N-Acetyl Cysteine + Corticosteroids for Lung Cancer

(RESPIRE-ILD Trial)

Recruiting at1 trial location

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: David Palma

Must not be taking: Corticosteroids, NAC

Disqualifiers: Prior lung radiotherapy, Pregnancy, Breastfeeding, Scleroderma, others

Prior Safety Data

Trial Summary

What is the purpose of this trial?

In this double-blind phase II randomized controlled trial, patients with lung cancer or ≤2 oligometastatic pulmonary lesions and a concomitant diagnosis of ILD who are planned for radical Radiation Therapy (RT) will be randomized using a 2 x 2 factorial design to oral N-acetylcysteine (NAC) versus placebo, and also to short course corticosteroids versus placebo.

Will I have to stop taking my current medications?

You may need to stop certain medications. Immunosuppressive drugs like mycophenolate, azathioprine, cyclophosphamide, and rituximab must be stopped for 2 weeks before and after Radiation Therapy. Other systemic therapies, including biologic targeted agents or immunotherapy, must also be stopped for 2 weeks before and after treatment. However, you can continue anti-fibrotic agents and corticosteroids if they are part of your current ILD treatment.

What data supports the effectiveness of the drug combination N-Acetyl Cysteine and Dexamethasone for lung cancer?

Research shows that dexamethasone, a part of this drug combination, can enhance the effectiveness of chemotherapy and reduce its side effects in lung cancer patients. It has also been found to suppress cancer growth by affecting hormone activity in non-small cell lung cancer. ^{1 2 3 4 5}

Is the combination of N-Acetyl Cysteine and corticosteroids safe for humans?

Dexamethasone, a corticosteroid, has been studied for safety in various cancer treatments. It is generally considered safe, with mild side effects like fatigue and headache reported. However, high doses may cause more delayed nausea and vomiting in some cases. ^{4 6 7 8 9}

How does the drug N-Acetyl Cysteine + Corticosteroids for lung cancer differ from other treatments?

This treatment combines N-Acetyl Cysteine (NAC), known for reducing lung inflammation and mucus in conditions like COPD, with corticosteroids, which are anti-inflammatory drugs. This combination may offer a unique approach by potentially enhancing lung function and reducing inflammation in lung cancer patients, which is different from standard chemotherapy or targeted therapies. ^{10 11 12 13 14}

Research Team

David Palma, MD

Principal Investigator

London Health Sciences Centre, Lawson Health Research Institute

Houda Bahig, MD

Principal Investigator

Centre Hospitalier de l'Universite de Montreal

Eligibility Criteria

This trial is for adults with lung cancer or up to two small lung tumors and Interstitial Lung Disease (ILD), who are set for radiation therapy. They should be relatively active, have a life expectancy over 6 months, and may continue their ILD treatments like nintedanib or corticosteroids. People can't join if they're allergic to N-Acetyl cysteine or dexamethasone, pregnant, previously had lung radiotherapy, or have certain medical conditions.

Inclusion Criteria

I don't have a confirmed cancer diagnosis, but it's highly suggested.

I have lung cancer or 1-2 small lung tumors and will receive high-dose radiation.

I have been diagnosed with a type of lung scarring disease by a lung specialist.

Exclusion Criteria

I am not allergic to dexamethasone or NAC and do not have conditions like scleroderma, active infections, glaucoma, or certain psychiatric disorders.

I have had radiation therapy for my lung before.

I am not planning to receive other local treatments for my cancer lesions while in this study, unless my disease gets worse.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation Therapy

Participants receive radical pulmonary radiation therapy

60 days

Daily visits for radiation therapy

Treatment

Participants receive N-acetylcysteine and/or corticosteroids or placebos

60 days

Regular monitoring visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

60 months

Visits at 6 weeks, 3, 6, 9, 12, 18, 24, 36, 48, and 60 months post radiation therapy

Treatment Details

Interventions

• Dexamethasone Oral (Corticosteroid)
• Dexamethasone Placebo (Corticosteroid)
• N-Acetyl cysteine (Other)
• N-Acetyl cysteine Placebo (Other)

Trial Overview The study tests whether adding oral N-acetylcysteine (NAC) or short-term corticosteroids reduces respiratory symptoms in patients receiving radiation therapy for lung cancer with ILD. It's a double-blind trial where patients randomly get either the real drugs or placebos alongside their standard treatment.

