Duloxetine and Amitriptyline for Refractory Chronic Cough

(MACS-1 Trial)

Recruiting in Palo Alto (17 mi)

+1 other 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, others

Disqualifiers: Smoking, COPD, Interstitial lung disease, others

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial is testing whether Amitriptyline and Duloxetine can help people who have a chronic cough that hasn't improved with other treatments. These medications are usually used for depression and anxiety but might also reduce coughing by changing how the brain processes signals. The study involves different doses to see which works best. Amitriptyline is an antidepressant used for various neurological conditions, including chronic cough, while Duloxetine is known for its efficacy in treating pain and anxiety symptoms.

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.

What data supports the effectiveness of the drug Duloxetine for treating chronic pain?

Duloxetine is effective in treating various chronic pain conditions, such as diabetic peripheral neuropathic pain, fibromyalgia, chronic low back pain, and osteoarthritis, with a safety profile that is generally mild to moderate. This suggests it may also be beneficial for managing chronic cough, as it shares characteristics with these pain 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 various conditions. Common side effects of Duloxetine include nausea, headache, and dizziness, while Amitriptyline can cause anticholinergic effects (like dry mouth and constipation). A case report noted a potential adverse effect called autonomic dysreflexia (a sudden increase in blood pressure) when both drugs were used together, but this is rare. ^{6 7 8 9 10}

How is the drug combination of Duloxetine and Amitriptyline unique for treating refractory chronic cough?

The combination of Duloxetine and Amitriptyline for refractory chronic cough is unique because these drugs are typically used to treat depression and anxiety, but they may help with chronic cough by affecting the nervous system pathways involved in cough reflexes. This approach is novel as there are no standard treatments specifically approved for refractory chronic cough. ^{11 12 13 14 15}

Research Team

Vivek Iyer, MD

Principal Investigator

Mayo Clinic

Eligibility Criteria

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

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 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.

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 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 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 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 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]

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]

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]

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]

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 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]

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]

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]

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]

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]

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]

References

1. 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]

2. England pubmed.ncbi.nlm.nih.gov

Evaluation of duloxetine for chronic pain conditions. [2014]

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

A comparative evaluation of amitriptyline and duloxetine in painful diabetic neuropathy: a randomized, double-blind, cross-over clinical trial. [2022]

4. Japan pubmed.ncbi.nlm.nih.gov

[Duloxetine for chronic pain management: pharmacology and clinical use]. [2015]

5. England pubmed.ncbi.nlm.nih.gov

Duloxetine for the treatment of major depressive disorder in older patients. [2022]

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. 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]

8. England pubmed.ncbi.nlm.nih.gov

Non-fatal overdose of duloxetine in combination with other antidepressants and benzodiazepines. [2022]

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

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

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

Long-term versus short-term amitriptyline side effects as measured by a postmarketing surveillance system. [2013]

11. United States 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. [2018]

12. England pubmed.ncbi.nlm.nih.gov

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

13. England 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. [2018]

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

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

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

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