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A Study to Investigate the Effect of SB-705498 on Chronic Cough

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01476098
First received: October 13, 2011
Last updated: November 30, 2016
Last verified: November 2016
  Purpose
This study is designed to loook at the affect of oral SB-705498 on cough following an inhaled capsaicin challenge

Condition Intervention Phase
Rhinitis
Drug: Placebo
Drug: SB-705498
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Two Part Study to Investigate Pharmacokinetics (PK) & Pharamcodynamics (PD) of SB-705498 in Cough. Part A:Open Label Study in Healthy Subjects to Determine Exposure to SB-705498. Part B:Double-blind, Placebo Controlled, Cross Over Study to Investigate Effect of SB-705498 on Capsaicin Induced Cough and 24 Hour Cough Counts in Cough Patients

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Pharmacokinetic parameter of area under the plasma concentration-time curve from time zero to 4 hours AUC(0-4) and from time zero (pre-dose) to last time of quantifiable concentration AUC(0-t)- Part A [ Time Frame: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 10 hours post-dose ] [ Designated as safety issue: No ]
    AUC(0-4) is a measure of the average amount of study drug in the blood plasma over a period of 4 hours after the dose and AUC(0-t) is a measure average amount of study drug in the blood plasma over a period of last time of quantifiable concentration. Both the parameters were calculated by standard non-compartmental analysis. Blood samples for PK analysis were obtained at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 10 hours post-dose.

  • Maximum observed concentration (Cmax) following 10 hour sampling of a single dose of SB-705498 - Part A [ Time Frame: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 10 hours post-dose Day 1 ] [ Designated as safety issue: No ]
    Cmax is defined as the maximum or "peak" concentration of a drug observed after its administration. Cmax is one of the parameters of particular use in estimating the bioavailability of drugs, by measuring the total amount of drug absorbed. It was calculated by standard non-compartmental analysis. Blood samples for PK analysis were obtained at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 10 hours post-dose.

  • Time of occurrence of Cmax (Tmax) following 10 hour sampling of a single dose of SB-705498 -Part A [ Time Frame: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 10 hours post-dose ] [ Designated as safety issue: No ]
    Tmax is defined as the time of occurrence of Cmax. Blood samples for PK analysis were obtained at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 10 hours post-dose.

  • Capsaicin concentration required to achieve Five or more coughs (C5) following a single dose of SB-705498 at Tmax as compared to baseline- Part A [ Time Frame: Day -1 (baseline) and Day 1 (2 hours post dose ] [ Designated as safety issue: No ]
    The concentration of capsaicin required to elicit 5 coughs was analyzed. The distributional properties were investigated, and the endpoint was logged (base 2) for analysis and the difference from Day -1 (baseline) was taken (equivalent to ratio on log scale).

  • Capsaicin concentration required to achieve C5 following a single dose of SB-705498 or placebo- Part B [ Time Frame: Day -1, Day 1 (2hrs and 24 hrs post dose) ] [ Designated as safety issue: No ]
    The concentration of capsaicin required to elicit 5 coughs was analyzed. The distributional properties were investigated, and the endpoint was logged (base 2) for analysis and the difference from Day -1 (baseline) was taken (equivalent to ratio on log scale).

  • Cough Count Per 24 hour following single dose of SB-705498 as compared to placebo- Part B [ Time Frame: Day -1 and Day 1 (2 and 24 hours) ] [ Designated as safety issue: No ]
    24 hour cough count (rate/h) following single dose of SB-705498 as compared to placebo were analyzed by first log transforming the cough counts taken on Day -1 and on Day 1 of each period in the 24 hours post dose. The cough count rates were log(10) transformed.


Secondary Outcome Measures:
  • Capsaicin concentration required to achieve two or more coughs (C2) following a single dose of SB-705498 at Tmax as compared to baseline- Part A [ Time Frame: Day -1 and Day 1 (2 hours post dose) ] [ Designated as safety issue: No ]
    The concentration of capsaicin required to elicit 2 coughs was analyzed. The distributional properties were investigated, and the endpoint was logged (base 2) for analysis and the difference from Day -1 (baseline) was taken (equivalent to ratio on log scale).

  • Capsaicin concentration required to achieve C2 following a single dose of SB-705498 at Tmax as compared to baseline- Part B [ Time Frame: Day 1 (2 and 24 hours post dose) ] [ Designated as safety issue: No ]
  • Changes in the Cough Quality of Life Questionnaire (CQLQ) following a single dose of SB-705498 compared to placebo- Part B [ Time Frame: Day -1 and 14 ] [ Designated as safety issue: No ]
    It is a validated, 28-item assessment tool designed to evaluate decrements in quality of life due to chronic cough. This questionnaire measures cough-related symptoms, as well as the social implications and psychological impact. Examples of items include, "I cannot sleep at night" and "I cough and it makes me retch." The final score is obtained by summing the responses to 28 questions, each scored on a 1-4 scale, where 1 is "strongly disagree," and 4 is "strongly agree." The minimum and maximum CQLQ scores are 28 and 112 respectively, with increasing score indicating more severe impairment.

  • Urge to cough Visual Analogue Scale (VAS) following single dose of SB-705498- Part B [ Time Frame: Day -1 and Day 1 (pre-dose 2 and 24 hours) ] [ Designated as safety issue: No ]
    VAS following single dose of SB-705498 was summarized on Day -1, and Day 1 pre-dose, 2 and 24 hours.

  • Capsaicin concentration required to achieve C5 following a single dose of SB-705498 at 24 hours as compared to baseline-Part B [ Time Frame: Day -1 and Day 1 (2 and 24 hours post dose) ] [ Designated as safety issue: No ]
    The concentration of capsaicin required to elicit 5 coughs was analyzed. The distributional properties were investigated, and the endpoint was logged (base 2) for analysis and the difference from Day -1 (baseline) was taken (equivalent to ratio on log scale).

  • Capsaicin concentration required to achieve C2 following a single dose of SB-705498 at 24 hours as compared to baseline- Part B [ Time Frame: Day -1 and Day 1 (2 and 24 hours post dose) ] [ Designated as safety issue: No ]
    The concentration of capsaicin required to elicit 2 coughs was analyzed. The distributional properties were investigated, and the endpoint was logged (base 2) for analysis and the difference from Day -1 (baseline) was taken (equivalent to ratio on log scale).

  • The 24-hour cough count (rate) subdivided by day and night cough counts (rates) to give day/night specific values by treatment group-Part B [ Time Frame: Up to Day 2 (Period 2) ] [ Designated as safety issue: No ]
    Different cough intervals were investigated, such as a day and night time rate. Participants were treated as a random effect in the model. The mean treatment difference and associated 95% confidence interval was back-transformed to provide a treatment ratio and 95% confidence interval for the ratio.

  • Number participants with Adverse Events(AEs) and serious adverse events (SAEs)- Part A [ Time Frame: Up to Day 7 ] [ Designated as safety issue: No ]
    An adverse event (AE) was defined as any untoward medical occurrence that occurred during the course of the trial after study treatment had started. An adverse event was therefore any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose results in death, are life threatening, requires hospitalization or prolongation of hospitalization or results in disability/incapacity, and congenital anomaly/birth defect.

  • Number participants with AEs and SAEs- Part B [ Time Frame: up to Day 42 ] [ Designated as safety issue: No ]
    An adverse event (AE) was defined as any untoward medical occurrence that occurred during the course of the trial after study treatment had started. An adverse event was therefore any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose results in death, are life threatening, requires hospitalization or prolongation of hospitalization or results in disability/incapacity, and congenital anomaly/birth defect.

  • Summary of vital signs -systolic and diastolic blood pressure (Part A) [ Time Frame: Up to Day 7 ] [ Designated as safety issue: No ]
    Systolic and diastolic blood pressure was assessed on pre dose and 2, 10 hours post dose.

  • Summary of vital signs -systolic and diastolic blood pressure (Part B) [ Time Frame: Up to Day 42 ] [ Designated as safety issue: No ]
    Systolic and diastolic blood pressure was assessed on pre dose and 4 hours post dose.

  • Summary of Vital Signs- Heart rate (Part A) [ Time Frame: Up to Day 7 ] [ Designated as safety issue: No ]
    Heart rate was assessed on pre dose and 2, 10 hours post dose.

  • Summary of Vital Signs- Heart rate (Part B) [ Time Frame: Up to Day 42 ] [ Designated as safety issue: No ]
    Heart rate was assessed on pre dose and 4 hours post dose.

  • Summary of Vital Signs- Body temperature (Part A) [ Time Frame: Up to Day 7 ] [ Designated as safety issue: No ]
    Body temperature was measured with a tympanic thermometer at pre-dose, 1, 2, 4, 10 hours post dose.

  • Summary of Vital Signs- Body temperature (Part B) [ Time Frame: Up to Day 42 ] [ Designated as safety issue: No ]
    Body temperature was measured with a tympanic thermometer at pre-dose, 1, 2, 4, 24 hours post dose.

  • Number of participants with ECG findings- Part A [ Time Frame: Up to Day 7 ] [ Designated as safety issue: No ]
    Single 12-lead ECGs was obtained at each time point during the study using an ECG machine. Participants with abnormal values have been presented.

  • Number of participants with ECG findings- Part B [ Time Frame: Up to Day 42 ] [ Designated as safety issue: No ]
    Single 12-lead ECGs was obtained at each time point during the study using an ECG machine. Participants with abnormal values have been presented.

  • Number of participants with potential clinical importance (PCI) laboratory assessments- hematology Part A [ Time Frame: Up to 4 weeks ] [ Designated as safety issue: No ]
    Hematology PCI values were: White Blood Cell Count; 0.67 (low) and 1.82 (high), Neutrophil Count; 0.83 (low), Hemoglobin (male); 1.03 (high), Hemoglobin (female); 1.13 (high), Hematocrit (male); 1.02 (high), Hematocrit (female); 1.17(high), Platelet Count; 0.67 and 1.57 (high), Lymphocytes; 0.81 (low).

  • Number of participants with potential clinical importance (PCI) laboratory assessments- hematology Part B [ Time Frame: Up to 13 weeks ] [ Designated as safety issue: No ]
    Hematology PCI values were: White Blood Cell Count; 0.67 (low) and 1.82 (high), Neutrophil Count; 0.83 (low), Hemoglobin (male); 1.03 (high), Hemoglobin (female); 1.13 (high), Hematocrit (male); 1.02 (high), Hematocrit (female); 1.17(high), Platelet Count; 0.67 and 1.57 (high), Lymphocytes; 0.81 (low).

  • Number of participants with potential clinical importance (PCI) laboratory assessments- clinical biochemistry Part A [ Time Frame: Up to 4 weeks ] [ Designated as safety issue: No ]
    Clinical biochemistry PCI values were: Albumin; 0.86 (low), Calcium; 0.91(low) and 1.06 (high), Glucose; 0.71 (low) and 1.41 (high), Potassium; 0.86 (low) and 1.10 (high), Sodium; 0.96(low) and 1.03(high).

  • Number of participants with potential clinical importance (PCI) laboratory assessments- clinical biochemistry Part B [ Time Frame: Up to 13 weeks ] [ Designated as safety issue: No ]
    Clinical biochemistry PCI values were: Albumin; 0.86 (low), Calcium; 0.91(low) and 1.06 (high), Glucose; 0.71 (low) and 1.41 (high), Potassium; 0.86 (low) and 1.10 (high), Sodium; 0.96(low) and 1.03(high).


