NCT02795754 - Single and Repeated Dose Escalation Study of GSK2838232 | Crick

Eligibility

Sex: ALLMin age: 18 YearsMax age: 55 YearsHealthy volunteers:

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Inclusion Criteria: * Age: Between 18 and 55 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, and 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 * A creatinine clearance (CLcr) \>80milliliter/minute (mL/min) as determined by Cockcroft-Gault equation CLcr (mL/min) = (140 - age) \* weight (Wt) / (72 \* serum creatinine \[Scr\]) (times 0.85 if female) where age is in years, Wt is in kilogram (kg), and Scr is in units of milligram / decilitre (mg/dL);. * Body weight \>= 50.0 kg (110 pounds \[lbs.\]) for men and \>= 45.0kg (99lbs) for women and body mass index (BMI) * Male or females of non-reproductive potential: A female subject is eligible to participate if she is not pregnant \[as confirmed by a negative serum human chorionic gonadotrophin (hCG) test\], not lactating, and of non-reproductive potential which is defined as: Pre-menopausal females with one of the following: Documented tubal ligation; Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion ; Hysterectomy; Documented Bilateral Oophorectomy Post menopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause (refer to laboratory reference ranges for confirmatory levels)\]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. Male subjects with female partners of child bearing potential must comply with the following contraception requirements from the time of first dose of study medication until one week after the last dose of study medication. Vasectomy with documentation of azoospermia, or Male condom plus partner use of one of the contraceptive options following: Contraceptive subdermal implant that meets the standard operating procedure (SOP) effectiveness criteria including a \<1% rate of failure per year, as stated in the product label; Intrauterine device or intrauterine system that meets the SOP effectiveness criteria including a \<1% rate of failure per year, as stated in the product label; Oral Contraceptive, either combined or progestogen alone. Injectable progestogen; Contraceptive vaginal ring; Percutaneous contraceptive patches. These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label. The Investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception. * Capable of giving signed informed consent as described in Study protocol which includes compliance with the requirements and restrictions listed in the consent form and in protocol. Exclusion Criteria: * Alanine aminotransferase and bilirubin \>1.0\* upper limit of normal (ULN). * Current or chronic history of liver disease, or known hepatic or biliary abnormalities. * Subjects who have asthma or a history of asthma. * Medical history of cardiac arrhythmias or cardiac disease or a family and personal history of long QT syndrome * Unable to refrain from the use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GlaxoSmithKline (GSK) Medical Monitor, the medication will not interfere with the study procedures or compromise subject safety * History of regular alcohol consumption within 6 months of the study defined as: For US sites: an average weekly intake of \>14 drinks for males or \>7 drinks for females. One drink is equivalent to 12 grams (g) of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150mL) of wine or 1.5 ounces (45mL) of 80 proof distilled spirits. * Regular use of tobacco- or nicotine-containing products within 6 months prior to screening. * 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 * Presence of hepatitis B surface antigen (HBsAg), or positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment. * Screening or baseline cardiac troponin I greater than the 99% cut-off (\>.045 nanograms/mL by the Dimension Vista Cardiac troponin assay) for a given assay. * A positive pre-study drug/alcohol screen. * A positive test for HIV antibody. * Where participation in the study would result in donation of blood or blood products in excess of 500mL within 56 days. * The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer). * Exposure to more than four new chemical entities within 12 months prior to the first dosing day. * Exclusion Criteria for 48-Hour Screening Holter: Any symptomatic arrhythmia (except isolated extra systoles). Sustained cardiac arrhythmias (such as atrial fibrillation or flutter, supraventricular tachycardia (\>=10 consecutive beats), complete heart block). Non-sustained or sustained ventricular tachycardia (defined as \>= 3 consecutive ventricular ectopic beats). Any conduction abnormality (including but not specific to left or right incomplete or complete bundle branch block, atrioventricular (AV) block \[2nd degree or higher\], Wolf Parkinson White (WPW) syndrome etc.). Sinus Pauses \> 3 seconds. 300 or more supraventricular ectopic beats in 24 hours. 250 or more ventricular ectopic beats in 24 hours. * Any clinically significant abnormal echocardiogram finding. Abnormal echocardiogram findings should be discussed with the Medical Monitor prior to enrolment. * Exclusion criteria for screening ECG (a single repeat is allowed for eligibility determination): Heart rate for Males \<45 and \>100 beats per minute (bpm), for females \<50 and \>100bpm PR Interval \<120 and \>220 millisecond (msec) QRS duration \<70 and \>120msec QT interval corrected (Fridericia's) \>450msec

