Pharmacokinetic and Safety of GSK573719 and GW642444 Administered Individually and Concurrently, With Verapamilin in Healthy Subjects

A Single-Centre, Randomised, Open-label Study to Evaluate the Effects of Steady-State Verapamil, a Moderate P-Glycoprotein and CYP3A4 Inhibitor, on the Pharmacokinetics of GSK573719 and GSK573719 in Combination With GW642444

The purpose of this study is to see if the Pharmacokinetics and the Safety Profile of GSK573719 and GSK573719/GW642444 are effected by concurrent dosing with the PGP inhibitor verapamil.

Study Overview

• Status: Completed
• Conditions: Pulmonary Disease, Chronic Obstructive
• Intervention / Treatment: Drug: GSK573719; Drug: GW573719/GW573719

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, NW10 7EW
    • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• AST, ALT, alkaline phosphatase and bilirubin < 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
• Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring.
• Male or female between 18 and 65 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 including pre-menopausal females with documented (medical report verification) hysterectomy, double oophorectomy or bilateral salpingectomy., or postmenopausal defined as 12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL and estradiol < 40 pg/ml (<140 pmol/L) or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy.
• Male subjects must agree to use one of the contraception methods listed in Section 8.1. This criterion must be followed from the time of the first dose of study medication until completion of the follow up visit.
• Body weight > 45 kg and BMI within the range 18 - 28 kg/m2 (inclusive).
• Capable of giving written informed consent and a signed and dated written informed consent is obtained, which includes compliance with the requirements and restrictions listed in the consent form.
• Normal spirometry (FEV1 ≥ 80% of predicted, FEV1/FVC ≥ 70%).
• Non-smokers (never smoked or not smoking for >6 months with <10 pack years history (Pack years = (cigarettes per day smoked/20) x number of years smoked))
• Available to complete the study

Exclusion Criteria:

• Any clinically important abnormality identified at the screening medical assessment (physical examination/medical history), clinical laboratory tests, ECG (12-lead) or from 24hr Holter monitoring. If the Investigator and the GSK Medical Monitor agree that a finding is unlikely to introduce additional risk factors and will not interfere with the study procedures a subject can be included.
• A mean QTc(B) value at screening >450msec, or an ECG that is not suitable for QT measurements (e.g. LBBB or poorly defined termination of the T wave).
• A history of elevated resting blood pressure or a mean blood pressure higher than 140/90 mmHg at screening.
• A mean heart rate outside the range 40-90 bpm at screening.
• The subject has a positive pre-study drug/alcohol screen. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates and benzodiazepines. The detection of drugs with a legitimate medical use would not necessarily be an exclusion to study participation. The detection of alcohol would not be an exclusion at screening but would need to be negative pre-dose and during the study.
• 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).
• A positive test for HIV antibody (if testing required by local SOP's).
• History of regular alcohol consumption within 3months of the study defined as:

an average weekly intake of greater than 21 units or an average daily intake of greater than 3 units (males), or defined as an average weekly intake of greater than 14 units or an average daily intake of greater than 2 units (females). One unit is equivalent to a half-pint (220mL) of beer or 1 (25ml) measure of spirits or 1 glass (125ml) of wine.

• 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 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.
• History of sensitivity to any of the study medications, verapamil or components thereof, known allergy or hypersensitivity to milk protein or the excipients lactose monohydrate and MgSt, or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
• Unwillingness or inability to follow the procedures outlined in the protocol.
• The subject is unable to use the novel dry powder inhaler correctly.
• The subject has a known allergy or hypersensitivity to ipratropium bromide, tiotropium, atropine and any of its derivatives.
• Any adverse reaction including immediate or delayed hypersensitivity to any β2 agonist or sympathomimetic drug,.
• Subject is kept under regulatory of judicial order in an institution.
• Subject is mentally or legally incapacitated.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: GSK573719	Drug: GSK573719; 13 days dosing with GSK573719, once daily dosing from day 1 to 13, concurrent dosing with verapamil from day 9 to 13.
Other: GSK573719/GW642444	Drug: GW573719/GW573719; 13 days dosing with GSK573719/GW573719, once daily dosing from day 1 to 13, concurrent dosing with verapamil from day 9 to 13.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Pharmacokinetic parameters of plasma and urine	15 days

Secondary Outcome Measures

Outcome Measure	Time Frame
General safety and tolerability endpoints: adverse events, heart rate, systolic and diastolic blood pressure, 12- lead ECG (QTc(B), QTc(F)) and clinical laboratory safety tests. 24hr Holter monitoring	From first dose on day 1 through to Follow Up visit

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

General Publications

• Mehta R, Kelleher D, Preece A, Hughes S, Crater G. Effect of verapamil on systemic exposure and safety of umeclidinium and vilanterol: a randomized and open-label study. Int J Chron Obstruct Pulmon Dis. 2013;8:159-67. doi: 10.2147/COPD.S40859. Epub 2013 Mar 27.

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 4, 2010
• Primary Completion (Actual): April 26, 2010
• Study Completion (Actual): April 26, 2010

Study Registration Dates

• First Submitted: May 20, 2010
• First Submitted That Met QC Criteria: May 20, 2010
• First Posted (Estimate): May 24, 2010

Study Record Updates

• Last Update Posted (Actual): June 14, 2017
• Last Update Submitted That Met QC Criteria: June 13, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: Verapamil; LABA; LAMA; Anticholinergic, β2 agonist; P-GP; Muscarinic Receptor Antagonist
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
• Other Study ID Numbers: 113950

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. Clinical Study Report
   Information identifier: 113950
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Annotated Case Report Form
   Information identifier: 113950
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Individual Participant Data Set
   Information identifier: 113950
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Study Protocol
   Information identifier: 113950
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Informed Consent Form
   Information identifier: 113950
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Dataset Specification
   Information identifier: 113950
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
7. Statistical Analysis Plan
   Information identifier: 113950
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register