Enrollment: 21
Study Start Date: April 2011
Study Completion Date: January 2012
Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Arm 1
incremental doses capsaicin
Drug: Placebo
SB-705498 placebo
Drug: SB-705498
400 or 600mg oral SB-705498
Active Comparator: Arm 2
incremenrtal doses casaicin
Drug: Placebo
SB-705498 placebo
Drug: SB-705498
400 or 600mg oral SB-705498

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or female between 30 -75 (Part A) and 18-75 (Part B) years of age inclusive.
  • Non-child bearing women or women of child bearing potential if they agree to use contraception as indicated by the protocol
  • Non-smoker for at least 6 months with a pack history <5 pack years (Pack years = (No. of cigarettes smoked/day/20) x No. of years smoked).
  • Body weight > 50 kg and body mass index (BMI) within the range 19 - 30.0 kg/m2 (inclusive).
  • Capable of giving written informed consent.
  • Agree to use contraception listed as acceptable
  • Normal 12-lead ECG at screening.
  • Chronic cough (Part B only)
  • Good general health, apart from chronic cough (part B only), as determined by a responsible physician.

Exclusion Criteria:

  • A history of gastrointestinal, hepatic, renal or multiple cardiovascular risk factors.
  • Positive pre-study drug/alcohol screen.
  • Positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
  • A positive test for human immunodeficiency virus (HIV) antibody (if determined by the local standard operating procedures (SOPs)).
  • History of regular alcohol consumption within 6 months of the study.
  • Exposure to more than four new chemical entities within 12 months prior to the start of the study.
  • Participation in a clinical trial with a new molecule entity or any other clinical trial within 30 days of the start of the study.
  • Use of prescription or non-prescription drugs, as well as of vitamins, herbal and dietary supplements (including St John's Wort) within 7 days prior to study.
  • known history of lung cancer
  • current treatment with oral corticosteriods or other immunosupressive agents
  • FEV1 less than 80% of predicted value at screening
  • Any subject who does not reach C5 following 250uM oral capsaicin
  • History of drug or other allergy that, in the opinion of the Investigator or GSK Medical Monitor, contraindicates their participation.
  • Donation of blood or blood products in excess of 500mL within a 56 day period prior the start study.
  • Pregnant females as determined by positive serum or urine human chorionic gonadotropin (hCG) test at screening or prior to dosing.
  • Lactating females.
  • Unwillingness or inability to follow the procedures outlined in the protocol.
  • Cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening.
  • consumption of red wine, seville oranges, grapefruit or grapefruit juice from 7 days prior to dosing.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01476098

Locations
United Kingdom
GSK Investigational Site
Manchester, United Kingdom, M23 9QZ
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

Additional Information:
Study Data/Documents: Statistical Analysis Plan  This link exits the ClinicalTrials.gov site
Identifier: 114693
For additional information about this study please refer to the GSK Clinical Study Register
Clinical Study Report  This link exits the ClinicalTrials.gov site
Identifier: 114693
For additional information about this study please refer to the GSK Clinical Study Register
Informed Consent Form  This link exits the ClinicalTrials.gov site
Identifier: 114693
For additional information about this study please refer to the GSK Clinical Study Register
Individual Participant Data Set  This link exits the ClinicalTrials.gov site
Identifier: 114693
For additional information about this study please refer to the GSK Clinical Study Register
Study Protocol  This link exits the ClinicalTrials.gov site
Identifier: 114693
For additional information about this study please refer to the GSK Clinical Study Register
Annotated Case Report Form  This link exits the ClinicalTrials.gov site
Identifier: 114693
For additional information about this study please refer to the GSK Clinical Study Register
Dataset Specification  This link exits the ClinicalTrials.gov site
Identifier: 114693
For additional information about this study please refer to the GSK Clinical Study Register

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01476098     History of Changes
Other Study ID Numbers: 114693 
Study First Received: October 13, 2011
Last Updated: November 30, 2016
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
Individual Participant Data  
Plan to Share IPD: Yes
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.

Additional relevant MeSH terms:
Rhinitis
Nose Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Otorhinolaryngologic Diseases
Capsaicin
Antipruritics
Dermatologic Agents
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on December 02, 2016