Outcomes

Primary Outcomes

Number of participants with adverse events (AEs)

An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

Time frame: Approximately 10 weeks

Safety as assessed by absolute values and change from Baseline in hematology parameters -Part 1

Hematology parameters includes platelet count, red blood cells (RBC) count, mean corpuscular volume (MCV), neutrophils, white blood cells (WBC) count (absolute), mean corpuscular hemoglobin (MCH), lymphocytes, reticulocyte count, mean corpuscular hemoglobin concentration (MCHC), monocytes, hemoglobin, eosinophils, hematocrit and basophils. Hematology parameters will be evaluated at Day -2, Day -1, Day 2, Day 4, Day 14 of each visit.

Time frame: Baseline (Day -1) and up to 10 weeks

Safety as assessed by absolute values and change from Baseline in hematology parameters - Part 2

Hematology parameters includes platelet count, RBC count, MCV, neutrophils, WBC count (absolute), MCH, lymphocytes, reticulocyte count, MCHC, monocytes, hemoglobin, eosinophils, hematocrit and basophils. Hematology parameters will be evaluated at Day -1, Day 2, Day 4, day 8, Day 11, Day 14, Day 17, Day 31 for each cohort

Time frame: Baseline (Day-1) and up to Day 31 for each cohort.

Safety as assessed by absolute values and change from Baseline in clinical chemistry parameters -Part 1

Clinical chemistry parameters includes blood urine nitrogen (BUN), potassium, aspartate aminotransferase (AST), Lipase, Creatinine, Sodium, alanine aminotransferase (ALT), total protein, glucose, chloride, alkaline phosphatase, albumin, magnesium, total carbon dioxide (CO2), total and direct bilirubin, uric acid, calcium, phosphorus and gamma-glutamyl transferase (GGT). Clinical chemistry parameters will be evaluated at Day -2, Day -1, Day 2, Day 4, Day 14 of each visit.

Time frame: Baseline (Day -1) and up to 10 weeks

Safety as assessed by absolute values and change from Baseline in clinical chemistry parameters- Part 2

Clinical chemistry parameters includes BUN, potassium, AST, lipase, creatinine, sodium, ALT, total protein, glucose, chloride, alkaline phosphatase, albumin, magnesium, total CO2, total and direct bilirubin, uric acid, calcium, phosphorus and GGT. Clinical chemistry parameters will be evaluated at Day -1, Day 2, Day 4, day 8, Day 11, Day 14, Day 17, Day 31 for each cohort

Time frame: Baseline (Day-1) and up to Day 31 for each cohort.

Safety as assessed by absolute values and change from Baseline in urinalysis parameters-Part 1

Urinalysis parameters includes specific gravity, pH, glucose, protein, blood and ketones by dipstick, microscopic examination. Urinalysis parameters will be evaluated at Day -2, Day -1, Day 2, Day 4, Day 14 of each visit.

Time frame: Baseline (Day -1) and up to 10 weeks

Safety as assessed by absolute values and change from Baseline in urinalysis parameters-Part 2

Time frame: Baseline (Day-1) and up to Day 31 for each cohort.

Safety as assessed by Blood pressure-Part 1

Systolic and diastolic blood pressure will be measured on Day 1, pre-dose (triplicate) and 1, 2, 4, 6, 8, 12, 24, 48, and 72hr post-dose during each visit.

Time frame: 10 weeks

Safety as assessed by Heart rate -Part 1

Heart rate will be measured on Day 1, pre-dose (triplicate) and 1, 2, 4, 6, 8, 12, 24, 48, and 72hr post-dose during each visit.

Time frame: 10 weeks

Safety as assessed by Blood pressure-Part 2

Systolic and diastolic blood pressure will be measured on Day -1, Day 1 at pre dose (triplicate), and 1hr, 4hr, 24hr, 48hr and 72hr post dose, Day 4, Day 5, Day 6, Day 7, Day 8, Day 9, Day 10, Day 11 at pre dose (triplicate), and 1hr, 4hr, 24hr, 48hr and 72hr post dose and at follow up during each cohort.

