Clinical Trial to Investigate the Safety, Tolerability and Pharmacokinetics of BVL-GSK098 in Healthy Volunteers

Study Overview
=================
Brief Summary
-----------------
This is a phase I single-center, double-blind, randomized, placebo-controlled study to investigate the safety, tolerability and pharmacokinetics and food effect of BVL-GSK098 administered as single and multiple oral doses to healthy volunteers

Detailed Description
-----------------
This is an exploratory, first-in-human (FIH), double-blind, randomized, placebo-controlled, single and multiple ascending oral dose study in healthy volunteers.The study will be divided into two parts that will be conducted sequentially. Part A is a SAD study to determine the safety, tolerability and PK of single oral doses of BVL-GSK098 in healthy volunteers. In addition, the last cohort of Part A will investigate the effect of food on the PK of BVL-GSK098. Part B is a MAD study to determine the safety, tolerability and PK of BVL-GSK098 following multiple daily oral doses in healthy volunteers.

Official Title
-----------------
A Phase I, Double-blind, Randomized, Placebo-controlled Study to Investigate the Safety, Tolerability and Pharmacokinetics and Food Effect of BVL-GSK098 Administered as Single and Multiple Oral Doses to Healthy Volunteers

Conditions
-----------------
Healthy Volunteers

Intervention / Treatment
-----------------
* Drug: BVL-GSK098 capsule, placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Volunteers aged 18 to 55 years inclusive and between 19 and 30 kg/m2 body mass index (BMI) with a minimum weight of 50 kg or men and 45 kg for women, at the time of signing the informed consent. Volunteers who are healthy as determined by the investigator based on medical evaluation including medical history, physical examination and cardiac monitoring. Volunteers who have a clinically acceptable temperature, blood pressure and pulse rate in supine and standing position (systolic blood pressure between 100-140 mm Hg/ diastolic blood pressure between 50-90 mm Hg / HR between 50-100 bpm). Blood pressure and pulse will be measured after a minimum of 3 minutes of resting. Volunteers whose clinical laboratory test results are not clinically relevant and are acceptable to the Investigator. Male volunteers must use appropriate contraception (e.g. condoms as part of a double barrier method) from the time of the first dose until 3 months after the post-study visit. A female volunteer is eligible to participate if she is of non-childbearing potential, defined as: Is equal to or older than 45 years of age and has not had menses for greater than 1 year, Amenorrheic for less than 2 years without a hysterectomy and oophorectomy and a follicle-stimulating hormone value in the postmenopausal range upon pretrial (screening) evaluation, Whose status is post hysterectomy, oophorectomy or tubal ligation. Nonsmokers (i.e., one who has abstained from use of tobaccco and other nicotine-containing products for the last 6 months). Willingness to stay in the investigational site for up to 11 days. Volunteers are capable of giving signed informed consent which included compliance with the requirements and restrictions listed in the consent form and in this protocol. Exclusion Criteria: Women of childbearing potential Pregnant or lactating women Men with female partners who are lactating or are pregnant Glomerular Filtration Rate (GFR) < 90 mL/min/1.73m2 as calculated by the Chronic Kidney Disease Epidemiology Collaboration formula. Alanine aminotransferase (ALT), Gamma glutamyl transferase (GGT), Aspartate aminotransferase (AST), alkaline phosphatase or serum bilirubin levels must not exceed the upper limit of normal (ULN) A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening. A positive test for HIV antibody. A positive pre-study drug/alcohol screen. Volunteers who consume more than 21 units of alcohol per week or who have a significant history of alcoholism or drug/chemical abuse (one unit of alcohol equals ½ pint [285 mL] of beer or lager, one glass [125 mL] of wine, or 30 mL of 40% of alcohol by volume distilled spirits). Volunteers who are study site employees, or immediate family members of a study site or sponsor employee. Volunteers with ECG abnormalities (history, or evidence of second-degree heart block of Mobitz type II, third degree heart block, or any abnormality considered relevant by the Investigator), QTcB or QTcF >450 ms or PR>220 ms). Volunteers with a history of additional risk factors for torsade de pointes (TdP) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome) History of clinically significant cardiovascular, renal, hepatic, chronic respiratory or gastrointestinal disease, neurological or psychiatric disorder, as judged by the investigator. History of seizures. Volunteers who have received any prescribed systemic or topical medication within 4 weeks of the first dose administration. Volunteers who have used any non-prescribed systemic or topical medication (including herbal remedies) or megadose vitamins (i.e. 20 to 600 times the recommended daily supplement dose) within 7 days of the first dose administration, unless in the opinion of the Investigator the medication will not interfere with the study procedures or compromise safety. Volunteers who have received any medications, including St John's Wort, known to chronically alter drug absorption or elimination processes within 30 days of the first dose administration. Volunteers who have participated in other clinical trials during the previous 90 days (drug to drug period) in which an investigational drug or a commercially available drug was tested. Exposure to more than 4 new chemical entities in the last 12 months before the first dosing day in this study. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56-day period. Failure to satisfy the investigator of fitness to participate for any other reason

