Efficacy of Two Doses of Duloxetine and Amitriptyline in Subjects With Refractory Chronic Cough

Phase 2

Recruiting

• Conditions: Refractory Chronic Cough
• Interventions: Drug: Duloxetine 30 MG; Drug: Amitriptyline 25 MG; Drug: Amitriptyline 50 MG; Drug: Placebo 30 MG; Drug: Placebo 60 MG; Drug: Duloxetine 60 MG

• Registration Number: NCT05110144
• Lead Sponsor: Mayo Clinic

Brief Summary

This research study is evaluating the effectiveness of escalating doses of Amitriptyline and Duloxetine in reducing cough frequency in patients with refractory chronic cough (RCC)

Detailed Description

This is a randomized, double-blind, placebo-controlled, parallel-arm, dose escalation study of Duloxetine \& Amitriptyline in subjects with refractory chronic cough. Subjects will be screened during a period of up to 2 week and will undergo screening/ baseline cough monitoring. A total of 50 subjects who meet entry criteria will be randomly assigned in a 1: 1: 1: 1: 1 ratio to one of five treatment arms using stratified randomization in blocks of 10. Each arm will have two successive 4-week treatment periods (Blinded Period 1 \& 2). After this, patients will be unblinded and receive routine clinical care. During the unblinded (routine clinical care) follow up phase; subjects will be initially offered the option of continuing amitriptyline or duloxetine based on their initial randomization arm. Subjects could also choose an alternative chronic cough therapy (e.g. pregabalin, gabapentin, 1% tetracaine lollipop or nebulized lidocaine or combination therapy).

Subjects in treatment arm 5, who received placebo during the 8 weeks blinded period will have a discussion regarding all available cough therapies. Patients will be offered the flexibility of therapy options during the unblinded follow up as they would during routine clinical care. Participation in the unblinded follow-up period will be optional.

Treatment Arm 1:

Blinded Period 1 (1st 4 weeks): 30mg of Duloxetine Blinded Period 2 (2nd 4 weeks): 30mg of Duloxetine \& 30mg of Placebo Unblinded (routine clinical care) follow up period: (up to 52 weeks): Subjects will be offered routine clinical care management for their chronic cough

Treatment Arm 2:

Blinded Period 1 (1st 4 weeks): 30mg of Duloxetine Blinded Period 2 (2nd 4 weeks): 60mg of Duloxetine (2 pills of 30mg each) Unblinded (routine clinical care) follow up period: (up to 52 weeks): Subjects will be offered routine clinical care management for their chronic cough

Treatment Arm 3:

Blinded Period 1 (1st 4 weeks): 25mg of Amitriptyline Blinded Period 2 (2nd 4 weeks): 25mg of Amitriptyline + 25mg of Placebo Unblinded (routine clinical care) follow up period: (up to 52 weeks): Subjects will be offered routine clinical care management for their chronic cough

Treatment Arm 4:

Blinded Period 1 (1st 4 weeks): 25mg of Amitriptyline Blinded Period 2 (2nd 4 weeks): 50mg of Amitriptyline (2 pills of 25mg each) Unblinded (routine clinical care) follow up period: (up to 52 weeks): Subjects will be offered routine clinical care management for their chronic cough

Treatment Arm 5:

Blinded Period 1 (1st 4 weeks): 30mg of Placebo Blinded Period 2 (2nd 4 weeks): 60mg of Placebo (2 pills of 30mg each) Unblinded (routine clinical care) follow up period: (up to 52 weeks): Subjects will be offered routine clinical care management for their chronic cough

Study Timeline

• Study Start: 2021-11-01
• Study First Submitted: 2021-11-03
• Study First Submitted QC: 2021-11-03
• Study First Posted: 2021-11-05
• Status Verified: 2024-03
• Last Update Submitted: 2024-03-29
• Last Update Posted: 2024-04-01
• Primary Completion: 2025-12
• Study Completion: 2025-12

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 50

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Duloxetine and Placebo	Duloxetine 30 MG	Subjects will receive 30mg of Duloxetine for blinded period 1 (first 4 week treatment period) and 30mg of Duloxetine plus 30mg Placebo for blinded period 2 (additional 4 week treatment period). After this, subjects will be unblinded and receive routine clinical care for follow up phase (up to 52 weeks).
Amitriptyline dose escalation	Amitriptyline 25 MG	Subjects will receive 25mg of Amitriptyline for blinded period 1 (first 4 week treatment period) and 50mg of Amitriptyline for blinded period 2 (additional 4 weeks treatment period). After this, subjects will be unblinded and receive routine clinical care for follow up phase (up to 52 weeks).
Amitriptyline dose escalation	Amitriptyline 50 MG	Subjects will receive 25mg of Amitriptyline for blinded period 1 (first 4 week treatment period) and 50mg of Amitriptyline for blinded period 2 (additional 4 weeks treatment period). After this, subjects will be unblinded and receive routine clinical care for follow up phase (up to 52 weeks).
Duloxetine and Placebo	Placebo 30 MG	Subjects will receive 30mg of Duloxetine for blinded period 1 (first 4 week treatment period) and 30mg of Duloxetine plus 30mg Placebo for blinded period 2 (additional 4 week treatment period). After this, subjects will be unblinded and receive routine clinical care for follow up phase (up to 52 weeks).
Placebo	Placebo 60 MG	Subjects will receive 30mg of Placebo for blinded period 1 (first 4 week treatment period) and 60mg of Placebo for blinded period 2 (additional 4 weeks treatment period). After this, subjects will be unblinded and receive routine clinical care for follow up phase (up to 52 weeks).
Duloxetine dose escalation	Duloxetine 60 MG	Subjects will receive 30mg of Duloxetine for blinded period 1 (first 4 week treatment period) and 60mg of Duloxetine for blinded period 2 (additional 4 weeks treatment period). After this, subjects will be unblinded and receive routine clinical care for follow up phase (up to 52 weeks).
Duloxetine dose escalation	Duloxetine 30 MG	Subjects will receive 30mg of Duloxetine for blinded period 1 (first 4 week treatment period) and 60mg of Duloxetine for blinded period 2 (additional 4 weeks treatment period). After this, subjects will be unblinded and receive routine clinical care for follow up phase (up to 52 weeks).
Amitriptyline and Placebo	Amitriptyline 25 MG	Subjects will receive 25mg of Amitriptyline for blinded period 1 (first 4 week treatment period) and 25mg of Amitriptyline plus 30mg Placebo for blinded period 2 (additional 4 week treatment period). After this, subjects will be unblinded and receive routine clinical care for follow up phase (up to 52 weeks).
Placebo	Placebo 30 MG	Subjects will receive 30mg of Placebo for blinded period 1 (first 4 week treatment period) and 60mg of Placebo for blinded period 2 (additional 4 weeks treatment period). After this, subjects will be unblinded and receive routine clinical care for follow up phase (up to 52 weeks).
Amitriptyline and Placebo	Placebo 30 MG	Subjects will receive 25mg of Amitriptyline for blinded period 1 (first 4 week treatment period) and 25mg of Amitriptyline plus 30mg Placebo for blinded period 2 (additional 4 week treatment period). After this, subjects will be unblinded and receive routine clinical care for follow up phase (up to 52 weeks).

Primary Outcome Measures

Name	Time	Method
Change in awake objective cough frequency (at 4 & 8 weeks)	4 weeks, 8 weeks	The primary objective is to evaluate awake cough frequency at 4 and 8 weeks using the Leicester Cough Monitor. The acoustic cough monitor recordings will be analyzed using the Leicester Cough Monitor program V2.3-MB. This will also be performed at months 4, 6, 9 \& 12 for subjects who choose to continue with the optional unblinded continuation of the study after the initial 8 weeks.

Secondary Outcome Measures

Name	Time	Method
Change from Baseline in Leicester Cough Questionnaire (LCQ-acute) individual domain and total scores	4 weeks, 8 weeks	The Leicester Cough Questionnaire (Acute) is a validated tool for the assessment of chronic cough. It evaluates physical, psychological and social domains and how they are impacted by chronic cough. The physical domain consists of 8 questions, the psychological domain consists of 7 questions, and the social domain consists of 4 questions. The domain score will be calculated as the total score from questions in the domain divided by the number of items in the domain (range 1-7). The total score is the sum of individual domain scores and ranges from 3-21. The individual domain as well as the total score will be reported on weeks 4 \& 8. This will also be performed at months 4, 6, 9 \& 12 for subjects who choose to continue with the optional unblinded continuation of the study after the initial 8 weeks.
Change in 24-Hour cough frequency	4 weeks, 8 weeks	This will also be evaluated using using the Leicester Cough Monitor and recordings will be analyzed using the Leicester Cough Monitor program V2.3-MB. All recordings will be kept confidential on a secure encrypted device. This will also be performed at months 4, 6, 9 \& 12 for subjects who choose to continue with the optional unblinded continuation of the study after the initial 8 weeks.
Change in Cough Severity Diary score	4 weeks, 8 weeks	Measured using self-reported Cough Severity Diary that patients will fill at baseline and on daily basis. Change in self-reported Cough Severity Diary score at 4 and 8 weeks will be evaluated.; Patients will be asked a series of 6 questions including and will provide an answer using a 5-point Likert scale (never, rarely, sometimes, often, constantly). The following questions will be evaluated: 1. In the past 24 hours, how often did you cough?; 2. In the past 24 hours, how often did you experience coughing fits?; 3. In the past 24 hours, how severe was your cough?; 4. In the past 24 hours, how often did you have an urge to cough?; 5. In the past 24 hours, how often could you control your cough?; 6. In the past 24 hours, how severe was your pain from coughing?; This will also be performed at months 4, 6, 9 \& 12 for subjects who choose to continue with the optional unblinded continuation of the study after the initial 8 weeks.
Change in Cough Severity Visual Analogue Scale (VAS)	4 weeks, 8 weeks	Scored on a 100 mm visual analogue scale at Screening/ Baseline visit (Day -14 to Day 0), and on Days 28, and 56. This will also be performed at months 4, 6, 9 \& 12 for subjects who choose to continue with the optional unblinded continuation of the study after the initial 8 weeks.

Trial Locations

Locations (1)

Mayo Clinic in Rochester; 🇺🇸 Rochester, Minnesota, United States