Oedema, Pulmonary
Conditions
Keywords
First Time in Human, TRPV4 inhibitor, Heart failure
Brief summary
This study is the first administration of GSK2798745 in humans. This will be a sponsor un-blinded, placebo-controlled study to investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of GSK2798745, given as single and repeat oral doses to healthy subjects and stable heart failure (HF) subjects. Approximately 28 healthy subjects will be enrolled in the study cohorts (Cohort 1-3) involving single and repeat dose escalations of GSK2798745, while up to 24 stable heart failure subjects will be enrolled in Cohort 4 involving single and repeat dose administration of GSK2798745, with the dose selected based on data from healthy subject cohorts. This would be followed by enrollment of up to 8 subjects with heart failure in Cohort 5 involving repeat dose administration of GSK2798745. The study duration, including screening and follow-up, is not expected to exceed 17 weeks for subjects in the study (in any cohort).
Interventions
DRUGGSK2798745 solution
Clear, colourless GSK2798745 (0.1 to 0.4mg) solution in aqueous citrate buffer with 4% captisol
DRUGGSK2798745 suspension
Aqueous suspension of GSK2798745 (\>=0.5 mg)
DRUGGSK2798745 capsule
White Opaque granule filled capsules of GSK2798745 (\>=0.5 mg)
DRUGPlacebo solution
Clear, colourless solution of aqueous citrate buffer with 4% captisol
Visually matching aqueous suspension of hypromellose acetate succinate powder
DRUGPlacebo capsule
Matching white opaque placebo blend filled capsule
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
For Healthy Subject Cohorts (1-3): * Male or female 18-75 years of age inclusive, at the time of signing the informed consent. * Healthy as determined by a responsible and experienced physician, based on an evaluation including medical history, physical examination, laboratory tests and cardiac evaluation including ECG and echocardiogram. A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or
Exclusion criteria
, outside the reference range for the population being studied may be included only if the Investigator in consultation with the GSK Medical Monitor agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. * Body weight \>=50 kilogram (kg) and Body Mass Index (BMI) within the range 18-32 kilogram/ square meter (kg/m\^2) (inclusive). * A female subject is eligible to participate if she is of Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy for this definition, documented refers to the outcome of the Investigator's/designee's review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records; or postmenopausal defined as 12 months of spontaneous amenorrhea. In questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 milli-International Units per milliliter (mIU/mL) and estradiol \<40 picogram/millilitre (pg/mL) \[\<147 picomoles/liter (pmol/L)\] is confirmatory. * Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods listed in the protocol. This criterion must be followed from the time of the first dose of study medication until 2 weeks post last dose. * Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. * Alanine transaminase (ALT), alkaline phosphatase and bilirubin \<= 1.5x Upper limit of normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%). * Based on averaged QTc values of triplicate ECGs obtained over a brief recording period: QTc \<450 milliseconds (msec); or QTc \<480 msec in subjects with Bundle Branch Block. For Heart Failure Subjects (Cohorts 4 and 5): * Established diagnosis of mild or moderate heart failure of any aetiology with symptoms defined as corresponding to the New York Heart Association (NYHA) Class II or III on stable heart failure therapy for at least 1 month and was not hospitalized for HF for the last three months. * Male or female 18 years or older, age inclusive, at the time of signing the informed consent. * ALT, alkaline phosphatase and bilirubin \<=1.5xULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%). * Based on averaged QTc values of triplicate ECGs obtained over a brief recording period: QTc \<450msec; or QTc \<480msec in subjects with Bundle Branch Block. * Female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy for this definition, documented refers to the outcome of the Investigator's/designee's review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records; or postmenopausal defined as 12 months of spontaneous amenorrhea. In questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \>40mIU/mL and estradiol \<40pg/mL (\<147pmol/L) is confirmatory. * Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods listed in the protocol. This criterion must be followed from the time of the first dose of study medication until 2 weeks post-last dose. * Body weight \>=50kg and BMI within the range 18-40kg/m\^2 (inclusive). * Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) in Stable Heart Failure Participants | Up to 17 weeks | 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. A 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 or incapacity, is a congenital anomaly or birth defect, any other situation according to medical or scientific judgment, or is associated with liver injury and impaired liver function will be categorized as SAE. |
| Number of Participants With Hematology Parameter Laboratory Values of Potential Clinical Concern in Healthy Participants | Up to 17 weeks | Blood samples were collected from participants to evaluate hematology parameters of potential clinical concern. Hematology parameters included platelet count, red blood cells count, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, neutrophils, white blood cells count, lymphocytes, reticulocyte count, monocytes, hemoglobin, eosinophil, hematocrit, and basophiles. The number of participants with hematology values of potential clinical concern have been presented. |
| Number of Participants With Hematology Parameter Laboratory Values of Potential Clinical Concern in Stable Heart Failure Participants | Up to 17 weeks | Blood samples were collected from participants to evaluate hematology parameters of potential clinical concern. Hematology parameters included platelet count, red blood cells count, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, neutrophils, white blood cells count, lymphocytes, reticulocyte count, monocytes, hemoglobin, eosinophil, hematocrit, and basophiles. The number of participants with hematology values of potential clinical concern have been presented. |