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Ascending Dose (SAD)<br>There are multiple dose levels or cohorts. Each cohort has 6 subjects randomized to BVL-GSK098 and 2 subjects randomized to placebo. | Drug: BVL-GSK098 capsule, placebo<br>* Oral QD<br>|
| Experimental: Multiple Ascending Dose (MAD)<br>There are multiple dose levels or cohorts. Each cohort has 6 subjects randomized to BVL-GSK098 and 2 subjects randomized to placebo. | Drug: BVL-GSK098 capsule, placebo<br>* Oral QD<br>|
| Experimental: Food Effect<br>This cohort has 6 subjects randomized to BVL-GSK098 and 2 subjects randomized to placebo. Each participant will receive a single oral dose of BVL-GSK098 or placebo administered after the participant eats a high-fat, high calorie breakfast. | Drug: BVL-GSK098 capsule, placebo<br>* Oral QD<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) | All AEs will be counted and described within each cohort/dose level, by treatment received and tabulated. | From screening visit (Day -3 to -30) to end of study (7-10 days post last dose) | 
| Number of participants with clinically significant abnormal findings in hematology parameters | Blood samples will be collected for the assessment of hematology parameters. | Day 1 until end of study (7-10 days post last dose) | 
| Number of participants with clinically significant abnormal findings in clinical chemistry parameters | Blood samples will be collected for the assessment of chemistry parameters. | Day 1 until end of study (7-10 days post last dose) | 
| Number of participants with urinalysis findings | Urine samples will be collected for the assessment of urinalysis parameters. | Day 1 until end of study (7-10 days post last dose) | 
| Number of participants with clinically significant abnormal findings in vital signs | Number of participants with abnormal vital signs will be assessed. | Day 1 until end of study (7-10 days post last dose) | 
| Number of participants with clinically significant abnormal findings in Electrocardiogram (ECG) Parameters | Triplicate 12-lead ECGs will be obtained | Day 1 until end of study (7-10 days post last dose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed plasma drug concentration (Cmax) of BVL-GSK098 | Blood samples will be collected to evaluate Cmax of BVL-GSK098 | Single dose: up to 72 hours; Multiple dose: up to 10 days | 
| Time to maximum observed plasma drug concentration (tmax) of BVL-GSK098 | Blood samples will be collected to evaluate tmax of BVL-GSK098 | Single dose: up to 72 hours; Multiple dose: up to 10 days | 
| Area under the plasma drug concentration versus time curve (AUC) of BVL-GSK098 | Blood samples will be collected to evaluate AUC of BVL-GSK098 | Single dose: up to 72 hours; Multiple dose: up to 10 days | 
| Apparent terminal half-life (t1/2) of BVL-GSK098 as appropriate | Blood samples will be collected to evaluate t1/2 of BVL-GSK098 | Single dose: up to 72 hours; Multiple dose: up to 10 days | 
| The effect of food on the plasma concentrations of BVL-GSK098 | Blood samples will be collected to evaluate the food effect on plasma concentrations of BVL-GSK098 | up to 72 hours | 
| Observed accumulation ratio following BVL-GSK098 repeat dosing |  | up to 10 days |