Last updated: 07/17/2024 17:33:52

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

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GSK study ID

207546

See study documents

Clinicaltrials.gov ID

NCT03426995

See results summary

EudraCT ID

2017-003997-15

EU CT Number

Not applicable

Trial status

Other

Overview

Eligibility

Locations

Study documents

Results summary

Plain language summaries

Additional information

Trial overview

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

Trial description: 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.

Primary purpose:

Treatment

Trial design:

Crossover Assignment

Masking:

Double (Participant, Investigator)

Allocation:

Randomized

Primary outcomes:

Part A: Number of subjects with adverse events (AEs) and Serious adverse events (SAEs)

Timeframe: Up to 17 weeks

Part B: Number of subjects with AEs and SAEs

Timeframe: Up to 4 weeks

Part C: Number of subjects with AEs and SAEs

Timeframe: Up to 7 weeks

Part A: Number of subjects with abnormal clinical chemistry parameter’s as measure of safety

Timeframe: Up to 12 weeks

Part B: Number of subjects with abnormal clinical chemistry parameter’s as measure of safety

Timeframe: Up to 4 weeks

Part C: Number of subjects with abnormal clinical chemistry parameter’s as measure of safety

Timeframe: Up to 2 weeks

Part A: Number of subjects with abnormal hematology parameter’s as measure of safety

Timeframe: Up to 12 weeks

Part B: Number of subjects with abnormal hematology parameter’s as measure of safety

Timeframe: Up to 4 weeks

Part C: Number of subjects with abnormal hematology parameter’s as measure of safety

Timeframe: Up to 2 weeks

Part A: Number of subjects with abnormal urinalysis parameter’s as measure of safety

Timeframe: Up to 12 weeks

Part B: Number of subjects with abnormal urinalysis parameter’s as measure of safety

Timeframe: Up to 4 weeks

Part C: Number of subjects with abnormal urinalysis parameter’s as measure of safety

Timeframe: Up to 2 weeks

Part A: Number of subjects with abnormal 12 lead electrocardiograms (ECGs) findings

Timeframe: Up to 12 weeks

Part B: Number of subjects with abnormal 12 lead ECGs findings

Timeframe: Up to 4 weeks

Part C: Number of subjects with abnormal 12 lead ECG findings

Timeframe: Up to 2 weeks

Part A: Number of subjects with abnormal vital signs-systolic and diastolic blood pressure

Timeframe: Up to 17 weeks

Part B: Number of subjects with abnormal vital signs-systolic and diastolic blood pressure

Timeframe: Up to 4 weeks

Part C: Number of subjects with abnormal vital signs-systolic and diastolic blood pressure

Timeframe: Up to 7 weeks

Part A: Number of subjects with abnormal vital signs-temperature

Timeframe: Up to 17 weeks

Part B: Number of subjects with abnormal vital signs-temperature

Timeframe: Up to 4 weeks

Part C: Number of subjects with abnormal vital signs-temperature

Timeframe: Up to 7 weeks

Part A: Number of subjects with abnormal vital signs-heart rate

Timeframe: Up to 17 weeks

Part B: Number of subjects with abnormal vital signs-heart rate

Timeframe: Up to 4 weeks

Part C: Number of subjects with abnormal vital signs-heart rate

Timeframe: Up to 7 weeks

Part A: Number of subjects with abnormal vital signs-respiratory rate

Timeframe: Up to 17 weeks

Part B: Number of subjects with abnormal vital signs-respiratory rate

Timeframe: Up to 4 weeks

Part C: Number of subjects with abnormal vital signs-respiratory rate

Timeframe: Up to 7 weeks

Secondary outcomes:

Part A: Plasma concentrations of GSK3358699

Timeframe: Day 1 (pre-dose, 15, and 30 minutes, 1 hour, 2 ,4, 6, 8, 12 hour), Day 2 (24 hour), Day 3 (48 hour) in each period

Part C: PLASMA concentrations of GSK3358699

Timeframe: Day 1: pre-dose, 15 and 30 minutes, 1 hour, 2, 4, 6, 8, 12 and 24 hour post-dose; Pre-dose samples on Days 4, 8 and 12; Day 14: pre-dose, 15 and 30 minutes, 1 hour, 2, 4, 6, 8, 12 hour); Day 15: 24 hour; Day 16: 48 hour.