| Number of Participants With Abnormal Routine Urinalysis in Healthy Participants | Up to 17 weeks | Urine samples were collected to analyze specific gravity, determining potential of hydrogen (pH), glucose, protein, blood, and ketones by dipstick method, and microscopic examination (if blood or protein is abnormal). The number of participants with abnormal urinalysis data have been presented. |
| Number of Participants With Abnormal Routine Urinalysis in Stable Heart Failure Participants | Up to 17 weeks | Urine samples were collected to analyze specific gravity, determining potential of hydrogen (pH), glucose, protein, blood, and ketones by dipstick method, and microscopic examination (if blood or protein is abnormal). The number of participants with abnormal urinalysis data have been presented. |
| Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) in Healthy Participants | Up to 17 weeks | 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. A 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 or incapacity, is a congenital anomaly or birth defect, any other situation according to medical or scientific judgment, or is associated with liver injury and impaired liver function will be categorized as SAE. |
| Number of Participants With Vital Sign Values of Potential Clinical Concern in Healthy Participants | Up to 17 Weeks | Vital signs included seated supine systolic blood pressure (SBP) and diastolic blood pressure (DBP), heart rate (HR), and respiratory rate (RR). Vital signs criteria of potential clinical concern were SBP: \<100 and \>170 millimeters of mercury (mmHg); DBP: \<50 and \>110 mmHg and HR: \<50 and \>120 beats per minute (bpm). Only those parameters for which at least one value of potential clinical concern was reported are summarized. All Subjects Population includes any participant enrolled into the study who received at least one dose of study medication within a cohort |
| Number of Participants With Vital Sign Values of Potential Clinical Concern in Stable Heart Failure Participants | Up to 17 weeks | Vital signs included seated supine systolic blood pressure (SBP) and diastolic blood pressure (DBP), heart rate (HR), and respiratory rate (RR). Vital signs criteria of potential clinical concern were SBP: \<100 and \>170 millimeters of mercury (mmHg); DBP: \<50 and \>110 mmHg and HR: \<50 and \>120 beats per minute (bpm). Only those parameters for which at least one value of potential clinical concern was reported are summarized. All Subjects Population includes any participant enrolled into the study who received at least one dose of study medication within a cohort |
| Number of Participants With Electrocardiogram (ECG) Values of Potential Clinical Concern in Healthy Participants | Up to 17 weeks | ECGs will be obtained in the semi-supine position after at least 5 minutes. The potential clinical concern range for ECG parameters are: QRS interval: \>200 milliseconds (msec); time from ECG Q wave to the end of the T wave corresponding to electrical systole corrected for heart rate using Bazett's formula (QTcB):\>500msec; time from ECG Q wave to the end of the T wave corresponding to electrical systole corrected for heart rate using Fridericia's formula (QTcF interval): \>500 msec; PR interval:\>300msec. The number of participants with ECG values of potential clinical concern have been presented. |
| Number of Participants With Electrocardiogram (ECG) Values of Potential Clinical Concern in Stable Heart Failure Participants | Up to 17 weeks | ECGs will be obtained in the semi-supine position after at least 5 minutes. The potential clinical concern range for ECG parameters are: QRS interval: \>200 milliseconds (msec); time from ECG Q wave to the end of the T wave corresponding to electrical systole corrected for heart rate using Bazett's formula (QTcB):\>500msec; time from ECG Q wave to the end of the T wave corresponding to electrical systole corrected for heart rate using Fridericia's formula (QTcF interval): \>500 msec; PR interval:\>300msec. The number of participants with ECG values of potential clinical concern have been presented. |
| Number of Participants With Clinical Chemistry Laboratory Values of Potential Clinical Concern in Healthy Participants | Up to 17 weeks | Blood samples were collected from participants to evaluate clinical parameters of potential clinical concern. Clinical parameters included blood urea nitrogen, potassium, total and direct bilirubin, creatinine chloride, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase, alkaline phosphatase, uric acid, glucose, fasting troponin, albumin, sodium calcium total protein, and creatine phosphokinase. The number of participants with clinical chemistry values of potential clinical concern have been presented. |
| Number of Participants With Clinical Chemistry Laboratory Values of Potential Clinical Concern in Stable Heart Failure Participants | Up to 17 weeks | Blood samples were collected from participants to evaluate clinical parameters of potential clinical concern. Clinical parameters included blood urea nitrogen, potassium, total and direct bilirubin, creatinine chloride, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase, alkaline phosphatase, uric acid, glucose, fasting troponin, albumin, sodium calcium total protein, and creatine phosphokinase. The number of participants with clinical chemistry values of potential clinical concern have been presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) Following Single and Repeat Dose Administration of GSK2798745 in Healthy Participants | Day 1 (Cohort 1,2,3) and Day 14 (Cohort 3) | Blood samples for PK analysis were obtained at Day 1 and Day 14 of each treatment period for analysis of Cmax. Log transformed values for Cmax has been presented. |
