A First Time in Human (FTIH) Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Repeat Doses of GSK3884464 in Healthy Participants

Phase 1TerminatedNCT05044325

GlaxoSmithKline27 enrolled

Overview

This will be a FTIH study which aims to evaluate safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single and repeat oral doses of GSK3884464 administered to healthy participants.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Heart Failure

Interventions

GSK3884464DRUG

GSK3884464 will be administered

PlaceboDRUG

Placebo to match GSK3884464 will be administered.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 50 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion criteria: * Healthy as determined by the experienced investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring/assessment. * Part 1: Body weight greater than or equal to (\>=)50 kilograms (kg), body mass index (BMI) \>=18 and less than or equal to (\<=)30 kilograms per square meter (kg/m\^2) (inclusive). Part 2: Body weight \>=50 kg, BMI \>=22 and \<=30 kg/m\^2 (inclusive). * Participants with 18 to 50 years of age inclusive at the time of signing the informed consent. * Male or females of non-childbearing potential. * Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol. Exclusion criteria: * History or presence of significant cardiovascular, respiratory, hepatic, renal, gastrointestinal (Gastroesophageal reflux disease \[GERD\], nausea, vomiting or dysphagia), endocrine, hematological or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study treatment; or interfering with the interpretation of data. * History of current or past significant renal diseases. * Clinically significant high blood pressure and/or history of hypertension as determined by the investigator. * Serum troponin I or troponin-T greater than (\>) the upper limit of normal (ULN). * Lymphoma, leukemia, or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years. * Breast cancer within the past 10 years. * Any clinically relevant abnormality on the screening medical assessments. * Alanine transaminase (ALT) \> ULN. * Bilirubin \> ULN. * Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). * Unable to refrain from the use of prescription or non-prescription drug including vitamins, herbal and dietary supplements within 7 days (or 14 days if the drug is a potential enzyme inducer \[ for example (e.g.) Rifampin, St John's Wort extract\]) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GlaxoSmithKline (GSK) Medical Monitor the medication will not interfere with the study procedures or compromise participant safety. By exception, all participants may take Paracetamol (\<=2 grams/day) up to 48 hours prior to the first dose of study drug. * A positive laboratory confirmation of Coronavirus Disease-2019 (COVID-19) infection, or high clinical index of suspicion for COVID-19. * Participants with Glycated hemoglobin (HbA1c) greater than (\>)48 millimoles per mol (mmol/mol) at screening. * Presence of Hepatitis B surface antigen at screening. * Positive Hepatitis C antibody test result at screening. * Positive Hepatitis C RNA test result at screening or within 3 months prior to first dose of study treatment. * Positive pre-study drug/alcohol screen. * Positive Human immunodeficiency virus (HIV) antibody test. * Screening urine albumin to creatinine ratio \>=30 milligrams/grams (mg/gm) (\>=3 mg/mmol). * Regular use of known drugs of abuse. * Regular alcohol consumption within six months prior to the study defined as: An average weekly intake of \>=14 units for males \>=14 units for females. One unit is equivalent to 8 gm of alcohol: a half-pint (approximately 240 milliliters \[mL\]) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits. * Smokelyzer test levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products (e.g.nicotine patches or vaporizing devices) within 3 months prior to screening. * Participants with a history or current evidence of depression, bipolar disorder, suicidal ideation and behavior, or a lifetime history of suicide attempt will be excluded.

Locations (1)

GSK Investigational Site

Cambridge, United Kingdom

Outcomes

Primary Outcomes

Parts 1: Number of Participants With Adverse Events (AEs)

An AE is defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention.