Part B: Plasma concentrations of GSK3358699

Timeframe: Day 1 (pre-dose, 15, 30 minutes; 1,2,4,6,8,12 hour; Day 2 (24 hour), Day 3 (48 hour) in each period

Part A: Area under the plasma concentration (AUC) from time zero (pre-dose) to last time of quantifiable concentration (AUC[0-t]) for Gsk3358699

Timeframe: Day 1 (pre-dose, 15, and 30 minutes, 1 hour, 2 ,4, 6, 8, 12 hour), Day 2 (24 hour), Day 3 (48 hour) in each period

Part B: AUC (0-t) for GSK3358699

Timeframe: Day 1 (pre-dose, 15, 30 minutes; 1,2,4,6,8,12 hour; Day 2 (24 hour), Day 3 (48 hour) in each period

Part C: AUC (0-t) for GSK3358699

Part A: AUC pre dose to infinite (inf) time (AUC [0-inf]) of GSK3358699

Timeframe: Day 1 (pre-dose, 15, and 30 minutes, 1 hour, 2 ,4, 6, 8, 12 hour), Day 2 (24 hour), Day 3 (48 hour) in each period

Part B: AUC (0-inf) time of GSK3358699

Timeframe: Day 1 (pre-dose, 15, 30 minutes; 1 hour, 2,4, 6, 8, 12 hour; Day 2 (24 hour), Day 3 (48 hour) in each period

Part C: AUC (0-inf) time of GSK3358699

Part A: Maximum plasma concentration (Cmax) of GSK3358699

Timeframe: Day 1 (pre-dose, 15, and 30 minutes, 1 hour, 2 ,4, 6, 8, 12 hour), Day 2 (24 hour), Day 3 (48 hour) in each period

Part B: Cmax of GSK3358699

Timeframe: Day 1 (pre-dose, 15, 30 minutes; 1 hour, 2,4, 6, 8, 12 hour; Day 2 (24 hour), Day 3 (48 hour) in each period

Part C: Cmax of GSK3358699

Part A: Time to maximum plasma concentration (tmax) of GSK3358699

Timeframe: Day 1 (pre-dose, 15, and 30 minutes, 1 hour, 2 ,4, 6, 8, 12 hour), Day 2 (24 hour), Day 3 (48 hour) in each period

Part B: tmax of GSK3358699

Timeframe: Day 1 (pre-dose, 15, 30 minutes; 1 hour, 2,4, 6, 8, 12 hour; Day 2 (24 hour), Day 3 (48 hour) in each period

Part C: tmax of GSK3358699

Part A: Terminal elimination half-life (t1/2) of GSK3358699 in plasma

Timeframe: Day 1 (pre-dose, 15, and 30 minutes, 1 hour, 2 ,4, 6, 8, 12 hour), Day 2 (24 hour), Day 3 (48 hour) in each period

Part B: t1/2 of GSK3358699 in plasma

Timeframe: Day 1 (pre-dose, 15, 30 minutes; 1 hour, 2,4, 6, 8, 12 hour; Day 2 (24 hour), Day 3 (48 hour) in each period

Part C: t1/2 of GSK3358699 in plasma

Part A: AUC pre-dose to 24 hours post-dose: AUC (0-24) for GSK3358699

Timeframe: Day 1 (pre-dose, 15, and 30 minutes, 1 hour, 2 ,4, 6, 8, 12 hour), Day 2 (24 hour), Day 3 (48 hour) in each period

Part B: AUC (0-24) for GSK3358699

Timeframe: Day 1 (pre-dose, 15, 30 minutes; 1 hour, 2,4, 6, 8, 12 hour; Day 2 (24 hour), Day 3 (48 hour) in each period

Part C: AUC (0-24) for GSK3358699

Part A: AUC (0-t) for GSK3206944

Timeframe: Day 1 (pre-dose, 15, and 30 minutes, 1 hour, 2 ,4, 6, 8, 12 hour), Day 2 (24 hour), Day 3 (48 hour) in each period

Part B: AUC (0-t) for GSK3206944

Timeframe: Day 1 (pre-dose, 15, 30 minutes; 1 hour, 2,4, 6, 8, 12 hour; Day 2 (24 hour), Day 3 (48 hour) in each period

