Phase 1
Completed N=8
Effect of Therapeutic and Supratherapeutic Oral Doses of GSK3640254 on Cardiac Conduction Compared to Placebo and a Single Oral Dose of Moxifloxacin
Source: ClinicalTrials.gov NCT04563845 ↗Enrolled (actual)
8
Serious AEs
0.0%
Results posted
Dec 2023
Primary outcomePrimary: Part 1: Area Under the Plasma Concentration-time Curve From Time Zero to Time t (AUC[0-t]) of GSK3640254 — 102400 Hours*nanograms per milliliter
Summary
This study will aim to evaluate the effect of therapeutic and supratherapeutic oral doses of GSK3640254 on cardiac conduction compared to placebo and a single oral dose of Moxifloxacin in healthy adult participants. The study has 2 parts: Part 1 will determine the supratherapeutic dose for Part 2, which will be the main corrected QT interval (QTc) study. Part 1 will evaluate once daily (QD) dosing of GSK3640254 or placebo and Part 2 will investigate the safety, tolerability and Pharmacokinetics (PK) of GSK3640254 doses on cardiac conduction as compared to placebo and a single oral dose of Moxifloxacin in healthy adult participants. Moxifloxacin will be included as a positive control.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Part 1: Area Under the Plasma Concentration-time Curve From Time Zero to Time t (AUC[0-t]) of GSK3640254 |
102400 | — |
| PRIMARY Part 1: AUC From Time Zero to the End of the Dosing Interval at Steady State (AUC[0-tau]) of GSK3640254 |
68790 | — |
| PRIMARY Part 1: Maximum Observed Concentration (Cmax) of GSK3640254 |
4439 | — |
| PRIMARY Part 1: Plasma Concentration at the End of the Dosing Interval (Ctau) of GSK3640254 |
2081 | — |
| PRIMARY Part 1: Time of Maximum Observed Concentration (Tmax) of GSK3640254 |
4.500 | — |
| PRIMARY Part 1: Plasma Concentration of GSK3640254 |
2168; 2000; 2579; 3513; 4228; 4155 | — |
| PRIMARY Part 1: Plasma Concentration of Major Metabolites of GSK3640254 |
— | — |
| PRIMARY Part 1: Number of Participants With Serious Adverse Events (SAEs) and Non-SAEs |
2; 1; 0; 0 | — |
| PRIMARY Part 1: Absolute Values for Hematology Parameter: Hemoglobin |
143.5; 131.8; 149.5; 137.3; 151.5; 140.5 | — |
| PRIMARY Part 1: Absolute Values for Hematology Parameter: Hematocrit |
0.4155; 0.3920; 0.4365; 0.4048; 0.4405; 0.4140 | — |
| PRIMARY Part 1: Absolute Values for Hematology Parameter: Erythrocytes Mean Corpuscular Volume |
87.70; 84.42; 87.30; 83.95; 87.30; 84.05 | — |
| PRIMARY Part 1: Absolute Values for Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin |
30.35; 28.35; 29.85; 28.43; 30.00; 28.50 | — |
| PRIMARY Part 1: Absolute Values for Hematology Parameter: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets and Leukocytes |
0.070; 0.057; 0.065; 0.053; 0.065; 0.048 | — |
| PRIMARY Part 1: Absolute Values for Hematology Parameter: Erythrocytes |
4.740; 4.647; 5.010; 4.820; 5.060; 4.915 | — |
| PRIMARY Part 1: Change From Baseline in Hematology Parameter: Hemoglobin |
6.0; 5.5; 8.0; 8.7; 8.5; 5.8 | — |
| PRIMARY Part 1: Change From Baseline in Hematology Parameter: Hematocrit |
0.0210; 0.0128; 0.0250; 0.0220; 0.0310; 0.0142 | — |
| PRIMARY Part 1: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Volume |
-0.40; -0.47; -0.40; -0.37; 0.50; -0.75 | — |
| PRIMARY Part 1: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin |
-0.50; 0.08; -0.35; 0.15; -0.35; -0.02 | — |
| PRIMARY Part 1: Change From Baseline in Hematology Parameter: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets and Leukocytes |
-0.005; -0.003; -0.005; -0.008; -0.010; 0.008 | — |
