Study to Assess the Safety and PK of GSK573719 and GSK573719/GW642444(VI) Combination in Healthy Subjects and Subjects With Severe Renal Impairment

A Single-blind, Non-randomized Pharmacokinetic and Safety Study of Single Dose of GSK573719 and GSK573719 + GW642444 Combination in Healthy Subjects and in Subjects With Severe Renal Impairment

This study will assess the safety and pharmacokinetics of inhaled GSK573719 and GSK573719/vilanterol combination in healthy subjects and in subjects with severe renal impairment. The results of the study will provide guidance on the use of this product in subjects with severe renal impairment.

Study Overview

• Status: Completed
• Conditions: Pulmonary Disease, Chronic Obstructive
• Intervention / Treatment: Drug: Inhaled GSK573719; Drug: Inhaled GSK573719/vilanterol

Detailed Description

GSK573719 monotherapy and GSK573719/vilanterol combination are currently under development for the treatment of COPD. This study will assess the pharmacokinetics and safety of inhaled GSK573719 and GSK573719/vilanterol (VI) in healthy subjects and in subjects with severe renal impairment. Nine subjects with severe renal impairment (as defined by a Clcr<30mL/min) will be recruited along with healthy control subjects (as defined by a Clcr>80mL/min matched to the severe renal impairment subjects based on gender, ethnicity, body mass index (±15%) and age (±5 years)). The results from this study will provide guidance on the use of GSK573719 and GSK573719/VI in severe renally impaired patients.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 1

Contacts and Locations

Study Locations

• Czechia
  • Prague 7, Czechia, 170 00
    • GSK Investigational Site
• Hungary
  • Budapest, Hungary, H-1076
    • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female between 18 and 70 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 or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea or, child-bearing potential and is abstinent or agrees to use one of the contraception methods listed in the protocol for an appropriate period of time prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until follow-up.

• Body weight greater than or equal to 45 kg and body mass index (BMI) within the range 18 - 33 kg/m2 (inclusive)
• Single QTcF less than 450 msec; or QTc less than 480 msec in subjects with Bundle Branch Block.

Healthy Subjects:

• Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring
• Alanine aminotransferase (ALT), alkaline phosphatase and bilirubin less than or equal to 1.5x Upper Limit of Normal (ULN)
• Creatinine clearance greater than 80mL/min calculated by the Cockcroft-Gault equation using serum creatinine

Renally Impaired subjects:

• ALT less than 2xULN; alkaline phosphatase and bilirubin less than or equal to 1.5xULN
• Creatinine clearance less than 30mL/min calculated by the Cockcroft-Gault equation using serum creatinine.
• Subjects with renal insufficiency must have stable renal function defined as less than or equal to a 25% difference in creatinine clearance assessed on two occasions. Renal function will be based on estimated creatinine clearance (CLcr) calculated by the Cockcroft-Gault equation using serum creatinine obtained on two occasions separated by at least 4 weeks within the last 3 months

Exclusion Criteria:

• Suffered a lower respiratory tract infection in the 4 weeks before the screening visit
• A supine mean heart rate outside the range 40-90 beats per minute (BPM) at screening
• A positive pre-study drug/alcohol screen
• A positive test for HIV antibody
• Current or chronic history of liver disease, including documented cirrhosis or a history consistent with a diagnosis of cirrhosis, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
• 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
• Use of nephrotoxic medications 4 weeks before dosing
• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period
• Pregnant females as determined by positive serum or urine hCG test at screening or prior to dosing.
• Lactating females
• The subject has been treated for or diagnosed with depression within six months of screening or has a history of significant psychiatric illness
• Unwillingness or inability to follow the procedures outlined in the protocol
• Subject is mentally or legally incapacitated
• Subjects with smoking history of greater than 10 cigarettes per day 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 GSK Medical Monitor, contraindicates their participation.
• Unable to refrain from consumption of red wine, seville oranges, grapefruit or grapefruit juice and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices from 7 days prior to the first dose of study medication.

Healthy Subjects:

• Subjects with any predisposing condition that might interfere with the absorption, distribution, metabolism or excretion of drugs or any previous gastrointestinal (GI) surgery which the investigator considers sufficiently significant to interfere with the conduct, completion, or results of this trial or constitutes an unacceptable risk to the subject.
• Urinary tract or bladder infection within 4 weeks of the first scheduled administration of study drug.
• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
• History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of greater than 21 units for males or greater than 14 units for females.
• 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 GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.

