To Evaluate Effects of GSK2256294 on Pulmonary Artery Pressure in Healthy Volunteers Under Normoxic and Hypoxic Conditions

NCT02262689 | Completed Phase 1

• 1 other identifier: 201402
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

The study evaluates the effect of GSK2256294 exposure at steady state on pulmonary artery systolic pressure (PASP) in healthy volunteers, under hypoxic conditions, after 7 days of dosing. It is single centre, double blind, randomized, placebo-controlled study to be conducted in approximately 30 healthy volunteers. Subjects will be screened no more than 30 days. Subject will be admitted in clinical unit on Day -1. Subject will be dosed for 7 days in unit in morning on all days except for dosing on Days 3 -6. Dosing on Days 3 -6 will occur at home. Subjects will return to the unit on the evening of Day 6 and remain there until Day 8. Subjects will undergo echocardiography under normoxic and hypoxic on Day 1 pre-dose and on Day 7 post-dose. Subject will be followed up for 28- 32 days after discharge. The maximum estimated time that a subject will be enrolled in the study is 62 days from the screening visit to follow up.

Conditions

Pulmonary Disease, Chronic Obstructive

Keywords

GSK2256294; normoxic; hypoxic; Pulmonary artery systolic pressure (PASP)

Outcome Measures

Primary Outcomes (1)

• Change from baseline of PASP under hypoxic conditions

  PASP is an indicator of cardiac hemodynamic status and is non-invasively estimated by echocardiography. Change from baseline in PASP under hypoxic conditions following 7 days of GSK2256294 15 milligrams (mg) once daily. Change from baseline was calculated as the Day 7 value minus the Day1 value.

  Day 1 and Day 7

Secondary Outcomes (6)

• Change from baseline of PASP under normoxic conditions

  Day 1 and Day 7

• Number of subjects with Adverse events (AEs)

  Up to Day 32

• Assessment of 12-lead electrocardiogram (ECG)

  Up to Day 32

• Assessment of vital sign measurements

  Up to Day 32

• Assessment of physical examination findings

  Up to Day 32

Study Arms (2)

GSK2256294 15 mg

EXPERIMENTAL

Randomised subjects will be instructed to take three capsules of GSK2256294 15 mg, each morning for 7 days. Subjects will undergo echocardiography under normoxic and hypoxic conditions on Day 1 pre-dose and on Day 7 post-dose.

Drug: GSK2256294

Placebo

PLACEBO COMPARATOR

Randomised subjects will be instructed to take three capsules of matching placebo, each morning for 7 days. Subjects will undergo echocardiography under normoxic and hypoxic conditions on Day 1 pre-dose and on Day 7 post-dose.

Drug: Placebo

Interventions

GSK2256294 DRUG

GSK2256294 will be supplied as gelatin capsule to be administered orally with the unit dose 5 mg / dose level 15 mg

GSK2256294 15 mg

Placebo DRUG

Matched Placebo will be supplied as gelatin capsule to be administered orally

Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• AGE: Between 18 and 65 years of age inclusive, at the time of signing the informed consent
• Screening echocardiogram of at least good quality, without clinically significant abnormalities, and with mild-moderate tricuspid regurgitation sufficient for the reliable estimation of PASP, as determined by the echocardiography core laboratory or responsible cardiologist.
• Screening PASP within the normal range according to site standards
• 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.

You may not qualify if:

• Body weight \>= 60 kilogram and body mass index within the range 19 - 35 kilogram per square meter (inclusive)
• Female subject is eligible to participate if she is of non-reproductive potential 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, and documented bilateral oophorectomy. Postmenopausal criteria is 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) must discontinue their HRT before the start of the study; for those whose menopausal status is in doubt, they will be required to use one of the highly effective contraception methods and may need to have a blood sample taken to check FSH/estradiol levels.
• 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 two weeks after the last dose of study medication; vasectomy with documentation of azoospermia; male condom plus partner use of one of the contraceptive options below: 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 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 protocol, which includes compliance with the requirements and restrictions listed in the consent form and in protocol
• Subjects with sickle cell trait.
• History of pulmonary hypertension.
• Alanine aminotransferase (ALT) and bilirubin \>1.5x Upper limit of normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• QTcF \> 450 milliseconds (msec) NOTE: The QTc is the QT interval corrected for heart rate according to Fridericia's formula (QTcF). The specific formula that will be used to determine eligibility and discontinuation for an individual subject should be determined prior to initiation of the study. In other words, several different formulae cannot be used to calculate the QTc for an individual subject and then the lowest QTc value used to include or discontinue the subject from the trial. For purposes of data analysis, QTcF will be used as specified in the Reporting and Analysis Plan (RAP).
• Permitted Medications and Non-Drug Therapies: Acetaminophen, at doses of =\< 2 grams/day is permitted for use any time during the study. Other concomitant medication may be considered on a case by case basis by the investigator in consultation with the GSK Medical Monitor. All concomitant medications taken during the study will be recorded in the case report form. The minimum requirement is that drug name, dose administered and the dates of administration be recorded.
• Prohibited Medications and Non-Drug Therapies: Subjects must abstain from taking prescription or non-prescription drugs (including vitamins and dietary or herbal supplements), 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 until completion of the follow-up visit, unless in the opinion of the Investigator and sponsor the medication will not interfere with the study. - 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 of alcohol: 12 ounces (360 milliliter \[ml\]) of beer, 5 ounces (150 ml) of wine or 1.5 ounces (45 ml) of 80 proof distilled spirits.
• Urinary cotinine levels indicative of smoking or history or 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), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment. For potent immunosuppressive agents, subjects with presence of hepatitis B core antibody (HBcAb) should also be excluded.
• A positive pre-study drug/alcohol screen.

Sponsors & Collaborators

• GlaxoSmithKline: lead
• Parexel: collaborator

Study Sites (1)

GSK Investigational Site

Baltimore, Maryland, 21225, United States

Location

Related Links

• Results for study 201402 can be found on the GSK Clinical Study Register.
• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive; Hypoxia

Interventions

N-((4-cyano-2-(trifluoromethyl)phenyl)methyl)-3-((4-methyl-6-(methylamino)-1,3,5-triazin-2-yl)amino)cyclohexanecarboxamide

Condition Hierarchy (Ancestors)

Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Signs and Symptoms, Respiratory; Signs and Symptoms

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 9, 2014
• First Posted: October 13, 2014
• Study Start: January 8, 2015
• Primary Completion: April 24, 2015
• Study Completion: April 24, 2015
• Last Updated: May 9, 2017

Record last verified: 2017-05

Data Sharing

• IPD Sharing: Will share

Locations

US (1)