| PRIMARY Part 1: Change From Baseline in Hematology Parameter: Erythrocytes |
0.270; 0.173; 0.320; 0.268; 0.325; 0.205 | — |
| PRIMARY Part 1: Absolute Values for Chemistry Parameters: Glucose, Cholesterol, Magnesium, Triglycerides, Anion Gap, Calcium, Carbon Dioxide, Chloride, Phosphate, Potassium, Sodium, and Blood Urea Nitrogen |
5.050; 4.682; 4.495; 4.745; 4.465; 4.728 | — |
| PRIMARY Part 1: Absolute Values for Chemistry Parameters: Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST), Gamma-glutamyl Transferase (GGT), Creatine Kinase, and Lactate Dehydrogenase |
33.0; 19.7; 37.5; 16.8; 33.5; 17.7 | — |
| PRIMARY Part 1: Absolute Values for Chemistry Parameters: Creatinine, Urate, Total Bilirubin, and Direct Bilirubin |
89.75; 74.85; 83.10; 72.20; 86.60; 70.13 | — |
| PRIMARY Part 1: Absolute Values for Chemistry Parameters: Albumin, Globulin, and Total Protein |
46.5; 43.0; 46.0; 41.8; 47.5; 44.3 | — |
| PRIMARY Part 1: Absolute Values for Chemistry Parameters: Amylase and Lipase |
64.5; 63.8; 64.0; 61.8; 67.0; 62.8 | — |
| PRIMARY Part 1: Change From Baseline in Chemistry Parameters: Glucose, Cholesterol, Magnesium, Triglycerides, Anion Gap, Calcium, Carbon Dioxide, Chloride, Phosphate, Potassium, Sodium, Blood Urea Nitrogen |
-0.555; 0.063; -0.585; 0.047; -0.415; -0.077 | — |
| PRIMARY Part 1: Change From Baseline in Chemistry Parameters: ALT, ALP, AST, GGT, Creatine Kinase, Lactate Dehydrogenase |
4.5; -2.8; 0.5; -2.0; -4.5; -1.5 | — |
| PRIMARY Part 1: Change From Baseline in Chemistry Parameters: Creatinine, Urate, Total Bilirubin, Direct Bilirubin |
-6.65; -2.65; -3.15; -4.72; -4.45; -3.85 | — |
| PRIMARY Part 1: Change From Baseline in Chemistry Parameters: Albumin, Globulin, and Total Protein |
-0.5; -1.2; 1.0; 1.3; -1.0; 0.2 | — |
| PRIMARY Part 1: Change From Baseline in Chemistry Parameters: Amylase and Lipase |
-0.5; -2.0; 2.5; -1.0; 0.0; -4.3 | — |
| PRIMARY Part 1: Absolute Values for Urinalysis Parameter: Specific Gravity |
1.0080; 1.0092; 1.0150; 1.0125; 1.0190; 1.0167 | — |
| PRIMARY Part 1: Absolute Values for Urinalysis Parameter: Potential of Hydrogen (pH) |
6.50; 7.08; 6.50; 6.33; 6.25; 6.25 | — |
| PRIMARY Part 1: Change From Baseline in Urinalysis Parameter: Specific Gravity |
0.0070; 0.0033; 0.0110; 0.0075; 0.0065; 0.0005 | — |
| PRIMARY Part 1: Change From Baseline in Urinalysis Parameter: pH |
0.00; -0.75; -0.25; -0.83; 0.00; -0.83 | — |
| PRIMARY Part 1: Number of Participants With Clinically Significant Abnormal 12-Lead Electrocardiogram (ECG) Findings |
0; 0; 0; 0; 0; 0 | — |
| PRIMARY Part 1: Absolute Values for Vital Parameters: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) |
120.0; 109.2; 115.5; 103.8; 123.0; 106.8 | — |
| PRIMARY Part 1: Absolute Values for Vital Parameter: Pulse Rate |
70.5; 67.8; 63.0; 68.7; 70.5; 65.0 | — |
| PRIMARY Part 1: Absolute Values for Vital Parameter: Temperature |
35.90; 36.50; 36.10; 36.53; 36.10; 36.58 | — |
| PRIMARY Part 2: Placebo-corrected Change From Baseline in QT Interval Corrected for Heart Rate Using Fridericia's Formula (QTcF) Following Administration of GSK3640254 100 mg and GSK3640254 500 mg Using Concentration-QTc (C-QTc) Analysis |
2.72; 11.49 | — |
| PRIMARY Part 2: Plasma Concentration of GSK3640254 |
496.0; 2357; 462.3; 2252; 486.6; 2339 | — |
| PRIMARY Part 2: Plasma Concentration of Major Metabolites of GSK3640254 |
— | — |
| SECONDARY Part 2: Change From Baseline in Heart Rate (HR) - For GSK3640254 100 mg, GSK3640254 500 mg and Placebo Arms |
0.0; 2.8; 0.3; 4.4; 8.5; 4.6 | — |
| SECONDARY Part 2: Change From Baseline in QT Interval Corrected for Heart Rate Using Fridericia's Formula (QTcF) - For GSK3640254 100 mg, GSK3640254 500 mg and Placebo Arms |
4.2; 9.8; 2.7; -0.9; 5.3; -1.9 | — |
| SECONDARY Part 2: Change From Baseline in PR Interval - For GSK3640254 100 mg, GSK3640254 500 mg and Placebo Arms |
2.5; 3.1; 1.1; 3.6; 5.7; 3.2 | — |
| SECONDARY Part 2: Change From Baseline in QRS Interval - For GSK3640254 100 mg, GSK3640254 500 mg and Placebo Arms |
0.5; 1.0; 0.4; 0.7; 1.1; 0.5 | — |
| SECONDARY Part 2: Placebo-corrected Change From Baseline in QT Interval Corrected for Heart Rate Using Fridericia's Formula (QTcF) Following Administration of GSK3640254 100 mg and GSK3640254 500 mg By-time Point Analysis |
1.4; 7.1; 1.0; 7.2; 0.6; 4.1 | — |
| SECONDARY Part 2: Placebo-corrected Change From Baseline in HR Following Administration of GSK3640254 100 mg and GSK3640254 500 mg |
-0.3; 2.5; -0.2; 3.9; 0.2; 4.0 | — |
| SECONDARY Part 2: Placebo-corrected Change From Baseline in PR Following Administration of GSK3640254 100 mg and GSK3640254 500 mg |
1.5; 2.1; 0.4; 2.5; 1.2; 0.1 | — |
| SECONDARY Part 2: Placebo-corrected Change From Baseline in QRS Following Administration of GSK3640254 100 mg and GSK3640254 500 mg |
0.1; 0.6; 0.2; 0.5; 0.3; 0.7 | — |
| SECONDARY Part 2: Number of Participants With Outlier Results for HR, QTcF, ΔQTcF, PR Interval and QRS Interval for GSK3640254 100 mg and GSK3640254 500 mg |
0; 0; 0; 0; 0; 0 | — |
| SECONDARY Part 2: Number of Participants With Treatment Emergent Changes of T-wave Morphology and Presence of U-wave Following Administration of GSK3640254 100 mg and GSK3640254 500 mg |
2; 1; 0; 0; 1; 0 | — |
| SECONDARY Part 2: Placebo-corrected Change From Baseline in QTcF Following Administration of Moxifloxacin |
0.6; -0.2; -0.8; 5.6; 7.9; 8.9 | — |
| SECONDARY Part 2: AUC(0-t) of GSK3640254 100 mg and GSK3640254 500 mg |
13840; 67520 | — |
| SECONDARY Part 2: AUC(0-tau) of GSK3640254 100 mg and GSK3640254 500 mg |
13830; 67490 | — |
| SECONDARY Part 2: Cmax of GSK3640254 100 mg and GSK3640254 500 mg |
830.3; 4261 | — |
| SECONDARY Part 2: Ctau of GSK3640254 100 mg and GSK3640254 500 mg |
459.9; 2137 | — |
| SECONDARY Part 2: Tmax of GSK3640254 100 mg and GSK3640254 500 mg |
5.008; 5.000 | — |
| SECONDARY Part 2: Cmax of Moxifloxacin 400 mg |
1964 | — |
| SECONDARY Part 2: Tmax of Moxifloxacin 400 mg |
4.000 | — |
| SECONDARY Part 2: Number of Participants With Non-SAEs and SAEs |
7; 4; 5; 10; 0; 0 | — |
| SECONDARY Part 2: Absolute Values for Hematology Parameter: Hemoglobin |
141.8; 140.5; 141.6; 141.7; 139.9; 140.3 | — |
| SECONDARY Part 2: Absolute Values for Hematology Parameter: Hematocrit |
0.4163; 0.4131; 0.4157; 0.4167; 0.4099; 0.4120 | — |
| SECONDARY Part 2: Absolute Values for Hematology Parameter: Erythrocytes Mean Corpuscular Volume |
85.93; 85.96; 86.26; 85.92; 85.95; 85.57 | — |
| SECONDARY Part 2: Absolute Values for Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin |
29.27; 29.23; 29.37; 29.21; 29.34; 29.13 | — |
| SECONDARY Part 2: Absolute Values for Hematology Parameter: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets and Leukocytes |
0.035; 0.036; 0.037; 0.031; 0.035; 0.032 | — |
| SECONDARY Part 2: Absolute Values for Hematology Parameter: Erythrocytes |
4.859; 4.815; 4.829; 4.864; 4.775; 4.833 | — |
| SECONDARY Part 2: Change From Baseline in Hematology Parameter: Hemoglobin |
-2.7; 0.1; -0.9; 0.3; -0.6; -1.3 | — |
| SECONDARY Part 2: Change From Baseline in Hematology Parameter: Hematocrit |
-0.0068; 0.0002; -0.0018; -0.0040; -0.0009; -0.0076 | — |
| SECONDARY Part 2: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Volume |
-0.57; -0.26; -0.45; -0.55; 0.15; 0.10 | — |
| SECONDARY Part 2: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin |
-0.25; -0.08; -0.18; 0.15; -0.05; 0.27 | — |
| SECONDARY Part 2: Change From Baseline in Hematology Parameter: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets and Leukocytes |
-0.002; -0.003; -0.004; 0.005; 0.002; -0.003 | — |
| SECONDARY Part 2: Change From Baseline in Hematology Parameter: Erythrocytes |
-0.049; 0.022; 0.008; -0.015; -0.023; -0.090 | — |
| SECONDARY Part 2: Absolute Values for Chemistry Parameters: Glucose, Cholesterol, Magnesium, Triglycerides, Anion Gap, Calcium, Carbon Dioxide, Chloride, Phosphate, Potassium, Sodium, Blood Urea Nitrogen |
4.813; 4.739; 4.810; 4.753; 4.777; 4.749 | — |
| SECONDARY Part 2: Absolute Values for Chemistry Parameters: ALT, ALP, AST, GGT, Creatine Kinase, Lactate Dehydrogenase |
18.3; 16.8; 17.5; 16.3; 14.0; 17.2 | — |
| SECONDARY Part 2: Absolute Values for Chemistry Parameters: Creatinine, Urate, Total Bilirubin, Direct Bilirubin |
80.51; 79.38; 81.86; 79.83; 78.45; 88.55 | — |
| SECONDARY Part 2: Absolute Values for Chemistry Parameters: Albumin, Globulin, Total Protein |
43.8; 44.0; 43.6; 44.5; 41.7; 42.0 | — |
| SECONDARY Part 2: Absolute Values for Chemistry Parameters: Amylase and Lipase |
55.7; 55.9; 58.2; 56.2; 52.4; 59.1 | — |
| SECONDARY Part 2: Change From Baseline in Chemistry Parameters: Glucose, Cholesterol, Magnesium, Triglycerides, Anion Gap, Calcium, Carbon Dioxide, Chloride, Phosphate, Potassium, Sodium, Blood Urea Nitrogen |
-0.041; 0.029; -0.023; -0.024; 0.023; -0.119 | — |
| SECONDARY Part 2: Change From Baseline in Chemistry Parameters: ALT, ALP, AST, GGT, Creatine Kinase, Lactate Dehydrogenase |
-2.1; -0.9; -2.5; 2.0; 0.7; -0.9 | — |
| SECONDARY Part 2: Change From Baseline in Chemistry Parameters: Creatinine, Urate, Total Bilirubin, Direct Bilirubin |
-0.03; 7.07; -1.15; 1.74; 1.59; 3.23 | — |
| SECONDARY Part 2: Change From Baseline in Chemistry Parameters: Albumin, Globulin, Total Protein |
-2.5; -2.0; -1.6; -2.2; 0.4; -0.5 | — |
| SECONDARY Part 2: Change From Baseline in Chemistry Parameters: Amylase, Lipase |
-0.8; -0.1; -3.6; -2.5; 3.1; 2.1 | — |
| SECONDARY Part 2: Absolute Values for Urinalysis Parameter: Specific Gravity |
1.0152; 1.0153; 1.0167; 1.0161; 1.0180; 1.0164 | — |
| SECONDARY Part 2: Absolute Values for Urinalysis Parameter: pH |
6.10; 6.19; 6.09; 6.13; 5.90; 5.88 | — |
| SECONDARY Part 2: Change From Baseline in Urinalysis Parameter: Specific Gravity |
0.0034; 0.0030; 0.0019; 0.0026; 0.0015; 0.0015 | — |
| SECONDARY Part 2: Change From Baseline in Urinalysis Parameter: pH |
-0.19; -0.33; -0.08; -0.18; -0.35; -0.23 | — |
| SECONDARY Part 2: Number of Participants With Clinically Significant Abnormal 12-Lead ECG Findings |
0; 0; 0; 0; 0; 0 | — |
| SECONDARY Part 2: Absolute Values for Vital Parameters: SBP and DBP |
106.0; 106.7; 106.8; 105.4; 103.9; 104.5 | — |
| SECONDARY Part 2: Absolute Values for Vital Parameter: Pulse Rate |
62.5; 60.4; 61.8; 61.0; 61.9; 62.4 | — |
| SECONDARY Part 2: Absolute Values for Vital Parameter: Temperature |
36.25; 36.28; 36.22; 36.32; 36.14; 36.29 | — |
Eligibility Criteria
Inclusion criteria
- Participant must be 18 to 50 years of age inclusive, at the time of signing the informed consent.