Participant Groups

Group I: NAC + Dexamethasone Placebo Active Control 3 Interventions

Participants will take 600 mg of active NAC orally, three times daily, for 60 days. Participants will also take matching dexamethasone placebo (4 mg for 10 days, then 2 mg for 5 days, then 1 mg for 5 days), orally, once daily. All participants will be treated with radical pulmonary radiation therapy.

Group II: NAC + Corticosteroids Active Control 3 Interventions

Participants will take 600 mg of active NAC orally, three times daily, for 60 days. Participants will also take 4 mg of active dexamethasone, orally, once daily for 10 days, then 2 mg, orally, once daily for 5 days, then 1 mg, orally, once daily for 5 days. All participants will be treated with radical pulmonary radiation therapy.

Group III: Corticosteroids + NAC Placebo Active Control 3 Interventions

Participants will take 4 mg of active dexamethasone, orally, once daily for 10 days, then 2 mg, orally, once daily for 5 days, then 1 mg, orally, once daily for 5 days. Participants will also take matching NAC placebo orally, three times daily, for 60 days. All participants will be treated with radical pulmonary radiation therapy.

Group IV: NAC Placebo + Dexamethasone Placebo Placebo Group 3 Interventions

Participants will take matching NAC placebo orally, three times daily, for 60 days. Participants will also take matching dexamethasone placebo (4 mg for 10 days, then 2 mg for 5 days, then 1 mg for 5 days), orally, once daily. All participants will be treated with radical pulmonary radiation therapy.

Who Is Running the Clinical Trial?

David Palma

Lead Sponsor

Trials

4

Recruited

530+

Lawson Health Research Institute

Lead Sponsor

Trials

684

Recruited

432,000+

Dr. Michael Strong

Lawson Health Research Institute

Chief Medical Officer

MD

Roy Butler

Lawson Health Research Institute

Chief Executive Officer

PhD in Health Sciences

Centre Hospitalier de l'Universite de Montreal (CHUM)

Collaborator

Trials

1

Recruited

100+

London Health Sciences Centre

Collaborator

Trials

151

Recruited

60,400+

Dr. Alex Barron

London Health Sciences Centre

Chief Medical Officer since 2023

MD from Western University

David Musyj

London Health Sciences Centre

Chief Executive Officer

Bachelor of Laws (LLB) from the University of Windsor

Findings from Research

In a phase II trial involving 56 patients with Stage IV non-small cell lung cancer, pre-treatment with dexamethasone (DEX) significantly reduced severe hematologic toxicity from chemotherapy, with lower rates of neutrophil (13% vs. 40%) and platelet (23% vs. 44%) toxicity compared to those not receiving DEX.

Patients receiving DEX also showed trends towards improved response rates and overall survival, suggesting that DEX not only helps in reducing side effects but may also enhance the effectiveness of chemotherapy, although these results were not statistically significant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II randomized trial of carboplatin and gemcitabine with or without dexamethasone pre-treatment in patients with Stage IV non-small cell lung cancer. Rinehart, J., Arnold, S., Kloecker, G., et al.[2022]

Dexamethasone (DEX) has shown potential as an anti-estrogenic agent in treating non-small cell lung cancer (NSCLC), as it significantly suppressed tumor growth in A549 xenograft mice over a 32-day treatment period.

While DEX exhibited mild cytotoxicity to NSCLC cells, it effectively inhibited cell proliferation and increased the expression of estrogen sulfotransferase (EST), leading to reduced estrogen levels in tumors, suggesting a mechanism for its anti-cancer effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dexamethasone suppresses the growth of human non-small cell lung cancer via inducing estrogen sulfotransferase and inactivating estrogen. Wang, LJ., Li, J., Hao, FR., et al.[2018]

In a Phase 1/2 clinical trial involving 30 patients with advanced non-small cell lung cancer, pretreatment with dexamethasone significantly improved the efficacy of chemotherapy (gemcitabine and carboplatin) by increasing the number of patients who completed the treatment and achieved partial responses.

Dexamethasone also reduced hematopoietic toxicity, as evidenced by improved absolute granulocyte count (AGC) and platelet recovery times, without increasing non-hematologic toxicities, suggesting a safer treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intensive anti-inflammatory therapy with dexamethasone in patients with non-small cell lung cancer: effect on chemotherapy toxicity and efficacy. Leggas, M., Kuo, KL., Robert, F., et al.[2022]

In a study of 254 advanced non-squamous NSCLC patients, prophylactic dexamethasone did not significantly affect progression-free survival (PFS) or overall survival when used alongside PD-1 blockade therapy and chemotherapy.

