Testing Duloxetine and Amitriptyline for Cough in Lung Disease

A Randomized, Double-blind, Placebo Controlled, Dose Escalation Pilot Study Evaluating the Efficacy of Two Doses of Duloxetine and Amitriptyline in Interstitial Lung Disease-related Cough

This study is testing if two medications, Duloxetine and Amitriptyline, can help reduce coughing in people with chronic cough caused by lung disease.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 25 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: Mayo Clinic (other)
• Locations: 1 site (Rochester, Minnesota)
• Trial ID: NCT05120934 on ClinicalTrials.gov

What this trial studies

This clinical trial evaluates the effectiveness of two doses of Duloxetine and Amitriptyline in reducing cough frequency in patients suffering from interstitial lung disease-related chronic cough. It is a randomized, double-blind, placebo-controlled study involving 25 participants who will be assigned to one of five treatment arms. Each treatment arm consists of two successive 4-week periods, followed by an optional unblinded follow-up phase where patients can choose to continue their assigned medication or switch to alternative therapies. The study aims to provide insights into the efficacy of these medications for managing chronic cough in this patient population.

Who should consider this trial

Good fit: Ideal candidates are individuals diagnosed with interstitial lung disease who have experienced chronic cough for at least three months.

Not a fit: Patients without a diagnosis of interstitial lung disease or those who have not experienced chronic cough for the required duration may not benefit from this study.

Why it matters

Potential benefit: If successful, this study could provide a new effective treatment option for patients with chronic cough related to interstitial lung disease.

How similar studies have performed: Other studies have explored the use of similar medications for cough management, but this specific approach is novel in the context of interstitial lung disease.

Eligibility criteria

Inclusion Criteria

* Have a diagnosis of interstitial lung disease according to the American Thoracic Society Guidelines
* Have a chronic cough for at least 3 months prior to the screening visit
* Patients should be on a stable dose of ILD-directed therapies for 3 months prior to enrollment and will be allowed to continue their ILD-directed therapies. These include -but are not limited to- corticosteroids, immunosuppressing agents such as azathioprine and mycophenolate, as well as antifibrotic medications including nintedanib and pirfenidone. Additional corticosteroids and adjustment of ILD-directed therapy doses is permitted if deemed appropriate by the treating physician
* Have a score of ≥ 40mm on the Cough Severity VAS at Screening.
* Women of child-bearing potential must agree to use 2 forms of acceptable birth control and make no donation of eggs from Screening through the end of the 8-week study period. Acceptable birth control methods include established use of oral, injected, or implanted hormonal methods of contraception; intrauterine device (IUD) or intrauterine system (IUS); tubal ligation; or male sterilization. Double-barrier method (diaphragm for female subject and condom for male partner with spermicidal) satisfies the requirement for 2 forms of acceptable birth control. When concordant with the preferred lifestyle of the subject, true and complete abstinence (not periodic abstinence) is acceptable.
* Male subjects and their partners of child-bearing potential must use 2 methods of acceptable birth control, 1 of which must be a barrier method, and make no donation of sperm from Screening until 3 months after the last dose of study drug at the end of 8 weeks.
* Have provided written informed consent.
* Are willing and able to comply with all aspects of the protocol.

Exclusion Criteria

* Current smoker (cigarettes, e-cigarettes or marijuana) or former smokers who have smoked within the past 12 months.
* Former smokers with \> 20 pack-year history of smoking
* Ongoing treatment with an ACE-inhibitor that is considered as the potential cause of a subject's cough or requiring treatment with an ACE-inhibitor during the study or within 12 weeks prior to the Screening/Baseline Visit (Day -14 to Day 0).
* History of upper or lower respiratory tract infection or recent significant change in pulmonary status within 4 weeks of the Screening/Baseline Visit (Day -14 to Day 0)
* History of opioid use specifically prescribed for chronic cough within 2 weeks of the Screening/Baseline Visit (Day -14 to Day 0). Use of opioids for other indications (for example, to treat pain) is permitted.
* History of baclofen use specifically prescribed for chronic cough within 2 weeks of the Screening/Baseline Visit (Day -14 to Day 0). Use of baclofen for other indications (for example, to treat spasticity) is permitted.
* Presence of an untreated or undertreated cause (other than ILD) for the patient's chronic cough (as determined by the treating/referring physician per ACCP guidelines). e.g. uncontrolled asthma, GERD or post-nasal drainage that could potentially explain the patient's chronic cough.
* Requiring concomitant therapy with prohibited medications (listed below).
* Treatment with any pharmaceutical or biological investigational therapy (excluding coronavirus disease of 2019 (COVID) vaccination and COVID related monoclonal antibody therapy)
* Participation in another clinical trial that does not allow co-enrollment within 4 weeks prior to the Screening/Baseline Visit (Day -14 to Day 0)
* Total bilirubin, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 3x the upper limit of normal (ULN) during screening.
* Serum creatinine \< 30 mL/min, hemodialysis or peritoneal dialysis
* Advanced liver disease as defined by the presence of cirrhosis and/or signs of portal hypertension
* History of previous hypersensitivity or intolerance to Duloxetine \& Amitriptyline (patients who have previously been on either amitriptyline or duloxetine for chronic cough or other reasons and have tolerated the medication will be offered participation regardless of previous response to therapy).
* Currently pregnant or breastfeeding female subject.
* Presence of any medical condition or disability that the investigators believe could interfere with the assessment of safety or efficacy in this trial or compromise the safety of the subject.
* Planned or anticipated major surgical procedure or other activity that would interfere with the subject's ability to comply with protocol-mandated assessments (e.g., extended travel) during the subject's participation in the study.
* Currently taking either another SSRI, SNRI or MAO inhibitor which the patient cannot safely discontinue at least 2 weeks prior to the screening period.

Therapies that are prohibited during the 8-week blinded phase of the study:

The following therapies are prohibited from 2 week prior to the Screening/Baseline Visit (Day -14 to Day 0) through the end of the 8-week blinded treatment period.

* Opioids (of any kind including tramadol \& codeine) specifically prescribed for treatment of cough
* Dextromethorphan
* Guaifenesin
* Chlorpheniramine
* Benzonatate
* Trazodone
* Pregabalin or gabapentin prescribed for chronic cough
* 1% tetracaine lollipops prescribed for chronic cough
* 4% nebulized lidocaine solution prescribed for chronic cough
* Any SSRI (selective serotonin reuptake inhibitor) e.g. bupropion, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine.
* Any SNRI (serotonin-norepinephrine reuptake inhibitor) e.g. venlafaxine, desvenlafaxine, milnacipran, levomilnacipran
* Any Tricyclic antidepressant e.g. doxepin, clomipramine, nortriptyline, imipramine, protriptyline, amoxapine, trimipramine
* Any MAO (Monoamine oxidase) inhibitor. e.g. phenelzine, selegiline, isocarboxacid or tranylcypromine
* Patients who were previously prescribed either amitriptyline or duloxetine for chronic cough will be eligible for the study as long as they had discontinued the medication at least 12 weeks prior to the Screening/Baseline Visit (Day -14 to Day 0).

The following therapies are prohibited from 4 week prior to the Screening/Baseline Visit (Day -14 to Day 0) through the end of the 8-week blinded treatment period.

• Investigational biologic or pharmaceutical therapies (excluding COVID vaccination and COVID related monoclonal antibody therapy)

The following therapies are prohibited from 12 week prior to the Screening/Baseline Visit (Day -14 to Day 0) through the end of the 8-week blinded treatment period.

• Treatment with an ACE-inhibitor

Where this trial is running

Rochester, Minnesota

• Mayo Clinic in Rochester — Rochester, Minnesota, United States (RECRUITING)

Study contacts

• Principal investigator: Vivek N Iyer, MD — Mayo Clinic

Conditions: Interstitial Lung Disease, ILD, cough, chronic cough, refractory, antitussives, IPF, fibrosis