Clinical trial NCT01899768: GSK2339345 Hypertussive Challenge Study
Official title: A Randomised, Double-Blind (Sponsor-Unblind), Placebo Controlled, Cross-Over Study to Investigate the Efficacy, Effect on Cough Reflex Sensitivity, Safety, Tolerability and Pharmacokinetics of Inhaled GSK2339345 in Patients With Chronic Idiopathic Cough Using an Aqueous Droplet Inhaler
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cough
Keywords: efficacy
hypertussive challenge
voltage gated sodium channels (VGSC)
anaesthesia
Safety and tolerability
capsaicin challenge
cough
citric acid challenge
pharmacokinetics
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: North West Lung Centre
First posted: 2013-07-15
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: This study is designed to evaluate the effect of GSK2339345 relative to placebo on the number of coughs in patients with Chronic Idiopathic Cough (CIC) administered by an Aqueous Droplet Inhaler (ADI). The primary aim is to investigate the efficacy of GSK2339345 on reducing objective cough frequency in CIC patients. The secondary aim of this study is to investigate the efficacy of GSK2339345 in inhibiting a hypertussive cough response elicited by capsaicin and citric acid in CIC patients which have a hyperresponsive cough reflex.

Following the screening visit, all eligible subjects will attend the unit for dosing at Visits 1-7. At Visits 1, 2 and 3 (Part A of the study), subjects will receive two doses of either GSK2339345 or placebo, 4 hours apart and will undergo 8 hours of cough monitoring. At Visits 4 and 5 (Part B of the study) and Visits 6 and 7 (Part C of the study), subjects will be administered a single dose of either GSK2339345 or placebo. Subjects will then undergo capsaicin (Part B) or citric acid (Part C) tussive challenge and will undergo cough monitoring for 1 hour post dose.

The maximum study duration will be approximately 11 weeks, including 3 weeks screening and 2 weeks follow-up. Approximately 30 patients will be randomised into the study, such that approximately 24 patients complete dosing and critical assessments.


Eligibility criteria: Inclusion Criteria

* Chronic Idiopathic Cough patients according to the criteria listed below, determined by a responsible and experienced physician, based on a medical evaluation: Idiopathic cough defined as chronic cough resistant to treatment targeted at potential triggers. Chronic cough defined as cough lasting for more than 8 weeks.
* A patient 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/females aged \>=18 years old, at the time of signing the informed consent.
* Non-smoker for at least 6 months with a cumulative history of \<= 10 pack years. Pack years = (No. of cigarettes smoked/day/20) x (No. of years smoked).
* Body weight \>= 50 kilograms.
* 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 \[for this definition, "documented" refers to the outcome of the investigator's/designee's review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records\]; or postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone \> 40 milli international unit/milliliter (mL) and estradiol \< 40 picogram/ml (\<147 picomoles/Liter \[L\]) is confirmatory\]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2 to4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.

Child-bearing potential with negative pregnancy test as determined by serum human chorionic gonadotropin test at screening or prior to dosing and Agrees to use one of the contraception methods for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until the follow up visit or has only same-sex partners, when this is her preferred and usual lifestyle.

* Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods. This criterion must be followed from the time of the first dose of study medication until the follow up visit.
* Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
* Aspartate amino transferase and alanine amino transferase \< 2xupper limit of normal (ULN); alkaline phosphatase and bilirubin \<= 1.5xULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
* Based on averaged QT interval corrected (QTc) values of triplicate electrocardiograms (ECGs) obtained over a brief recording period: QTc using Fridericia's formula (QTcF) \< 450 millisecond.
* 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 Based Upon Medical Histories