Time frame: 31 days in each cohort

Safety as assessed by Heart rate -Part 2

Heart rate will be measured on Day -1, Day 1 at pre dose (triplicate), and 1hr, 4hr, 24hr, 48hr and 72hr post dose, Day 4, Day 5, Day 6, Day 7, Day 8, Day 9, Day 10, Day 11 at pre dose (triplicate), and 1hr, 4hr, 24hr, 48hr and 72hr post dose and at follow up during each cohort.

Time frame: 31 days in each cohort

Safety as assessed by Electrocardiogram (ECG) parameters-Part 1

12-lead ECG will be conducted pre-dose on Day 1 (triplicate), and 1, 2, 4, 6, 8, 12, 24, 48 72 hour post dose.

Time frame: Up to 10 weeks

Safety as assessed by ECG parameters-Part 2

A single 12-Lead ECG will be conducted at screening and Day -1, Day 1 at pre dose (triplicate), and 1 hour, 12 hour, 24hour, 48 hour and 72 hour post dose, Day 5, Day 8 and Day 11 at pre dose (triplicate), and 1 hr, 12 hour, 24 hour, 48 hour, and 72 hour post dose and at follow up during each cohort.

Time frame: 31 days in for each cohort

Area under the concentration-time curve from time zero (pre-dose) to 24 hours (AUC[0-24]), Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC [0-inf]) in Part 1

Time frame: Plasma samples will be collected pre-dose (within 15 minutes prior to dosing) and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose at each study visit

Apparent oral clearance (CL/F) for single dose GSK2838232 in Part 1A

Time frame: Plasma samples will be collected pre-dose (within 15 minutes [min]prior to dosing) and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose at each study visit during Part 1A.

Area under the concentration-time curve over the dosing interval (AUC[0 tau]) for repeated dose GSK2838232 in Part 2

Time frame: Day 1; pre-dose (within 15 min prior to dosing) and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12 and 24 hr post dose.On Day 11; pre-dose (within 15 min prior to dosing) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hr post dose

Apparent oral clearance (CL/F) for repeated dose GSK2838232 in Part 2

Time frame: Plasma samples will be collected on Day 11; pre-dose (within 15 minutes prior to dosing) and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours post dose.

Tmax for repeated dose GSK2838232 in Part 2

Time frame: Day 1; pre-dose (within 15 min prior to dosing) and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12 and 24 hr post dose. On Day 11; pre-dose (within 15 min prior to dosing) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96,120 and 144 hr post dose

Tlag for repeated dose GSK2838232 in Part 2

Time frame: Day 1; pre-dose (within 15 min prior to dosing) and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12 and 24 hr post dose. On Day 11; pre-dose (within 15 min prior to dosing) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96,120 and 144 hr post dose

T1/2 for repeated dose GSK2838232 in Part 2

Time frame: Day 1; pre-dose (within 15 min prior to dosing) and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12 and 24 hr post dose. On Day 11; pre-dose (within 15 min prior to dosing) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96,120 and 144 hr post dose

Tlast for repeated dose GSK2838232 in Part 2

Time frame: Day 1; pre-dose (within 15 min prior to dosing) and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12 and 24 hr post dose. On Day 11; pre-dose (within 15 min prior to dosing) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96,120 and 144 hr post dose

Maximum observed concentration (Cmax) in Part 1

Concentration at 24 hours post dose (C24) in Part 1

Last measurable concentration (Clast) in Part 1

Time of occurence of Cmac (tmax) in Part 1

Lag time before observation of drug concentrations in sampled matrix (tlag) in Part 1

Terminal phase half life (t1/2) in Part 1

Time of last observed quantifiable concentration (t-last) in Part 1

Cmax of GSK2826232 in Part 2

Clast of GSK2826232 in Part 2

Concentration-time curve over the dosing interval (Ctau) of GSK2838232 in Part 2

Secondary Outcomes

AUC (0-inf) in Part 1

Cmax in Part 1

AUC(0-tau) in Part 2

Time frame: Day 1 pre-dose; 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24 hr post dose. Days 3-10 pre-dose; Day 11; pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hr post dose; all pre-dose within 15 min prior to dosing

Cmax in Part 2

Ctau in Part 2

Pre-dose GSK2838232 plasma concentrations on Day 2-11 in Part 2

Time frame: Up to Day 11

Accumulation ratios (Ro) for AUC (0-tau)

Accumulation ratios (Ro) for Cmax

Single and Repeated Dose Escalation Study of GSK2838232

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes