Reducing Respiratory Symptoms of Pulmonary Irradiation in Interstitial Lung Disease (RESPIRE-ILD)

• ClinicalTrials.gov Identifier: NCT05986318
• Recruitment Status: Not yet recruiting
• First Posted: August 14, 2023
• Last Update Posted: February 29, 2024
• Sponsor: Lawson Health Research Institute
• Collaborators: London Health Sciences Centre; Centre Hospitalier de l'Universite de Montreal (CHUM)
• Information provided by (Responsible Party): David Palma, Lawson Health Research Institute

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Lung Cancer; Interstitial Lung Disease	Dietary Supplement: N-Acetyl cysteine; Drug: Dexamethasone Oral; Dietary Supplement: N-Acetyl cysteine Placebo; Drug: Dexamethasone Placebo; Radiation: Radiation Therapy	Phase 2

Detailed Description:

Radiation pneumonitis (RP) is the most common and main dose-limiting toxicity after thoracic RT. RP is characterized histologically by diffuse alveolar damage and acute vascular permeability induced by direct cytotoxic effect and oxidative stress, leading to the production of proinflammatory, profibrogenic and proangiogenic cytokines.

Patients with Interstitial Lung Disease (ILD) are at increased risk of developing lung cancer compared to the general population. Management of patients with lung cancer in the setting of a concomitant ILD is complex, as these patients are usually not good candidates for surgery or immunotherapy. In addition, patients with ILD, particularly fibrotic ILD, are also reportedly at increased risk of treatment-related toxicity from RT.

In the present study, investigators will test the following hypotheses:

1. The use of NAC with RT in patients with underlying ILD will lead to a clinically meaningful reduction in grade 2-5 dyspnea (as per Common Terminology Criteria for Adverse Events [CTCAE] version 5.0).
2. The use of corticosteroids with RT in patients with underlying ILD will lead to a clinically meaningful reduction in grade 2-5 dyspnea (as per CTCAE version 5.0).

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 98 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: Double (Participant, Investigator)
• Masking Description: double-blinded, placebo controlled
• Primary Purpose: Treatment
• Official Title: Reducing Respiratory Symptoms of Pulmonary Irradiation in Interstitial Lung Disease: A 2x2 Factorial Randomized Phase II Trial Testing N-Acetyl Cysteine and Dexamethasone
• Estimated Study Start Date: May 1, 2024
• Estimated Primary Completion Date: July 1, 2028
• Estimated Study Completion Date: December 31, 2032

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: NAC + Corticosteroids; 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.	Dietary Supplement: N-Acetyl cysteine; NAC capsules; Other Name: NAC; Drug: Dexamethasone Oral; Dexamethasone tablets; Other Name: Corticosteroid; Radiation: Radiation Therapy; All participants will receive radical pulmonary radiation therapy. Conventional techniques or stereotactic ablative radiotherapy will be used.
Active Comparator: Corticosteroids + NAC Placebo; 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.	Drug: Dexamethasone Oral; Dexamethasone tablets; Other Name: Corticosteroid; Dietary Supplement: N-Acetyl cysteine Placebo; Matching placebo for NAC capsules; Other Name: NAC Placebo; Radiation: Radiation Therapy; All participants will receive radical pulmonary radiation therapy. Conventional techniques or stereotactic ablative radiotherapy will be used.
Active Comparator: NAC + Dexamethasone Placebo; 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.	Dietary Supplement: N-Acetyl cysteine; NAC capsules; Other Name: NAC; Drug: Dexamethasone Placebo; Matching placebo for dexamethasone tablets; Other Name: Corticosteroid Placebo; Radiation: Radiation Therapy; All participants will receive radical pulmonary radiation therapy. Conventional techniques or stereotactic ablative radiotherapy will be used.
Placebo Comparator: NAC Placebo + Dexamethasone Placebo; 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.	Dietary Supplement: N-Acetyl cysteine Placebo; Matching placebo for NAC capsules; Other Name: NAC Placebo; Drug: Dexamethasone Placebo; Matching placebo for dexamethasone tablets; Other Name: Corticosteroid Placebo; Radiation: Radiation Therapy; All participants will receive radical pulmonary radiation therapy. Conventional techniques or stereotactic ablative radiotherapy will be used.