* Subjects who have evidence of current asthma, as confirmed by the Investigator or designee.
* Subjects with any clinically significant respiratory condition or lung pathology that could cause cough (apart from chronic idiopathic cough).
* Known lung cancer or other active malignancy, or history of.
* Subjects with current or a chronic history of cardiovascular disease (including uncontrolled hypertension, ischemic heart disease, angina, myocardial infarct, congestive heart failure, and stroke).
* Subjects with current central nervous system / peripheral nervous system conditions e.g. epilepsy and myasthenia gravis.
* Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
* Any subject with a respiratory tract infection within 4 weeks of screening.
* Radiological imaging prior to the study, including chest X-rays, that have shown any evidence of clinically significant lung disease, as judged by the Investigator or designee.
* 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 grams of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
* Any subject who has a history of an allergic reaction to a local anesthetic. 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 GlaxoSmithKline (GSK) Medical Monitor, contraindicates their participation.
* Any subject who has a known hypersensitivity to capsaicin or citric acid. Exclusion Criteria Based Upon Diagnostic Assessment
* A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
* 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. oropharyngeal candidiasis.
* FEV1 less than 80% of the predicted normal value prior to first dosing of the study
* Any subject who does not reach C5 following an oral inhalation of capsaicin at a dose level of 250 micromolar at screening.
* Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening.
* A positive pre-study drug/alcohol screen. Other Exclusion Criteria
* Subjects who are unable to use the inhaler satisfactorily.
* Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
* Lactating females.
* 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.

