14/GAR/002

Manchester University NHS Foundation Trust

Oxford Road, Manchester, United Kingdom, M13 9WL

Jaclyn Smith, University of Manchester, +44 01612915863, jacky.smith@manchester.ac.uk

Jaclyn Smith, University of Manchester, +44 01612915863, jacky.smith@manchester.ac.uk

No

No

No

Final

30 Aug 2017

No

Yes

30 Aug 2017

No

To evaluate the effect of 2 weeks of Lesogaberan treatment compared with 2 weeks of placebo treatment on 24 hour cough frequency. Lay description: To test what effect a drug called Lesogaberan has on how much a person coughs in a 24 hour period compared to if that person was taking a dummy drug with no active ingredients (called placebo).

Patients may experience side effects after taking Lesogaberan or placebo during the study. Lesogaberan has been previously been given to 489 healthy volunteers and 930 patients. The drug was generally well tolerated. The most common side effect of taking Lesogaberan (seen in 1 in 4 people)is tingling or numbness of the fingers, which only mild and temporary. The other side effects were headache (1 in 10), feeling hot, diarrhoea, flatulence and dizziness. During the study patients will be asked to perform a number of tests which may have side effects. Oesophageal studies (high resolution manometry and 24 hour pH impedance). This is a combination of 2 procedures where the patient has a small tube passed through their nose into their stomach, one of the tubes will be left in place for 24 hours. This procedure is not painful, there maybe some slight discomfort when the tube is passed through the nose, thus a numbing agent will be applied to the nasal area to reduce this. there may be some mild gagging or coughing too. Most patients tolerated this procedure well. A cough challenge involves inhaling capsaicin, which is a component of chilli peppers. Capsaicin can cause tightening of the airways, although this is rare. Breathing tests are performed during and after the test to monitor any chest tightening, which is easily treated by inhaling salbutamol (a medication to open up the airways. Blood tests sometimes cause bruising at the site of the needle puncture. Some people feel faint whilst blood is being withdrawn. Rarely a small blood clot or infection can occur. The electrodes and sticky pads placed on the skin during ECG tests and 24 hour cough monitoring can occasionally lead to skin irritation. Although lung function tests are not painful, they can be tiring to perform. Patients may experience shortness of breath, coughing or chest tightness. Some people can feel lightheaded or faint. A doctor will be present in the department at all times.

23 Jul 2015

No

No

United Kingdom: 22

22

22

0

0

0

0

0

0

12

10

0

Overall Trial (overall period)

Randomised - controlled

Randomisation sequences were generated by an external contractor independent to the study site. Blinded study medication and unblinding scratch cards were supplied to the hospital pharmacy department.

No

Lesogaberan

Capsule

Oral use

120mg Lesogaberan (modified release) was taken twice a day at approximately 12 hour intervals. The first dose plus the morning doses on the last two treatment days were taken during study visits whilst in the department to allow measurement of secondary endpoints (blood pK and capsaicin cough response) at peak plasma levels (2 hours post dose).

Matched placebo

Capsule

Oral use

Matched placebo administered twice a day at approximately 12 hour intervals for 2 weeks. The first dose and morning doses on final two treatment days were taken in the department to allow secondary endpoint measurements to be taken at peak plasma levels at 2 hours (capsaicin coughs and pK bloods)

Overall Trial

SAP Analysis

All patients for whom reflux symptom association data were available (n=19)

Reflux Analysis

Patients with fully available reflux data (n=20)

Lesogaberan

Placebo

SAP Analysis

All patients for whom reflux symptom association data were available (n=19)

Reflux Analysis

Patients with fully available reflux data (n=20)

Primary

Cough frequency over 24 hours measured after two weeks treatment with Lesogaberan or matched placebo

Generalised Estimating Equation (GEE) models were used to analyze the data assessing the influence of treatment period and sequence. We adjusted for period specific baseline. Potential carryover effects were examined by the sequence in the model. Based on previous cough frequency data in an unselected chronic cough group, the study had approximately 80% power to detect a 43% reduction in cough with lesogaberan over placebo, assuming a SD of log cough frequency of 0.42. Sig level p<0.05.

Lesogaberan v Placebo

39

Pre-specified

Incremental concentrations of capsaicin were inhaled through a dose controlled nebuliser up to the maximum tolerated dose or the end of the challenge. Emax is defined as the maximum number of coughs evoked by any concentration of capsaicin.

Secondary

Capsaicin challenge was performed at screening and at baseline and at the end of both treatment periods. The challenge was administered at 2 hours post final dose of medication intended to capture peak drug plasma levels.

Generalised Estimating Equation (GEE) models were used to analyze the data assessing the influence of treatment period and sequence. We adjusted for period specific baseline. Potential carryover effects were examined by the sequence in the model. Significance was set at p <0.05.

Lesogaberan v Placebo

32

Pre-specified

Capsaicin challenge was performed at screening and at baseline and at the end of both treatment periods. The challenge was administered at 2 hours post final dose of medication intended to capture peak drug plasma levels. Incremental concentrations of capsaicin solution were inhaled through a dose controlled nebuliser up to the maximum tolerated dose or the end of the challenge. ED50 is defined as the dose or concentration of capsaicin that elicits half of the maximum cough response (Emax).

Secondary

ED50 dose compared after 2 weeks treatment with lesogaberan or matched placebo.

Generalised Estimating Equation (GEE) models were used to analyze the data assessing the influence of treatment period and sequence. We adjusted for period specific baseline. Potential carryover effects were examined by the sequence in the model.

Lesogaberan v Placebo

32

Pre-specified

100mm visual analogue scale where patients are asked to draw a vertical line to indicate their perceived cough severity during daytime hours on any particular day.

Secondary

Measured pre and post 2 weeks of treatment with lesogaberan or matched placebo.

Generalised Estimating Equation (GEE) models were used to analyze the data assessing the influence of treatment period and sequence. We adjusted for period specific baseline. Potential carryover effects were examined by the sequence in the model. Significance was set at p <0.05.

Lesogaberan v Placebo

38

Pre-specified

100mm visual analogue scale where patients are asked to draw a vertical line to indicate their perceived cough severity during overnight hours on any particular day.

Secondary

Measured pre and post 2 weeks of treatment with lesogaberan or matched placebo.

Generalised Estimating Equation (GEE) models were used to analyze the data assessing the influence of treatment period and sequence. We adjusted for period specific baseline. Potential carryover effects were examined by the sequence in the model. Significance was set at p <0.05.

Lesogaberan v Placebo

38

Pre-specified

Self-reported quality of life outcome measure - Leicester Cough Questionnaire (LCQ). 19 items with likert scale (1-7) reflecting on cough for previous 2 weeks.

Secondary

Measured pre and post 2 weeks of treatment with lesogaberan or matched placebo

Generalised Estimating Equation (GEE) models were used to analyze the data assessing the influence of treatment period and sequence. We adjusted for period specific baseline. Potential carryover effects were examined by the sequence in the model. Significance was set at p <0.05.

Lesogaberan v Placebo

41

Pre-specified

AEs were reported from administration of the first dose of study medication, throughout both dosing periods (2 weeks each), a 1-2 week washout period and until the final follow up visit (1-2 weeks after final dose of study medication).

AEs were assessed by the investigator at each study visit via patient reporting, routine safety blood testing, vital signs and ECGs

17.1

Placebo treatment

Lesogaberan treatment