Outcome Measures

Primary Outcome Measures :

1. Rate of Grade 2-5 Dyspnea within 6 Months Post Radiation Measured by the Common Terminology Criteria for Adverse Events (CTCAE) Version 5 [ Time Frame: Up to 6 months post radiation therapy ]

Secondary Outcome Measures :

1. Patient Scored Dyspnea Measured by Visual Analogue Scale (VAS) [ Time Frame: 6 weeks, 3, 6, 9, 12,18, 24, 36, 48, and 60 months post radiation therapy ]
   Dyspnea (shortness of breath) severity will be reported by participants via a scale, where a score of 100 is no shortness of breath and a score of 0 is the worst shortness of breath ever.
2. Patient Scored Cough Measured by Visual Analogue Scale (VAS) [ Time Frame: 6 weeks, 3, 6, 9, 12,18, 24, 36, 48, and 60 months post radiation therapy ]
   Cough severity will be reported by participants via a scale, where a score of 100 is no cough and a score of 0 is the worst cough ever.
3. Quality of Life Measured by FACIT.org Functional Assessment of Cancer Therapy - Lung (FACT-L) Questionnaire [ Time Frame: 6 weeks, 3, 6, 9, 12,18, 24, 36, 48, and 60 months post radiation therapy ]
   The Functional Assessment of Cancer Therapy - Lung (FACT-L ) is a standardized questionnaire used to measure quality of life. The questionnaire consists of 5 scales measuring 37 items in total. Categories of the 5 scales are: physical well-being, social/family well-being, emotional well-being, functional well-being, and additional concerns related to symptoms, cognitive function, and regret of smoking. The score for each item in the scale ranges from 0 to 4, where 0 is not at all and 4 is very much. The scores from each scale are added up, and can be combined to provide a total score.
4. Quality of Life Measured by EuroQOL Group EQ-5D-5L Questionnaire [ Time Frame: 6 weeks, 3, 6, 9, 12,18, 24, 36, 48, and 60 months post radiation therapy ]
   The EQ-5D-5L is a standardized questionnaire used to measure quality of life and health. The first section includes 5 categories: mobility, self-care, usual activities (e.g. work, family), pain/discomfort, and anxiety/depression. Each category contains 5 statements ranging from no problems to extreme problems, where no problems is assigned a code of 1 and extreme problems is assigned a code of 5. Participants are asked to select the statement that best describes their health that day. No score is generated, rather a 5 digit code is generated based on the response provided, which can then be combined into a data set and interpreted in a variety of ways. The second section includes a 20 cm analogue scale from 0 to 100, where 100 is the best health ever imagined and 0 is the worst health imagined. The participant will mark a score on the scale representing the state of their health on that day.
5. Local Control as Determined by Radiographic Evidence [ Time Frame: 9 years ]
   Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 will be used to measure tumors in the lung (by size), on imaging, to determine how tumors are responding to treatment.
6. Progression Free Survival [ Time Frame: 9 years ]
   Time from enrollment to death from any cause or any progression of disease (local, regional, or distant).
7. Overall Survival [ Time Frame: 9 years ]
   Time from enrollment to death from any cause .
8. Cancer Specific Survival [ Time Frame: 9 years ]
   Time from enrollment to death from lung cancer, censored at last follow-up or death from other causes.
9. Rates of Radiation Treatment Completion [ Time Frame: 50 months ]
10. Rates of Study Drug Completion Rates [ Time Frame: 50 months ]
11. Rates of Participant Unblinding Related to Adverse Events Development [ Time Frame: 50 months ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Lung cancer or 1-2 oligometastatic pulmonary lesions planned for radical intent radiotherapy [minimal Biologically Effective Does (BED) of 48 Gy10 (Gray) or biological equivalent].

• Pathologically (histologically or cytologically) proven diagnosis of cancer is not required, but strongly recommended.

  • If the risk of biopsy is unacceptable, pathologic confirmation is not required providing there is growth over time on Computed Tomography (CT) imaging and/or Fluorodeoxyglucose (FDG) avidity that is strongly suggestive of malignancy.
• Fibrotic Interstitial Lung Disease (ILD) of any subtype, as diagnosed by a respirologist and confirmed by central review
• Eastern Cooperative Oncology Group (ECOG) performance status 0-3
• Age ≥ 18
• Life expectancy > 6 months
• Patients are allowed to receive anti-fibrotic agents used in the treatment of Idiopathic Pulmonary Fibrosis (IPF) or non-IPF fibrotic ILD (e.g. nintedanib, pirfenidone) and/or corticosteroids, if those are part of their current ILD treatment regimen. Other immunosuppressive drugs such as mycophenolate, azathioprine, cyclophosphamide, and rituximab must be stopped for 2 weeks prior and 2 weeks after Radiation Therapy (RT).
• Concurrent standard chemotherapy is allowed where indicated. All other systemic therapies, including biologic targeted agents or immunotherapy, or any drugs with known radiosensitive effects, must be stopped for 2 weeks prior and 2 weeks after treatment.

