A Study to Assess the Effectiveness and Side Effects of GSK2798745 in Participants With Chronic Cough

Study Overview
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Brief Summary
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GSK2798745 is a potent and selective transient receptor potential vanilloid 4 (TRPV4) channel blocker being investigated for the treatment of chronic cough. This is a multi-center, randomized, placebo-controlled, double-blind, two-period crossover study with a purpose to evaluate efficacy and safety of GSK2798745. Each subject will have 2 treatment periods, and will be randomized to one of the following treatments in each period: A) Placebo matching to GSK2798745 once daily for 7 days. B) 4.8 milligrams (mg) GSK2798745 on Day 1, followed by 2.4 mg GSK2798745 once daily for 6 days. There will be a washout period of 14 to 21 days between the treatment periods. A maximum of 48 subjects will be enrolled in the study and the total duration of participation in the study will be maximum of 10 and a half weeks including follow-up visit.

Official Title
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A Placebo-controlled, Double-blind (Sponsor Open), Randomized, Crossover Study to Assess the Efficacy, Safety, and Tolerability of GSK2798745 in Participants With Chronic Cough

Conditions
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Cough

Intervention / Treatment
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* Drug: GSK2798745
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 18 and 75 years of age inclusive, at the time of signing the informed consent. Chronic idiopathic cough for >=1 year (before screening), defined as: a cough that is unresponsive to at least 8 weeks of targeted treatment, or a cough for which no objective evidence of an underlying trigger has been determined, despite medical investigations. No significant findings on chest imaging (chest X-ray [CXR] or Computed tomography scan) within 12 months before screening (subjects with an abnormal CXR within 12 months, from a temporary process, will be allowed to participate if a repeat CXR is normal). Forced expiratory volume in one second (FEV1) >=80% of the predicted normal value (at screening), or documented evidence of FEV1 >=80% within the 6 months before screening. Score of >=40 millimeters (mm) on the Cough Severity Visual Analogue Scale (VAS) at Screening. Body weight >=50 kilogram (kg) and body mass index (BMI) within the range 18 to 40 kilogram per meter square (kg/m^2) (inclusive) at screening. A male participant must agree to follow the contraception requirements stated in the protocol from the time of first dose of study treatment until 2 weeks after last dose of study treatment, and refrain from donating sperm during this period. A female participant is eligible to participate if she is not of childbearing potential. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Exclusion Criteria: History or current evidence of any serious or clinically significant gastrointestinal, renal, endocrine, neurologic, hematologic or other condition that is uncontrolled on permitted therapies or that would, in the opinion of the investigator or the medical monitor, make the subject unsuitable for inclusion in this study. History or current evidence of chronic productive cough. History of acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting within the 6 months before screening. Active ulcer disease or gastrointestinal bleeding at the time of screening (positive fecal occult blood test [FOBT] at screening). History of stroke or seizure disorder within 5 years of screening. Respiratory tract infection within 6 weeks of screening. Subject who, in the investigator's opinion, poses a significant suicide risk. Evidence of serious suicide risk may include any history of suicidal behavior and/or any evidence of suicidal ideation on any questionnaires e.g. Type 4 or 5 on the Columbia Suicidality Severity Rating Scale (C-SSRS) in the last 6 months (assessed at screening). Alanine transferase (ALT) > twice the upper limit of normal (ULN) at screening. Bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) at screening. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). QT interval corrected (QTc) >450 milliseconds (msec) or QTc >480 msec in subjects with bundle branch block at screening. Use of a listed prohibited medication within the restricted timeframe relative to the first dose of study treatment. Use of a strong inhibitors or inducers of cytochrome P450 (CYP) 3A or pglycoprotein. Participation in the study would result in loss of blood or blood products in excess of 500 milliliters (mL) within 3 months of screening. Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day. Current enrollment or past participation within the 3 months before screening in any clinical study involving an investigational study treatment or any other type of medical research. Positive human immunodeficiency virus (HIV) antibody test at screening. Presence of Hepatitis B surface antigen (HBsAg) at screening. Positive Hepatitis C antibody test result at screening or within 3 months prior to starting study treatment. Positive Hepatitis C ribonucleic acid (RNA) test result at screening or within 3 months prior to first dose of study treatment. Cardiac troponin at screening > ULN for the assay. History of alcohol abuse within 6 months of screening, in the opinion of the investigator. Current smoker or history of smoking within the 6 months before screening, or a cumulative history of >= 20 pack years. Pack years = (Number of cigarettes smoked/day/20) x (Number of years smoked) Sensitivity to any of the study treatments, or components thereof, or drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates participation in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: This is a multi-center, randomized, placebo-controlled, double-blind, two-period crossover study. Each subject will be screened (screening may be conducted across more than 1 visit); each subject will have 2 treatment periods (each 7 days) with a washout period of 14 to 21 days between the treatment periods; and each subject will have a follow-up visit (within 7 to 10 days after their last dose). Each subject will be involved in the study for a maximum of 10 and a half weeks.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Sequence AB<br>Subjects will receive GSK2798745 matching placebo tablets (two tablets on Day 1 followed by one tablet once daily for 6 days), via oral route (treatment period of total 7 days). After a washout period of 14 to 21 days, subjects will then receive 4.8 mg (two tablets of 2.4 mg) GSK2798745 on Day 1, followed by 2.4 mg GSK2798745 tablets once daily for 6 days via oral route (treatment period of total 7 days). | Drug: GSK2798745<br>* GSK2798745 tablets will be available as white to almost white, round, film-coated tablets (micronized active pharmaceutical ingredient [API]) to be taken with a glass of water (approximately 240 mL).<br>Drug: Placebo<br>* Placebo tablets will be available as white to almost white, round, film-coated tablets to be taken with a glass of water (approximately 240 mL).<br>|
| Experimental: Treatment Sequence BA<br>Subjects will receive 4.8 mg (two tablets of 2.4 mg) GSK2798745 on Day 1, followed by 2.4 mg GSK2798745 tablets once daily for 6 days via oral route (treatment period of total 7 days). After a washout period of 14 to 21 days, subjects will then receive GSK2798745 matching placebo tablets (two tablets on Day 1 followed by one tablet once daily for 6 days), via oral route (treatment period of total 7 days). | Drug: GSK2798745<br>* GSK2798745 tablets will be available as white to almost white, round, film-coated tablets (micronized active pharmaceutical ingredient [API]) to be taken with a glass of water (approximately 240 mL).<br>Drug: Placebo<br>* Placebo tablets will be available as white to almost white, round, film-coated tablets to be taken with a glass of water (approximately 240 mL).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Cough Counts During Day Time Hours Following 7-days of Dosing | Coughs were monitored using the VitaloJAK cough monitor. The total cough counts during day-time (10 hours) was calculated from the time of the monitor being attached i.e. immediately after dosing on Day 7 to 10 hours past the time of monitoring. Total cough counts were log-transformed prior to analysis. A non-informative prior was used. Analysis was performed using a Bayesian mixed model adjusting for subject-level and period-adjusted baselines, treatment and period. Subject-level baseline is defined as the mean of the two period-specific baselines. Period-adjusted baseline is defined as the difference between the period-specific baseline and subject-level baseline for each period. Posterior median and 95% credible interval is reported. All Subjects Population included all randomized participants who took at least 1 dose of study treatment. Participants were analyzed according to the treatment they actually received. | Up to 10 hours post-dose on Day 7 of each treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, associated with liver injury and impaired liver function or any other situations as per medical or scientific judgment. | Up to 45 days | 
| Change From Baseline Values for Clinical Chemistry Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Amino Transferase (AST) and Creatinine Kinase (CK) | Blood samples were collected for the analysis of clinical chemistry parameters including ALP, ALT, AST and CK. Baseline was defined as latest pre-dose assessment with a non-missing value in each treatment period. Change from Baseline was calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day -1) and Day 8 of each treatment period | 
| Change From Baseline Values for Clinical Chemistry Parameter: Direct Bilirubin, Total Bilirubin and Creatinine | Blood samples were collected for the analysis of clinical chemistry parameters including direct bilirubin, total bilirubin and creatinine. Baseline was defined as latest pre-dose assessment with a non-missing value in each treatment period. Change from Baseline was calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day -1) and Day 8 for each treatment period | 
| Change From Baseline Values for Clinical Chemistry Parameters: Calcium, Glucose, Potassium, Sodium and Urea | Blood samples were collected for the analysis of clinical chemistry parameters including calcium, glucose, potassium, sodium and urea/blood urea nitrogen (BUN). Baseline was defined as latest pre-dose assessment with a non-missing value in each treatment period. Change from Baseline was calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day -1) and Day 8 of each treatment period | 
