A Study to Evaluate the Safety, Tolerability, Pharmacokinetics (PK), Pharmacodynamics (PD) and Food Effect of Single or Repeat Doses of GSK2793660 in Healthy Subjects

Bronchiectasis Clinical Trial

Official title:

A Randomised, Double-blind (Sponsor Unblind), Placebo-controlled, Two Part Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of Single or Repeat Doses of GSK2793660 in Healthy Subjects

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02058407
• Other study ID #: 200186
• Status: Terminated
• Phase: Phase 1
• Start date: January 28, 2014
• Est. completion date: October 31, 2014

Study information

• Verified date: September 2018
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is the first administration of GSK2793660 to humans and will evaluate the safety, tolerability, PK and PD of single oral ascending doses of GSK2793660, and of repeat oral doses of GSK2793660 in healthy subjects. The study will comprise two parts (Part A and Part B). Part A will consist of two cohorts of subjects, each taking part in a three-way cross over study, with ascending doses of GSK2793660 and placebo. Available safety, PK and PD data will be reviewed before each dose escalation. This will be followed by a food-effect arm in the cohort that received what is deemed to be the target clinical dose. Part B is planned to consist of up to two cohorts of subjects, each taking part in one 14 day repeat dose study period. Subjects will be dosed on Day 1 and then on Days 3-15. It is planned that two doses will be evaluated. The dose(s) to be tested will be selected based on safety, PK, and PD from Part A. The study is intended to provide sufficient confidence in the safety profile of the molecule and information on target engagement to allow progression to further studies.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 33
• Est. completion date: October 31, 2014
• Est. primary completion date: October 31, 2014
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

Inclusion Criteria:

• Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, and laboratory tests. A subject with a clinical abnormality or laboratory parameters outside the reference range, and which is not a part of an eligibility criterion, for the population being studied may be included only if the Investigator and GSK medical monitor consider the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures and outcome.

• Male or female between 18 and 55 years of age inclusive, at the time of signing the informed consent.

• A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation, removal of both ovaries or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) >21.7 International units per liter (IU/L) and oestradiol <110 picomole per liter (pmol/L) is confirmatory]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods listed in the protocol 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 enrollment. For most forms of HRT, at least 2-4 weeks should elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.

• Male subjects with female partners of child-bearing potential must agree to use one of the approved contraception methods as detailed in the protocol. This criterion must be followed from the time of the first dose of study medication until the follow-up visit.

• Body weight >=50 Kilogram (kg) and Body Mass Index (BMI) within the range 19.9-30.0 kg/meter square (m^2) (inclusive).

• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

• Based on averaged QT duration corrected for heart rate by Fridericia's formula (QTcF) values of triplicate ECGs obtained over a brief recording period: Average QTcF <450 milliseconds (msec)

• Systolic blood pressure <=130 millimeters of mercury (mmHg) and diastolic blood pressure 80 mmHg based on average values of triplicate blood pressure readings obtained over a brief period.

• Alanine aminotransferase (ALT), alkaline phosphatase and bilirubin <=1.5x Upper Limit of Normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).

Exclusion Criteria:

• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).

• ECG finding of second or third degree heart block.

• History of regular alcohol consumption within 6 months of the study defined as: an average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 gram of alcohol: a half-pint (approximately 240 milliliter [mL]) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.

• 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 GSK Medical Monitor, contraindicates their participation.

• History of sensitivity to heparin or heparin-induced thrombocytopenia.

• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.

• Urinary cotinine or exhaled breath carbon monoxide (CO) levels indicative of current smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening.

• A positive pre-study drug/alcohol screen.

• A positive test for human immunodeficiency virus (HIV) antibody.

• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period. Blood donation will not exceed 500 mL for the entire study.

• 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.