| Time to Occurrence of Cmax (Tmax) Following Single and Repeat Doses of GSK2798745 in Healthy Participants | Day 1 (Cohort 1,2,3) and Day 14 (Cohort 3) | Blood samples for PK analysis were obtained at Day 1 of each treatment period and Day 14 of Cohort 3 for analysis of tmax. Log untransformed values for tmax has been presented. |
| Maximum Observed Plasma Concentration (Cmax) Following Single and Repeat Dose Administration of GSK2798745 in Stable Heart Failure Participants | Day 1 and Day 7 | Blood samples for PK analysis were obtained at Day 1 and Day 7 of each treatment period for analysis of Cmax. Log untransformed values for Cmax has been presented. |
| Area Under the Concentration-time Curve From Pre-dose to 24 Hours Post-dose (AUC [0-24]) Following Single and Repeat Doses of GSK2798745 in Stable Heart Failure Participants | Day 1 and Day 7 | Blood samples for PK analysis were obtained at Day 1 and Day 7 of each treatment period for analysis of AUC (0-24). Log untransformed values for Cmax has been presented. |
| Area Under the Plasma Concentration-time Curve Extrapolated to Infinity (AUC[0-inf]) Following Single and Repeat Doses of GSK2798745 in Healthy Subjects | Day 1 | Blood samples for Pharmacokinetic (PK) analysis were obtained at Day 1 of each treatment period for analysis of AUC\[0-inf\]. Log untransformed values for AUC\[0-inf\] has been presented. The 'PK Population' includes 'All Subjects' population for whom a pharmacokinetic sample was obtained and analyzed. |
Countries
United Kingdom
Participant flow
Recruitment details
This study is a placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single dose (SD) and repeat, ascending doses (RD) of GSK2798745 in healthy participants (par.) and stable heart failure par. This study was conducted at two centers in the United Kingdom
Pre-assignment details
Sixty one par. entered this 5-cohort study where Cohorts 1-3 were healthy par. and Cohorts 4 and 5 were par. with stable heart failure. Of those,1 par. was withdrawn pre-dose due to issues with ECG values. In Cohort 1 and 2, par. were randomized to sequence and in Cohorts 3, 4 and 5 par. were randomized to drug or placebo
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Healthy participants received single oral doses of GSK2798745 0.25 milligram (mg), 1 mg, 5 mg, 12.5 mg and one dose of GSK2798745 matching placebo in fasted state. Participants fasted from midnight to four hours post-dose. GSK2798745 was administered in a liquid form (suspension) in this single dose escalation cohort. | 9 |
| Cohort 2 Healthy participants received three single oral doses of GSK2798745 5 mg in fasted state and following a standard meal. GSK2798745 was administered in a liquid suspension and capsule formulation to evaluate food effect and relative bioavailability. | 12 |
| Cohort 3 Healthy participants received repeat oral doses of GSK2798745 5 mg or matching placebo (ratio 3:1) in fasted state. Participants fasted from midnight to four hours post-dose. GSK2798745 was administered in a liquid formulation (suspension) | 8 |
| Cohort 4 (GSK2798745 2.4 mg SD and RD) Participants with heart failure received single oral and subsequent 7-days repeat-dose evaluation of GSK2798745 2.4 mg . GSK2798745 was administered in capsule formulation | 10 |
| Cohort 4 (Placebo RD) Participants with heart failure received placebo. Placebo was administered in capsule formulation | 13 |
| Cohort 5 (GSK2798745 2.4 mg RD) Participants with heart failure received repeat-doses of GSK2798745 2.4 mg. GSK2798745 was administered in capsule formulation | 6 |
| Cohort 5 (Placebo RD) Participants with heart failure received placebo. Placebo was administered in capsule formulation | 2 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrew consent | 0 | 1 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort 1 | Cohort 2 | Cohort 3 | Cohort 4 (GSK2798745 2.4 mg SD and RD) | Cohort 4 (Placebo RD) | Cohort 5 (GSK2798745 2.4 mg RD) | Cohort 5 (Placebo RD) | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 41.3 Years STANDARD_DEVIATION 6.4 | 42.8 Years STANDARD_DEVIATION 10.5 | 43.0 Years STANDARD_DEVIATION 10.43 | 71.0 Years STANDARD_DEVIATION 7.18 | 64.1 Years STANDARD_DEVIATION 7.87 | 70.7 Years STANDARD_DEVIATION 6.92 | 54.0 Years STANDARD_DEVIATION 9.9 | 55.3 Years STANDARD_DEVIATION 8.5 |
| Race/Ethnicity, Customized African American/African Heritage & White | 0 Count of Participants | 0 Count of Participants | 1 Count of Participants | 0 Count of Participants | 1 Count of Participants | 0 Count of Participants | 0 Count of Participants | 2 Count of Participants |
| Race/Ethnicity, Customized Asian - Central/South Asian Heritage | 1 Count of Participants | 0 Count of Participants | 0 Count of Participants | 0 Count of Participants | 1 Count of Participants | 0 Count of Participants | 0 Count of Participants | 2 Count of Participants |
| Race/Ethnicity, Customized Asian & White | 0 Count of Participants | 0 Count of Participants | 1 Count of Participants | 0 Count of Participants | 0 Count of Participants | 0 Count of Participants | 0 Count of Participants | 1 Count of Participants |
| Race/Ethnicity, Customized White-White/Caucasian/European Heritage | 8 Count of Participants | 12 Count of Participants | 6 Count of Participants | 10 Count of Participants | 11 Count of Participants | 6 Count of Participants | 2 Count of Participants | 55 Count of Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 5 Participants | 0 Participants | 0 Participants | 7 Participants |
| Sex: Female, Male Male | 9 Participants | 12 Participants | 8 Participants | 8 Participants | 8 Participants | 6 Participants | 2 Participants | 53 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 12 | 0 / 8 | 0 / 23 | 0 / 8 |
| other Total, other adverse events | 5 / 9 | 7 / 12 | 6 / 8 | 22 / 23 | 8 / 8 |
| serious Total, serious adverse events | 0 / 9 | 0 / 12 | 0 / 8 | 0 / 23 | 0 / 8 |
Outcome results
Primary
Number of Participants With Abnormal Routine Urinalysis in Healthy Participants
Urine samples were collected to analyze specific gravity, determining potential of hydrogen (pH), glucose, protein, blood, and ketones by dipstick method, and microscopic examination (if blood or protein is abnormal). The number of participants with abnormal urinalysis data have been presented.
