A Dose-ranging Study of Orvepitant in Patients With Chronic Refractory Cough

Study Overview
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Brief Summary
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The purpose of this study is to determine the effectiveness of three doses of orvepitant, taken once a day, in the treatment of chronic refractory cough.

Detailed Description
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A multi-center, double-blind, randomized, parallel group, placebo-controlled dose range study in subjects with chronic refractory cough (CRC). Doses of orvepitant (10 mg/day, 20 mg/day and 30 mg/day) and placebo will be investigated in four parallel groups. Each group will compromise of approximately 73 subjects, randomized 1:1:1:1 (approximately 292 subjects in total). All subjects will enter a three-week screening period to determine eligibility. Eligible subjects will be randomized at the Baseline/Day 1 visit and enter a 12-week double-blind dosing period. During this period there will be four visits at Weeks 2, 4, 8 and 12. There will be a final safety follow-up visit at Week 14.

Official Title
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A Double-Blind, Randomized, Placebo Controlled Study of the Efficacy and Safety of Three Doses of Orvepitant in Subjects With Chronic Refractory Cough

Conditions
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Chronic Refractory Cough

Intervention / Treatment
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* Drug: Orvepitant Maleate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Male and female subjects ≥18 years of age. Diagnosis of CRC or unexplained cough for at least 1 year (see ACCP/BTS guidelines attached). An awake average cough frequency of ≥10 coughs/ hour, as assessed using an ACM during the screening period. Key Exclusion Criteria: Subjects with respiratory tract infection (<4 weeks prior to study start) Current smokers or ex-smokers with <6 months' abstinence or cumulative history of >10 pack years Treatment with Angiotensin Converting Enzyme (ACE) inhibitors within 3 months of screening FEV1 <80% predicted, measured at screening using spirometry History of cystic fibrosis, idiopathic pulmonary fibrosis, clinically significant bronchiectasis, moderate to severe asthma, chronic obstructive pulmonary disease (COPD) Any clinically significant abnormal laboratory test result(s) Inability to comply with the use of prohibited and allowed medications as described in the protocol.

Ages Eligible for Study
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Minimum Age: 18 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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Orvepitant 10mg<br>Orvepitant 10mg tablet, once daily for 12 weeks | Drug: Orvepitant Maleate<br>* Tablet, once daily, oral<br>|
| Experimental: Orvepitant 20mg<br>Orvepitant 20mg tablet, once daily for 12 weeks | Drug: Orvepitant Maleate<br>* Tablet, once daily, oral<br>|
| Experimental: Orvepitant 30mg<br>Orvepitant 30mg tablet, once daily for 12 weeks | Drug: Orvepitant Maleate<br>* Tablet, once daily, oral<br>|
| Placebo Comparator: Placebo<br>Placebo to match tablet, once daily for 12 weeks | Drug: Placebo<br>* Tablet, once daily, oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 12 in Awake Objective Cough Frequency | Objective cough frequency measured by ambulatory cough monitoring device | Baseline to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Awake Objective Cough Frequency at Week 2 Compared to Baseline | Objective cough frequency measured by ambulatory cough monitoring device | Baseline to Week 2 | 
| Change in Awake Objective Cough Frequency at Week 4 Compared to Baseline | Objective cough frequency measured by ambulatory cough monitoring device | Week 4 | 
| Change in the Leicester Cough Questionnaire (LCQ) at Week 2 Compared to Baseline | The Leicester Cough Questionnaire (LCQ) is a 19 item questionnaire that assessed cough related quality of life. It has three domains (physical, psychological and social) and subjects were asked to complete it based on their experience in a recall period of 2 weeks. The total score range is 3 to 21 and domain scores each range from 1 to 7; a higher score indicated a better quality of life. Subjects completed the LCQ whilst in the clinic at baseline/Day 1 (pre dose) and at Weeks 2, 4, 8, and 12. | Baseline to Week 2 | 
