Amyloidosis
Conditions
Keywords
Pro-arrhythmic, Holter ECG, SAP, Cardiac telemetry, Benign arrhythmic
Brief summary
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.
Interventions
DRUGGSK3039294
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.
DRUGPlacebo
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.
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
This will be a double-blinded (Sponsor unblinded) study in which the subjects and site staff (Pharmacist unblinded to prepare study drug) will be blinded for the duration of the study
Intervention model description
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, cross-over study. The decision to initiate Part B will be made based on an evaluation of data from Part A which will include an overall assessment of safety, PK and PD. Part B will also employ a randomized, double-blind, repeat dose, cross-over study design and will follow the same assessments and procedures as Part A.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
Eligibility Criteria Inclusion Criteria: * 18 to 65 years of age inclusive at the time of signing the informed consent. * Non-smokers only (defined as a non-smoker during the last 3 months prior to screening). * Body weight \> 50 kilograms and body mass index (BMI) and \<=30 kilograms/meter square. * Male subjects and women of non-child bearing potential only will be eligible. * Male subjects with female partners of childbearing potential must comply with one of the following contraception requirements from the time of first dose of study medication until completion of the follow-up visit. * Vasectomy with documentation of azoospermia. * Male condom plus partner use of one of the contraceptive options: Contraceptive sub dermal implant that meets the effectiveness criteria of a \<1% rate of failure per year, as stated in the product label; Intrauterine device or intrauterine system that meets the standard operating procedure (SOP) effectiveness criteria including a \<1% rate of failure per year, as stated in the product label; Oral Contraceptive, either combined or progestogen alone; Contraceptive vaginal ring; Occlusive cap (female diaphragm or cervical/vault cap) with a vaginal spermicide (foam, gel, cream or suppository). * Capable of giving signed informed. * Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. * 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 Medical Monitor if required agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. * Aspartate aminotransferase, Alanine aminotransferase, Alkaline phosphatase and bilirubin \<=1.5 ULN (Upper Limit of Normal) (isolated bilirubin \>1.5 ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of subjects with abnormal cardiac telemetry findings: Part B | Up to 23 days | Continuous telemetry will be performed for the assessments of cardiac arrhythmias. |
| Number of subjects with abnormal results on core urine monitoring: Part B | Up to 44 days | 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. |
| Number of subjects with abnormal vital sign parameters: Part A | Up to 58 days | 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. |
| Number of subjects with abnormal vital sign parameters: Part B | Up to 41 days | 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. |
| Number of subjects with abnormal 12-lead ECG findings: Part A | Up to 58 days | 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). |
| Number of subjects with abnormal 12-lead ECG findings: Part B | Up to 41 days | 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). |
| Number of subjects with abnormal cardiac telemetry findings: Part A | Up to 38 days | Continuous telemetry will be performed for the assessments of cardiac arrhythmias. |
| Number of subjects with benign arrhythmic events measured by Holter Electrocardiogram (ECG): Part A | Up to 44 days | 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, |
| Number of subjects with benign arrhythmic events measured by Holter ECG: Part B | Up to 27 days | 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, |
| Number of subjects with benign arrhythmic events as measured by cardiac telemetry: Part A | Up to 38 days | 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. |
| Number of subjects with benign arrhythmic events as measured by cardiac telemetry: Part B | Up to 23 days | 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. |
| Number of subjects with adverse events (AE) and serious adverse events (SAE): Part A | Up to 58 days | 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. |
| Number of subjects with AE and SAE: Part B | Up to 41 days | 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. |
| Number of subjects with abnormal hematology parameters: Part A | Up to 49 days | 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. |
| Number of subjects with abnormal hematology parameters: Part B | Up to 35 days | 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. |
| Number of subjects with abnormal clinical chemistry parameters: Part A | Up to 49 days | 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. |
| Number of subjects with abnormal clinical chemistry parameters: Part B | Up to 35 days | 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. |
| Number of subjects with abnormal urinalysis parameters: Part A | Up to 49 days | 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). |
| Number of subjects with abnormal urinalysis parameters: Part B | Up to 35 days | 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). |
| Number of subjects with abnormal results on core urine monitoring: Part A | Up to 52 days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma concentration of GSK3039294; Part A | 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 | Blood samples for PK analysis of GSK3039294 (pro-drug) will be collected at the time points indicated. |
| Plasma concentration of GSK2315698 (miridesap); Part A | 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 | Blood samples for PK analysis of GSK2315698 (miridesap) will be collected at the time points indicated. |
| Plasma concentration of GSK2315698 (miridesap); Part B | 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 | Blood samples for PK analysis of GSK2315698 (miridesap) will be collected at the time points indicated. |
| Plasma SAP levels; Part A | Up to 58 days | 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. |
| Plasma SAP levels; Part B | Up to 41 days | 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. |
| Plasma concentration of GSK3039294; Part B | 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 | Blood samples for PK analysis of GSK3039294 (pro-drug) will be collected at the time points indicated. |
Countries
United Kingdom
Outcome results
None listed