Duloxetine and Amitriptyline for Refractory Chronic Cough

(MACS-1 Trial)

Recruiting at 1 trial location

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Mayo Clinic

Must not be taking: Opioids, SSRIs, SNRIs, others

Disqualifiers: Smoking, COPD, Interstitial lung disease, others

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

Compensation: Varies

Number of Visits: 9

Duration: 8 weeks

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the medications Duloxetine and Amitriptyline to determine if they can reduce coughing frequency in individuals with refractory chronic cough, a persistent cough lasting over a year that does not respond to standard treatments. Participants will receive varying doses of these medications or a placebo (a substance with no active treatment) over several weeks. Ideal candidates have experienced a chronic cough for at least a year, not caused by smoking or a specific lung condition. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

You may need to stop taking certain medications before joining the trial. Specifically, you cannot take certain cough medications, antidepressants, or ACE-inhibitors for a period before and during the study. It's best to discuss your current medications with the study team to see if any changes are needed.

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

Research has shown that duloxetine and amitriptyline are under study for their safety in treating stubborn chronic cough. In studies, some participants taking duloxetine reported side effects such as nausea (11%), dizziness (16%), and sleepiness (9%). While duloxetine may alleviate symptoms, it might cause discomfort for some individuals.

For amitriptyline, the information remains less clear. It is commonly used for other conditions, and its safety profile is generally understood. However, insufficient research exists to specifically recommend or advise against its use for chronic cough. Safety data includes information on very high doses, which exceed typical prescriptions. Overall, both drugs have known side effects but are generally well-tolerated at doses typically used for other conditions. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using Duloxetine and Amitriptyline for refractory chronic cough because these drugs offer a novel approach compared to the usual treatments like cough suppressants and antihistamines. Duloxetine and Amitriptyline are typically used as antidepressants, but their potential to address chronic cough lies in their ability to modulate nerve signals, which might reduce the cough reflex. This mechanism is different from standard cough treatments that mainly target symptoms rather than the underlying nerve activity. By potentially calming the nerves responsible for the cough reflex, these medications could offer relief to patients who haven't responded to traditional therapies.

What evidence suggests that this trial's treatments could be effective for refractory chronic cough?

Research has shown that both Duloxetine and Amitriptyline can reduce coughing in individuals with stubborn chronic coughs. This trial will assign participants to different treatment arms to evaluate these medications. Studies have found that Duloxetine, an antidepressant, can significantly decrease coughing frequency. In a controlled trial, participants taking Duloxetine experienced fewer coughing episodes compared to those taking a placebo, which contains no active medicine. Meanwhile, Amitriptyline, another antidepressant, has also proven effective. One study found that 67% of participants reported their cough symptoms improved by at least half after using Amitriptyline. Both treatments appear promising for managing persistent coughs unresponsive to other treatments. ^{2 3 6 7 8}

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 a persistent cough lasting over a year, not explained by other lung conditions. Participants must use two forms of birth control and cannot be pregnant or breastfeeding. They should not have severe liver issues, recent infections, or be on certain medications like SSRIs, SNRIs, MAO inhibitors, or specific cough treatments.

Inclusion Criteria

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

Currently pregnant or breastfeeding female subject.

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

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 different doses of Duloxetine (30 MG & 60 MG) and Amitriptyline (25 MG & 50 MG), compared to placebos (30 MG & 60 MG), can reduce the frequency of chronic cough in patients who haven't responded to usual treatments.

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 week 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 week 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

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]

Duloxetine is a safe and well-tolerated medication for treating major depressive disorder, anxiety disorder, and painful diabetic neuropathy, with few serious side effects reported.

It has a favorable side effect profile, with nausea being the most common side effect, which can be minimized by starting at a lower dose of 30 mg per day and increasing to 60 mg after a week, allowing for pain relief within that timeframe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Duloxetine for chronic pain management: pharmacology and clinical use]. Masuda, R., Itoh, M., Suzuki, T.[2015]

Docetaxel is an effective treatment for advanced non-small cell lung cancer (NSCLC), showing improved overall survival compared to best supportive care in both first- and second-line therapies, based on randomized trials.

When combined with gemcitabine, docetaxel resulted in similar efficacy to combinations with cisplatin but caused significantly fewer severe side effects, making it a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The current status of docetaxel for advanced non-small cell lung cancer. Green, MR.[2018]

Docetaxel has been established as the preferred treatment for advanced non-small cell lung cancer that does not respond to initial chemotherapy, based on the results of two recent trials.

Ongoing trials are exploring the use of docetaxel not only as a primary treatment but also in combination with radiation therapy, indicating its potential versatility in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Docetaxel (Taxotere) in the treatment of non-small cell lung cancer: an international update. Kris, MG., Manegold, C.[2019]

In a study involving 58 patients with painful diabetic neuropathy, both duloxetine and amitriptyline were found to significantly reduce pain levels, with 55% of patients achieving good pain relief on amitriptyline and 59% on duloxetine.

Duloxetine was associated with fewer adverse effects, particularly dry mouth, which occurred in 55% of patients taking amitriptyline compared to only 24% for duloxetine, suggesting it may be a safer option for some patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparative evaluation of amitriptyline and duloxetine in painful diabetic neuropathy: a randomized, double-blind, cross-over clinical trial. Kaur, H., Hota, D., Bhansali, A., et al.[2022]

Docetaxel has been established as the preferred treatment for advanced non-small cell lung cancer that does not respond to initial chemotherapy, based on the results of two recent trials.

Ongoing trials are exploring the use of docetaxel not only as a primary treatment but also in combination with radiation therapy, indicating its potential versatility in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Docetaxel (Taxotere) in the treatment of non-small cell lung cancer: An international update. Kris, MG., Manegold, C.[2019]

A case of duloxetine overdose involved a patient who ingested over 500 mg of the drug along with other antidepressants and benzodiazepines, leading to confusion and electrolyte imbalances but ultimately resulted in a non-fatal outcome due to prompt medical intervention.

This case highlights the potential risks of combining duloxetine with other antidepressants, suggesting that healthcare providers should exercise caution when prescribing multiple medications to patients, especially those at risk of suicide.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-fatal overdose of duloxetine in combination with other antidepressants and benzodiazepines. Menchetti, M., Gozzi, BF., Saracino, MA., et al.[2022]

In a study of 85 outpatients taking amitriptyline, it was found that both short-term (mean 10.1 days) and long-term (mean 227.2 days) users reported anticholinergic side effects at similar rates, challenging the belief that these side effects diminish over time.

Long-term patients were less able to attribute new adverse clinical events to amitriptyline, suggesting that side effects may fluctuate and become more noticeable once a certain level of tolerance is exceeded.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term versus short-term amitriptyline side effects as measured by a postmarketing surveillance system. Bryant, SG., Fisher, S., Kluge, RM.[2013]

Duloxetine is an effective nonopioid analgesic for chronic pain conditions, including diabetic peripheral neuropathic pain, fibromyalgia, chronic low back pain, and osteoarthritis, showing comparable efficacy to other common pain medications.

Most side effects from duloxetine are mild to moderate and typically occur early in treatment, suggesting a favorable safety profile for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of duloxetine for chronic pain conditions. Mease, PJ., Walker, DJ., Alaka, K.[2014]

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]

In a phase I/II study involving 19 patients with unresectable non-small cell lung cancer (NSCLC), the combination of docetaxel and vinorelbine showed promising antitumor activity, with a 26% partial response rate and 47% of patients experiencing stable disease.

The treatment regimen had a low incidence of hematologic toxicity, with only 2.5% of cycles resulting in febrile neutropenia, indicating that this combination can be safely administered with granulocyte-colony stimulating factor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Docetaxel (Taxotere) and vinorelbine in the treatment of advanced non-small cell lung cancer: preliminary results of a phase I/II trial. Miller, VA.[2018]

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 31-year-old woman with a spinal cord injury developed recurrent autonomic dysreflexia (AD) while on a combination of duloxetine and amitriptyline for neuropathic pain, highlighting a potential adverse reaction to this medication combination.

Discontinuing duloxetine resolved the AD episodes, suggesting that while secondary hypertension is a known side effect of these medications, their link to AD is not well-documented and warrants further investigation in similar patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Autonomic Dysreflexia as a Potential Adverse Effect of Duloxetine and Amitriptyline Combination Therapy: A Case Report. Parke, SC., Reyes, MR.[2020]

In a phase I/II study involving 27 patients with advanced non-small cell lung cancer (NSCLC) who had previously failed platinum-based chemotherapy, a weekly dose of 25 mg/m2 docetaxel combined with 20 mg/m2 vinorelbine was established, but the regimen was highly myelosuppressive, leading to significant toxicities like severe neutropenia in 62% of patients.

Despite some patients showing partial responses (21%) and stable disease (33%), the overall survival rate was modest, with a median survival of 8 months and no significant improvement in response rates compared to single-agent docetaxel, indicating that this combination therapy may not be beneficial for further development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Weekly vinorelbine and docetaxel as second-line chemotherapy for pretreated non-small cell lung cancer patients: a phase I-II trial. Nelli, F., Naso, G., De Pasquale Ceratti, A., et al.[2018]

Duloxetine, at a dose of 60 mg/day, was found to be significantly more effective than placebo in treating major depressive disorder (MDD) in patients aged 55 and older, with a remission rate of 44.1% compared to 16.1% for placebo.

In addition to improving depressive symptoms, duloxetine also significantly reduced pain symptoms, including overall pain and back pain, although it had a higher discontinuation rate due to adverse events (21.0% for duloxetine vs. 6.7% for placebo).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Duloxetine for the treatment of major depressive disorder in older patients. Nelson, JC., Wohlreich, MM., Mallinckrodt, CH., et al.[2022]

Citations

1. 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.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12123101/

Predictive Factors and Treatment Effects of Neuromodulators ... This study investigated the treatment efficacy and adverse effects of neuromodulators (NM), Amitriptyline and Gabapentin, in the treatment of CRC, and the ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05110144

Efficacy of Two Doses of Duloxetine and Amitriptyline in ... This is a randomized, double-blind, placebo-controlled, parallel-arm, dose escalation study of Duloxetine & Amitriptyline in subjects with refractory ...

4. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/abs/10.1002/lary.25978

Long‐term follow‐up of amitriptyline treatment for ... Eighty-nine percent were taking the medication at the first clinical follow-up at a mean 2.6 months, and overall, 67% reported ≥50% improvement.

5. jtd.amegroups.org jtd.amegroups.org/article/view/10038/html

The efficacy of specific neuromodulators on human refractory ... Our reviews confirmed that baclofen, amitriptyline, and gabapentin show promise in the treatment of cough for select cases of refractory chronic cough.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7501523/

Management of chronic refractory cough in adults - PMC Four patients with no response or intolerable side effects were prescribed gabapentin [45]. Amitriptyline is neither recommended nor discouraged ...

7. ajmc.com ajmc.com/view/updates-in-treatment-of-adults-with-chronic-cough

Updates in Treatment of Adults With Chronic Cough Amitriptyline was shown to be significantly more effective compared with the combination of codeine/guaifenesin in complete cough response and ...

8. go.drugbank.com go.drugbank.com/drugs/DB00321

Amitriptyline: Uses, Interactions, Mechanism of Action Toxicity Data: Oral TDLO (child): 4167 μg/kg; Oral TDLO (man): 714 μg/kg/1D (intermittent); Oral TDLO (woman): 10 mg/kg. Ingestion of 750 mg or more by an adult ...