Time frame: Up to 17 weeks
Population: All Subjects Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Number of Participants With Abnormal Routine Urinalysis in Healthy Participants | 4 Participants |
| Cohort 2 | Number of Participants With Abnormal Routine Urinalysis in Healthy Participants | 3 Participants |
| Cohort 3 | Number of Participants With Abnormal Routine Urinalysis in Healthy Participants | 2 Participants |
Primary
Number of Participants With Abnormal Routine Urinalysis in Stable Heart Failure Participants
Urine samples were collected to analyze specific gravity, determining potential of hydrogen (pH), glucose, protein, blood, and ketones by dipstick method, and microscopic examination (if blood or protein is abnormal). The number of participants with abnormal urinalysis data have been presented.
Time frame: Up to 17 weeks
Population: All Subjects Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Number of Participants With Abnormal Routine Urinalysis in Stable Heart Failure Participants | 14 Participants |
| Cohort 2 | Number of Participants With Abnormal Routine Urinalysis in Stable Heart Failure Participants | 3 Participants |
Primary
Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) in Healthy Participants
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. A 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 or incapacity, is a congenital anomaly or birth defect, any other situation according to medical or scientific judgment, or is associated with liver injury and impaired liver function will be categorized as SAE.
Time frame: Up to 17 weeks
Population: All Subjects Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) in Healthy Participants | Any AE | 5 Participants |
| Cohort 1 | Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) in Healthy Participants | Any SAE | 0 Participants |
| Cohort 2 | Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) in Healthy Participants | Any AE | 7 Participants |
| Cohort 2 | Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) in Healthy Participants | Any SAE | 0 Participants |
| Cohort 3 | Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) in Healthy Participants | Any AE | 6 Participants |
| Cohort 3 | Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) in Healthy Participants | Any SAE | 0 Participants |
Primary
Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) in Stable Heart Failure Participants
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. A 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 or incapacity, is a congenital anomaly or birth defect, any other situation according to medical or scientific judgment, or is associated with liver injury and impaired liver function will be categorized as SAE.
Time frame: Up to 17 weeks
Population: All Subjects Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) in Stable Heart Failure Participants | Any AE | 22 Participants |
| Cohort 1 | Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) in Stable Heart Failure Participants | Any SAE | 0 Participants |
| Cohort 2 | Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) in Stable Heart Failure Participants | Any AE | 8 Participants |
| Cohort 2 | Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) in Stable Heart Failure Participants | Any SAE | 0 Participants |
Primary
Number of Participants With Clinical Chemistry Laboratory Values of Potential Clinical Concern in Healthy Participants
Blood samples were collected from participants to evaluate clinical parameters of potential clinical concern. Clinical parameters included blood urea nitrogen, potassium, total and direct bilirubin, creatinine chloride, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase, alkaline phosphatase, uric acid, glucose, fasting troponin, albumin, sodium calcium total protein, and creatine phosphokinase. The number of participants with clinical chemistry values of potential clinical concern have been presented.
Time frame: Up to 17 weeks
Population: All Subjects Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Number of Participants With Clinical Chemistry Laboratory Values of Potential Clinical Concern in Healthy Participants | 3 Participants |
| Cohort 2 | Number of Participants With Clinical Chemistry Laboratory Values of Potential Clinical Concern in Healthy Participants | 6 Participants |
| Cohort 3 | Number of Participants With Clinical Chemistry Laboratory Values of Potential Clinical Concern in Healthy Participants | 4 Participants |
Primary
Number of Participants With Clinical Chemistry Laboratory Values of Potential Clinical Concern in Stable Heart Failure Participants
Blood samples were collected from participants to evaluate clinical parameters of potential clinical concern. Clinical parameters included blood urea nitrogen, potassium, total and direct bilirubin, creatinine chloride, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase, alkaline phosphatase, uric acid, glucose, fasting troponin, albumin, sodium calcium total protein, and creatine phosphokinase. The number of participants with clinical chemistry values of potential clinical concern have been presented.