Primary outcomes:
measure: Total Cough Count Over 8 Hours at Visits 1, 2 and 3 (Part A)
timeFrame: Up to 8 hours post-dose at Visits 1, 2 and 3 (Part A)
measure: Total Cough Count Excluding Transient Coughs Over 8 Hours at Visits 1, 2 and 3 (Part A)
timeFrame: Up to 8 hours post-dose at Visits 1, 2 and 3 (Part A)
Secondary outcomes:
measure: Number of Participants With Any Adverse Events (AEs) and Any Serious Adverse Events (SAEs)
timeFrame: From the start of study treatment and until the follow-up contact (up to 8 Weeks)
measure: Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C
timeFrame: Pre-dose, 5 min, 15 min (only in Part A), 30 min, and 1 hr post each dose administered in Parts A, B and C (up to 8 weeks)
measure: Mean Heart Rate at the Indicated Time Points in Parts A, B and C
timeFrame: Pre-dose, 5 min, 15 min (only in Part A), 30 min, and 1 hr after each dose administered in Parts A, B and C (up to 8 weeks)
measure: Mean Body Temperature at the Indicated Time Points in Parts A, B and C
timeFrame: 1 hr post the second dose administered in Part A and 1 hr post each dose administered in Parts B and C (up to 8 Weeks)
measure: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings in Parts A, B and C
timeFrame: Pre-dose and 5min to 1 hr after each dose administered in Parts A, B and C (up to 8 Weeks)
measure: Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cells (WBC) Count Values at the Indicated Time Points in Part A
timeFrame: Pre-dose and 1 hr post each dose administered in Part A (up to 3 Weeks)
measure: Mean Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points in Part A
timeFrame: Pre-dose and 1 hr post each dose administered in Part A (up to 3 Weeks)
measure: Mean Hematocrit Values at the Indicated Time Points in Part A
timeFrame: Pre-dose and 1 hr post each dose administered in Part A (up to 3 Weeks)
measure: Mean Corpuscle Hemoglobin Values at the Indicated Time Points in Part A
timeFrame: Pre-dose and 1 hr post each dose administered in Part A (up to 3 Weeks)
measure: Mean Corpuscle Volume Values at the Indicated Time Points in Part A
timeFrame: Pre-dose and 1 hr post each dose administered in Part A (up to 3 Weeks)
measure: Mean Red Blood Cell Count Values at the Indicated Time Points in Part A
timeFrame: Pre-dose and 1 hr post each dose administered in Part A (up to 3 Weeks)
measure: Mean Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points in Part A
timeFrame: Pre-dose and 1 hr post each dose administered in Part A (up to 3 Weeks)
measure: Mean Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points in Part A
timeFrame: Pre-dose and 1 hr post each dose administered in Part A (up to 3 Weeks)
measure: Mean Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values at the Indicated Time Points in Part A
timeFrame: Pre-dose and 1 hr post each dose administered in Part A (up to 3 Weeks)
measure: Mean Troponin I Values at the Indicated Time Points in Part A
timeFrame: Pre-dose and 1 hr post each dose administered in Part A (up to 3 Weeks)
measure: Mean Forced Expiratory Volume in One Second (FEV1) Values at the Indicated Time Points in Parts A, B and C
timeFrame: Pre-dose and 30 min post each dose administered in Parts A, B and C (up to 8 Weeks)
measure: Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A
timeFrame: From 2 min -2 hr post each dose administered at Visits 1, 2 and 3 in Part A (up to 8 weeks)
measure: Mean Transient Cough Counts at the Indicated Time Points in Part A
timeFrame: 0-4 hr, 4-8 hr, 0-8 hr post each dose at Visits 1, 2 and 3 in Part A (up to 8 weeks)
measure: Plasma Concentrations of GSK2339345 at the Indicated Time Points at Visits 1, 2 and 3 (Part A)
timeFrame: From 0-4 hr post each dose administered at Visits 1, 2 and 3 in Part A (up to 3 weeks)
measure: Area Under the Concentration (AUC) Time (0-1) and AUC(0-t) of GSK2339345 Following Two Repeated Doses
timeFrame: From 0-4 hr post each dose administered at Visits 1, 2 and 3 in Part A (up to 3 weeks)
measure: Maximum Observed Concentration (Cmax) of GSK2339345 Following Two Repeated Doses
timeFrame: From 0-4 hr post each dose administered at Visits 1, 2 and 3 in Part A (up to 3 weeks)
measure: Time to Reach the Observed Maximum Concentration (Tmax) of GSK2339345 Following Two Repeated Doses
timeFrame: From 0-4 hr post each dose administered at Visits 1, 2 and 3 in Part A (up to 3 weeks)
measure: Mean Cough Count Over 4 Hours at Visits 1, 2 and 3 (Part A)
timeFrame: Up to 8 hours post-dose at Visits 1, 2 and 3 (Part A)
measure: Total Cough Count Excluding Transient Coughs Over 4 Hours at Visits 1, 2 and 3 (Part A)
timeFrame: Up to 8 hours post-dose at Visits 1, 2 and 3 (Part A)
measure: Mean Cough Counts by 1 hr Epoch at Visits 1, 2 and 3 (Part A)
timeFrame: Up to 8 hours post-dose at Visits 1, 2 and 3 in Part A (up to 3 weeks)
measure: Mean Cough Counts by 30 Min Epoch at Visits 1, 2 and 3 (Part A)
timeFrame: Up to 8 hours post-dose in Visits 1, 2 and 3 in Part A (up to 3 weeks)
measure: Mean Cough Counts by 15 Min Epoch in Part A
timeFrame: Up to 8 hours post-dose at Visits 1, 2 and 3 in Part A (up to 3 weeks)
measure: Mean Visual Analogue Scale (VAS) Score of Cough Severity and Urge to Cough at the Indicated Time Points at Visits 1, 2 and 3 (Part A)
timeFrame: Prior to first dose and 1hr post second dose at Visits 1, 2 and 3 in Part A (up to 3 weeks)
measure: Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Capsaicin Challenge (CC) at Visits 4 and 5 (Part B)
timeFrame: After the administration of GSK2339345 or placebo (first and second 15 seconds following each dose) at Visits 4 and 5 in Part B (up to 2 weeks)
measure: Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Citric Acid Challenge (CAC)at Visits 6 and 7 (Part C)
timeFrame: After the administration of GSK2339345 or placebo (first and second 15 seconds following each dose) at Visits 6 and 7 in Part C (up to 2 weeks)
measure: CC Agent Dose Concentration Required to Achieve C2, C5 and C6 at Visits 4 and 5 (Part B)
timeFrame: After the administration of GSK2339345 or placebo at Visits 4 and 5 in Part B (up to 2 weeks)
measure: CAC Agent Dose Concentration Required to Achieve C2, C5 and C6 at Visits 6 and 7 (Part C)
timeFrame: After the administration of GSK2339345 or placebo at Visits 6 and 7 in Part C (up to 2 weeks)
measure: CC Agent Imputed Dose Concentration Required to Achieve C2, C5 and C6 at Visits 4 and 5 (Part B)
timeFrame: After the administration of GSK2339345 or placebo at Visits 4 and 5 in Part B (up to 2 weeks)
measure: CAC Agent Imputed Dose Concentration Required to Achieve C2, C5 and C6 at Visits 6 and 7 (Part C)
timeFrame: After the administration of GSK2339345 or placebo at Visits 6 and 7 in Part C (up to 2 weeks)
Other outcomes:
Locations:
city: Manchester
country: United Kingdom
facility: GSK Investigational Site
state: Lancashire
city: Belfast
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: