NCT01899768 - GSK2339345 Hypertussive Challenge Study | Crick

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Total Cough Count Over 8 Hours at Visits 1, 2 and 3 (Part A)

Total cough count (8 hours \[hr\] of recording) was conducted at Visits 1, 2 and 3. Coughs were counted by a cough monitor fitted to the participants for 8 hr post Dose 1. The cough count was calculated as the sum of two four hour cough count totals, with the first four hours starting from the time of the first dose and the second four hours starting at the time of the second dose. The cough counts were sum-up by the treatments received by the participants. Number of coughs in 8 hr period was loge transformed and used for the analysis. Values were imputed pro-rata if 8 hr epoch was less than 8 hr. Mean of the total cough counts recorded post dose of every treatment i.e. placebo or GSK2339345 1000mcg was reported.

Time frame: Up to 8 hours post-dose at Visits 1, 2 and 3 (Part A)

Total Cough Count Excluding Transient Coughs Over 8 Hours at Visits 1, 2 and 3 (Part A)

Total cough count (8 hr of recording) was conducted at Visits 1, 2 and 3. Coughs were counted by a cough monitor fitted to the participants for 8 hr post Dose 1. The cough count was calculated as the sum of two four hour cough count totals, with the first 4-hrs starting from the time of the first dose and the second four hours starting at the time of the second dose. The cough counts were sum-up by the treatments received by the participants. Transient cough was the total number of coughs experienced in the two mins from the start of the first inhalation of a dose. Number of coughs excluding transient cough in 8 hr period was loge transformed and used for the analysis. Values were imputed pro-rata if 8 hr epoch was less than 8 hr. Mean of the total cough counts excluding transient cough recorded post dose of every treatment i.e. placebo or GSK2339345 1000 mcg was reported.

Time frame: Up to 8 hours post-dose at Visits 1, 2 and 3 (Part A)

Secondary Outcomes

Number of Participants With Any Adverse Events (AEs) and Any Serious Adverse Events (SAEs)

An AE is defined as any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect, or is an important medical events that jeopardize the participants or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition, or a drug-induced liver injury.

Time frame: From the start of study treatment and until the follow-up contact (up to 8 Weeks)

Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C

Systolic blood pressure (SBP) and diastolic blood pressure (DBP) measurements were obtained at following time points: pre-dose, 5 minutes (min), 15 min (only in Part A), 30 min, and 1 hr after first administration (FA) and second administration (SA) in Part A and each dose administration of Parts B and C. FA is the first of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A. SA is the second of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A. Pre-Dose is the average (avg) of the triplicate readings taken at the pre-dose assessment.

Time frame: 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)

Mean Heart Rate at the Indicated Time Points in Parts A, B and C

Heart rate measurements were obtained at following time points: pre-dose, 5 min, 15 min (only in Part A), 30 min, and 1 hr after FA and SA in Part A and each dose administration in Parts B and C. FA is the first of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A. SA is the second of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A. Pre-Dose is the average of the triplicate readings taken at the pre-dose assessment.

Time frame: 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)

Mean Body Temperature at the Indicated Time Points in Parts A, B and C

Body temperature measurements were obtained at1 hr post-dose 2 FA and SA in Part A and each administration in Parts B, and C. FA is the first of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A. SA is the second of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A.

Time frame: 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)

Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings in Parts A, B and C

A 12-lead ECG was recorded in a seated position after the participant was kept at rest in this position for at least 10 minutes. ECGs were obtained at pre-dose and 5 min, 15 min (only in Part A) 30 min, and 1 hr after FA and SA in Part A and each administration in Parts B, and C. FA is the first of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A. SA is the second of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A. Data are presented as clinically significant (CS) or not clinically significant (NCS) abnormal findings any time during study. The study investigator determined if the abnormal ECG finding was CS or NCS.

Time frame: Pre-dose and 5min to 1 hr after each dose administered in Parts A, B and C (up to 8 Weeks)

Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cells (WBC) Count Values at the Indicated Time Points in Part A

Blood samples were collected for the measurement of basophils, eosinophils, lymphocytes, monocytes, total neutrophils (ANC - absolute neutrophil count), platelet count, and white blood cells count at pre-dose and 1 hr after each dose of FA and SA in Part A. FA is the first of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A. SA is the second of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A.