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 Japanese 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 Japanese subjects.

Study Overview

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

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

Contacts and Locations

Study Locations

• United Kingdom
  • Stepney Green, United Kingdom, E1 4NL
    • 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. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator and the GSK Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
• Japanese ethnic origin (defined as having been born in Japan with four ethnic Japanese grandparents and able to speak Japanese)
• 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 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 90 days post-last dose.
• Body weight > 45 kg and body mass index within the range of 18-28 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 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.
• 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 (Hypericum)) 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: OTHER
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: QUADRUPLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Long acting muscarinic receptor antagonist (LAMA); Inhaled Long acting muscarinic receptor antagonist (LAMA which is in development as a treatment for Chronic Obstructive Pulmonary Disease.	Drug: GSK233705; Inhaled Long acting muscarinic receptor antagonist (LAMA which is in development as a treatment for Chronic Obstructive Pulmonary Disease.
EXPERIMENTAL: Long acting Beta 2 agonist (LABA); Inhaled Long Acting Beta 2 agonist (LABA) which is in development as a treatment for Chronic Obstructive Pulmonary Disease.	Drug: GW642444; Inhaled Long acting Beta 2 agonist (LABA)
EXPERIMENTAL: LAMA with LABA; Inhaled Long Acting Muscarinic receptor Antagonist (LAMA) and a inhaled Long Acting Beta 2 Agonist (LABA), both in development for treatment of Chronic Obstructive Pulmonary Disease and taken in combination.	Drug: GSK233705 and GW642444; Inhaled Long acting muscarinic receptor antagonist (LAMA) and a inhaled Long acting Beta 2 agonist (LABA) both in development as treatment for Chronic Obstructive Pulmonary Disease, taken in combination.
PLACEBO_COMPARATOR: Placebo; Matching placebo, no intervention.	Drug: Placebo; Matching placebo.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Heart rate	24 hours
Systolic and diastolic blood pressure	24 hours
12 lead ECG	24 hours
Lung Function	24 hours
Clinical laboratory safety tests	24 hours
Adverse events	Duration of study

Secondary Outcome Measures

Outcome Measure	Time Frame
Plasma concentrations of GSK233705 and derived pharmacokinetic parameters.	24 hours
Plasma concentrations of GW642444 and derived pharmacokinetic parameters.	24 hours
Weighted mean and minimum value potassium	0 to 4 hours post dose

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

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): November 10, 2008
• Primary Completion (ACTUAL): February 6, 2009
• Study Completion (ACTUAL): February 6, 2009

Study Registration Dates

• First Submitted: October 30, 2008
• First Submitted That Met QC Criteria: October 30, 2008
• First Posted (ESTIMATE): October 31, 2008

Study Record Updates

• Last Update Posted (ACTUAL): July 18, 2017
• Last Update Submitted That Met QC Criteria: July 13, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Keywords: Safety; Pharmacokinetics; Tolerability; Anticholinergic; Muscarinic Receptor Antagonist, Anticholinergic; ß2 agonist
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
• Other Study ID Numbers: 112146

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. Dataset Specification
   Information identifier: 112146
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Clinical Study Report
   Information identifier: 112146
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Annotated Case Report Form
   Information identifier: 112146
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Individual Participant Data Set
   Information identifier: 112146
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Informed Consent Form
   Information identifier: 112146
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Statistical Analysis Plan
   Information identifier: 112146
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
7. Study Protocol
   Information identifier: 112146
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register