be approximately 19 weeks for subjects taking part in all three dose escalation treatment Periods and 23 weeks if a subject takes part in all four treatment Periods of Part A. For replacement subjects only taking part in the challenge treatment Period (Period 4), approximate study duration will be 10 weeks. Total duration for participation will be approximately 9 weeks for Part B and 12 weeks for Part C. The study will be conducted in up to 80 subjects.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Arthritis, Rheumatoid
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Crossover Assignment
Model Description
Study will be conducted as Part A, B and C. Part A will consist of 2-interlocking cohorts, where each subject will receive maximum 2-single ascending oral doses of GSK3358699 and 1 dose of placebo, in Treatment Periods (TP) 1 to 3. In TP 4 subjects will receive GSK3358699, dose evaluated in TP (1 to 3) or placebo, with cantharidin induced blisters and either LPS or GM-CSF in vivo challenge. Part B will comprise of single cohort taking part in two-way cross over, with open label phase where each subject will receive single oral dose of GSK3358699 (based on Part A), under fed and fasted conditions in each TP. Part C will consist of 3 cohorts with multiple ascending doses, with every cohort having one repeat dose TP with 14 days of daily dosing of either GSK3358699 or placebo. Subjects on Day 14 will receive cantharidin induced blisters with either LPS or GM-CSF in vivo challenge. An optional, cohort 7 may be included for further dose evaluation of GSK3358699 or alternate dosing schedule.
Masking
ParticipantInvestigator
Masking Description
This will be a double blind (sponsor open) study with respect to allocation of GSK3358699 or placebo to subjects. All site staff will be blinded with the exception of un-blinded pharmacists. Investigators will be un-blinded with respect to the LPS and GM-CSF allocation. The food effect part of the study (Part B) will be open-label
Allocation
Randomized
Enrollment
48 (Actual)
8. Arms, Groups, and Interventions
Arm Title
GSK3358699, Part A, Cohort 1
Arm Type
Experimental
Arm Description
Part A will comprise of 4 TPs. The subjects in this cohort will receive GSK3358699, as single escalation dose, during TP (1 to 3) with planned escalated doses as 1 mg, 10 mg and 35 mg. Dose of 1 mg will be given as solution and doses of 10 mg and 35 mg, will be given as a capsule. Each TP will be of 1 day and separated by a washout Period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 1 will receive GSK3358699 at a dose level already given in TP 1-3, and will then receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram post administration of GSK3358699. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge. LPS dose will be based on data of study 207654 (NCT03306589).
Arm Title
GSK3358699, Part A, Cohort 2
Arm Type
Experimental
Arm Description
Part A will comprise of 4 TPs. The subjects in this cohort will receive GSK3358699, as single escalation dose during TP (1 to 3) with planned escalated doses as 3 mg, 20 mg and 45 mg. Dose of 3 mg will be given as solution and that of 20 and 45 mg, as capsule. Each TP will be of 1 day and separated by a washout Period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 2 will receive GSK3358699 at a dose level already given in TP 1-3, and will then receive 60 microgram per meter^2 of in vivo GM CSF challenge as an intravenous infusion during TP 4, post administration of GSK3358699. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge GM-CSF infusion. GM-CSF dose will be based on data of study 207654 (NCT03306589).
Arm Title
Placebo, Part A, Cohort 1
Arm Type
Placebo Comparator
Arm Description
Part A will comprise of 4 TPs. The subjects in this cohort will receive matching Placebo solution to the study drug GSK3358699 solution for 1 mg and a matching placebo capsule to the study drug GSK3358699, 10 mg and 35 mg capsule, during TP (1 to 3). Each TP will be of 1 day and separated by a washout Period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 1 will receive Placebo at a dose level already given in TP 1-3, and will then receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram post administration of Placebo. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge. LPS dose will be based on data of study 207654 (NCT03306589).
Arm Title
Placebo, Part A, Cohort 2
Arm Type
Placebo Comparator
Arm Description
Part A will comprise of 4 TPs. The subjects in this cohort will receive matching Placebo solution to the study drug GSK3358699 solution for 3 mg and a matching placebo capsule to the study drug GSK3358699, for 20 and 45 mg capsule, during TP (1 to 3). Each TP will be of 1 day and separated by a washout Period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 2 will receive Placebo at a dose level already given in TP 1-3, and will then receive 60 microgram per meter^2 of in vivo GM CSF challenge as an intravenous infusion during TP 4, post administration of Placebo. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge GM-CSF infusion. GM-CSF dose will be based on data of study 207654 (NCT03306589).
Arm Title
Part B, GSK3358699 under Fasted followed by Fed conditions
Arm Type
Experimental
Arm Description
The subjects in this arm will receive single oral dose of GSK3358699, at a dose level evaluated in Part A, under fasted condition in TP1 followed by fed condition in TP2. This cohort intended to evaluate the effect of food.
Arm Title
Part B, GSK3358699 under Fed followed by Fasted conditions
Arm Type
Experimental
Arm Description
The subjects in this arm will receive single oral dose of GSK3358699, at a dose level evaluated in Part A, under fed condition in TP1 followed by fasted condition in TP2. This cohort intended to evaluate the effect of food.
Arm Title
GSK3358699, Part C
Arm Type
Experimental
Arm Description
The dose level for the first cohort in Part C will be decided following completion of Part A of the study for GSK3358699. The subjects in this arm will constitute 3 cohorts each (cohort 4 to 6), where the subjects will receive GSK3358699, as one repeat dose treatment once daily for 14-consecutive days. Subjects will have control blisters induced on the forearm (0.2% cantharidin) on Day -10. On the Day 14 of each cohort, each subject will receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram or an intravenous infusion of GM-CSF, in vivo as 60 microgram per meter^2. The administration of LPS or GM CSF will be followed by blister induction on forearm (0.2 % cantharidin).
Arm Title
Placebo, Part C
Arm Type
Placebo Comparator
Arm Description
The subjects in this cohort will receive a matching placebo to GSK3358699, Part C, as a single oral dose once daily for 14 consecutive days. The subjects in this arm will constitute 3 cohorts each (cohort 4 to 6), where the subjects will receive placebo, as one repeat dose treatment once daily for 14-consecutive days. Subjects will have control blisters induced on the forearm (0.2% cantharidin) on Day -10. On the Day 14 of each cohort, each subject will receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram or an intravenous infusion of GM-CSF, in vivo as 60 microgram per meter^2. The administration of LPS or GM CSF will be followed by blister induction on forearm (0.2 % cantharidin).
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo will be administered as a matching oral solution or matching capsule to study drug GSK3358699, during Part A and C once daily
Intervention Type
Drug
Intervention Name(s)
GSK3358699
Intervention Description
GSK3358699, will be administered from 1 mg to 45 mg as an oral solution (1 to 10 mg) or as a capsule (3 to 45 mg), in Part A, B and Part C once daily.
Intervention Type
Biological
Intervention Name(s)
GM-CSF
Intervention Description
The GM-CSF will be administered as an intravenous infusion to subjects as 60 microgram per meter^2 in Part A (Day 1) and Part C (Day 14).This will be administered for 2 hours approximately, no later than 24 hours post -dose of the GSK3358699 or placebo in Part C
Intervention Type
Biological
Intervention Name(s)
LPS
Intervention Description
LPS will be administered as an intravenous injection to subjects not exceeding 0.75 nanogram per kilogram in Part A (Day 1) and Part C (Day 14). This will be administered no later than 24 hours post -dose of the GSK3358699 or placebo in Part C.
Intervention Type
Other
Intervention Name(s)
Cantharidin
Intervention Description
This will be applied as a topical application with 0.7% cantharidin liquid which will be diluted with acetone to 0.2%.
Primary Outcome Measure Information:
Title
Part A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description
An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, important medical events that may jeopardize the participant or require medical or surgical intervention to prevent one of the outcomes listed before. Safety Population consisted of all randomized participants who took at least 1 dose of study treatment.
Time Frame
Up to Day 193
Title
Part B: Number of Participants With AEs and SAEs
Description
An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, important medical events that may jeopardize the participant or require medical or surgical intervention to prevent one of the outcomes listed before.