The use of dexamethasone for preventing chemotherapy-associated adverse events (CAAEs) was found to be safe, as it did not lead to increased immune-related adverse effects (irAEs) or negatively impact clinical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of prophylactic dexamethasone on the efficacy of immune checkpoint inhibitors plus platinum-based chemotherapy in patients with advanced Non-Squamous Non-Small-Cell lung cancer. Yu, H., Chen, J., Zhou, Y., et al.[2023]

In a study comparing breast cancer patients undergoing chemotherapy with and without dexamethasone, those receiving dexamethasone experienced significantly lower rates of nausea and vomiting (p < 0.025).

The findings support the use of dexamethasone as an effective and safe antiemetic during CMF chemotherapy, enhancing patient comfort during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Use of dexamethasone as an antiemetic in patients with breast cancer treated with the CMF regimen]. Domaradzka-Woźniak, A., Wojtacki, J., Dziewulska-Bokiniec, A.[2013]

In a study of 68 lung cancer patients undergoing cisplatin chemotherapy, dexamethasone (DEX) 16 mg provided complete protection against acute nausea (100% vs. 76.5% in the DEX 8 mg group) and significantly better protection against delayed emesis.

The DEX 16 mg group required less rescue medication for nausea and vomiting, with no severe nausea or vomiting reported, indicating it is a more effective and safe option for managing chemotherapy-induced emesis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Comparison of dexamethasone 8 mg and 16 mg for the prevention of acute and delayed cisplatin-induced emesis in patients with lung cancer]. Hayakawa, T., Sato, M., Hirohata, T., et al.[2019]

In a study of 64 patients undergoing cisplatin-based chemotherapy, high-dose dexamethasone showed a modest antiemetic effect, with a shorter median duration of nausea (0.5 hours) compared to placebo (3.5 hours).

Despite some benefits, only a small percentage of patients (28%) did not vomit with dexamethasone, indicating that its effectiveness as an antiemetic agent is limited in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antiemetic efficacy of high-dose dexamethasone versus placebo in patients receiving cisplatin-based chemotherapy: a randomized double-blind controlled clinical trial. D'Olimpio, JT., Camacho, F., Chandra, P., et al.[2017]

In a study involving 104 chemotherapy-naive ovarian cancer patients, a single high dose of dexamethasone (20 mg) given after cisplatin did not improve control of delayed nausea and vomiting and was associated with increased symptoms compared to placebo.

The findings suggest that dexamethasone may have a 'boomerang effect,' worsening delayed nausea and vomiting, particularly in patients who did not experience acute symptoms, indicating it may not be suitable for managing delayed chemotherapy-induced nausea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single high-dose dexamethasone improves the effect of ondansetron on acute chemotherapy-induced nausea and vomiting but impairs the control of delayed symptoms. Peterson, C., Hursti, TJ., Börjeson, S., et al.[2019]

N-acetylcysteine (NAC) significantly reduced the rate of healthcare resource utilization (HCU) events related to COPD exacerbations by 20% compared to placebo, with an even greater reduction of 23% in current and ex-smokers.

In patients using long-acting bronchodilators without inhaled corticosteroids (ICS), NAC led to a remarkable 60% reduction in exacerbation rates compared to those receiving placebo, suggesting NAC could be a beneficial alternative to ICS in certain COPD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of smoking status and concomitant medications on the effect of high-dose N-acetylcysteine on chronic obstructive pulmonary disease exacerbations: A post-hoc analysis of the PANTHEON study. Papi, A., Zheng, J., Criner, GJ., et al.[2020]

In a randomized, double-blind, placebo-controlled trial involving 100 COPD patients with chronic bronchitis, high-dose N-acetylcysteine (NAC) (900 mg twice daily) did not show significant improvements in respiratory health as measured by the St. George's Respiratory Questionnaire after 3 months.

The study concluded that high-dose NAC does not provide marked clinical benefits for patients suffering from both COPD and chronic bronchitis, indicating that its efficacy in this population may be limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of N-Acetylcysteine for Chronic Obstructive Pulmonary Disease and Chronic Bronchitis. Zhang, L., Xiong, Y., Du, L.[2023]

A randomized, controlled trial involving 51 patients with COPD and chronic bronchitis found that high-dose N-acetylcysteine (1,800 mg twice daily) did not improve respiratory health status compared to placebo over 8 weeks.