Time frame: Up to Day 17

Parts 2: Number of Participants With Adverse Events (AEs)

Time frame: Up to Day 29

Part 1: 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 chemistry parameters. PCI ranges were \>2\*Upper limit of normal (ULN) units per liter (U/L)(Alanine Aminotransferase \[ALT\]), \>2\*ULN (U/L) (Aspartate Aminotransferase (\[AST\]), \>2\*ULN (Alkaline Phosphatase \[ALP\]) (U/L), \>1.5\*ULN (micromoles per liter) (bilirubin), \<2 or \>2.75 millimoles/liter (L) (mmol/L)(calcium), \<3 or \>7.5 mmol/L (glucose), \<3 or \>5.3 mmol/L (potassium), \<130 or \>149 mmol/L (sodium). Participants were counted in worst case category that their value changes to (low, within \[w/in\] range or no change \[NC\], or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (e.g., High to High), or whose value became within range, are recorded in 'To within Range No Change' category. Participants were counted twice if participant had values that changed 'To Low' and 'To High', so percentages may not add to 100 percentage (%).

Time frame: Up to Week 10

Part 1: Number of Participants With Worst Case Hematology Results by Potential Clinical Importance (PCI) Criteria Post-Baseline Relative to Baseline

Blood samples were collected for analysis of hematology parameters. The ranges for hematology parameters are as follows: Hematocrit\[\>51 percent(%)-male, \>45%-female\], Hemoglobin \[Higher: \>175 grams/Liter(g/L) in male, \>150g/L in female and Low: less than(\<) 100g/L in male, \<95g/L in female\], Lymphocytes\[\<0.97 10\^9/L\], Neutrophils\[\<1.5 10\^9/L\], Platelets\[High: \>550 10\^9/ L and Low: \<100 10\^9/ L\], White blood cells\[High:\>18 10\^9/L Low:\<2 10\^9/L\], Red blood cells\[Low: \<3.0 10\^12/L in male, \<2.5 10\^12/L\]. Participants were counted in worst case category that their value changes to (low, within range \[W/in\] or no change or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (for example-High to High), or whose value became within range, were recorded in "To within Range or No Change" category. Participants were counted twice if participant has values that changed 'To Low' \& 'To High', so the percentages may not add to 100%.

Data from ClinicalTrials.gov

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Time frame: Up to Week 10

Part 1: Number of Participants With Worst Case Urinalysis Results by Potential Clinical Importance (PCI) Criteria Post-Baseline Relative to Baseline

Urine samples were collected to assess urine glucose, protein and ketones using dipstick method. The dipstick test gave results in a semi-quantitative manner, and results for urinalysis parameters were recorded as negative, trace, 1+, 2+, 3+ indicating proportional concentrations in the urine sample. Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date. Result for urinalysis parameters were recorded as no change/decreased and any increase.

Time frame: Up to Week 10

Part 1: Number of Participants With Clinically Significant Changes in Hepatobiliary Laboratory Values

Blood samples were collected to evaluate hepatobiliary abnormalities. Number of participants with Bilirubin (BIL), Alkaline phosphatase (ALP), Alanine Aminotransferase (ALT)/combination of these with levels more than the defined hepatobiliary abnormality criteria were presented. Hepatocellular injury is defined as (\[ALT/ALT ULN\]/\[ALP/ALP ULN\]) \>= 5 and ALT \>=3xULN.

Time frame: Up to Week 10

Part 1: Number of Participants With Clinically Significant Changes in 12-lead Electrocardiogram (ECG) Laboratory Values

Twelve lead ECG was obtained using an ECG machine that automatically calculated the heart rate and measured QTc, PR, QRS intervals. Abnormal findings were categorized as clinically significant and not clinically significant. Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. Data for number of participants with worst case post-Baseline abnormal ECG findings have been presented.

Time frame: Up to Week 10

Part 1: Number of Participants With Worst Case Vital Signs Results by Potential Clinical Importance (PCI) Criteria Post-Baseline Relative to Baseline

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

Time frame: Up to Week 10

Part 1: Number of Participants With Clinically Significant Changes in Continuous Telemetry

Continuous cardiac telemetry was performed in a supine position after at least 5 minutes of rest. Number of participants who had abnormal findings upon cardiac telemetry assessment have been presented.