Time Frame
Up to Day 30
Title
Part C: Number of Participants With AEs and SAEs
Description
An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, important medical events that may jeopardize the participant or require medical or surgical intervention to prevent one of the outcomes listed before.
Time Frame
Up to Day 49
Title
Part A: Number of Participants With Worst Case Chemistry Results by Potential Clinical Importance (PCI) Criteria Post-Baseline Relative to Baseline
Description
Blood samples were collected for analysis of clinical chemistry parameters. PCI ranges were <30 grams per liter (g/L) (albumin), <2 or >2.75 millimoles/L (mmol/L) (calcium), >1.3* upper limit of normal (ULN) mmol/L (creatinine), <3 or >9 mmol/L (glucose), <3 or >5.5 mmol/L (potassium), and <130 or >150 mmol/L (sodium). 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, were recorded in To within Range or No Change (NC) category. Participants were counted twice if participant had values that changed To Low and To High, so the percentages may not add to 100%.
Time Frame
Up to Day 193
Title
Part A: Number of Participants With Worst Case Chemistry Results Relative to Normal Range Post-Baseline Relative to Baseline
Description
Clinical chemistry parameters assessed were alanine aminotransferase(ALT)(<10 or >50 international units per liter[IU/L]),alkaline phosphatase(ALP)(<40 or >129 IU/L),aspartate aminotransferase(AST)(<0 or >37 IU/L),cholesterol(<2.3 or >4.9 mmol/L),direct bilirubin(DB)(<0 or >5 micromoles[mcmol]/L),high density lipoprotein (DL)(<0.9 or >1.5 mmol/L),C-reactive protein(CRP)(<0.0 or >5.0mg/liter),low DL(<0 or >3.0 mmol/L), total bilirubin (<0 or >20 mcmol/L),total protein(<63 or >83 grams/L),triglycerides(<0 or >2.3 mmol/L) and blood urea nitrogen(BUN)(<4.76 or >23.24 mg/deciliter).Participants were counted in worst case category that their value changes to (low, normal or high), unless there is NC in their category.Participants whose laboratory value category was unchanged(e.g.,High to High) or whose value became normal, are recorded in "To Normal or NC" category.Participants were counted twice if participant had values that changed To Low and To High, so percentages may not add to 100%.
Time Frame
Up to Day 193
Title
Part B: Number of Participants With Worst Case Chemistry Results by PCI Criteria Post-Baseline Relative to Baseline
Description
Blood samples were planned to be collected to analyze the chemistry parameters.
Time Frame
Up to Day 30
Title
Part B: Number of Participants With Worst Case Chemistry Results Relative to Normal Range Post-Baseline Relative to Baseline
Description
Blood samples were planned to be collected to analyze the chemistry parameters.
Time Frame
Up to Day 30
Title
Part C: Number of Participants With Worst Case Chemistry Results by PCI Criteria Post-Baseline Relative to Baseline
Description
Blood samples were collected for analysis of chemistry parameters. PCI ranges were <30 g/L (albumin), <2 or >2.75 mmol/L (calcium), >1.3* ULN mmol/L (creatinine), <3 or >9 mmol/L (glucose), <3 or >5.5 mmol/L (potassium), and <130 or >150 mmol/L (sodium). 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, were recorded in To within Range or No Change category. Participants were counted twice if participant had values that changed To Low and To High, so the percentages may not add to 100%.
Time Frame
Up to Day 28
Title
Part C: Number of Participants With Worst Case Chemistry Results Relative to Normal Range Post-Baseline Relative to Baseline
Description
Clinical chemistry parameters assessed were ALT (<10 or >50 IU/L), ALP (<40 or >129 IU/L), AST (<0 or >37 IU/L), cholesterol (<2.3 or >4.9 mmol/L), DB (<0 or >5 mcmol/L), high DL (<0.9 or >1.5 mmol/L), CRP (<0.0 or >5.0 mg/liter), low DL (<0 or >3.0 mmol/L), total bilirubin (<0 or >20 mcmol/L), total protein (<63 or >83 grams/L), triglycerides (<0 or >2.3 mmol/L) and BUN (<4.76 or >23.24 mg/deciliter). Participants were counted in worst case category that their value changes to (low, normal or high), unless there is NC in their category. Participants whose laboratory value category was unchanged (e.g., High to High) or whose value became normal, are recorded in "To Normal or NC" category. Participants were counted twice if participant had values that changed To Low and To High, so percentages may not add to 100%.
