Heart Failure, Congestive
Conditions
Keywords
Healthy, Pharmacokinetics, Phase I, GSK2798745, Tablet
Brief summary
GSK2798745 is being developed as a novel therapeutic intervention for the treatment of pulmonary edema associated with heart failure (HF) and is currently under investigation in the form of a compounded capsule. This is an open-label, randomized, single-dose, crossover study with the purpose to determine the pharmacokinetics (PK) of three 2.4 milligrams (mg) tablet formulations of GSK2798745 in 12 healthy subjects. The three formulations developed for this study will be micronized GSK2798745 active pharmaceutical ingredient (API) (Tablet A), micronized GSK2798745 API with sodium lauryl sulfate (SLS) and hypromellose (Tablet B), milled GSK2798745 API with SLS and hypermellose (Tablet C), and Tablet D, which will be either A/B/C based on interim PK analysis of data from the first three treatment periods. Following a 30-day screening period, subjects will be randomized to one of the 6 treatment sequences: Treatment sequence 1: ABCD, 2=CABD, 3=ACBD, 4=BACD, 5=BCAD, 6=CBAD over three 4-day treatment periods. For treatment period 4, the best formulation based on the interim analysis data from the three treatment periods will be evaluated under fed conditions. Each treatment period will be separated by a minimum of 7 (+14)-day washout period. The total duration of participation in the study will be approximately 11 weeks including the follow-up visit.
Interventions
DRUGGSK2798745 Micronized API without SLS and hypermellose (Tablet A)
This is an immediate release tablet containing 2.4 mg of micronized GSK2798745 API; to be administered orally with 240 mL of water under fasted/fed conditions
DRUGGSK2798745 Micronized API with SLS and hypermellose (Tablet B)
This is an immediate release tablet containing 2.4 mg of micronized GSK2798745 API with SLS and hypermellose; to be administered orally in fasted/fed conditions with 240 mL of water
DRUGGSK2798745 milled API without SLS and hypermellose (Tablet C)
This is an immediate release tablet containing 2.4 mg of milled GSK2798745 API with SLS and hypermellose; to be administered orally in fasted/fed conditions, with 240 mL of water
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
* Between 18 and 75 years of age inclusive, at the time of signing the informed consent * Healthy as determined by the investigator or medically qualified designee 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 * Body weight \>=50 kg and body mass index within the range 18 - 32 kilogram (kg)/meter (m)\^2 (inclusive) * Male or female of non-child bearing potential: A male subject with a female partner of child bearing potential is eligible to participate if he agrees to use contraception as mentioned in the protocol during the treatment period and for at least 7 days after the last dose of study treatment and refrain from donating sperm during this period A female subject is eligible to participate if she is not a woman of childbearing potential (WOCBP) as defined in the protocol. * Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area under the curve (AUC) of GSK2798745 | Blood samples will be collected at the following time points: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 15 (Day 1), 24 and 36 (Day 2), 48 (Day 3) and 72 hours (Day 4) post dose in each of the treatment periods | AUC will be determined following a single oral dose of GSK2798745 under fasted conditions (Treatment periods 1-3) and fed conditions (Treatment period 4) |
| Maximum plasma concentration (Cmax) of GSK2798745 | Blood samples will be collected at the following time points: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 15 (Day 1), 24 and 36 (Day 2), 48 (Day 3) and 72 hours (Day 4) post dose in each of the treatment periods | Cmax will be determined following a single oral dose of GSK2798745 under fasted conditions (Treatment periods 1-3) and fed conditions (Treatment period 4) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Elimination half-life (T1/2) of GSK2798745 | Blood samples will be collected at the following time points: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 15 (Day 1), 24 and 36 (Day 2), 48 (Day 3) and 72 hours (Day 4) post dose in each of the treatment periods | T1/2 will be determined following a single oral dose of GSK2798745 |
