GSK Medicine: Study Number: Title: Rationale: Phase: Study Period: Study Design: Centres: Indication: Treatment: Objectives:

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1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. GSK Medicine: GSK Study Number: PNV 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 GSK in patients with chronic idiopathic cough using an aqueous droplet inhaler Rationale: In two previous studies in healthy male volunteers GSK demonstrated an acceptable safety and tolerability profile at all of the doses studied (25 to 2000 µg), however GSK had no clear effect on cough reflex sensitivity in this population (assessed by capsaicin tussive challenge), perhaps due to a lack of a hyperresponsive cough reflex. The emerging picture is that the absence of antitussive effect in healthy volunteers does not necessarily imply the absence of a therapeutic effect in a population with pathologic cough. The primary aim of this study (PNV117270) was to investigate the efficacy of GSK on reducing objective cough frequency in Chronic Idiopathic Cough (CIC) subjects. The secondary aim of the study was to demonstrate target engagement in subjects with CIC using a modification of the standard tussive challenge and two tussive agents (citric acid and capsaicin) and to assess safety, tolerability and PK of GSK in CIC subjects. Phase: IIa Study Period: 20-NOV OCT-2014 Study Design: This was a three-part, randomised, double-blind (sponsor unblind) cross-over study design aimed to investigate efficacy (cough counts), pharmacodynamic responses (tussive challenges) and safety, tolerability and PK of GS in individual subjects with CIC. The study included a screening visit, seven treatment visits with a washout period between each visit and a follow-up visit. All eligible subjects attended the unit for dosing at Visits 1-3. At Visits 1, 2 and 3 (Part A of the study), subjects received two doses of either GSK or placebo, four hours apart and underwent 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 were administered a single dose of either GSK or placebo and performed a capsaicin (Part B) or citric acid (Part C) tussive challenge 5 minutes post dose. There was a washout of 48 hours to 7 days between visits. Follow-up of each subject occurred 3-14 days after the last dose. Following a protocol amendment subjects could choose to opt out of Part B and/or Part C of the study. Centres: 2 sites UK Indication: Chronic Idiopathic Cough Treatment: During Visits 1-3 (Part A of the study), each subject received either 1000 µg GSK or matching placebo administered on two occasions 4 hours apart. During Visits 4-7 (Part B and Part C of the study) each subject received a single dose of either 1000 µg GSK or matching placebo. Each part of the study had a crossover design. Dose 1 on each treatment day was administered at the same time each morning throughout all parts of the study. GSK and placebo were administered as solutions for oral inhalation via an aqueous droplet inhaler (ADI). Objectives: To evaluate the effect of a single dose of GSK , administered on two occasions, four hours apart, versus placebo on objective cough counts in patients with chronic idiopathic cough. Primary Outcome (Endpoints)/Efficacy: Total cough counts (8 hours of recording) at Visits 1, 2 and 3 (4 hours of post-dose recording for each of the two doses administered). Secondary Outcome (Endpoints)/Efficacy: Number of coughs following each dose of capsaicin and citric acid, following a single dose of GSK or placebo. Cough counts following GSK or placebo at Visits 1, 2 and 3 over shorter epochs (e.g. 1 hour or 15 minute intervals). Subjective assessments of urge to cough and cough severity by Visual Analogue Scales (VAS) 1 hour postlast dose at Visits 1, 2 and 3. Safety parameters: AEs, vital signs, ECGs, body temperature, laboratory assessments (including haematology, clinical chemistry and cardiac troponin), FEV1, and oropharyngeal sensate changes (four point scale). Plasma concentrations of GSK and derived pharmacokinetic parameters including Cmax, tmax, AUC(0-1) and AUC(0-4) as appropriate and predicted AUC(0-24) following two repeated doses where data 1