Time Frame
Up to Day 28
Title
Part A: Number of Participants With Worst Case Hematology Results by PCI Criteria Post-Baseline Relative to Baseline
Description
Blood samples collected for analysis of hematology parameters. PCI ranges were >0.54 proportion of red blood cells in blood (hematocrit), >180 grams/liter (hemoglobin), <0.8 *10^9 cells/L (lymphocyte count), <1.5 *10^9 cells/L (total absolute neutrophil count [ANC]), <100 or >550 *10^9 cells/L (platelet count), and <3 or >20*10^9 cells/L (white blood cell [WBC] count). 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, were recorded in To within Range or No Change category. Participants were counted twice if the participant had values that changed To Low and To High, so the percentages may not add to 100%.
Time Frame
Up to Day 193
Title
Part A: Number of Participants With Worst Case Hematology Results Relative to Normal Range Post-Baseline Relative to Baseline
Description
Hematology parameters assessed were activated partial thromboplastin time (APTT) (<25 or >37 seconds), basophil count (<0.0 or >0.1*10^9 cells/L), eosinophil count (<0.0 or >0.4*10^9 cells/L), fibrinogen (<1.5 or >4.0 g/L), mean corpuscle hemoglobin (MCH) (<26.0 or >33.5 picogram), mean corpuscle volume (MCV) (<80 or >99 femtoliter), monocyte count (<0.2 or >1.0*10^9 cells/L), prothrombin time (PT) (<10 or >12 seconds), red blood cell (RBC) count (<4.4 or >5.8*10^12 cells/L) and reticulocyte count (<0.38 or >2.64 percentage of reticulocytes). Participants were counted in worst case category that their value changes to (low, normal or high), unless there is NC in their category. Participants whose laboratory value category was unchanged (e.g., High to High) or whose value became normal, are recorded in "To Normal or NC" category. Participants were counted twice if participant had values that changed To Low and To High, so percentages may not add to 100%.
Time Frame
Up to Day 193
Title
Part B: Number of Participants With Worst Case Hematology Results by PCI Criteria Post-Baseline Relative to Baseline
Description
Blood samples were planned to be collected to analyze hematology parameters.
Time Frame
Up to Day 30
Title
Part B: Number of Participants With Worst Case Hematology Results Relative to Normal Range Post-Baseline Relative to Baseline
Description
Blood samples were planned to be collected to analyze hematology parameters.
Time Frame
Up to Day 30
Title
Part C: Number of Participants With Worst Case Hematology Results by PCI Criteria Post-Baseline Relative to Baseline
Description
Blood samples were collected for analysis of hematology parameters. PCI ranges were >0.54 proportion of red blood cells in blood (hematocrit), >180 grams/liter (hemoglobin), <0.8*10^9 cells/L (lymphocyte count), <1.5*10^9 cells/L (total ANC), <100 or >550*10^9 cells/L (platelet count), and <3 or >20*10^9 cells/L (WBC count). 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, were recorded in To within Range or No Change category. Participants were counted twice if the participant had values that changed To Low and To High, so the percentages may not add to 100%.
Time Frame
Up to Day 28
Title
Part C: Number of Participants With Worst Case Hematology Results Relative to Normal Range Post-Baseline Relative to Baseline
Description
Hematology parameters assessed were APTT (<25 or >37 seconds), basophil count (<0.0 or >0.1*10^9 cells/L), eosinophil count (<0.0 or >0.4*10^9 cells/L), fibrinogen (<1.5 or >4.0 g/L), MCH (<26.0 or >33.5 picogram), MCV (<80 or >99 femtoliter), monocyte count (<0.2 or >1.0*10^9 cells/L), PT (<10 or >12 seconds), RBC count (<4.4 or >5.8*10^12 cells/L) and reticulocyte count (<0.38 or >2.64 percentage of reticulocytes). Participants were counted in worst case category that their value changes to (low, normal or high), unless there is NC in their category. Participants whose laboratory value category was unchanged (e.g., High to High) or whose value became normal, are recorded in "To Normal or NC" category. Participants were counted twice if participant had values that changed To Low and To High, so percentages may not add to 100%.
