A Study to Assess the Safety and Pharmacokinetics of Inhaled Doses of GSK233705 and GW642444 in Healthy Subjects.

A Single Centre, Randomised, Placebo-controlled, Four-way Cross Over Study to Assess the Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of Single Inhaled Doses of GSK233705 and GW642444 as Monotherapies and in Combination in Healthy Subjects.

GW642444 and GSK233705 are in development for treatment of Chronic Obstructive Pulmonary Disease. Development of these two inhaled drugs as a combination therapy would have potential for improved patient benefit as they both work through different mechanisms and the combined bronchodilatory effect might be additive. This study will look at the this combination, for the first time, in healthy subjects.

Study Overview

• Status: Completed
• Conditions: Pulmonary Disease, Chronic Obstructive
• Intervention / Treatment: Drug: GSK233705; Drug: GW642444; Drug: GSK233705 and GW642444; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, NW10 7NS
    • 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:

• Healthy as determined by a responsible 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.
• Female subjects must be of non childbearing potential including pre-menopausal females with documented (medical report verification) hysterectomy or double oophorectomy or postmenopausal
• Male subjects must agree to use one of the contraception methods listed in protocol. This criterion must be followed from the time of the first dose of study medication until 90 days post-last dose.
• BMI within the range 18 - 30 kg/m2 (inclusive).
• Average QTc(B)≤450 msec taken from triplicate assessments at screening.
• No clinically active and relevant abnormality on 12-lead ECG at screening or 24h Holter ECG.
• 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))
• A signed and dated written informed consent is obtained from the subject
• The subject is capable of giving informed consent, which includes compliance with the requirements and restrictions listed in the consent form
• Available to complete the study

Exclusion Criteria:

• Any clinically important abnormality identified at the screening medical assessment (physical examination/medical history), clinical laboratory tests, or ECG (12-lead). 24hr Holter monitoring outside normal limits.
• A history of breathing problems (i.e. history of asthmatic symptomatology, unless asthma in childhood that has now resolved and no longer requires maintenance therapy which should not be an exclusion).
• 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 positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
• A positive test for HIV antibody (if determined by the local SOP's).
• History of high 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, (except for simple analgesics eg paracetamol), 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, 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.
• 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.
• Urinary cotinine levels indicative of smoking or history of regular use of tobacco- or nicotine-containing products prior to screening.
• 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,
• The subject has a known allergy or hypersensitivity to milk protein or the excipients lactose monohydrate and MgSt.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Period 1; Subjects will receive first placebo, then GSK233705, GW642444 and combination of GSK233705 and GW642444	Drug: GSK233705; Subjects will receive 200 (mcg) microgram once daily as a single dose; Drug: GW642444; Subjects will receive 50 mcg once daily as a single dose; Other Names: GSK233705; Drug: GSK233705 and GW642444; Subjects will receive combination of GSK233705 200 mcg and GW642444 50 mcg as a single oral dose; Drug: Placebo; Placebo matching study medication will be inhaled by subjects
Experimental: Period 2; Subjects will receive first combination of GSK233705 and GW642444, then placebo, GSK233705 and GW642444	Drug: GSK233705; Subjects will receive 200 (mcg) microgram once daily as a single dose; Drug: GW642444; Subjects will receive 50 mcg once daily as a single dose; Other Names: GSK233705; Drug: GSK233705 and GW642444; Subjects will receive combination of GSK233705 200 mcg and GW642444 50 mcg as a single oral dose; Drug: Placebo; Placebo matching study medication will be inhaled by subjects
Experimental: Period 3; Subjects will receive first GSK233705, then GW642444, combination of GSK233705 and GW642444 and later placebo	Drug: GSK233705; Subjects will receive 200 (mcg) microgram once daily as a single dose; Drug: GW642444; Subjects will receive 50 mcg once daily as a single dose; Other Names: GSK233705; Drug: GSK233705 and GW642444; Subjects will receive combination of GSK233705 200 mcg and GW642444 50 mcg as a single oral dose; Drug: Placebo; Placebo matching study medication will be inhaled by subjects
Experimental: Period 4; Subjects will receive first GW642444, then combination of GSK233705 and GW642444, placebo, and later GSK233705	Drug: GSK233705; Subjects will receive 200 (mcg) microgram once daily as a single dose; Drug: GW642444; Subjects will receive 50 mcg once daily as a single dose; Other Names: GSK233705; Drug: GSK233705 and GW642444; Subjects will receive combination of GSK233705 200 mcg and GW642444 50 mcg as a single oral dose; Drug: Placebo; Placebo matching study medication will be inhaled by subjects

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
General safety endpoints: measured over 24 hours post dose for all 4 dose periods, heart rate, systolic and diastolic blood pressure, 12- lead ECG and lung function and clinical laboratory safety tests. Adverse events over whole study.	Up to Day 2

Secondary Outcome Measures

Outcome Measure	Time Frame
Blood levels of GW642444, Blood levels of GSK233705, Blood Levels of potassium	Pre-dose; Day 1- 5, 15 and 30 minutes, 1, 2, 4, 5,6, 8, 12, 16 and 24 hours and Day 2

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

General Publications

• GSK has concluded that it is not feasible to publish this study in a peer-reviewed scientific journal because the nature of the study is unlikely to be of interest to a journal. GSK is providing the attached study results summary.

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): May 20, 2008
• Primary Completion (Actual): July 7, 2008
• Study Completion (Actual): July 7, 2008

Study Registration Dates

• First Submitted: April 30, 2008
• First Submitted That Met QC Criteria: May 2, 2008
• First Posted (Estimate): May 5, 2008

Study Record Updates

• Last Update Posted (Actual): October 4, 2017
• Last Update Submitted That Met QC Criteria: October 2, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: tolerability; safety; pharmacokinetics; healthy subjects; pharmacodynamics; Anticholinergic; ß2 agonist; Muscarinic Receptor Antagonist; GS642444; GSK233705
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
• Other Study ID Numbers: DB1111509

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. Individual Participant Data Set
   Information identifier: DB1111509
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Study Protocol
   Information identifier: DB1111509
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Statistical Analysis Plan
   Information identifier: DB1111509
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Annotated Case Report Form
   Information identifier: DB1111509
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Informed Consent Form
   Information identifier: DB1111509
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Clinical Study Report
   Information identifier: DB1111509
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
7. Dataset Specification
   Information identifier: DB1111509
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register