Time frame: Up to 17 weeks
Population: All Subjects Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Number of Participants With Clinical Chemistry Laboratory Values of Potential Clinical Concern in Stable Heart Failure Participants | 4 Participants |
| Cohort 2 | Number of Participants With Clinical Chemistry Laboratory Values of Potential Clinical Concern in Stable Heart Failure Participants | 3 Participants |
Primary
Number of Participants With Electrocardiogram (ECG) Values of Potential Clinical Concern in Healthy Participants
ECGs will be obtained in the semi-supine position after at least 5 minutes. The potential clinical concern range for ECG parameters are: QRS interval: \>200 milliseconds (msec); time from ECG Q wave to the end of the T wave corresponding to electrical systole corrected for heart rate using Bazett's formula (QTcB):\>500msec; time from ECG Q wave to the end of the T wave corresponding to electrical systole corrected for heart rate using Fridericia's formula (QTcF interval): \>500 msec; PR interval:\>300msec. The number of participants with ECG values of potential clinical concern have been presented.
Time frame: Up to 17 weeks
Population: All Subjects Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Number of Participants With Electrocardiogram (ECG) Values of Potential Clinical Concern in Healthy Participants | 4 Participants |
| Cohort 2 | Number of Participants With Electrocardiogram (ECG) Values of Potential Clinical Concern in Healthy Participants | 7 Participants |
| Cohort 3 | Number of Participants With Electrocardiogram (ECG) Values of Potential Clinical Concern in Healthy Participants | 2 Participants |
Primary
Number of Participants With Electrocardiogram (ECG) Values of Potential Clinical Concern in Stable Heart Failure Participants
ECGs will be obtained in the semi-supine position after at least 5 minutes. The potential clinical concern range for ECG parameters are: QRS interval: \>200 milliseconds (msec); time from ECG Q wave to the end of the T wave corresponding to electrical systole corrected for heart rate using Bazett's formula (QTcB):\>500msec; time from ECG Q wave to the end of the T wave corresponding to electrical systole corrected for heart rate using Fridericia's formula (QTcF interval): \>500 msec; PR interval:\>300msec. The number of participants with ECG values of potential clinical concern have been presented.
Time frame: Up to 17 weeks
Population: All Subjects Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Number of Participants With Electrocardiogram (ECG) Values of Potential Clinical Concern in Stable Heart Failure Participants | 10 Participants |
| Cohort 2 | Number of Participants With Electrocardiogram (ECG) Values of Potential Clinical Concern in Stable Heart Failure Participants | 3 Participants |
Primary
Number of Participants With Hematology Parameter Laboratory Values of Potential Clinical Concern in Healthy Participants
Blood samples were collected from participants to evaluate hematology parameters of potential clinical concern. Hematology parameters included platelet count, red blood cells count, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, neutrophils, white blood cells count, lymphocytes, reticulocyte count, monocytes, hemoglobin, eosinophil, hematocrit, and basophiles. The number of participants with hematology values of potential clinical concern have been presented.
Time frame: Up to 17 weeks
Population: All subjects population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Number of Participants With Hematology Parameter Laboratory Values of Potential Clinical Concern in Healthy Participants | 1 Participants |
| Cohort 2 | Number of Participants With Hematology Parameter Laboratory Values of Potential Clinical Concern in Healthy Participants | 3 Participants |
| Cohort 3 | Number of Participants With Hematology Parameter Laboratory Values of Potential Clinical Concern in Healthy Participants | 1 Participants |
Primary
Number of Participants With Hematology Parameter Laboratory Values of Potential Clinical Concern in Stable Heart Failure Participants
Blood samples were collected from participants to evaluate hematology parameters of potential clinical concern. Hematology parameters included platelet count, red blood cells count, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, neutrophils, white blood cells count, lymphocytes, reticulocyte count, monocytes, hemoglobin, eosinophil, hematocrit, and basophiles. The number of participants with hematology values of potential clinical concern have been presented.