- Participants who are healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination (including cardiopulmonary examination), laboratory tests, and cardiac monitoring (history and ECG).
- Body weight more than or equal to (>=)50.0 kilograms (kg) (110 pounds [lbs]) for men and >=45.0 kg (99 lbs) for women and body mass index within the range 18.5 to 31.0 kilograms per square meter (kg/m^2) (inclusive).
- Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
- Male or female participants:
- Male participants should not engage in intercourse while confined in the clinic. There is no need for an extended period of double barrier use or prolonged abstinence after study discharge.
- Female participants:
(i) A female participant is eligible to participate if she is not pregnant, planning to become pregnant within the next 6 months, or breastfeeding, and at least 1 of the following conditions applies: Is not a woman of childbearing potential (WOCBP) OR Is a WOCBP and using a non-hormonal contraceptive method that is highly effective, with a failure rate of less than ( ]6 months) outpatient treatment. Participants with other conditions such as adjustment disorder or dysthymia that have required shorter term medical therapy ( =1.5 times upper limit of normal (ULN). A single repeat of ALT is allowed within a single Screening period to determine eligibility.
- Bilirubin >=1.5 times ULN (isolated bilirubin >=1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin 150 millimeters of mercury (mm Hg) or 95 mm Hg or 100 bpm when vital signs are measured at Screening or Check-in (Day -2). A HR from 100 to 110 bpm can be rechecked by ECG or vital signs within up to 2 hours to verify eligibility.
- An uninterpretable ECG or any significant arrhythmia or ECG finding (e.g., prior myocardial infarction in the past 3 months, significant pathological Q-waves (defined as Q-wave >40 ms or depth greater than 0.4-0.5 millivolts [mV], symptomatic bradycardia, non-sustained or sustained atrial arrhythmias, ventricular pre-excitation, non-sustained or sustained ventricular tachycardia, any degree of atrioventricular block, complete left bundle branch block, or conduction abnormality) which, in the opinion of the investigator or VH/GSK Medical Monitor, will interfere with the safety of the individual participant.
- Exclusion criteria for Screening ECG (a single repeat is allowed for eligibility determination):
(i) HR: 100 bpm (ii) QTcF interval1: >450 ms (iii) QRS interval: >110 ms (iv) PR interval: >200 ms
- Screening Holter (24 hours) with any of the following:
(i) Sinus bradycardia less than or equal to ( 60 bpm for 10 seconds or longer.
(ii) Non-sustained ventricular tachycardia or more than 30 ventricular premature depolarizations during an hour.
(iii) Atrial arrhythmia >100 bpm for 3 seconds or longer or more than 40 atrial premature depolarizations during an hour.
- History of alcoholism and/or drug/chemical abuse or regular alcohol consumption within 6 months of screening, defined as an average weekly intake of >14 units. One unit is equivalent to 8 grams of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine, or 1 (25 mL) measure of spirits.
- Unable to refrain from tobacco or nicotine-containing products within 3 months prior to Screening and for the duration of the study.
- History of sensitivity to any of the study medications or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.
Data sourced from ClinicalTrials.gov (NCT04563845). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.