Part C: AUC(0-t) for GSK3206944

Part A: AUC (0-inf) of GSK3206944

Timeframe: Day 1 (pre-dose, 15, and 30 minutes, 1 hour, 2 ,4, 6, 8, 12 hour), Day 2 (24 hour), Day 3 (48 hour) in each period

Part B: AUC (0-inf) of GSK3206944

Timeframe: Day 1 (pre-dose, 15, 30 minutes; 1 hour, 2,4, 6, 8, 12 hour; Day 2 (24 hour), Day 3 (48 hour) in each period

Part C: AUC (0-inf) of GSK3206944

Part A: Cmax of GSK3206944

Timeframe: Day 1 (pre-dose, 15, and 30 minutes, 1 hour, 2 ,4, 6, 8, 12 hour), Day 2 (24 hour), Day 3 (48 hour) in each period

Part B: Cmax of GSK3206944

Timeframe: Day 1 (pre-dose, 15, 30 minutes; 1 hour, 2,4, 6, 8, 12 hour; Day 2 (24 hour), Day 3 (48 hour) in each period

Part C: Cmax of GSK3206944

Part A: tmax of GSK3206944

Timeframe: Day 1 (pre-dose, 15, and 30 minutes, 1 hour, 2 ,4, 6, 8, 12 hour), Day 2 (24 hour), Day 3 (48 hour) in each period

Part B: tmax of GSK3206944

Timeframe: Day 1 (pre-dose, 15, 30 minutes; 1 hour, 2,4, 6, 8, 12 hour; Day 2 (24 hour), Day 3 (48 hour)

Part C: tmax of GSK3206944

Part A: t1/2 of GSK3206944 in plasma

Timeframe: Day 1 (pre-dose, 15, and 30 minutes, 1 hour, 2 ,4, 6, 8, 12 hour), Day 2 (24 hour), Day 3 (48 hour)

Part B: t1/2 of GSK3206944 in plasma

Timeframe: Day 1 (pre-dose, 15, 30 minutes; 1 hour, 2,4, 6, 8, 12 hour; Day 2 (24 hour), Day 3 (48 hour)

Part C: t1/2 of GSK3206944 in plasma

Part A: AUC (0-24) for GSK3206944

Timeframe: Day 1 (pre-dose, 15, and 30 minutes, 1 hour, 2 ,4, 6, 8, 12 hour), Day 2 (24 hour), Day 3 (48 hour)

Part B: AUC (0-24) for GSK3206944

Timeframe: Day 1 (pre-dose, 15, 30 minutes; 1 hour, 2,4, 6, 8, 12 hour; Day 2 (24 hour), Day 3 (48 hour)

Part C: AUC (0-24) for GSK3206944

Part A: Plasma concentrations of GSK3206944

Timeframe: Day 1 (pre-dose, 15, and 30 minutes, 1 hour, 2 ,4, 6, 8, 12 hour), Day 2 (24 hour), Day 3 (48 hour) in each period

Part B: Plasma concentrations of GSK3206944

Timeframe: Day 1 (pre-dose, 15, 30 minutes; 1,2,4,6,8,12 hour; Day 2 (24 hour), Day 3 (48 hour) in each period

Part C: Plasma concentrations of GSK3206944

Part A: Monocyte intracellular concentration of GSK3206944

Timeframe: Day 1 (1 hour, 4 and 8 hour), Day 2 (24 hour), and Day 3 (48 hour)

Part B: Monocyte intracellular concentration of GSK3206944

Timeframe: Day 1 (1 hour,4 hour, 8 hour), Day 2 (24 hour), Day 3 (48 hour)

Part C: Monocyte intracellular concentration of GSK3206944

Timeframe: Day 1 (1, 4 and 8 hour), Pre dose on Days 4, 8 and 12, Day 14 (1, 4 and 8 hour), Day 15 (24 hour), Day 16 (48 hour)

Part A: Plasma concentrations of monocyte chemoattractant protein (MCP)-1, in blood stimulated ex vivo with lipopolysaccharide (LPS) over time

Timeframe: Day -1, Day 1 (pre-dose, 1 hour, 4, 8, and 12 hour); Day 2 (24 hour), and Day 3 (48 hour)

Part A: Plasma concentrations of interleukin (IL)-6 in blood stimulated ex vivo with LPS over time