Time frame: Up to 17 weeks
Population: All Subjects Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Number of Participants With Hematology Parameter Laboratory Values of Potential Clinical Concern in Stable Heart Failure Participants | 3 Participants |
| Cohort 2 | Number of Participants With Hematology Parameter Laboratory Values of Potential Clinical Concern in Stable Heart Failure Participants | 1 Participants |
Primary
Number of Participants With Vital Sign Values of Potential Clinical Concern in Healthy Participants
Vital signs included seated supine systolic blood pressure (SBP) and diastolic blood pressure (DBP), heart rate (HR), and respiratory rate (RR). Vital signs criteria of potential clinical concern were SBP: \<100 and \>170 millimeters of mercury (mmHg); DBP: \<50 and \>110 mmHg and HR: \<50 and \>120 beats per minute (bpm). Only those parameters for which at least one value of potential clinical concern was reported are summarized. All Subjects Population includes any participant enrolled into the study who received at least one dose of study medication within a cohort
Time frame: Up to 17 Weeks
Population: All Subjects Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Number of Participants With Vital Sign Values of Potential Clinical Concern in Healthy Participants | DBP | 0 Participants |
| Cohort 1 | Number of Participants With Vital Sign Values of Potential Clinical Concern in Healthy Participants | SBP | 0 Participants |
| Cohort 1 | Number of Participants With Vital Sign Values of Potential Clinical Concern in Healthy Participants | HR | 0 Participants |
| Cohort 2 | Number of Participants With Vital Sign Values of Potential Clinical Concern in Healthy Participants | DBP | 0 Participants |
| Cohort 2 | Number of Participants With Vital Sign Values of Potential Clinical Concern in Healthy Participants | SBP | 0 Participants |
| Cohort 2 | Number of Participants With Vital Sign Values of Potential Clinical Concern in Healthy Participants | HR | 0 Participants |
| Cohort 3 | Number of Participants With Vital Sign Values of Potential Clinical Concern in Healthy Participants | SBP | 8 Participants |
| Cohort 3 | Number of Participants With Vital Sign Values of Potential Clinical Concern in Healthy Participants | HR | 8 Participants |
| Cohort 3 | Number of Participants With Vital Sign Values of Potential Clinical Concern in Healthy Participants | DBP | 3 Participants |
Primary
Number of Participants With Vital Sign Values of Potential Clinical Concern in Stable Heart Failure Participants
Vital signs included seated supine systolic blood pressure (SBP) and diastolic blood pressure (DBP), heart rate (HR), and respiratory rate (RR). Vital signs criteria of potential clinical concern were SBP: \<100 and \>170 millimeters of mercury (mmHg); DBP: \<50 and \>110 mmHg and HR: \<50 and \>120 beats per minute (bpm). Only those parameters for which at least one value of potential clinical concern was reported are summarized. All Subjects Population includes any participant enrolled into the study who received at least one dose of study medication within a cohort
Time frame: Up to 17 weeks
Population: All Subjects Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Number of Participants With Vital Sign Values of Potential Clinical Concern in Stable Heart Failure Participants | SBP | 7 Participants |
| Cohort 1 | Number of Participants With Vital Sign Values of Potential Clinical Concern in Stable Heart Failure Participants | HR | 4 Participants |
| Cohort 1 | Number of Participants With Vital Sign Values of Potential Clinical Concern in Stable Heart Failure Participants | DBP | 2 Participants |
| Cohort 2 | Number of Participants With Vital Sign Values of Potential Clinical Concern in Stable Heart Failure Participants | SBP | 6 Participants |
| Cohort 2 | Number of Participants With Vital Sign Values of Potential Clinical Concern in Stable Heart Failure Participants | HR | 5 Participants |
| Cohort 2 | Number of Participants With Vital Sign Values of Potential Clinical Concern in Stable Heart Failure Participants | DBP | 0 Participants |
| Cohort 3 | Number of Participants With Vital Sign Values of Potential Clinical Concern in Stable Heart Failure Participants | DBP | 1 Participants |
| Cohort 3 | Number of Participants With Vital Sign Values of Potential Clinical Concern in Stable Heart Failure Participants | SBP | 4 Participants |
| Cohort 3 | Number of Participants With Vital Sign Values of Potential Clinical Concern in Stable Heart Failure Participants | HR | 0 Participants |
| Cohort 5 (Placebo RD) | Number of Participants With Vital Sign Values of Potential Clinical Concern in Stable Heart Failure Participants | SBP | 1 Participants |
| Cohort 5 (Placebo RD) | Number of Participants With Vital Sign Values of Potential Clinical Concern in Stable Heart Failure Participants | HR | 0 Participants |
| Cohort 5 (Placebo RD) | Number of Participants With Vital Sign Values of Potential Clinical Concern in Stable Heart Failure Participants | DBP | 0 Participants |
Secondary
Area Under the Concentration-time Curve From Pre-dose to 24 Hours Post-dose (AUC [0-24]) Following Single and Repeat Doses of GSK2798745 in Stable Heart Failure Participants
Blood samples for PK analysis were obtained at Day 1 and Day 7 of each treatment period for analysis of AUC (0-24). Log untransformed values for Cmax has been presented.
