Duloxetine + Amitriptyline for Interstitial Lung Disease-related Cough

(MACS-2 Trial)

Recruiting at1 trial location

Overseen by Vivek Iyer, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Mayo Clinic

Must not be taking: Opioids, SSRIs, SNRIs, MAO inhibitors

Disqualifiers: Smoking, Respiratory infection, Advanced liver disease, others

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial is testing whether Amitriptyline and Duloxetine can reduce coughing in people with interstitial lung disease. These medications, usually used for depression and anxiety, might help by changing how the brain processes signals that cause coughing. The study involves different doses of these medications.

Will I have to stop taking my current medications?

You can continue your current ILD-directed therapies, but you must stop taking certain medications like opioids for cough, SSRIs, SNRIs, tricyclic antidepressants, and MAO inhibitors at least 2 weeks before the trial. If you're on an ACE-inhibitor, you need to stop it 12 weeks before the trial.

What data supports the effectiveness of the drugs duloxetine and amitriptyline for treating interstitial lung disease-related cough?

While there is no direct evidence for using duloxetine and amitriptyline specifically for interstitial lung disease-related cough, both drugs have shown effectiveness in treating pain and symptoms in conditions like fibromyalgia and major depressive disorder. Duloxetine is known for its pain-relieving properties, and amitriptyline is used off-label for fibromyalgia, suggesting potential benefits for managing symptoms in other conditions. ^{1 2 3 4 5}

Is the combination of Duloxetine and Amitriptyline generally safe for humans?

Duloxetine and Amitriptyline have been studied for safety in conditions like fibromyalgia and depression. Common side effects of Duloxetine include nausea, headache, dry mouth, insomnia, fatigue, constipation, and dizziness. Amitriptyline is also used for fibromyalgia, but specific safety data for the combination of these drugs is not provided in the available research. ^{1 2 5 6 7}

How is the drug combination of Duloxetine and Amitriptyline unique for treating interstitial lung disease-related cough?

This drug combination is unique because it targets both the sensory nerve hyperresponsiveness and potential underlying depression associated with chronic cough, using Duloxetine's dual action on serotonin and norepinephrine and Amitriptyline's effectiveness in treating idiopathic cough, which may offer a novel approach compared to standard cough treatments. ^{1 8 9 10 11}

Research Team

Vivek Iyer, MD

Principal Investigator

Mayo Clinic

Eligibility Criteria

This trial is for adults with interstitial lung disease who've had a chronic cough for at least 3 months, are on stable ILD treatments, and can follow the study plan. Women must use two birth control methods or practice complete abstinence; men also need to use two forms of contraception. Smokers, those with certain liver issues, pregnant/breastfeeding women, and people on conflicting medications or other trials cannot participate.

Inclusion Criteria

Have a diagnosis of interstitial lung disease according to the American Thoracic Society Guidelines

Are willing and able to comply with all aspects of the protocol

Your cough is very severe, with a score of 40mm or higher on a scale used to measure cough severity.

Exclusion Criteria

You used to smoke a lot, at least 20 packs of cigarettes per year.

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

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2 weeks

1 visit (in-person)

Treatment

Participants receive escalating doses of Duloxetine or Amitriptyline over two 4-week blinded periods

8 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with optional continuation of therapy

up to 52 weeks

Visits at months 4, 6, 9, and 12 (in-person or virtual)

Treatment Details

Interventions

• Amitriptyline (Tricyclic Antidepressant)
• Duloxetine (Serotonin-Norepinephrine Reuptake Inhibitor)

Trial Overview The study tests whether increasing doses of Amitriptyline (25mg or 50mg) and Duloxetine (30mg or 60mg) can reduce coughing in ILD patients compared to placebo. Participants will be randomly assigned to receive one of these drugs or a matching placebo over an eight-week period while continuing their usual ILD therapies.

Participant Groups

Group I: Duloxetine dose escalation Experimental Treatment 2 Interventions

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).

Group II: Duloxetine and Placebo Experimental Treatment 2 Interventions

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 weeks treatment period). After this, subjects will be unblinded and receive routine clinical care for follow up phase (up to 52 weeks).

Group III: Amitriptyline dose escalation Experimental Treatment 2 Interventions

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).

Group IV: Amitriptyline and Placebo Experimental Treatment 2 Interventions

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 weeks treatment period). After this, subjects will be unblinded and receive routine clinical care for follow up phase (up to 52 weeks).

Group V: Placebo Placebo Group 2 Interventions

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 is already approved in Canada for the following indications:

Approved in Canada as Elavil for:

• Depression
• Anxiety and stress
• Chronic pain
• Fibromyalgia
• Headache
• Migraine prevention
• Neuropathic pain

Who Is Running the Clinical Trial?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

Dr. Gianrico Farrugia

Mayo Clinic

Chief Executive Officer since 2019

MD from University of Malta Medical School

Dr. Richard Afable

Mayo Clinic

Chief Medical Officer

MD from Loyola Stritch School of Medicine

Findings from Research

Duloxetine and amitriptyline are both effective in treating fibromyalgia, but their efficacy varies based on specific symptoms; duloxetine shows high evidence for mood disorders, while amitriptyline has high evidence for improving quality of life.

Duloxetine is generally safer for older patients and has higher acceptability, while amitriptyline is considered safer for younger individuals, indicating that treatment choice should be tailored to the patient's age and symptom profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparing the efficacy and safety of duloxetine and amitriptyline in the treatment of fibromyalgia: overview of systematic reviews. de Farias, ÁD., Eberle, L., Amador, TA., et al.[2021]

Amitriptyline, although used off-label, significantly improves sleep disturbances, fatigue, and overall quality of life in fibromyalgia patients, showing better acceptability compared to other treatments.

Duloxetine at 120 mg is the most effective option for reducing pain and depression symptoms in fibromyalgia, but all treatments, except amitriptyline, had higher dropout rates due to adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Amitriptyline and US Food and Drug Administration-Approved Treatments for Fibromyalgia: A Systematic Review and Network Meta-analysis. Farag, HM., Yunusa, I., Goswami, H., et al.[2023]

In a 6-month study involving 520 fibromyalgia patients, duloxetine at doses of 60 mg/day and 120 mg/day significantly reduced pain severity compared to placebo, showing efficacy in both patients with and without major depressive disorder.

Duloxetine was found to be safe, with no clinically significant differences in vital signs, laboratory measures, or ECG results between treatment groups, indicating it is a well-tolerated option for managing fibromyalgia pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of duloxetine for treatment of fibromyalgia in patients with or without major depressive disorder: Results from a 6-month, randomized, double-blind, placebo-controlled, fixed-dose trial. Russell, JI., Mease, PJ., Smith, TR., et al.[2022]

Duloxetine was found to be equally effective in patients switching from other antidepressants (like SSRIs or venlafaxine) and those starting it for the first time, with similar improvements in depression and anxiety scores over 12 weeks.

Patients who switched to duloxetine experienced fewer discontinuation rates due to adverse events (6.3%) compared to those who initiated treatment (16.1%), indicating that switching is a well-tolerated option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An open-label study of duloxetine for the treatment of major depressive disorder: comparison of switching versus initiating treatment approaches. Wohlreich, MM., Martinez, JM., Mallinckrodt, CH., et al.[2019]

Duloxetine treatment for fibromyalgia has a generally safe profile, with the most common mild to moderate side effects being nausea (29.3%), headache (20.0%), and dry mouth (18.2%), observed in short-term studies involving multiple patients.

Long-term use of duloxetine (up to 1 year) showed a similar safety profile to short-term use, with no new significant adverse events emerging, and serious adverse events were rare, indicating that duloxetine can be a viable long-term treatment option for fibromyalgia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of duloxetine in the treatment of patients with fibromyalgia: pooled analysis of data from five clinical trials. Choy, EH., Mease, PJ., Kajdasz, DK., et al.[2021]

A case report highlights the serious risks associated with high doses of Duloxetine, including acute pulmonary thromboembolism leading to death, particularly in vulnerable populations like the elderly.

Excessive intake of Duloxetine can significantly amplify side effects such as somnolence, dry mouth, and increased blood pressure, emphasizing the importance of adhering to prescribed dosages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute massive pulmonary thromboembolism due to acute intoxication by duloxetine: a case report. Mari, F., Gualco, B., Rensi, R., et al.[2015]

Duloxetine, at doses of 80 mg and 120 mg per day, significantly reduced depression symptoms in adults with major depressive disorder compared to placebo, with remission rates of 51% and 58% respectively after 8 weeks.

The safety profile of duloxetine was comparable to placebo, with no significant difference in discontinuation rates due to adverse events, although some side effects like constipation and increased sweating were more common in duloxetine-treated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Duloxetine in the acute and long-term treatment of major depressive disorder: a placebo- and paroxetine-controlled trial. Detke, MJ., Wiltse, CG., Mallinckrodt, CH., et al.[2022]

This study is the first randomized, double-blind, controlled trial investigating duloxetine as a treatment for refractory cough, involving 98 participants over a treatment period of 42 days.

Duloxetine, a medication known for treating pain and depression, may reduce cough frequency and improve cough-related quality of life by targeting sensory nerve hyperresponsiveness, potentially offering a new therapeutic option for patients with chronic cough.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized, double-blinded, placebo-controlled clinical trial of duloxetine hydrochloride enteric-coated tablets in the treatment of refractory chronic cough. Wang, S., Li, S., Wu, H., et al.[2023]

In a study of 28 patients with chronic cough due to postviral vagal neuropathy, amitriptyline (10 mg) was significantly more effective than codeine/guaifenesin, with most patients in the amitriptyline group achieving a complete response.

Amitriptyline was found to be a strong predictor of a greater than 50% reduction in cough severity compared to codeine/guaifenesin, highlighting its potential as a more effective treatment option for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of amitriptyline versus cough suppressants in the treatment of chronic cough resulting from postviral vagal neuropathy. Jeyakumar, A., Brickman, TM., Haben, M.[2020]

Amitriptyline was found to be effective for managing idiopathic cough, with 67% of patients reporting at least a 50% improvement within 2.6 months, although this dropped to 53% after 2 to 3 years.

The study highlighted that while amitriptyline can be well-tolerated, side effects were a common reason for discontinuation, and many patients needed to adjust their dosage or restart the medication over time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term follow-up of amitriptyline treatment for idiopathic cough. Ryan, MA., Cohen, SM.[2018]

References

1. England pubmed.ncbi.nlm.nih.gov

Comparing the efficacy and safety of duloxetine and amitriptyline in the treatment of fibromyalgia: overview of systematic reviews. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Comparison of Amitriptyline and US Food and Drug Administration-Approved Treatments for Fibromyalgia: A Systematic Review and Network Meta-analysis. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Efficacy and safety of duloxetine for treatment of fibromyalgia in patients with or without major depressive disorder: Results from a 6-month, randomized, double-blind, placebo-controlled, fixed-dose trial. [2022]

4. England pubmed.ncbi.nlm.nih.gov

The relationship between antidepressant and analgesic responses: findings from six placebo-controlled trials assessing the efficacy of duloxetine in patients with major depressive disorder. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

An open-label study of duloxetine for the treatment of major depressive disorder: comparison of switching versus initiating treatment approaches. [2019]

6. Germany pubmed.ncbi.nlm.nih.gov

Safety and tolerability of duloxetine in the treatment of patients with fibromyalgia: pooled analysis of data from five clinical trials. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Acute massive pulmonary thromboembolism due to acute intoxication by duloxetine: a case report. [2015]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Duloxetine in the acute and long-term treatment of major depressive disorder: a placebo- and paroxetine-controlled trial. [2022]

9. England pubmed.ncbi.nlm.nih.gov

A randomized, double-blinded, placebo-controlled clinical trial of duloxetine hydrochloride enteric-coated tablets in the treatment of refractory chronic cough. [2023]

10. United States pubmed.ncbi.nlm.nih.gov

Effectiveness of amitriptyline versus cough suppressants in the treatment of chronic cough resulting from postviral vagal neuropathy. [2020]

11. United States pubmed.ncbi.nlm.nih.gov

Long-term follow-up of amitriptyline treatment for idiopathic cough. [2018]