Time Frame
Up to Day 28
Title
Part A: Number of Participants With Abnormal Urinalysis Parameters
Description
Urine samples were collected from participants for analyzing the following urine parameters: potential of hydrogen (pH) and glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocytes levels by dipstick. Urine samples showing any abnormality were sent for microscopic examination to detect the presence of RBC, WBC, cellular casts, granular casts, hyaline casts, and were counted as cells per high-power field (cells/HPF). Number of participants with abnormal urinalysis result by microscopic examination have been presented.
Time Frame
Up to Day 193
Title
Part B: Number of Participants With Abnormal Urinalysis Parameters
Description
Urine samples were planned to be collected to analyze urine parameters.
Time Frame
Up to Day 30
Title
Part C: Number of Participants With Abnormal Urinalysis Parameters
Description
Urine samples were collected from participants for analyzing the following urine parameters: pH and glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocytes levels by dipstick. Urine samples showing any abnormality were sent for microscopic examination to detect the presence of RBC, WBC, cellular casts, granular casts, hyaline casts, and were counted as cells/HPF. Number of participants with abnormal urinalysis result by microscopic examination have been presented.
Time Frame
Up to Day 28
Title
Part A: Number of Participants With Worst Case Vital Sign Results by PCI Criteria Post-Baseline Relative to Baseline
Description
Vital signs included systolic blood pressure(SBP), diastolic blood pressure(DBP), heart rate, respiratory rate and body temperature and were measured in a semi-supine position after 5 minutes rest. 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): <11(low) or >20(high) and body temperature (degrees Celsius) <35.5 (low) or >38.0 (high). Participants were counted in the 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 vital signs 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 were counted twice if the participant had values that changed "To Low" and "To High", so the percentages may not add to 100%.
Time Frame
Up to Day 193
Title
Part B: Number of Participants With Worst Case Vital Sign Results by PCI Criteria Post-Baseline Relative to Baseline
Description
Vital signs were planned to be measured in a semi-supine position after 5 minutes of rest.
Time Frame
Up to Day 30
Title
Part C: Number of Participants With Worst Case Vital Sign Results by PCI Criteria Post-Baseline Relative to Baseline
Description
Vital signs included SBP, DBP, heart rate, respiratory rate and body temperature and were measured in a semi-supine position after 5 minutes rest. 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): <11 (low) or >20 (high) and body temperature (degrees Celsius) <35.5 (low) or >38.0 (high). Participants were counted in the 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 vital signs 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 were counted twice if the participant had values that changed "To Low" and "To High", so the percentages may not add to 100%.
Time Frame
Up to Day 49
Title
Part A: Number of Participants With Worst Case Post-Baseline Abnormal Electrocardiogram (ECG) Findings
Description
Twelve lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, and QT interval corrected using the Fridericia's formula (QTcF) intervals. Abnormal findings were categorized as clinically significant (CS) and not clinically significant (NCS). 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.
Time Frame
Up to Day 193
Title
Part B: Number of Participants With Worst Case Post-Baseline Abnormal ECG Findings
Description
Twelve lead ECGs were planned to be performed to measure PR interval, QRS duration, QT interval and QTcF.
Time Frame
Up to Day 30
Title
Part C: Number of Participants With Worst Case Post-Baseline Abnormal ECG Findings
Description
Twelve lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, and QTcF 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.
