Efficacy of Two Doses of Duloxetine & Amitriptyline in Interstitial Lung Disease-related Cough (MACS-2)


About this study

The purpose of this study is to evaluate the effectiveness of two escalating doses of Duloxetine & Amitriptyline in reducing awake objective cough frequency (at 4 & 8 weeks).



Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Inclusion Criteria:

Subjects who meet all the following criteria will be eligible for the study:

  • Women and men between 18 and 85 years of age.
  • Have a diagnosis of interstitial lung disease (ILD) 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 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:

Subjects are NOT eligible for this study if they meet any of the following 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 (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.
  • Treatment with any pharmaceutical or biological investigational therapy (excluding 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.

Eligibility last updated 6/3/22. Questions regarding updates should be directed to the study team contact.


Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Rochester, Minn.

Mayo Clinic principal investigator

Vivek Iyer, M.D., M.P.H.

Open for enrollment

Contact information:

Sue Ann Donlinger

(507) 284-9259


More information


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