| Change in the Leicester Cough Questionnaire (LCQ) at Week 4 Compared to Baseline | The Leicester Cough Questionnaire (LCQ) is a 19 item questionnaire that assessed cough related quality of life. It has three domains (physical, psychological and social) and subjects were asked to complete it based on their experience in a recall period of 4 weeks. The total score range is 3 to 21 and domain scores each range from 1 to 7; a higher score indicated a better quality of life. Subjects completed the LCQ whilst in the clinic at baseline/Day 1 (pre dose) and at Weeks 2, 4, 8, and 12. | Baseline to Week 4 | 
| Change in the Leicester Cough Questionnaire (LCQ) at Week 8 Compared to Baseline | The Leicester Cough Questionnaire (LCQ) is a 19 item questionnaire that assessed cough related quality of life. It has three domains (physical, psychological and social) and subjects were asked to complete it based on their experience in a recall period of 8 weeks. The total score range is 3 to 21 and domain scores each range from 1 to 7; a higher score indicated a better quality of life. Subjects completed the LCQ whilst in the clinic at baseline/Day 1 (pre dose) and at Weeks 2, 4, 8, and 12. | Baseline to Week 8 | 
| Change in the Leicester Cough Questionnaire (LCQ) at Week 12 Compared to Baseline | The Leicester Cough Questionnaire (LCQ) is a 19 item questionnaire that assessed cough related quality of life. It has three domains (physical, psychological and social) and subjects were asked to complete it based on their experience in a recall period of 12 weeks. The total score range is 3 to 21 and domain scores each range from 1 to 7; a higher score indicated a better quality of life. Subjects completed the LCQ whilst in the clinic at baseline/Day 1 (pre dose) and at Weeks 2, 4, 8, and 12. | Baseline to Week 12 | 
| Change in the Cough Severity Visual Analogue Scale (VAS) at Week 2 Compared to Baseline - Day-time | The cough VAS is a 100 mm scale on which subjects indicated their severity of cough over the previous 24 hours, both during the day-time and during night time separately. The VAS ranged from no cough (0 mm) on the left to worst cough (100 mm) on the right. Subjects completed the cough severity VAS at baseline/Day 1 (pre dose) and at Weeks 2, 4, 8, and 12. | Baseline to Week 2 | 
| Change in the Cough Severity Visual Analogue Scale (VAS) at Week 4 Compared to Baseline - Day-time | The cough VAS is a 100 mm scale on which subjects indicated their severity of cough over the previous 24 hours, both during the day-time and during night time separately. The VAS ranged from no cough (0 mm) on the left to worst cough (100 mm) on the right. Subjects completed the cough severity VAS at baseline/Day 1 (pre dose) and at Weeks 2, 4, 8, and 12. | Baseline to Week 4 | 
| Change in the Cough Severity Visual Analogue Scale (VAS) at Week 8 Compared to Baseline - Day-time | The cough VAS is a 100 mm scale on which subjects indicated their severity of cough over the previous 24 hours, both during the day-time and during night time separately. The VAS ranged from no cough (0 mm) on the left to worst cough (100 mm) on the right. Subjects completed the cough severity VAS at baseline/Day 1 (pre dose) and at Weeks 2, 4, 8, and 12. | Baseline to Week 8 | 
| Change in the Cough Severity Visual Analogue Scale (VAS) at Week 12 Compared to Baseline - Day-time | The cough VAS is a 100 mm scale on which subjects indicated their severity of cough over the previous 24 hours, both during the day-time and during night time separately. The VAS ranged from no cough (0 mm) on the left to worst cough (100 mm) on the right. Subjects completed the cough severity VAS at baseline/Day 1 (pre dose) and at Weeks 2, 4, 8, and 12. | Baseline to Week 12 | 
| Change in the Cough Severity Visual Analogue Scale (VAS) at Week 2 Compared to Baseline - Night-time | The cough VAS is a 100 mm scale on which subjects indicated their severity of cough over the previous 24 hours, both during the day-time and during night time separately. The VAS ranged from no cough (0 mm) on the left to worst cough (100 mm) on the right. Subjects completed the cough severity VAS at baseline/Day 1 (pre dose) and at Weeks 2, 4, 8, and 12. | Baseline to Week 2 | 