2 allowed, at Visits 1, 2 and 3. Sample Size: This study was designed to estimate the effect of GSK relative to placebo on daytime 8 hour cough count totals on a single day. This was investigated in this study by means of a Bayesian approach using a noninformative prior. A positive study was to be declared if the posterior probability that the true treatment ratio (GSK / placebo) is less than 0.7 was more than 70% (PP(ratio<0.7)>70%); a negative study was to be declared if the posterior probability that the true treatment ratio (GSK / placebo) is less than 0.7 was less than 30% (PP(ratio <0.7)<30%). A simulation approach was employed to investigate the chance of correctly or incorrectly determining a positive or negative study. Assuming a within subject variance of 0.28 and a variance of the treatment difference of (logged data), then with a sample size of 24 subjects, if the true treatment ratio is 0.5, then there was a 96.5% chance of correctly declaring a positive study and a 0.2% chance of incorrectly declaring a negative study. Similarly, if the true treatment ratio is 1, i.e. no drug effect, there was a 97.8% chance of correctly declaring a negative study and a 0.1% chance of incorrectly declaring a positive study. Statistical Analysis: Eight hour cough count was analysed by first log transforming the cough counts taken at Visits 1, 2 and 3. The difference between GSK and placebo in log-transformed count rates was investigated using a mixed effects model with fixed effects terms for treatment and period, and subject fitted as a random effect. The posterior probability that the ratio of the mean effect size of the test treatment and the mean effect size of the placebo treatment falls below thresholds of interest (ratios of 1, 0.7 and 0.5) was reported together with corresponding 90% credible intervals. The analysis was repeated excluding transient coughs (i.e. those recorded in the two minutes after the start of dosing). The two four hour cough counts per day were analysed using repeated measures modelling, and cough counts divided into epochs of shorter length were also summarised. For the capsaicin and citric acid challenges, the number of coughs following each dose of challenge agent was recorded over 30 seconds. For each challenge agent the dose-response relationship between the dose of challenge agent and cough response was investigated using population non-linear mixed effect modelling using Poisson and Negative Binomial distributions. Inter-individual variability (IIV) was investigated by fitting subject as a random effect on different model parameters (e.g. ED50, Emax), and reported as variance in the respective parameter ( 2 ). The difference between GSK and placebo was tested by adding GSK treatment as covariate to the model. In addition a number of further endpoints were then derived for each challenge. These included: C2 the dose of challenge agent at which 2 coughs were first observed, C5 the dose of challenge agent at which 5 coughs were first observed, CX, where X=6 the dose of challenge agent at which 6 coughs were first observed (the choice of X=6 was data driven). These endpoints were summarised. Plasma GSK concentration-time data were analyzed by non-compartmental methods with WinNonlin V5.2.1 and the resulting PK parameters and concentration-time data summarised. In addition, a population pharmacokinetic analysis was also performed on the plasma GSK concentration-time data. For the safety and tolerability data, no formal hypotheses were being tested and no statistical analyses were performed. The following analysis populations were utilised in the study: All Subjects Population: The All Subjects Population is defined as all subjects who received at least one dose of study medication. Capsaicin Challenge Population: The Capsaicin Challenge Population is defined as subjects in the All Subjects population for whom any capsaicin challenge data was available from one or both Part B study visits. Citric Acid Challenge Population: The Citric Acid Challenge Population is defined as subjects in the All Subjects population for whom any citric acid challenge data was available from one or both Part C study visits. Pharmacokinetic Population: The PK Population' is defined as subjects in the All Subjects population for whom a pharmacokinetic sample was obtained and analysed. Study Population: Male and female Chronic Idiopathic Cough patients 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 or chronic cough defined as cough lasting for more than 8 weeks), aged 18 years and over at the time of signing the informed consent with weight 50 kg and non-smoking for at least 6 months with a cumulative history of 20 pack years. Number of Subjects: Planned, N 30 Randomised, N 16 Completed, n (%) 11 (69) Total Number Subjects Withdrawn, N (%) 5 (31) 2