Time frame: Day 1 and Day 7
Population: Pharmacokinetic Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Area Under the Concentration-time Curve From Pre-dose to 24 Hours Post-dose (AUC [0-24]) Following Single and Repeat Doses of GSK2798745 in Stable Heart Failure Participants | Day 1 | 133.6 hour*ng/mL | Standard Deviation 57.9 |
| Cohort 1 | Area Under the Concentration-time Curve From Pre-dose to 24 Hours Post-dose (AUC [0-24]) Following Single and Repeat Doses of GSK2798745 in Stable Heart Failure Participants | Day 7 | 208.5 hour*ng/mL | Standard Deviation 115.2 |
| Cohort 2 | Area Under the Concentration-time Curve From Pre-dose to 24 Hours Post-dose (AUC [0-24]) Following Single and Repeat Doses of GSK2798745 in Stable Heart Failure Participants | Day 1 | 131.4 hour*ng/mL | Standard Deviation 11.5 |
| Cohort 2 | Area Under the Concentration-time Curve From Pre-dose to 24 Hours Post-dose (AUC [0-24]) Following Single and Repeat Doses of GSK2798745 in Stable Heart Failure Participants | Day 7 | 207.6 hour*ng/mL | Standard Deviation 36.6 |
Secondary
Area Under the Plasma Concentration-time Curve Extrapolated to Infinity (AUC[0-inf]) Following Single and Repeat Doses of GSK2798745 in Healthy Subjects
Blood samples for Pharmacokinetic (PK) analysis were obtained at Day 1 of each treatment period for analysis of AUC\[0-inf\]. Log untransformed values for AUC\[0-inf\] has been presented. The 'PK Population' includes 'All Subjects' population for whom a pharmacokinetic sample was obtained and analyzed.
Time frame: Day 1
Population: Pharmacokinetic Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Area Under the Plasma Concentration-time Curve Extrapolated to Infinity (AUC[0-inf]) Following Single and Repeat Doses of GSK2798745 in Healthy Subjects | 9.6 hour*nanogram per milliliter (h*ng/mL) | Standard Deviation 3.7 |
| Cohort 2 | Area Under the Plasma Concentration-time Curve Extrapolated to Infinity (AUC[0-inf]) Following Single and Repeat Doses of GSK2798745 in Healthy Subjects | 62.2 hour*nanogram per milliliter (h*ng/mL) | Standard Deviation 26.6 |
| Cohort 3 | Area Under the Plasma Concentration-time Curve Extrapolated to Infinity (AUC[0-inf]) Following Single and Repeat Doses of GSK2798745 in Healthy Subjects | 347.0 hour*nanogram per milliliter (h*ng/mL) | Standard Deviation 122.8 |
| Cohort 5 (Placebo RD) | Area Under the Plasma Concentration-time Curve Extrapolated to Infinity (AUC[0-inf]) Following Single and Repeat Doses of GSK2798745 in Healthy Subjects | 686.1 hour*nanogram per milliliter (h*ng/mL) | Standard Deviation 275 |
| Co 2 (GSK2798745 Fasted Suspension) | Area Under the Plasma Concentration-time Curve Extrapolated to Infinity (AUC[0-inf]) Following Single and Repeat Doses of GSK2798745 in Healthy Subjects | 287.7 hour*nanogram per milliliter (h*ng/mL) | Standard Deviation 101.2 |
| Co 2 (GSK2798745 Fasted Capsule) | Area Under the Plasma Concentration-time Curve Extrapolated to Infinity (AUC[0-inf]) Following Single and Repeat Doses of GSK2798745 in Healthy Subjects | 312.1 hour*nanogram per milliliter (h*ng/mL) | Standard Deviation 71 |
| Co 2 (GSK2798745 Fed Capsule) | Area Under the Plasma Concentration-time Curve Extrapolated to Infinity (AUC[0-inf]) Following Single and Repeat Doses of GSK2798745 in Healthy Subjects | 361.8 hour*nanogram per milliliter (h*ng/mL) | Standard Deviation 99.4 |
| Co 3 (GSK2798745 Day 1-5mg) | Area Under the Plasma Concentration-time Curve Extrapolated to Infinity (AUC[0-inf]) Following Single and Repeat Doses of GSK2798745 in Healthy Subjects | 223.2 hour*nanogram per milliliter (h*ng/mL) | Standard Deviation 31 |
| Co 3 (GSK2798745 Day 14-5mg) | Area Under the Plasma Concentration-time Curve Extrapolated to Infinity (AUC[0-inf]) Following Single and Repeat Doses of GSK2798745 in Healthy Subjects | 318.7 hour*nanogram per milliliter (h*ng/mL) | Standard Deviation 39.6 |
Secondary
Maximum Observed Plasma Concentration (Cmax) Following Single and Repeat Dose Administration of GSK2798745 in Healthy Participants
Blood samples for PK analysis were obtained at Day 1 and Day 14 of each treatment period for analysis of Cmax. Log transformed values for Cmax has been presented.