Timeframe: Day -1, Day 1 (pre-dose, 1 hour, 4, 8, and 12 hour); Day 2 (24 hour), and Day 3 (48 hour)

Part A: Plasma concentrations of monocyte chemoattractant protein tumor necrosis factor (TNF) in blood stimulated ex vivo with LPS over time

Timeframe: Day -1, Day 1 (pre-dose, 1 hour, 4, 8, and 12 hour); Day 2 (24 hour), and Day 3 (48 hour)

Part B: Plasma concentrations of MCP-1, in blood stimulated ex vivo with LPS over time

Timeframe: Day -1, Day 1 (pre-dose, 1 hour,4, 8, 12 hour), Day 2 (24 hour) and Day 3 (48 hour)

Part B: Plasma concentrations of IL-6 in blood stimulated ex vivo with LPS over time

Timeframe: Day -1, Day 1 (pre-dose, 1 hour,4, 8, 12 hour), Day 2 (24 hour) and Day 3 (48 hour)

Part B: Plasma concentrations of monocyte chemoattractant protein TNF in blood stimulated ex vivo with LPS over time

Timeframe: Day -1, Day 1 (pre-dose, 1 hour,4, 8, 12 hour), Day 2 (24 hour) and Day 3 (48 hour)

Part C: Plasma concentrations of MCP-1, in blood stimulated ex vivo with LPS over time

Timeframe: Day -1, Day 1: pre-dose and 1, 4 and 8 hours post-dose; pre-dose on Days 2,4,8 and 12; Day 14: pre-dose and 1, 4 and 8 hours post-dose; Day 15: 24 hour

Part C: Plasma concentrations of IL-6 in blood stimulated ex vivo with LPS over time

Timeframe: Day -1, Day 1: pre-dose and 1, 4 and 8 hours post-dose; pre-dose on Days 2,4,8 and 12; Day 14: pre-dose and 1, 4 and 8 hours post-dose; Day 15: 24 hour

Part C: Plasma concentrations of monocyte chemoattractant protein TNF in blood stimulated ex vivo with LPS over time

Timeframe: Day -1, Day 1: pre-dose and 1, 4 and 8 hours post-dose; pre-dose on Days 2,4,8 and 12; Day 14: pre-dose and 1, 4 and 8 hours post-dose; Day 15: 24 hour

Interventions:

Drug: Placebo

Drug: GSK3358699

Biological/vaccine: GM-CSF

Biological/vaccine: LPS

Other: Cantharidin

Enrollment:

Primary completion date:

2019-02-05

Observational study model:

Not applicable

Time perspective:

Not applicable

Clinical publications:

Jack Brown, Jo Bal, Monica Simeoni, Peter Williams, Palwinder K Mander, Peter E Soden, Shruti Draga, William A Fahy, Gabriel K Wong, Jackie C Bloomer, Lars Erwig, Yi Cui, Disala Fernando, Helen Carnaghan, Edward J Banham Hall, Sarah Hopkins, Bill Davis, Joao J Oliveira, Rab K Prinjha. A Randomized Study of the Safety and Pharmacokinetics of GSK3358699, a Mononuclear Myeloid-Targeted Bromodomain and Extra-Terminal Domain Inhibitor. Br J Clin Pharmacol. 2021; DOI: 10.1111/bcp.15137 PMID: 34773923

Medical condition

Arthritis, Rheumatoid

Product

sargramostim

Collaborators

Not applicable

Study date(s)

March 2018 to May 2019

Type

Interventional

Phase

Participation criteria

Sex

Male

Age

18 - 65 years

Accepts healthy volunteers

Yes

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.

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.

Trial location(s)

Location

Status

Location

GSK Investigational Site

Cambridge, United Kingdom, CB2 2GG

Status

Study Complete

Study documents

Clinical study report

Available language(s): English

Download document(s)

Protocol

Available language(s): English

Download document(s)

Statistical analysis plan

Available language(s): English

Download document(s)

If you wish to request for full study report, please contact - [email protected]

Results overview

Results posted on ClinicalTrials.gov

Recruitment status

Other

Actual primary completion date

2019-02-05

Actual study completion date

2019-02-05

Plain language summaries

Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.

Additional information about the trial

Additional information

Not applicable

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