Renally Impaired Subjects:

• Life expectancy less than 3 months
• Hemoglobin less than 8.5 g/dL (for sites in Hungary), or hemoglobin less than 11.0g/dL (for sites in the Czech Republic)
• Subjects on hemodialysis treatment
• Subjects who, within the past six months, have had a history of significant drug abuse or alcohol abuse
• Subjects who need to take any concomitant medication, either prescribed or overthe- counter, which may in the opinion of the Investigator, interfere in any way with the study procedure or be a safety concern. In particular subjects taking medications that significantly inhibit P450 CYP3A4 (e.g. ketaconazole) must not be included in this study
• If in the opinion of an examining physician an unstable cardiovascular, pulmonary or hepatic condition is present, or any other medical condition which the investigator considers sufficiently serious to interfere with the conduct, completion, or results of this trial or constitutes an unacceptable risk to the subject

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Severe renally impaired subjects; Approximately 9 subjects will complete each treatment arm	Drug: Inhaled GSK573719; All subjects will receive a single dose of GSK573719 (125mcg) in treatment period 1; Drug: Inhaled GSK573719/vilanterol; All subjects will receive a single dose of GSK573719 (125mcg)/vilanterol (25mcg) in treatment period 2
Experimental: Matched healthy volunteers; Matched to the severe renal impairment subjects based on gender, ethnicity, body mass index (±15%) and age (±5 years). Approximately 9 subjects will complete each treatment arm	Drug: Inhaled GSK573719; All subjects will receive a single dose of GSK573719 (125mcg) in treatment period 1; Drug: Inhaled GSK573719/vilanterol; All subjects will receive a single dose of GSK573719 (125mcg)/vilanterol (25mcg) in treatment period 2

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
GSK573719 and vilanterol plasma pharmacokinetic parameters	Including AUC(0-t), AUC(0-t'), Cmax, tmax, AUC(0-24), AUC(0-infinity), tlast, t1/2	Treatment Period 1 and 2: pre-dose, 5 mins, 15 mins, 30 mins, 1hr, 2hrs, 4hrs, 8hrs, 12hrs, 16hrs, 24hrs

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
GSK573719 urine pharmacokinetic parameters		Treatment Period 1 and 2: 0-4hrs, 4-8hrs, 8-12hrs, 12-24hrs
Vital Signs Measurements	Including systolic and diastolic blood pressure and heart rate	Screening (up to 21 days before dosing), Treatment Period 1 and 2: pre-dose, 5 mins, 15 mins, 30 mins, 1hr, 4hrs, 12hrs, 24hrs, Follow-up (7 to 14 days after last dose)
Adverse Events		From administration of first dose until follow-up (7 to 14 days after last dose)
Clinical Laboratory Tests	Including clinical chemistry, haematology and urinalysis tests	Screening (up to 21 days before dosing), Treatment Period 1 and 2: pre-dose, 24hrs, Follow-up (7 to 14 days after last dose)
12-lead ECG measurements		Screening (up to 21 days before dosing), Treatment Period 1 and 2: pre-dose, 5 mins, 15 mins, 30 mins, 1hr, 4hrs, 12hrs, 24hrs, Follow-up (7 to 14 days after last dose)

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

General Publications

• Mehta R, Hardes K, Brealey N, Tombs L, Preece A, Kelleher D. Effect of severe renal impairment on umeclidinium and umeclidinium/vilanterol pharmacokinetics and safety: a single-blind, nonrandomized study. Int J Chron Obstruct Pulmon Dis. 2014 Dec 18;10:15-23. doi: 10.2147/COPD.S68094. eCollection 2015.

Helpful Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Study record dates

Study Major Dates

• Study Start (Actual): March 29, 2012
• Primary Completion (Actual): June 22, 2012
• Study Completion (Actual): June 22, 2012

Study Registration Dates

• First Submitted: April 3, 2012
• First Submitted That Met QC Criteria: April 3, 2012
• First Posted (Estimate): April 5, 2012

Study Record Updates

• Last Update Posted (Actual): July 25, 2017
• Last Update Submitted That Met QC Criteria: July 24, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Keywords: safety; COPD; pharmacokinetics; renal impairment; GSK573719; GW642444; vilanterol
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Kidney Diseases; Urologic Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Renal Insufficiency
• Other Study ID Numbers: 114636

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Study Data/Documents

1. Study Protocol
   Information identifier: 114636
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Dataset Specification
   Information identifier: 114636
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Annotated Case Report Form
   Information identifier: 114636
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Informed Consent Form
   Information identifier: 114636
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Clinical Study Report
   Information identifier: 114636
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Individual Participant Data Set
   Information identifier: 114636
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
7. Statistical Analysis Plan
   Information identifier: 114636
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register