Time frame: Day 1 (Cohort 1,2,3) and Day 14 (Cohort 3)
Population: Pharmacokinetic Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Maximum Observed Plasma Concentration (Cmax) Following Single and Repeat Dose Administration of GSK2798745 in Healthy Participants | 1.1 ng/mL | Standard Deviation 0.4 |
| Cohort 2 | Maximum Observed Plasma Concentration (Cmax) Following Single and Repeat Dose Administration of GSK2798745 in Healthy Participants | 4.2 ng/mL | Standard Deviation 1.9 |
| Cohort 3 | Maximum Observed Plasma Concentration (Cmax) Following Single and Repeat Dose Administration of GSK2798745 in Healthy Participants | 22.9 ng/mL | Standard Deviation 2.4 |
| Cohort 5 (Placebo RD) | Maximum Observed Plasma Concentration (Cmax) Following Single and Repeat Dose Administration of GSK2798745 in Healthy Participants | 47.9 ng/mL | Standard Deviation 12.1 |
| Co 2 (GSK2798745 Fasted Suspension) | Maximum Observed Plasma Concentration (Cmax) Following Single and Repeat Dose Administration of GSK2798745 in Healthy Participants | 22.2 ng/mL | Standard Deviation 5.7 |
| Co 2 (GSK2798745 Fasted Capsule) | Maximum Observed Plasma Concentration (Cmax) Following Single and Repeat Dose Administration of GSK2798745 in Healthy Participants | 23.1 ng/mL | Standard Deviation 4.3 |
| Co 2 (GSK2798745 Fed Capsule) | Maximum Observed Plasma Concentration (Cmax) Following Single and Repeat Dose Administration of GSK2798745 in Healthy Participants | 25.7 ng/mL | Standard Deviation 7.9 |
| Co 3 (GSK2798745 Day 1-5mg) | Maximum Observed Plasma Concentration (Cmax) Following Single and Repeat Dose Administration of GSK2798745 in Healthy Participants | 23.9 ng/mL | Standard Deviation 5.6 |
| Co 3 (GSK2798745 Day 14-5mg) | Maximum Observed Plasma Concentration (Cmax) Following Single and Repeat Dose Administration of GSK2798745 in Healthy Participants | 29.9 ng/mL | Standard Deviation 3.9 |
Secondary
Maximum Observed Plasma Concentration (Cmax) Following Single and Repeat Dose Administration of GSK2798745 in Stable Heart Failure Participants
Blood samples for PK analysis were obtained at Day 1 and Day 7 of each treatment period for analysis of Cmax. Log untransformed values for Cmax has been presented.
Time frame: Day 1 and Day 7
Population: Pharmacokinetic Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Maximum Observed Plasma Concentration (Cmax) Following Single and Repeat Dose Administration of GSK2798745 in Stable Heart Failure Participants | Day 1 | 13.7 ng/mL | Standard Deviation 1.9 |
| Cohort 1 | Maximum Observed Plasma Concentration (Cmax) Following Single and Repeat Dose Administration of GSK2798745 in Stable Heart Failure Participants | Day 7 | 17.1 ng/mL | Standard Deviation 7.3 |
| Cohort 2 | Maximum Observed Plasma Concentration (Cmax) Following Single and Repeat Dose Administration of GSK2798745 in Stable Heart Failure Participants | Day 1 | 13.4 ng/mL | Standard Deviation 4.1 |
| Cohort 2 | Maximum Observed Plasma Concentration (Cmax) Following Single and Repeat Dose Administration of GSK2798745 in Stable Heart Failure Participants | Day 7 | 16.2 ng/mL | Standard Deviation 3.5 |
Secondary
Time to Occurrence of Cmax (Tmax) Following Single and Repeat Doses of GSK2798745 in Healthy Participants
Blood samples for PK analysis were obtained at Day 1 of each treatment period and Day 14 of Cohort 3 for analysis of tmax. Log untransformed values for tmax has been presented.
Time frame: Day 1 (Cohort 1,2,3) and Day 14 (Cohort 3)
Population: Pharmacokinetic Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Time to Occurrence of Cmax (Tmax) Following Single and Repeat Doses of GSK2798745 in Healthy Participants | 1.3 hours |
| Cohort 2 | Time to Occurrence of Cmax (Tmax) Following Single and Repeat Doses of GSK2798745 in Healthy Participants | 1.6 hours |
| Cohort 3 | Time to Occurrence of Cmax (Tmax) Following Single and Repeat Doses of GSK2798745 in Healthy Participants | 2.3 hours |
| Cohort 5 (Placebo RD) | Time to Occurrence of Cmax (Tmax) Following Single and Repeat Doses of GSK2798745 in Healthy Participants | 2.5 hours |
| Co 2 (GSK2798745 Fasted Suspension) | Time to Occurrence of Cmax (Tmax) Following Single and Repeat Doses of GSK2798745 in Healthy Participants | 2.0 hours |
| Co 2 (GSK2798745 Fasted Capsule) | Time to Occurrence of Cmax (Tmax) Following Single and Repeat Doses of GSK2798745 in Healthy Participants | 1.5 hours |
| Co 2 (GSK2798745 Fed Capsule) | Time to Occurrence of Cmax (Tmax) Following Single and Repeat Doses of GSK2798745 in Healthy Participants | 1.5 hours |
| Co 3 (GSK2798745 Day 1-5mg) | Time to Occurrence of Cmax (Tmax) Following Single and Repeat Doses of GSK2798745 in Healthy Participants | 1.8 hours |
| Co 3 (GSK2798745 Day 14-5mg) | Time to Occurrence of Cmax (Tmax) Following Single and Repeat Doses of GSK2798745 in Healthy Participants | 2.0 hours |