3 Withdrawn due to Adverse Events n (%) 3 (19) Withdrawn due to Lack of Efficacy n (%) 0 Withdrawn for other reasons n (%) 2 (13) Demographics N (ITT) 16 Females: Males 13:3 Mean Age, years (SD) 56.7 (9.58) White/Caucasian/European Heritage Race, n (%) 16 (100) Primary Efficacy Results: The primary outcome measure of the study was the total cough counts recorded (8 hours of recording) following administration of GSK or placebo in patients with Chronic Idiopathic Cough at Visits 1, 2 and 3 (4 hours of post-dose recording for each of the two doses administered). Endpoint Treatment Adjusted Geometric Mean Ratio of adjusted geometric means (90% Credible Intervals) % Decrease from placebo 8 hour cough count GSK (1.10, 1.44) -26% Placebo hour cough count GSK (0.87, 1.19) -1.6% excluding transient coughs Placebo Based on data from 14 subjects 21 8h counts per treatment due to replicate period Secondary Outcome Results: 4 hour cough counts following each dose of GSK or placebo at Visits 1, 2 and 3 were analysed: Endpoint Treatment Adjusted Geometric Mean Ratio of adjusted geometric means (90% Credible Intervals) % Decrease from placebo 4 hour cough count GSK Dose (0.86, 1.75) -23% Placebo Dose GSK Dose (1.07, 1.72) -35.8% Placebo Dose hour cough count excluding transient coughs GSK Dose (0.67, 1.40) 2.7% Placebo Dose GSK Dose (0.79, 1.36) -3.8% Placebo Dose Subjective assessments of urge to cough and cough severity by Visual Analogue Scale (VAS) 1 hour post-last dose at Visits 1, 2 and 3: Endpoint Treatment N Timepoint n Mean SD Median Min. Max. Urge to GSK Pre-dose cough 1 hour postdose Placebo 16 Pre-dose hour postdose Cough GSK Pre-dose severity 1 hour postdose Placebo 16 Pre-dose hour postdose Cough severity: 0=no severity, 100=maximum severity ever experienced Urge to cough: 0=no urge to cough, 100=maximum urge to cough ever experienced Note: Mean of replicate values per subject used where the same treatment taken during different periods 3

4 Cough counts over shorter epochs: The duration of effect of GSK versus placebo on objective cough counts over shorter epochs was assessed at 15 minute, 30 minute and hourly intervals over the 8 hour recording period: Epoch N Time relative n Mean SD Median Min. Max. length/treatment 15 min GSK to 1 st dose H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H min Placebo H H H H H H H H H H H H H H H H H H

5 H H H H H H H H H H H H H H N=No. of subjects who received at least one dose of study medication n=no. of subjects with a 15 minute cough count value Note: Mean cough count calculated per subject if the same treatment is taken during different periods Epoch N Time relative n Mean SD Median Min. Max. length/treatment 30 min GSK to 1 st dose H H H H H H H H H H H H H H H H min Placebo H H H H H H H H H H H H H H H H N=No. of subjects who received at least one dose of study medication n=no. of subjects with a 30 minute cough count value Note: Mean cough count calculated per subject if the same treatment is taken during different periods 5

6 Epoch length/treatment 1 hour GSK hour Placebo N Epoch n Mean SD Median Min. Max H H H H H H H H H H H H H H H H N=No. of subjects who received at least one dose of study medication n=no. of subjects with a 1 hour count value Note: Mean cough count calculated per subject if the same treatment is taken during different periods Note: Values are imputed pro-rata if 1 hour epoch is less than 60 minutes Tussive Challenges: The number of coughs following each dose of capsaicin and citric acid, following a single dose of GSK or placebo were analysed. Summary of Number of Coughs at Each Dose of Capsaicin Challenge (Part B): Treatment N Planned relative Concentration n Mean SD Median Min. Max. time (µmol/l) GSK Seconds Seconds Placebo Seconds

7 Seconds Summary of Number of Coughs at Each Dose of Citric Acid Challenge (Part C): Treatment N Planned relative Concentration n Mean SD Median Min. Max. time (mol/l) GSK Seconds Seconds Placebo Seconds Seconds

8 For the dose response modelling, a sigmoidal Emax model best described the Capsaicin challenge data. A negative binomial distribution model was marginally superior although the overdispersion parameter was estimated with low precision. Parameter Estimates and Standard Errors from best Capsaicin Challenge Models (Part B): Negative Binomial distribution Parameter Estimate SE Relative SE (%) E0 0 (fixed) NA NA ED50 (µm/l) Emax Hill factor (γ) Overdispersion parameter IIV ED IIV Emax Poisson distribution Parameter Estimate SE Relative SE (%) E0 0 (fixed) NA NA ED50 (µm/l) Emax Hill factor (γ) Proportional treatment difference in Emax IIV ED IIV Emax IIV = Inter-individual variability (estimated as variance, 2 ) Negative Binomial distribution becomes Poisson distribution when Overdispersion parameter = 0 The proportional treatment difference in Emax means that Emax is estimated to be 17.6% lower when treated with GSK compared to placebo A sigmoidal Emax model best described the Citric Acid challenge data. A negative binomial distribution model was marginally superior although the overdispersion parameter was estimated with low precision. Parameter Estimates and Standard Errors from best Citric Acid Challenge Models (Part C): Negative Binomial distribution Parameter Estimate SE Relative SE (%) E0 0 (fixed) NA NA ED50 (M/L) Emax Hill factor (γ) Overdispersion parameter IIV Emax IIV ED Poisson distribution Parameter Estimate SE Relative SE (%) E0 0 (fixed) NA NA ED50 (M/L) Emax Hill factor (γ) Proportional treatment difference in ED IIV Emax

9 IIV = Inter-individual variability (estimated as variance, 2 ) Negative Binomial distribution becomes Poisson distribution when Overdispersion parameter = 0 The proportional treatment difference in ED50 means that ED50 is estimated to be 41.6% higher when treated with GSK compared to placebo Summary of C2, C5 and C6 for Capsaicin Challenge (µmol/l) (Part B): Treatment N Planned Relative Time (Seconds) n Concentration evoking 2 coughs Concentration evoking 5 coughs Concentration evoking 6 coughs Geo. Mean 95% CI of Geo. Mean SD Logs CV (%) Placebo (2.422,7.218) (2.422,7.218) GSK (2.391,13.571) (2.167,11.635) Placebo (4.480,17.948) (4.418,15.843) GSK (3.757,34.557) (2.918,34.613) Placebo (4.487,31.211) (3.905,27.167) GSK (3.269,46.971) (3.237,65.631) CV (%)=100*sqrt(exp(SDlogs**2)-1) Note: All instances of missing values in this summary occurred where a subject did not achieve the required number of coughs for a parameter Summary of C2, C5 and C6 for Citric Acid Challenge (mol/l) (Part C): Treatment N Planned Relative Time (Seconds) n Concentration evoking 2 coughs Concentration evoking 5 coughs Concentration evoking 6 coughs Geo. Mean 95% CI of Geo. Mean SD Logs CV (%) Placebo (0.099,0.443) (0.090,0.410) GSK (0.070,0.350) (0.070,0.350) Placebo (0.117,0.795) (0.127,0.601) GSK (0.299,1.244) (0.312,1.605) Placebo (0.132,1.048) (0.128,0.887) GSK (0.397,1.389) (0.387,1.535) CV (%)=100*sqrt(exp(SDlogs**2)-1) Note: All instances of missing values in this summary occurred where a subject did not achieve the required number of coughs for a parameter Pharmacokinetics: Plasma concentrations of GSK and derived pharmacokinetic parameters were determined in CIC patients following two repeated doses of GSK at Visits 1, 2 and 3. Predicted AUC(0-24) could not be determined, since no robust population PK model could be defined. Administration Dose Cmax (ng/ml) 1 First Dose (224) Dose (138) tmax (h) ( ) 0.03 ( ) AUC(0-1) AUC(0-t) (h*ng/ml) 1 (h*ng/ml) 1, (109) (174) (76.8) 9

10 Second Dose (474) 0.07 ( ) Dose (416) ( ) 1 geometric mean (%CVb) 2 median (range) 3 AUC(0-t) estimated across both Doses 1 and 2 NA = Not applicable; insufficient data to derive summary measure (175) 1.24 NA (559) Safety Results: On therapy Adverse Events (AE) and Serious Adverse Events (SAE) were collected from the start of study treatment until the follow-up contact. Two ECG abnormalities that were considered clinically significant, both abnormalities were prolonged QTc >500 msec and occurred following dosing with placebo. There were no reports of anaesthesia in any subject assessed for oropharyngeal sensation perturbation and there were no reports of suicidal ideation or suicidal behaviour in any subject in the 6 months prior to screening or at follow-up. There were no Serious Adverse Events (SAE), Medical Device Incidents or Adverse Events associated with the ADI during the study. System Organ Class Preferred Term Placebo (N=16) n (%) mcg (N=14) n (%) Total (N=16) n (%) Any Event 10 (63) 5 (36) 12 (75) Nervous system disorders Any event 5 (31) 3 (21) 6 (38) Dysgeusia 1 (6) 1 (7) 2 (13) Headache 1 (6) 1 (7) 2 (13) Paraesthesia oral 1 (6) 1 (7) 2 (13) Dizziness 1 (6) 1 (7) 1 (6) Hypoaesthesia oral 1 (6) 0 1 (6) Respiratory, thoracic and mediastinal disorders Any event 3 (19) 2 (14) 5 (31) Cough 0 1 (7) 1 (6) Dyspnoea 1 (6) 0 1 (6) Oropharyngeal pain 1 (6) 0 1 (6) Rhinorrhoea 1 (6) 0 1 (6) Throat irritation 0 1 (7) 1 (6) Gastrointestinal disorders Any event 1 (6) 1 (7) 2 (13) Tongue discolouration 1 (6) 0 1 (6) 10

11 Vomiting 0 1 (7) 1 (6) Investigations Any event 2 (13) 0 2 (13) Electrocardiogram QT prolonged 1 (6) 0 1 (6) QRS axis abnormal 1 (6) 0 1 (6) Musculoskeletal and connective tissue disorders Any event 0 1 (7) 1 (6) Musculoskeletal pain 0 1 (7) 1 (6) Note: Total is total no. of subjects experiencing the event not total no. of events. Serious Adverse Events - On-Therapy n (%) [n considered by the investigator to be related to study medication] Subjects with non-fatal SAEs, n (%) 0 Subjects with fatal SAEs, n (%) 0 Summary of Oropharyngeal Sensation (Part A): Treatment N Dose Planned Time n Placebo First 16 Dose Administration 1 Placebo Second Administration GSK First Administration GSK Second Administration Dose 2 7 Dose 1 Dose 2 14 Dose 1 Dose 2 7 Dose 1 No Anaesthesia Mild Anaesthesia Moderate Anaesthesia 2 M (100%) M (100%) M (100%) M (100%) H (100%) Severe Anaesthesia 2 M (100%) M (100%) M (100%) M (100%) H (100%) M 7 7 (100%) M 7 7 (100%) M 7 7 (100%) M 7 7 (100%) H 7 7 (100%) M 7 7 (100%) M 7 7 (100%) M 7 7 (100%) M 7 7 (100%) H 7 7 (100%) M (100%) M (100%) M (100%) M (100%) H (100%) M (100%) M (100%) M (100%) M (100%) H (100%) M 7 7 (100%) M 7 7 (100%) M 7 7 (100%) M 7 7 (100%) H 7 7 (100%) Dose 2 M 7 7 (100%)

12 2 5 M 7 7 (100%) M 7 7 (100%) M 7 7 (100%) H 7 7 (100%) Transient cough (cough occurring in the first two minutes following administration) was recorded as a safety endpoint, however no instances of transient cough were considered clinically significant by the Investigator. Summary of number of transient coughs for each dose (Part A): Treatment N Dose n Mean SD Median Min. Max. 4 Hour Placebo First Administration H H Placebo Second Administration 7 0-4H H GSK First Administration H H GSK Second Administration 7 0-4H H Hour Placebo First Administration H Placebo Second Administration 7 0-8H GSK First Administration H GSK Second Administration 7 0-8H N=No. of subjects who received at least one dose of study medication. n=no. of subjects with a cough count value. Conclusions: There was no attenuation of cough in CIC patients over the 8 hour cough count analysis period for any subject on GSK compared to placebo. There was also no evidence that GSK was effective for a shorter duration since there was no attenuation of cough when the data was analysed in hourly epochs. Subjective assessments for urge to cough and cough severity also failed to show any benefit in subjects administered GSK versus placebo in the hour after dosing. GSK had a pro-tussive effect with all subjects coughing in the two minutes post administration, which was not seen on placebo. However there was no attenuation of cough once this initial pro-tussive response was removed from the 8 hour cough count analysis. Based on the capsaicin dose response, there did not appear to be a treatment effect of GSK compared to placebo on ED50. Whilst there was some evidence for a reduction in capsaicin Emax with GSK (approximately 17%), different tested models (Poisson or Negative Binomial) did not show a consistent treatment effect on Emax and the dataset was too small to make definitive conclusions. Based on the citric acid dose response, there did not appear to be a treatment effect of GSK compared to placebo on Emax. Whilst there was some evidence for an increase in capsaicin ED50 with GSK (approximately 41%), different tested models (Poisson or Negative Binomial) did not show a consistent treatment effect on ED50 and the dataset was too small to make definitive conclusions. GSK was rapidly absorbed (median tmax 2 4 minutes post-dose) across all dose administrations and systemically available GSK declined rapidly after Cmax (over the first 0.5 hour post-dose) with concentrations below the limit of quantification (0.2 ng/ml) within 4 hours of administration. Based on the 12

13 data, a robust population PK model could not be defined. In total there were 10 non-serious adverse events in subjects receiving placebo and 5 in subjects receiving GSK There were no significant or serious adverse events on GSK and there was no apparent effect on oropharyngeal sensation. Furthermore there were no adverse events associated with use of the ADI. 13