| Change in the Cough Severity Visual Analogue Scale (VAS) at Week 4 Compared to Baseline - Night-time | The cough VAS is a 100 mm scale on which subjects indicated their severity of cough over the previous 24 hours, both during the day-time and during night time separately. The VAS ranged from no cough (0 mm) on the left to worst cough (100 mm) on the right. Subjects completed the cough severity VAS at baseline/Day 1 (pre dose) and at Weeks 2, 4, 8, and 12. | Baseline to Week 4 | 
| Change in the Cough Severity Visual Analogue Scale (VAS) at Week 8 Compared to Baseline - Night-time | The cough VAS is a 100 mm scale on which subjects indicated their severity of cough over the previous 24 hours, both during the day-time and during night time separately. The VAS ranged from no cough (0 mm) on the left to worst cough (100 mm) on the right. Subjects completed the cough severity VAS at baseline/Day 1 (pre dose) and at Weeks 2, 4, 8, and 12. | Baseline to Week 8 | 
| Change in the Cough Severity Visual Analogue Scale (VAS) at Week 12 Compared to Baseline - Night-time | The cough VAS is a 100 mm scale on which subjects indicated their severity of cough over the previous 24 hours, both during the day-time and during night time separately. The VAS ranged from no cough (0 mm) on the left to worst cough (100 mm) on the right. Subjects completed the cough severity VAS at baseline/Day 1 (pre dose) and at Weeks 2, 4, 8, and 12. | Baseline to Week 12 | 
| Change in the Urge-to-cough Visual Analogue Scale (VAS) at Week 2 Compared to Baseline | The urge-to-cough VAS was a 100 mm scale on which subjects indicated their urge to cough over the previous 24 hours (day/awake time and night time combined). The VAS ranged from no urge to cough (0 mm) on the left to severe urge to cough (100 mm) on the right. Subjects completed the urge to cough VAS at baseline/Day 1 (pre dose) and at Weeks 2, 4, 8, and 12. | Baseline to Week 2 | 
| Change in the Urge-to-cough Visual Analogue Scale (VAS) at Week 4 Compared to Baseline | The urge-to-cough VAS was a 100 mm scale on which subjects indicated their urge to cough over the previous 24 hours (day/awake time and night time combined). The VAS ranged from no urge to cough (0 mm) on the left to severe urge to cough (100 mm) on the right. Subjects completed the urge to cough VAS at baseline/Day 1 (pre dose) and at Weeks 2, 4, 8, and 12. | Baseline to Week 4 | 
| Change in the Urge-to-cough Visual Analogue Scale (VAS) at Week 8 Compared to Baseline | The urge-to-cough VAS was a 100 mm scale on which subjects indicated their urge to cough over the previous 24 hours (day/awake time and night time combined). The VAS ranged from no urge to cough (0 mm) on the left to severe urge to cough (100 mm) on the right. Subjects completed the urge to cough VAS at baseline/Day 1 (pre dose) and at Weeks 2, 4, 8, and 12. | Baseline to Week 8 | 
| Change in the Urge-to-cough Visual Analogue Scale (VAS) at Week 12 Compared to Baseline | The urge-to-cough VAS was a 100 mm scale on which subjects indicated their urge to cough over the previous 24 hours (day/awake time and night time combined). The VAS ranged from no urge to cough (0 mm) on the left to severe urge to cough (100 mm) on the right. Subjects completed the urge to cough VAS at baseline/Day 1 (pre dose) and at Weeks 2, 4, 8, and 12. | Baseline to Week 12 | 
| Global Rating of Change in Cough Frequency at Week 2 | In the Global Rating of Change scale, subjects indicated if there had been a change in their symptoms (cough frequency and, separately, cough severity) since starting the IMP. Subjects responded with worse, about the same or better. If subjects indicated a change (either worse or better) they then indicated on a 7 point scale the degree of change ranging from 1 (almost the same, hardly any change) to 7 (a very great deal changed). Subjects documented their Global Rating of Change in cough frequency and cough severity at Weeks 2, 4, 8, and 12. | Baseline to Week 2 | 
| Global Rating of Change in Cough Frequency at Week 4 | In the Global Rating of Change scale, subjects indicated if there had been a change in their symptoms (cough frequency and, separately, cough severity) since starting the IMP. Subjects responded with worse, about the same or better. If subjects indicated a change (either worse or better) they then indicated on a 7 point scale the degree of change ranging from 1 (almost the same, hardly any change) to 7 (a very great deal changed). Subjects documented their Global Rating of Change in cough frequency and cough severity at Weeks 2, 4, 8, and 12. | Baseline to Week 4 | 
| Global Rating of Change in Cough Frequency at Week 8 | In the Global Rating of Change scale, subjects indicated if there had been a change in their symptoms (cough frequency and, separately, cough severity) since starting the IMP. Subjects responded with worse, about the same or better. If subjects indicated a change (either worse or better) they then indicated on a 7 point scale the degree of change ranging from 1 (almost the same, hardly any change) to 7 (a very great deal changed). Subjects documented their Global Rating of Change in cough frequency and cough severity at Weeks 2, 4, 8, and 12. | Baseline to Week 8 | 
| Global Rating of Change in Cough Frequency at Week 12 | In the Global Rating of Change scale, subjects indicated if there had been a change in their symptoms (cough frequency and, separately, cough severity) since starting the IMP. Subjects responded with worse, about the same or better. If subjects indicated a change (either worse or better) they then indicated on a 7 point scale the degree of change ranging from 1 (almost the same, hardly any change) to 7 (a very great deal changed). Subjects documented their Global Rating of Change in cough frequency and cough severity at Weeks 2, 4, 8, and 12. | Baseline to Week 12 | 
| Global Rating of Change in Cough Severity at Week 2 | In the Global Rating of Change scale, subjects indicated if there had been a change in their symptoms (cough frequency and, separately, cough severity) since starting the IMP. Subjects responded with worse, about the same or better. If subjects indicated a change (either worse or better) they then indicated on a 7 point scale the degree of change ranging from 1 (almost the same, hardly any change) to 7 (a very great deal changed). Subjects documented their Global Rating of Change in cough frequency and cough severity at Weeks 2, 4, 8, and 12. | Baseline to Week 2 | 
| Global Rating of Change in Cough Severity at Week 4 | In the Global Rating of Change scale, subjects indicated if there had been a change in their symptoms (cough frequency and, separately, cough severity) since starting the IMP. Subjects responded with worse, about the same or better. If subjects indicated a change (either worse or better) they then indicated on a 7 point scale the degree of change ranging from 1 (almost the same, hardly any change) to 7 (a very great deal changed). Subjects documented their Global Rating of Change in cough frequency and cough severity at Weeks 2, 4, 8, and 12. | Baseline to Week 4 | 
| Global Rating of Change in Cough Severity at Week 8 | In the Global Rating of Change scale, subjects indicated if there had been a change in their symptoms (cough frequency and, separately, cough severity) since starting the IMP. Subjects responded with worse, about the same or better. If subjects indicated a change (either worse or better) they then indicated on a 7 point scale the degree of change ranging from 1 (almost the same, hardly any change) to 7 (a very great deal changed). Subjects documented their Global Rating of Change in cough frequency and cough severity at Weeks 2, 4, 8, and 12. | Baseline to Week 8 | 
| Global Rating of Change in Cough Severity at Week 12 | In the Global Rating of Change scale, subjects indicated if there had been a change in their symptoms (cough frequency and, separately, cough severity) since starting the IMP. Subjects responded with worse, about the same or better. If subjects indicated a change (either worse or better) they then indicated on a 7 point scale the degree of change ranging from 1 (almost the same, hardly any change) to 7 (a very great deal changed). Subjects documented their Global Rating of Change in cough frequency and cough severity at Weeks 2, 4, 8, and 12. | Baseline to Week 12 |