GSK3039294 has been developed to offer an orally available alternative to parenteral GSK2315698 (miridesap) for plasma serum amyloid P component (SAP) depletion prior to and following use of anti-SAP Monoclonal Antibody (mAb) in the treatment of systemic amyloidosis. The primary objectives of the study are to assess the cardiac arrhythmic potential of GSK3039294 and evaluate safety and tolerability of repeat doses of GSK3039294, in healthy subjects relative to placebo for the same duration. This study will consist of two parts, Part A and a conditional Part B. Part A is designed as a randomized double-blinded, 3 period, placebo-controlled, repeat-dose, crossover study. The decision to initiate Part B will be based on an evaluation of data from Part A, which will include an overall assessment of safety, pharmacokinetics (PK) and pharmacodynamics (PD). In Part A, there will be three treatment periods with 7 days of dosing in each and minimum 7-day washout period between each treatment session. Each subject will receive two dose levels of GSK3039294 and placebo. In Part B, there will be two treatment periods with 7 days of dosing in each and minimum 7-day washout period. Each subject will receive one dose level of GSK3039294 and placebo. In Part A, approximately 48 subjects will be recruited for an estimated total of 36 completers. In Part B, approximately 32 subjects will be recruited for an estimated total of 24 completers. The study will last up to approximately 10 weeks from screening to follow-up.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
GSK3039294 capsules will be available with a dose strength of 100 mg and 200 mg to be taken as single or multiple capsules orally along with water depending on the dosage required.
Matching placebo capsules to match active 100 mg and 200 mg dose strength will be available and to be taken as single or multiple capsules orally along with water depending on the number of active capsules to blind.
GSK Investigational Site
London, United Kingdom
Number of subjects with benign arrhythmic events measured by Holter Electrocardiogram (ECG): Part A
Benign arrhythmia is defined as one of the following events: atrial fibrillation, supraventricular arrhythmia, ectopic atrial rhythm, ventricular trigeminy, non-sustained ventricular tachycardia, junctional rhythm, accelerated idioventricular rhythm, sinus pause \> 3 seconds that are of no clinical significance. Benign arrhythmic events as measured by Holter ECG will be presented,
Time frame: Up to 44 days
Number of subjects with benign arrhythmic events measured by Holter ECG: Part B
Benign arrhythmia is defined as one of the following events: atrial fibrillation, supraventricular arrhythmia, ectopic atrial rhythm, ventricular trigeminy, non-sustained ventricular tachycardia, junctional rhythm, accelerated idioventricular rhythm, sinus pause \> 3 seconds that are of no clinical significance. Benign arrhythmic events as measured by Holter ECG will be presented,
Time frame: Up to 27 days
Number of subjects with benign arrhythmic events as measured by cardiac telemetry: Part A
Benign arrhythmia is defined as one of the following events: atrial fibrillation, supraventricular arrhythmia, ectopic atrial rhythm, ventricular trigeminy, non-sustained ventricular tachycardia, junctional rhythm, accelerated idioventricular rhythm, sinus pause \> 3 seconds that are of no clinical significance. Benign arrhythmic events as measured by cardiac telemetry will be presented.
Time frame: Up to 38 days
Number of subjects with benign arrhythmic events as measured by cardiac telemetry: Part B
Benign arrhythmia is defined as one of the following events: atrial fibrillation, supraventricular arrhythmia, ectopic atrial rhythm, ventricular trigeminy, non-sustained ventricular tachycardia, junctional rhythm, accelerated idioventricular rhythm, sinus pause \> 3 seconds that are of no clinical significance. Benign arrhythmic events as measured by cardiac telemetry will be presented.
Time frame: Up to 23 days
Number of subjects with adverse events (AE) and serious adverse events (SAE): Part A
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. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant.
Time frame: Up to 58 days
Number of subjects with AE and SAE: Part B
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. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant.
Time frame: Up to 41 days
Number of subjects with abnormal hematology parameters: Part A
Blood samples will be collected for assessment of hematology parameters including platelet count, red blood cell count (RBC), hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, percentage of reticulocytes, neutrophils, lymphocytes, monocytes, eosinophil's and basophils.
Time frame: Up to 49 days
Number of subjects with abnormal hematology parameters: Part B
Blood samples will be collected for assessment of hematology parameters including platelet count, RBC, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, percentage of reticulocytes, neutrophils, lymphocytes, monocytes, eosinophil's and basophils.
Time frame: Up to 35 days
Number of subjects with abnormal clinical chemistry parameters: Part A
Blood samples will be collected for the assessment of clinical chemistry parameters blood urea nitrogen, creatinine, glucose fasting, potassium, sodium, calcium, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total and direct bilirubin and total protein.
Time frame: Up to 49 days
Number of subjects with abnormal clinical chemistry parameters: Part B
Blood samples will be collected for the assessment of clinical chemistry parameters blood urea nitrogen, creatinine, glucose fasting, potassium, sodium, calcium, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total and direct bilirubin and total protein.
Time frame: Up to 35 days
Number of subjects with abnormal urinalysis parameters: Part A
Routine urinalysis will be performed for parameters specific gravity, potential of hydrogen (pH), glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase by dipstick method and microscopic examination (if blood protein is abnormal).
Time frame: Up to 49 days
Number of subjects with abnormal urinalysis parameters: Part B
Routine urinalysis will be performed for parameters specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase by dipstick method and microscopic examination (if blood protein is abnormal).
Time frame: Up to 35 days
Number of subjects with abnormal results on core urine monitoring: Part A
Core urine monitoring will be performed for parameters Spot Urine Protein Creatinine (UPC) ratio and urine pH using a pH meter. Samples for urine pH to be taken in the morning.
Time frame: Up to 52 days
Number of subjects with abnormal results on core urine monitoring: Part B
Core urine monitoring will be performed for parameters Spot UPC) ratio and urine pH using a pH meter. Samples for urine pH to be taken in the morning.
Time frame: Up to 44 days
Number of subjects with abnormal vital sign parameters: Part A
Vital signs will be measured in a semi-supine position after 5 minutes rest and will include systolic and diastolic blood pressure, and pulse. Blood pressure (systolic and diastolic) and pulse measurements should be preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions.
Time frame: Up to 58 days
Number of subjects with abnormal vital sign parameters: Part B
Vital signs will be measured in a semi-supine position after 5 minutes rest and will include systolic and diastolic blood pressure, and pulse. Blood pressure (systolic and diastolic) and pulse measurements should be preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions.
Time frame: Up to 41 days
Number of subjects with abnormal 12-lead ECG findings: Part A
ECG's will be obtained as measurements at screening, pre-dose and 1hr post-dose. 12-lead ECGs will be measured in semi-supine position after 5 minutes rest (single electrocardiogram for the presence of any abnormal findings).
Time frame: Up to 58 days
Number of subjects with abnormal 12-lead ECG findings: Part B
ECG's will be obtained as measurements at screening, pre-dose and 1hr post-dose. 12-lead ECGs will be measured in semi-supine position after 5 minutes rest (single electrocardiogram for the presence of any abnormal findings).
Time frame: Up to 41 days
Number of subjects with abnormal cardiac telemetry findings: Part A
Continuous telemetry will be performed for the assessments of cardiac arrhythmias.
Time frame: Up to 38 days
Number of subjects with abnormal cardiac telemetry findings: Part B
Continuous telemetry will be performed for the assessments of cardiac arrhythmias.
Time frame: Up to 23 days
Plasma concentration of GSK3039294; Part A
Blood samples for PK analysis of GSK3039294 (pro-drug) will be collected at the time points indicated.
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16 hours post-dose on Day 1; Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24 hours post-dose on Day 7; Pre-dose on Day 2, 3, 4, 5 and 6 and until follow-up
Plasma concentration of GSK3039294; Part B
Blood samples for PK analysis of GSK3039294 (pro-drug) will be collected at the time points indicated.
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16 hours post-dose on Day 1; Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24 hours post-dose on Day 7; Pre-dose on Day 2, 3, 4, 5 and 6 and until follow-up
Plasma concentration of GSK2315698 (miridesap); Part A
Blood samples for PK analysis of GSK2315698 (miridesap) will be collected at the time points indicated.
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16 hours post-dose on Day 1; Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24 hours post-dose on Day 7; Pre-dose on Day 2, 3, 4, 5 and 6 and until follow-up
Plasma concentration of GSK2315698 (miridesap); Part B
Blood samples for PK analysis of GSK2315698 (miridesap) will be collected at the time points indicated.
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16 hours post-dose on Day 1; Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24 hours post-dose on Day 7; Pre-dose on Day 2, 3, 4, 5 and 6 and until follow-up
Plasma SAP levels; Part A
Venous blood samples of approximately 4 milliliters will be collected for measurement of SAP. PD effect of repeat doses of GSK3039294 on plasma SAP levels will be recorded.
Time frame: Up to 58 days
Plasma SAP levels; Part B
Venous blood samples of approximately 4 milliliters will be collected for measurement of SAP. PD effect of repeat doses of GSK3039294 on plasma SAP levels will be recorded.
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Time frame: Up to 41 days