| Change From Baseline Values for Clinical Chemistry Parameter: Total Protein | Blood samples were collected for the analysis of clinical chemistry parameter total protein. Baseline was defined as latest pre-dose assessment with a non-missing value in each treatment period. Change from Baseline was calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day -1) and Day 8 of each treatment period | 
| Number of Participants With Abnormal Values of Cardiac Troponin | Cardiac troponin values was measured in participants. | Up to 45 days | 
| Change From Baseline Values for Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count and White Blood Cell (WBC) Count | Blood samples were collected for the analysis of hematology parameters including basophils, eosinophils, lymphocytes, monocytes, total neutrophils, platelet count and WBC count. Baseline was defined as latest pre-dose assessment with a non-missing value in each treatment period. Change from Baseline was calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day -1) and Day 8 of each treatment period | 
| Change From Baseline Values for Hematology Parameter: Hemoglobin | Blood samples were collected for the analysis of hematology parameter: hemoglobin. Baseline was defined as latest pre-dose assessment with a non-missing value in each treatment period. Change from Baseline was calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day -1) and Day 8 for each treatment period | 
| Change From Baseline Values for Hematology Parameter: Hematocrit | Blood samples were collected for the analysis of hematology parameter: hematocrit. Baseline was defined as latest pre-dose assessment with a non-missing value in each treatment period. Change from Baseline was calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day -1) and Day 8 of each treatment period | 
| Change From Baseline Values for Hematology Parameter: Mean Corpuscular Hemoglobin (MCH) | Blood samples were collected for the analysis of hematology parameter: MCH. Baseline was defined as latest pre-dose assessment with a non-missing value in each treatment period. Change from Baseline was calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day -1) and Day 8 for each treatment period | 
| Change From Baseline Values for Hematology Parameter: Mean Corpuscular Volume (MCV) | Blood samples were collected for the analysis of hematology parameter: MCV. Baseline was defined as latest pre-dose assessment with a non-missing value in each treatment period. Change from Baseline was calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day -1) and Day 8 of each treatment period | 
| Change From Baseline Values for Hematology Parameter: Red Blood Cell (RBC) Count | Blood samples were collected for the analysis of hematology parameter: RBC count. Baseline was defined as latest pre-dose assessment with a non-missing value in each treatment period. Change from Baseline was calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day -1) and Day 8 for each treatment period | 
| Change From Baseline Values for Hematology Parameter: Reticulocytes | Blood samples were collected for the analysis of hematology parameter: reticulocytes. Baseline was defined as latest pre-dose assessment with a non-missing value in each treatment period. Change from Baseline was calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day -1) and Day 8 for each treatment period | 
| Number of Participants With Abnormal Urinalysis Data | Urine samples were collected for analysis of urinalysis data by dipstick method. Number of participants with abnormal urinalysis data has been presented. Abnormality was defined as value of potential clinical importance (PCI). PCI was flagged when a result changed from negative on Day 1 (pre-dose) to positive on Day 8. | Up to Day 8 | 
| Change From Baseline in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP) | Blood pressure was measured at indicated time points in supine position after 5 minutes rest for the participant. Baseline was defined as latest pre-dose assessment with a non-missing value in each treatment period. Change from Baseline was calculated as the value at the post-dose visit minus the Baseline value. | Baseline (pre-dose on Day 1) and Day 8 of each treatment period | 
| Change From Baseline in Temperature | Temperature was measured at indicated time points in supine position after 5 minutes rest for the participant. Baseline was defined as latest pre-dose assessment with a non-missing value in each treatment period. Change from Baseline was calculated as the value at the post-dose visit minus the Baseline value. | Baseline (pre-dose on Day 1) and Day 8 of each treatment period | 
| Change From Baseline in Heart Rate | Heart rate was measured at indicated time points in supine position after 5 minutes rest for the participant. Baseline was defined as latest pre-dose assessment with a non-missing value in each treatment period. Change from Baseline was calculated as the value at the post-dose visit minus the Baseline value. | Baseline (pre-dose on Day 1) and Day 8 of each treatment period | 
| Number of Participants With Abnormal Electrocardiogram (ECG) Findings | Twelve-lead ECG was obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, and corrected QT (QTc) intervals. Number of participants with abnormal-clinically significant and abnormal-not clinically significant values has been presented. | Baseline (pre-dose on Day 1) and Day 8 of each treatment period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GSK2798745, efficacy, safety, chronic cough, crossover study