Time Frame
Up to Day 28
Secondary Outcome Measure Information:
Title
Part A: Plasma Concentrations of GSK3358699
Description
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. Pharmacokinetic (PK) parameters were calculated using standard non-compartmental analysis. PK Population consisted of all participants in the Safety Population who received an active dose and for whom a PK sample was obtained and analyzed.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period
Title
Part B: Plasma Concentrations of GSK3358699
Description
Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3358699.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period
Title
Part C: Plasma Concentrations of GSK3358699
Description
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Days 4, 8 and 12: Pre-dose; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose
Title
Part A: Area Under the Plasma Concentration Curve From Time Zero to Last Time of Quantifiable Concentration (AUC[0-t]) of GSK3358699
Description
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period
Title
Part B: AUC(0-t) of GSK3358699
Description
Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3358699.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period
Title
Part C: AUC(0-t) of GSK3358699
Description
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose
Title
Part A: Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUC[0-infinity]) of GSK3358699
Description
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period
Title
Part B: AUC(0-infinity) of GSK3358699
Description
Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3358699.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period
Title
Part C: AUC(0-infinity) of GSK3358699
Description
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose
Title
Part A: Area Under the Plasma Concentration Curve From Time Zero to 24 Hours (AUC[0-24]) of GSK3358699
Description
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours post-dose in each treatment period
Title
Part B: AUC(0-24) of GSK3358699
Description
Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3358699.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours post-dose in each treatment period
Title
Part C: AUC(0-24) of GSK3358699
Description
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Time Frame
Days 1 and 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, and 24 hours post-dose
Title
Part A: Maximum Plasma Concentration (Cmax) of GSK3358699
Description
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period
Title
Part B: Cmax of GSK3358699
Description
Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3358699.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period
Title
Part C: Cmax of GSK3358699
Description
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose
Title
Part A: Time to Cmax (Tmax) of GSK3358699
Description
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period
Title
Part B: Tmax of GSK3358699
Description
Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3358699.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period
Title
Part C: Tmax of GSK3358699
Description
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose
Title
Part A: Apparent Terminal Phase Half-life (t1/2) of GSK3358699
Description
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period
Title
Part B: t1/2 of GSK3358699
Description
Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3358699.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period
Title
Part C: t1/2 of GSK3358699
Description
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose
Title
Part A: Plasma Concentrations of GSK3206944
Description
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period
Title
Part B: Plasma Concentrations of GSK3206944
Description
Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3206944. GSK3206944 is a metabolite of GSK3358699.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period
Title
Part C: Plasma Concentrations of GSK3206944
Description
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Days 4, 8 and 12: Pre-dose; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose
Title
Part A: AUC(0-t) of GSK3206944
Description
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period
Title
Part B: AUC(0-t) of GSK3206944
Description
Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3206944. GSK3206944 is a metabolite of GSK3358699.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period
Title
Part C: AUC(0-t) of GSK3206944
Description
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose
Title
Part A: AUC(0-infinity) of GSK3206944
Description
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period
Title
Part B: AUC(0-infinity) of GSK3206944
Description
Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3206944. GSK3206944 is a metabolite of GSK3358699.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period
Title
Part C: AUC(0-infinity) of GSK3206944
Description
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose
Title
Part A: AUC(0-24) of GSK3206944
Description
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours post-dose in each treatment period
Title
Part B: AUC(0-24) of GSK3206944
Description
Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3206944. GSK3206944 is a metabolite of GSK3358699.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours post-dose in each treatment period
Title
Part C: AUC(0-24) of GSK3206944
Description
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Time Frame
Days 1 and 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, and 24 hours post-dose
Title
Part A: Cmax of GSK3206944
Description
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period
Title
Part B: Cmax of GSK3206944
Description
Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3206944. GSK3206944 is a metabolite of GSK3358699.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period
Title
Part C: Cmax of GSK3206944
Description
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose
Title
Part A: Tmax of GSK3206944
Description
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period
Title
Part B: Tmax of GSK3206944
Description
Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3206944. GSK3206944 is a metabolite of GSK3358699.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period
Title
Part C: Tmax of GSK3206944
Description
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose
Title
Part A: t1/2 of GSK3206944
Description
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period
Title
Part B: t1/2 of GSK3206944
Description
Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3206944. GSK3206944 is a metabolite of GSK3358699.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period
Title
Part C: t1/2 of GSK3206944
Description
Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Time Frame
Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose
Title
Part A: Monocyte Intracellular Concentration of GSK3206944
Description
Blood samples were collected into sodium heparin tubes for the isolation of monocytes and for measurement of GSK3206944 concentrations in monocytes. GSK3206944 is a metabolite of GSK3358699.
Time Frame
Day 1: 1, 4, 8, 24 and 48 hours post-dose in each treatment period
Title
Part B: Monocyte Intracellular Concentration of GSK3206944
Description
Blood samples were planned to be collected into sodium heparin tubes for the isolation of monocytes and for measurement of GSK3206944 concentrations in monocytes. GSK3206944 is a metabolite of GSK3358699.
Time Frame
Day 1: 1, 4, 8, 24 and 48 hours post-dose in each treatment period
Title
Part C: Monocyte Intracellular Concentration of GSK3206944
Description
Blood samples were collected into sodium heparin tubes for the isolation of monocytes and for measurement of GSK3206944 concentrations in monocytes. GSK3206944 is a metabolite of GSK3358699.
Time Frame
Days 1 and 13: 1, 4 and 8 hour; Days 4, 8 and 12: Pre-dose; Day 14: 1, 4, 8, 24 and 48 hours post-dose
Title
Part A: Absolute Values of Monocyte Chemotactic Protein (MCP)-1, Interleukin (IL)6, Tumor Necrosis Factor (TNF) Alpha in Blood After Ex-vivo Lipopolysaccharide (LPS) Activation
Description
Whole blood samples of 1 milliliter (mL) were collected in TruCulture tubes, containing LPS and incubated for 24 hours, post which the inflammatory mediators (MCP-1, IL-6 and TNF alpha) were analyzed.
Time Frame
Day 1: 1, 4, 8, 12, 24 and 48 hours
Title
Part B: Absolute Values of MCP-1, IL6, TNF Alpha in Blood After Ex-vivo LPS Activation
Description
Whole blood samples were planned to be collected in TruCulture tubes, containing LPS and incubated for 24 hours, post which the inflammatory mediators (MCP-1, IL6 and TNF alpha) were planned to be analyzed.
Time Frame
Day 1: 1, 4, 8, 12, 24 and 48 hours
Title
Part C: Absolute Values of MCP-1, IL6, TNF Alpha in Blood After Ex-vivo LPS Activation
Description
Whole blood samples of 1 mL were collected in TruCulture tubes, containing LPS and incubated for 24 hours, post which the inflammatory mediators (MCP-1, IL-6 and TNF alpha) were analyzed.
Time Frame
Day 1: 1, 4 and 8 hours; Days 2, 4, 8 and 12: Pre-dose; Day 13: Pre-dose, 1, 4 and 8 hours; Day 14: Pre-dose, Pre-LPS challenge, 1, 4, 8, 24 and 48 hours
10. Eligibility
Sex
Male
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: - Subjects enrolled into the study, where they will be administered LPS or GM-CSF challenge, must be 18 to 55 years of age inclusive, at the time of signing the informed consent. Subjects enrolled into the study where they will not be administered LPS or GM-CSF challenge must be 18 to 65 years of age inclusive, at the time of signing the informed consent. - Subjects must be overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. - Body weight must be > = 50 kilogram (kg) and body mass index (BMI) within the range 18.5-35.0 kg per square meter (kg/m^2) (inclusive). - Male subjects agreeing to use contraceptive methods during the treatment Period and for at least 91 days, after the last dose of study treatment and refrain from donating sperm during this Period. - Capable of giving informed consent. Exclusion Criteria: - Current or chronic history of pancreatitis, diabetes mellitus or impaired glucose tolerance, gastrointestinal disease, liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones), anaphylaxis, and /or anaphylactoid (resembling anaphylaxis) reactions [Sampson et al 2006], cardiac disease including clinically significant ventricular arrhythmias or long QT syndrome, renal disease where clinically significant (minor abnormalities may be permitted base on discussion between investigator and medical monitor), respiratory disease or conditions including but not limited to asthma, chronic obstructive pulmonary disease (COPD), and bronchiectasis and any current respiratory infection (childhood asthma is not an exclusion criterion), sensitivity or severe allergic responses to any of the challenge agents or cantharidin, or components thereof or a history of drug or other allergy that, in the opinion of the Investigator or GlaxoSmithKline (GSK) Medical Monitor, contraindicates their participation; frequent vasovagal syncope, surgery requiring general anaesthetic or significant trauma in 3 months leading to study enrolment, relevant skin conditions (e.g. recent history of eczema or recurrent eczema, keloid, skin allergies, psoriasis, atopic dermatitis, and vitiligo) which in the opinion of the investigator could pose safety issues or cause interference with study procedures, sepsis, coagulation disorders, peripheral edema, lymphangitis, lymphedema, pleural or pericardial effusion, hemorrhage (eg sub-arachnoid) or hemophilia or a related bleeding disorder. - History of malignancies e.g. recurrent basal cell carcinoma, hematological malignancy. - For subjects receiving cantharidin: Presence on either forearm of tattoos, naevi, hypertrophic scars, keloids, hyper- or hypo- pigmentation that may, in the opinion of the Investigator, interfere with study assessments. Subjects with very fair skin, very dark skin, excessive hair or any skin abnormalities that may, in the opinion of the Investigator, interfere with study assessments. - Family history of premature cardiovascular disease or long QT syndrome. - QT interval with Fridericia's correction (QTcF) > 450 millisecond (msec), based on averaged QTcF values of triplicate ECGs obtained over a brief recording period. - Unable or unwilling to refrain from taking prescription or non-prescription drugs (including vitamins and dietary or herbal supplements) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) before the start of study treatment until completion of the follow-up visit. Paracetamol, at a dose of <= 2 grams per day was permitted for use anytime during the study. Other concomitant medications will be considered on case by case basis. - The subjects have participated in a clinical trial and received an investigational product within the following time period prior to the first dosing day in the study: 30 days; 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer) or currently in a study of an investigational device. - Exposure to more than four new chemical entities within 12 months prior to the first dosing day. - Previous exposure to intravenous lipopolysaccharide (LPS) in a clinical research setting. - Alanine transaminase (ALT) >1.5x upper limit of normal (ULN) at screening. - Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) at screening. - Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment. - A positive pre-study drug/alcohol screen at screening. - A positive test for human immunodeficiency virus (HIV) antibody at screening. - Persistent clinically significant abnormal C-reactive protein (CRP) levels at screening - Persistent clinically significant abnormal white cell count (WCC) levels at screening (if clinically significant abnormality is detected, WCC can be retested as clinically indicated) - Platelets < 150 x 10^9 per liter (L) at screening. - Fasted Triglycerides >3.4 millimole per liter (mmol/L) at screening. - Fasted Total cholesterol >7.7 mmol/L at screening. - Random glucose > = 11.1 mmol/L at screening. - Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 3 months prior to screening. - History of regular alcohol consumption within 6 months of the study defined as: an average weekly intake of >14 units. One unit is equivalent to 8 gram of alcohol: a half-pint (approximately 240 milliliter [mL]) of beer, 1 glass (125 mL) of wine or 1 (25 mL). - Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period. - Unable to comply with precautions to minimize phototoxicity risk.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
GSK Clinical Trials
Organizational Affiliation
GlaxoSmithKline
Official's Role
Study Director
Facility Information:
Facility Name
GSK Investigational Site
City
Cambridge
ZIP/Postal Code
CB2 2GG
Country
United Kingdom
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
IPD for this study will be made available via the Clinical Study Data Request site.
IPD Sharing Time Frame
IPD will be made available, within 6 months of publishing the results of the primary endpoints of the study.
IPD Sharing Access Criteria
Access is provided, after a research proposal is submitted and has submitted 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.
IPD Sharing URL
http://clinicalstudydatarequest.com
Citations:
PubMed Identifier
34773923
Citation
Brown JA, Bal J, Simeoni M, Williams P, Mander PK, Soden PE, Daga S, Fahy WA, Wong GK, Bloomer JC, Erwig L, Cui Y, Fernando D, Carnaghan H, Banham-Hall EJ, Hopkins S, Davis BG, Oliveira JJD, Prinjha RK. A randomized study of the safety and pharmacokinetics of GSK3358699, a mononuclear myeloid-targeted bromodomain and extra-terminal domain inhibitor. Br J Clin Pharmacol. 2022 May;88(5):2140-2155. doi: 10.1111/bcp.15137. Epub 2021 Dec 18.
Results Reference
derived
Learn more about this trial
First-time-in-Human (FTIH) Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single (in Both Fed and Fasted States) or Repeat Doses of GSK3358699
We'll reach out to this number within 24 hrs