Time frame: Upto Day 3

Part 2: Cohorts 4: 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 chemistry parameters. PCI ranges were \>=2\*Upper limit of normal (ULN) units per liter (U/L)(Alanine Aminotransferase \[ALT\]), \>=2\*ULN (U/L) (Aspartate Aminotransferase (\[AST\]), \>=2\*ULN (Alkaline Phosphatase \[ALP\]) (U/L), \>=1.5\*ULN (micromoles per liter) (bilirubin), \<2 or \>2.75 millimoles/liter (L) (mmol/L)(calcium), \<3 or \>11 mmol/L (glucose), \<3 or \>5.5 mmol/L (potassium), \<130 or \>150 mmol/L (sodium),\<50 or \>85 grams/liter (protein). Participants were counted in worst case category that their value changes to (low, within \[w/in\] range or no change \[NC\], or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (e.g., High to High), or whose value became within range, are recorded in 'To within Range No Change' category. Participants were counted twice if participant had values that changed 'To Low' and 'To High', so percentages may not add to 100 percentage (%)

Time frame: Upto Week 9

Part 2: Cohorts 4: Number of Participants With Worst Case Hematology Results by Potential Clinical Importance (PCI) Criteria Post-Baseline Relative to Baseline

Blood samples were collected for analysis of hematology parameters. The ranges for hematology parameters are as follows: Hematocrit\[\>51 % in male, \>45% in female\], Haemoglobin\[Higher: \> 175 grams/Litre (g/L) in male, \>150 g/L in female and Low: less than (\<) 100 g/L in male, \<95 g/L in female\], Lymphocytes\[\<0.97 10\^9/L\], Neutrophils\[\<1.5 10\^9/L\], Platelets\[High: \> 550 10\^9/ L and Low: \< 100 10\^9/ L\], White blood cells\[High:\>18 10\^9/L Low:\<2 10\^9/L\], Red blood cells\[Low: \<3.0 10\^12/L in male, \<2.5 10\^12/L\]. Participants were counted in worst case category that their value changes to (low, within range or no change or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (for example \[e.g.\], High to High), or whose value became within range, were recorded in "To within Range or No Change" category. Participants were counted twice if participant has values that changed 'To Low' \& 'To High', so the percentages may not add to 100%.

Time frame: Upto Week 9

Part 2: Cohorts 4: Number of Participants With Worst Case Urinalysis Results by Potential Clinical Importance (PCI) Criteria Post-Baseline Relative to Baseline

Urine samples were collected to assess urine glucose, protein, occult blood and ketones using dipstick method. The dipstick test gave results in a semi-quantitative manner, and results for urinalysis parameters were recorded as negative, trace, 1+, 2+, 3+ indicating proportional concentrations in the urine sample. Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date. Result for urinalysis parameters were recorded as no change/decreased and any increase.

Time frame: Upto Week 9

Part 2: Cohorts 4: Number of Participants With Clinically Significant Changes in Hepatobiliary Laboratory Values

Blood samples were collected to evaluate hepatobiliary abnormalities. Number of participants with Bilirubin (BIL), Alkaline phosphatase (ALP), Alanine Aminotransferase (ALT) in combination of these with levels more than the defined hepatobiliary abnormality criteria were presented. Hepatocellular injury is defined as (\[ALT/ALT ULN\]/\[ALP/ALP ULN\]) greater than or equal to (\>=) 5 and ALT \>=3xULN.

Time frame: Upto Week 9

Part 2: Cohorts 4: Number of Participants With Clinically Significant Changes in 12-lead ECG Laboratory Values

Time frame: Upto Week 9

Part 2: Cohorts 4: Number of Participants With Worst Case Vital Signs Results by Potential Clinical Importance (PCI) Criteria Post-Baseline Relative to Baseline

Time frame: Upto Week 9

Part 2: Cohorts 4: Number of Participants With Clinically Significant Changes in Echocardiogram

Echocardiography was performed at screening and Part 2 of the study using sound waves.

Time frame: Upto Week 9

Part 2: Cohorts 4: Number of Participants With Clinically Significant Changes in Continuous Telemetry

Time frame: Upto Day 14

Part 1: Area Under the Plasma Concentration Curve From Time Zero to Last Time of Quantifiable Concentration (AUC[0-t]) of GSK3884464 Following Single Dose Administration

Blood samples were collected at indicated time points for pharmacokinetic analysis of AUC\[0-t\].