A Study to Investigate the Safety, Tolerability and Pharmacokinetics of GSK2339345.

A Randomised, Double-blind, Placebo Controlled, Inhaled Single Escalating and Repeat Dose Study Using an Aqueous Droplet Inhaler to Investigate the Safety, Tolerability and Pharmacokinetics of GSK2339345.

This is a study of the sodium channel inhibitor, GSK2339345. Cohort 1 will assess the safety, tolerability and PK of single ascending doses of GSK2339345 administered via an aqueous droplet inhaler in healthy subjects. Cohort 2 will assess the safety, tolerability, and PK of repeat doses of GSK2339345 administered four times a day for two consecutive days via an aqueous droplet inhaler.

Study Overview

• Status: Completed
• Conditions: Cough
• Intervention / Treatment: Drug: GSK2339345 (Inhaled) Single Dose; Other: Placebo (Inhaled) Single Dose; Drug: GSK2339345 (Inhaled) Repeat Dose; Other: Placebo (Inhaled) Repeat Dose

Detailed Description

The purpose of this study is to assess the safety, tolerability, and pharmacokinetics (PK) effects of GSK2339345 in healthy subjects. GSK2339345 is a blocker of neuronal voltage gated sodium channels in development for the treatment of chronic cough, excessive cough and post-viral and viral (acute) cough. Inhaled pan NaV inhibitors are associated with oropharyngeal sensation perturbation and so this study will establish the potential local sensate effects of GSK2339345 at multiples of the predicted inhaled therapeutic dose. This study also aims to define the maximum tolerated dose of GSK2339345 administered via an aqueous droplet inhaler. Cohort 1 is a randomised, double-blind, placebo-controlled, cross-over, inhaled single-dose escalating study using an aqueous droplet inhaler. Cohort 1 will include assessments of sensate changes via a 4 point scale, assessment of taste via an 11 point scale, and PK assessments to investigate the PK profile of GSK2339345. Cohort 2 of this study is a randomised, double blind, placebo controlled, parallel group, inhaled repeat dose study using a aqueous droplet inhaler. Subjects will be randomised to receive 2000 microgram of GSK2339345 or placebo four times a day for two consecutive study days. Similar assessments of sensations to those used in Cohort 1 will be performed. The potential for systemic cardiovascular (CV) or central nervous system (CNS) effects will also be assessed throughout the study via observation. Cohort 2 will also include PK assessments to investigate the PK profile of GSK2339345. Placebo will be used throughout the study as a control.

• Study Type: Interventional
• Enrollment (Actual): 36
• 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: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• ALT, alkaline phosphatase and bilirubin ≤ 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
• Average QTcB < 450 msec
• Healthy as determined by a responsible and experienced 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.
• Male between 18 and 65 years of age inclusive, at the time of signing the informed consent.
• Male subjects with female partners of child-bearing potential 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 the follow up visit.
• Non-smoker for at least 6 months with a pack history ≤ 5pack years (Pack years = (No. of cigarettes smoked/day/20) x No. of years smoked).
• Body weight ≥ 50 kg and BMI within the range 19 - 32.0 kg/m2 (inclusive).
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
• A 24 hour Holter ECG at screening that demonstrates no clinically significant abnormalities or finding that could interfere with interpretation of the study results, when assessed by an appropriately trained and experienced reviewer.

Exclusion Criteria:

• 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).
• Current or chronic history of cardiovascular disease (e.g. hypertension, coronary heart disease, heart attack, angina, myocardial infarct, and stroke).
• A positive pre-study drug/alcohol screen.
• A positive test for HIV antibody.

• History of regular alcohol consumption within 6 months of the study defined as:

  • An average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (~240 ml) of beer, 1 glass (125 ml) of wine or 1 (25 ml) measure of spirits.

• 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.
• 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.
• FEV1 less than 80% of the predicted value prior to dosing.
• Any subject who, upon oropharyngeal examination, is deemed by the Investigator to be unsuitable for oropharyngeal sensation assessments. This includes any injuries to the mucosa of the mouth or pharynx that could potentially increase systemic absorption e.g candidiasis.
• Any subject who has a history of an allergic reaction to a local anaesthetic. 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.
• Subject is mentally or legally incapacitated.
• Subjects who have asthma or a history of asthma.
• Breath CO levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening.
• 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.
• Subjects who are unable to use the inhaler satisfactorily.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1. Inhaled GSK2339345/Placebo Single Dose (Cohort 1); administered three ascending doses of GSK2339345 or placebo as a solution via an aqueous droplet inhaler over four treatment periods, with at least 5 days washout between doses	Drug: GSK2339345 (Inhaled) Single Dose; 250, 1000 and 2000 microgram (proposed doses); Other: Placebo (Inhaled) Single Dose; Inhaled 0.9% sodium chloride solution
Experimental: 2. Inhaled GSK2339345/Placebo Repeat Dose (Cohort 2); administered a dose of GSK2339345 or placebo, four times a day on two consecutive days. Each subject will receive either GSK2339345 or matching placebo as a solution administered via an aqueous droplet inhaler	Drug: GSK2339345 (Inhaled) Repeat Dose; 2000 microgram (proposed dose) administered 4 times a day for two consecutive days; Other: Placebo (Inhaled) Repeat Dose; Inhaled 0.9% sodium cholride solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety parameters: AEs, vital signs, ECG, body temperature and laboratory assessments, including haematology, clinical biochemistry and cardiac troponin.	To assess the safety and tolerability of single and repeat inhaled doses of GSK2339345 administered by an aqueous droplet inhaler.	Approximately 5 weeks from first dose to the follow-up visit.
Assessment of oropharyngeal sensation perturbation via a 4 point scale.	To assess the changes in oropharyngeal sensation caused by single and repeat inhaled doses of GSK2339345 administered by an aqueous droplet inhaler.	Approximately 5 weeks from first dose to the follow-up visit.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma concentrations of GSK2339345 and single and repeat dose derived pharmacokinetic parameters including Cmax, tmax, AUC(0-t), AUC(0-inf), and AUC(0- τ), as appropriate where data allow.	To evaluate the systemic pharmacokinetics of single and repeat doses of inhaled GSK2339345 in healthy volunteers administered by an aqueous droplet inhaler.	Approximately 5 weeks from first dose to the follow-up visit.
Identification of taste of the solution and rating on 11 point scale to rate pleasantness or unpleasantness	To assess the palatability of GSK2339345 administered by an aqueous droplet inhaler	Approximately 5 weeks from first dose to the follow-up visit.

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): April 23, 2012
• Primary Completion (Actual): July 30, 2012
• Study Completion (Actual): July 30, 2012

Study Registration Dates

• First Submitted: April 19, 2012
• First Submitted That Met QC Criteria: April 26, 2012
• First Posted (Estimate): April 30, 2012

Study Record Updates

• Last Update Posted (Actual): July 26, 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 and tolerability, pharmacokinetics, cough, voltage gated sodium channels (VGSC), anaesthesia
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Signs and Symptoms, Respiratory; Cough
• Other Study ID Numbers: 115658 (Other Identifier: University of Leeds)

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: 115658
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Annotated Case Report Form
   Information identifier: 115658
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Individual Participant Data Set
   Information identifier: 115658
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Study Protocol
   Information identifier: 115658
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Informed Consent Form
   Information identifier: 115658
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Clinical Study Report
   Information identifier: 115658
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
7. Statistical Analysis Plan
   Information identifier: 115658
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register