| AUC of GSK2798745 following a standard Food Drug Administration (FDA) high fat, high calorie meal | Blood samples will be collected at the following time points: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 15 (Day 1), 24 and 36 (Day 2), 48 (Day 3) and 72 hours (Day 4) post dose in treatment period 4 | The effect of food on the PK of one of the three tablet formulations of GSK2798745 will be assessed by AUC following a single oral dose of GSK2798745 which was admininstered 30 minutes after start of a FDA high fat, high-calorie meal |
| Cmax of GSK2798745 following a standard FDA high fat, high calorie meal | Blood samples will be collected at the following time points: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 15 (Day 1), 24 and 36 (Day 2), 48 (Day 3) and 72 hours (Day 4) post dose in treatment period 4 | The effect of food on the pharmacokinetics of one of the three tablet formulations of GSK2798745 will be assessed by Cmax following a single oral dose of GSK2798745 which was admininstered 30 minutes after start of a FDA high fat, high-calorie meal |
| Systolic and diastolic blood pressure as a measure of safety and tolerability of GSK2798745 | Up to 11 weeks | This will be measured in triplicate in a semi-supine position after 5 minutes rest |
| Pulse rate as a measure of safety and tolerability of GSK2798745 | Up to 11 weeks | This will be measured in triplicate in a semi-supine position after 5 minutes rest |
| Respiratory rate as a measure of safety and tolerability of GSK2798745 | Up to 11 weeks | This will be measured in triplicate in a semi-supine position after 5 minutes rest |
| Safety and tolerability of single dose of GSK2798745 as assessed by electorcardiograms (ECGs) | Up to 11 weeks | Triplicate twelve-lead ECGs will be obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QT interval corrected according to Fridericia's formula (QTcF) intervals. ECGs will be measured after resting in semi-supine position for 5 minutes |
| Safety and tolerability of single dose of GSK2798745 as assessed by appetite assessments | Up to 11 weeks | Subject will be administered a four-item Simplified Nutritional Assessment Questionnaire (SNAQ) on Days -1 and 2 of each treatment period and at the Follow Up Visit; the sum of the scores for the individual items will constitute the SNAQ |
| Safety and tolerability of single dose of GSK2798745 as assessed by clinical chemistry | At Baseline (Day -1) | Clinical chemistry parameters included Blood urea nitrogen, Creatinine, Glucose (fasting), Uric acid, Potassium, Sodium, Calcium, Chloride, Total Protein, Albumin, and creatine phosphokinase |
| Safety and tolerability of single dose of GSK2798745 as assessed by urinalysis | At Baseline (Day -1) | The following urinalysis parameters will be measured: Protein, Blood, Ketones, glucose, specific gravity, power of hydrogen (pH) by dipstick method. If blood or protein is abnormal, microscopic examination will be performed |
| Safety and tolerability of single dose of GSK2798745 as assessed by liver function tests (LFTs) | At Baseline (Day -1) | The following parameters will be measured: Aspartate aminotransferase, Alanine aminotransferase, Alkaline phosphatase, Total and direct bilirubin |
| Safety and tolerability of single dose of GSK2798745 as assessed by weight assessments | Up to 11 weeks | — |
| Safety and tolerability of single dose of GSK2798745 as assessed by troponin measurement | At Baseline (Day -1) and 24 hours post dose on Day 2 | — |
| Number of subjects with any adverse events (AEs) as a measure of safety and tolerability of GSK2798745 | Up to 11 weeks | An AE is any untoward medical occurrence in a subject or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product |
| Safety and tolerability of single dose of GSK2798745 as assessed by hematology | At Baseline (Day -1) | Hematology parameters include platelet, red blood cell counts, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, neutrophils, lymphocytes, monocytes, eosinophils, and basophils |
| Time to maximum observed concentration (Tmax) of GSK2798745 | Blood samples will be collected at the following time points: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 15 (Day 1), 24 and 36 (Day 2), 48 (Day 3) and 72 hours (Day 4) post dose in each of the treatment periods | Tmax will be determined following a single oral dose of GSK2798745 |
Countries
United States
Outcome results
None listed