Related Conditions & MeSH terms

• Bronchiectasis

Intervention

Drug:
• GSK2793660 solution
Clear, colourless solution at a unit dose strength of 0.1 mg/mL, in a glass bottle
• GSK2793660 capsule
Size zero swedish orange capsule at a unit dose of 3 mg, 10 mg, 20 mg and 50 mg
• Placebo solution
Matching placebo to GSK2793660 solution
• Placebo capsule
Matching placebo to GSK2793660 capsule

Locations

Country	Name	City	State
United Kingdom	GSK Investigational Site	London

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety and tolerability of GSK2793660 as assessed by vital signs in Part A and Part B	Vital sign measurements will include systolic and diastolic blood pressure, pulse rate, respiratory rate and oral body temperature	Part A: Screening (SCR), Day 1 (Pre-dose, 0.25 hours (h), 0.5 h, 1.5 h, 2 h, 3 h, 4 h, 12 h), Day 2 (24 h), Day 3 (48 h), Day 4 (72 h) in each period and at follow-up (7-14 days post last dose); Part B: SCR, Day 1 to Day 18 and at follow-up
Primary	Safety and tolerability of GSK2793660 as assessed by cardiac telemetry in Part A and Part B	Continuous cardiac telemetry will be performed in Part A and Part B of the study	Part A: From 1 h pre-dose on Day 1 until 24 h post dose on Day 2 in each period. Part B: From 1 h prior to dosing on Day 3 until pre-dose on Day 5
Primary	Safety and tolerability of GSK2793660 as assessed by electrocardiograms (ECGs) in Part A and Part B	Cardiac safety will be assessed by 12-lead ECGs	Part A: SCR, Day 1 (Pre-dose, 0.25 h, 0.5 h, 1.5 h, 2 h, 3 h, 4 h, 12 h), Day 2 (24 h), Day 3 (48 h), Day 4 (72 h) in each period and at follow-up (7-14 days post last dose); Part B: SCR, Day 1 to Day 18 and at follow-up
Primary	Safety and tolerability of GSK2793660 as assessed by laboratory data in Part A and Part B	Laboratory assessments will include hematology, clinical chemistry and urinalysis parameters	Part A: SCR, Day -1, Day 1 (8 h), Day 2 (24 h), Day 4 (72 h) in each period and at follow-up (7-14 days post last dose); Part B: SCR, Day -1, Day 2, Day 4, Day 10, Day 15, Day 18 and at follow-up
Primary	Safety and tolerability of GSK2793660 as assessed by adverse events (AEs) in Part A and Part B		Part A: Approximately 22- 24 weeks. Part B: Approximately 9 weeks
Secondary	Composite of PK parameters for GSK2793660 in Part A and Part B	PK parameters for GSK2793660 in plasma will include: area under the plasma concentration-time curve (AUC[0-t], AUC[0-infinity]), maximum observed plasma concentration (Cmax), time to Cmax (Tmax), apparent terminal phase half-life (T1/2).	Part A: Pre-dose, 0.25, 0.5, 1.5, 2, 3, 6, 8, 12, 16, 24, 30, 48 and 72 h; Part B: Days 1 and 15 (Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 6, 8 and 12 h), Days 2 and 16 (16, 24 and 30 h), Days 3 and 17 (48 h), Day 18 (72 h), Days 4, 7, 9, 11, 13 (pre-dose)
Secondary	To evaluate biomarker activity following oral administration of GSK2793660 in Part A and Part B	Blood biomarkers that will provide information on target engagement and downstream PD activity will be assessed. Biomarker endpoints including, but not limited to, cathepsin C enzyme activity in whole blood following single dose administration. Neutrophil serine protease activity (i.e. neutrophil elastase, cathepsin G, proteinase 3 [PR3]) following repeat dose administration. Other endpoints may include LL37 in cell extracts and surface expression of PR3 on neutrophils following repeat dose administration.	Part A: Pre-dose, 1 h, 2 h, 3 h, 6 h, 8 h, 12 h, 24 h, 30 h, 48 h, 72 h, 144 h in each period; Part B: Day 1 and Day 15 (Pre-dose, 1 h, 3 h, 6 h, 8 h and 12 h), Day 2 and Day 16 (24 h and 30 h), Day 3 and Day 17 (48 h), Day 18 (72 h)
Secondary	Effect of food on PK of GSK2793660 in Part A	PK parameters for GSK2793660 in plasma will include: AUC(0-t), AUC(0-infinity), Cmax, Tmax, and T1/2.	Pre-dose, 0.25, 0.5, 1.5, 2, 3, 6, 8, 12, 16, 24, 30, 48 and 72 h

External Links

•   Results for study 200186 can be found on the GSK Clinical Study Register.