The study was terminated early due to potential safety concerns, and no significant differences were observed in secondary outcomes related to lung function or inflammation, indicating that high-dose NAC may not be beneficial for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose oral N-acetylcysteine fails to improve respiratory health status in patients with chronic obstructive pulmonary disease and chronic bronchitis: a randomized, placebo-controlled trial. Johnson, K., McEvoy, CE., Naqvi, S., et al.[2018]

Oral N-acetylcysteine (NAC) significantly reduces the risk of exacerbations in chronic bronchitis patients, with a relative benefit of 1.56 and a number-needed-to-treat of 5.8 based on a systematic review of 11 trials involving 2,011 patients.

NAC also improves symptoms in 61.4% of patients compared to 34.6% in the placebo group, with a relative benefit of 1.78 and a number-needed-to-treat of 3.7, while showing no increase in gastrointestinal adverse effects compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of oral N-acetylcysteine in chronic bronchitis: a quantitative systematic review. Stey, C., Steurer, J., Bachmann, S., et al.[2019]

A meta-analysis of 13 studies involving 4155 COPD patients found that N-acetylcysteine (NAC) significantly reduces the frequency of exacerbations in chronic bronchitis and COPD, with a relative risk of 0.75, indicating a protective effect especially in patients without airway obstruction.

NAC was well tolerated across different doses, and while higher doses (≥ 1200 mg per day) are recommended for patients with airway obstruction, a lower dose (600 mg per day) is effective for those without obstruction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of N-acetylcysteine on chronic bronchitis or COPD exacerbations: a meta-analysis. Cazzola, M., Calzetta, L., Page, C., et al.[2022]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Phase II randomized trial of carboplatin and gemcitabine with or without dexamethasone pre-treatment in patients with Stage IV non-small cell lung cancer. [2022]

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

Dexamethasone suppresses the growth of human non-small cell lung cancer via inducing estrogen sulfotransferase and inactivating estrogen. [2018]

3. Germany pubmed.ncbi.nlm.nih.gov

Intensive anti-inflammatory therapy with dexamethasone in patients with non-small cell lung cancer: effect on chemotherapy toxicity and efficacy. [2022]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Impact of prophylactic dexamethasone on the efficacy of immune checkpoint inhibitors plus platinum-based chemotherapy in patients with advanced Non-Squamous Non-Small-Cell lung cancer. [2023]

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

Docetaxel as neoadjuvant therapy for radically treatable stage III non-small-cell lung cancer: a multinational randomised phase III study. [2020]

6. Poland pubmed.ncbi.nlm.nih.gov

[Use of dexamethasone as an antiemetic in patients with breast cancer treated with the CMF regimen]. [2013]

7. Japan pubmed.ncbi.nlm.nih.gov

[Comparison of dexamethasone 8 mg and 16 mg for the prevention of acute and delayed cisplatin-induced emesis in patients with lung cancer]. [2019]

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

Antiemetic efficacy of high-dose dexamethasone versus placebo in patients receiving cisplatin-based chemotherapy: a randomized double-blind controlled clinical trial. [2017]

9. Germany pubmed.ncbi.nlm.nih.gov

Single high-dose dexamethasone improves the effect of ondansetron on acute chemotherapy-induced nausea and vomiting but impairs the control of delayed symptoms. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Impact of smoking status and concomitant medications on the effect of high-dose N-acetylcysteine on chronic obstructive pulmonary disease exacerbations: A post-hoc analysis of the PANTHEON study. [2020]

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

Efficacy and Safety of N-Acetylcysteine for Chronic Obstructive Pulmonary Disease and Chronic Bronchitis. [2023]

12. New Zealand pubmed.ncbi.nlm.nih.gov

High-dose oral N-acetylcysteine fails to improve respiratory health status in patients with chronic obstructive pulmonary disease and chronic bronchitis: a randomized, placebo-controlled trial. [2018]

13. England pubmed.ncbi.nlm.nih.gov

The effect of oral N-acetylcysteine in chronic bronchitis: a quantitative systematic review. [2019]

14. England pubmed.ncbi.nlm.nih.gov

Influence of N-acetylcysteine on chronic bronchitis or COPD exacerbations: a meta-analysis. [2022]