Duloxetine + Amitriptyline for Interstitial Lung Disease-related Cough

(MACS-2 Trial)

Recruiting at 1 trial location

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Mayo Clinic

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

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 9

Duration: 8 weeks

25 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two medications, Duloxetine and Amitriptyline, to determine their effectiveness in reducing coughs related to interstitial lung disease (ILD). Participants will receive either one of these medications, a combination with a placebo, or just a placebo. The goal is to identify which treatment most effectively decreases cough frequency. Individuals with a chronic cough for at least three months who are stable on their ILD medications may be suitable for this study. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, allowing participants to contribute to important early findings.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that both Duloxetine and Amitriptyline have been studied for their safety in people. Duloxetine is usually well-tolerated, though some reports have linked it to lung issues when used for other conditions. One study found a few cases of Duloxetine-related lung problems, but these are rare.

Amitriptyline has also been studied for its effects and safety. Previous research indicates it can effectively reduce cough without major safety concerns. In one study, most patients taking Amitriptyline for cough reported improvements, and no significant negative effects were observed.

Both medications have FDA approval for other uses, providing some assurance about their safety. However, the current study is in an earlier phase, so while safety data is promising, it is still being evaluated specifically for treating cough in interstitial lung disease. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because duloxetine and amitriptyline offer a fresh approach to managing interstitial lung disease-related cough. Unlike traditional treatments that often focus on suppressing the cough reflex or treating inflammation, duloxetine and amitriptyline work by modulating neurotransmitters in the brain, which can alter the perception of cough. This mechanism not only provides a novel way to tackle the persistent cough associated with interstitial lung disease but also holds promise for improved symptom management. Additionally, the dose-escalation approach in the trial could help determine the most effective and tolerable dosage for patients, potentially leading to better outcomes than current standards.

What evidence suggests that this trial's treatments could be effective for ILD-related cough?

This trial will compare the effects of Duloxetine and Amitriptyline on interstitial lung disease-related cough. Studies have shown that both medications can help reduce coughing in people with interstitial lung disease (ILD). Research indicates that Duloxetine, which participants in this trial may receive, can ease symptoms in those with a long-term cough, potentially benefiting people with ILD-related cough. Early findings suggest that Amitriptyline, another treatment option in this trial, might also be effective, with some patients experiencing a significant reduction in cough frequency. Specifically, one study reported a 75% to 100% decrease in coughing with Amitriptyline, which is promising for managing ILD-related cough. Overall, both medications have shown potential in reducing cough symptoms in these patients. ^{1 2 4 6 7}

Who Is on the Research Team?

Vivek Iyer, MD

Principal Investigator

Mayo Clinic

Are You a Good Fit for This Trial?

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

Timeline for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

Interventions

• Amitriptyline
• Duloxetine

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.

How Is the Trial Designed?

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 United States, European Union, Canada for the following indications:

Approved in United States as Elavil for:

• Depression
• Anxiety and Stress
• Chronic Pain
• Fibromyalgia
• Headache
• Migraine Prevention
• Neuropathic Pain

Approved in European Union as Amitriptyline for:

• Depression
• Anxiety disorders
• Chronic pain
• Fibromyalgia
• Headache
• Migraine prevention
• Neuropathic pain

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+

Published Research Related to This Trial

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]

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 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]

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 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]

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]

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]

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]

In a post-hoc analysis of six trials involving duloxetine for major depressive disorder, significant pain relief was observed within 2 weeks, which occurred faster than the onset of antidepressant effects as measured by the HAMD(17) scale.

The study found that the analgesic effect of duloxetine operates independently from its antidepressant effect, suggesting that the two mechanisms do not influence each other in terms of response time.

NCBI (Pubmed)

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. Fishbain, DA., Detke, MJ., Wernicke, J., 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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05120934?cond=%22Antitussive%20Agents%22&aggFilters=status:not%20rec&rank=1

Efficacy of Two Doses of Duloxetine & Amitriptyline in ... This research study is evaluating the effectiveness of escalating doses of Amitriptyline and Duloxetine in reducing cough frequency in patients with ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/17146380/

Effectiveness of amitriptyline versus cough suppressants in ... Those patients experiencing a 75% to 100% reduction were recorded as having a complete response, 25% to 50% a partial response, and 0% as having no response.

3. connect.careboxhealth.com connect.careboxhealth.com/en-US/trial/listing/311080

Amitriptyline in Interstitial Lung Disease-related Cough This research study is evaluating the effectiveness of escalating doses of Amitriptyline and Duloxetine in reducing cough frequency in patients with ...

4. journal.chestnet.org journal.chestnet.org/article/S0012-3692(23)05025-0/fulltext

A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED ... A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, DOSE ESCALATION STUDY EVALUATING THE EFFICACY OF DULOXETINE AND AMITRIPTYLINE IN INTERSTIITAL LUNG DISEASE- ...

5. mayo.edu mayo.edu/research/clinical-trials/cls-20527349

Efficacy of Two Doses of Duloxetine & Amitriptyline in ... The purpose of this study is to evaluate the effectiveness of two escalating doses of Duloxetine & Amitriptyline in reducing awake objective cough frequency.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12071652/

Updates on the Prevalence, Quality of Life, and ... A systematic review of neuromodulators for idiopathic chronic cough showed that use of gabapentin, pregabalin, amitriptyline, or baclofen could decrease cough ...

7. publications.ersnet.org publications.ersnet.org/content/breathe/21/2/240176

Cough in idiopathic pulmonary fibrosis: what is new In the amitriptyline group, the majority of patients achieved a complete response in the subjective rate of reduction in the frequency and cough severity. None ...