Exclusion Criteria:

• Prior lung radiotherapy
• Plans for the patient to receive other local therapy to the target lesion(s) while on this study, except at disease progression
• Any medical condition that could, in the opinion of the investigator, preclude radiotherapy or prevent follow-up after radiotherapy
• Pregnancy

• Contraindications to dexamethasone or N-Acetyl Cysteine (NAC). These include:

  • Previous intolerance or allergy to dexamethasone or NAC
  • Scleroderma
  • Active infection
  • Glaucoma
  • Psychiatric disorder that could be exacerbated by dexamethasone
  • Any other condition that the treating physician believes to be a contraindication to dexamethasone or NAC

Contacts and Locations

Contacts

Contact: David Palma, MD; 519-685-8650; david.palma@lhsc.on.ca

Contact: Houda Bahig, MD; 514-890-8254; houda.bahig.chum@ssss.gouv.qc.ca

Locations

Canada, Ontario

London Regional Cancer Program, London Health Sciences Centre

London, Ontario, Canada, N6A 5W9

Contact: David Palma, MD 519-685-8650 David.Palma@lhsc.on.ca

Canada, Quebec

Centre Hospitalier de l'Universite de Montreal (CHUM)

Montreal, Quebec, Canada, H2X 0A9

Principal Investigator: Houda Bahig, MD

Sponsors and Collaborators

Lawson Health Research Institute

London Health Sciences Centre

Centre Hospitalier de l'Universite de Montreal (CHUM)

Investigators

• Study Chair: David Palma, MD; London Health Sciences Centre, Lawson Health Research Institute
• Study Chair: Houda Bahig, MD; Centre Hospitalier de l'Universite de Montreal

More Information

Publications:

Verstegen NE, Lagerwaard FJ, Hashemi SM, Dahele M, Slotman BJ, Senan S. Patterns of Disease Recurrence after SABR for Early Stage Non-Small-Cell Lung Cancer: Optimizing Follow-Up Schedules for Salvage Therapy. J Thorac Oncol. 2015 Aug;10(8):1195-200. doi: 10.1097/JTO.0000000000000576.

Choi YW, Munden RF, Erasmus JJ, Park KJ, Chung WK, Jeon SC, Park CK. Effects of radiation therapy on the lung: radiologic appearances and differential diagnosis. Radiographics. 2004 Jul-Aug;24(4):985-97; discussion 998. doi: 10.1148/rg.244035160.

Kainthola A, Haritwal T, Tiwari M, Gupta N, Parvez S, Tiwari M, Prakash H, Agrawala PK. Immunological Aspect of Radiation-Induced Pneumonitis, Current Treatment Strategies, and Future Prospects. Front Immunol. 2017 May 2;8:506. doi: 10.3389/fimmu.2017.00506. eCollection 2017.

Tsoutsou PG, Koukourakis MI. Radiation pneumonitis and fibrosis: mechanisms underlying its pathogenesis and implications for future research. Int J Radiat Oncol Biol Phys. 2006 Dec 1;66(5):1281-93. doi: 10.1016/j.ijrobp.2006.08.058.

Niska JR, Schild SE, Rule WG, Daniels TB, Jett JR. Fatal Radiation Pneumonitis in Patients With Subclinical Interstitial Lung Disease. Clin Lung Cancer. 2018 Jul;19(4):e417-e420. doi: 10.1016/j.cllc.2018.02.003. Epub 2018 Feb 17. No abstract available.

Axelsson GT, Putman RK, Aspelund T, Gudmundsson EF, Hida T, Araki T, Nishino M, Hatabu H, Gudnason V, Hunninghake GM, Gudmundsson G. The associations of interstitial lung abnormalities with cancer diagnoses and mortality. Eur Respir J. 2020 Dec 17;56(6):1902154. doi: 10.1183/13993003.02154-2019. Print 2020 Dec.

Ozawa Y, Abe T, Omae M, Matsui T, Kato M, Hasegawa H, Enomoto Y, Ishihara T, Inui N, Yamada K, Yokomura K, Suda T. Impact of Preexisting Interstitial Lung Disease on Acute, Extensive Radiation Pneumonitis: Retrospective Analysis of Patients with Lung Cancer. PLoS One. 2015 Oct 13;10(10):e0140437. doi: 10.1371/journal.pone.0140437. eCollection 2015.

Sanuki N, Ono A, Komatsu E, Kamei N, Akamine S, Yamazaki T, Mizunoe S, Maeda T. Association of computed tomography-detected pulmonary interstitial changes with severe radiation pneumonitis for patients treated with thoracic radiotherapy. J Radiat Res. 2012;53(1):110-6. doi: 10.1269/jrr.110142.

Makimoto T, Tsuchiya S, Hayakawa K, Saitoh R, Mori M. Risk factors for severe radiation pneumonitis in lung cancer. Jpn J Clin Oncol. 1999 Apr;29(4):192-7. doi: 10.1093/jjco/29.4.192.

Lee YH, Kim YS, Lee SN, Lee HC, Oh SJ, Kim SJ, Kim YK, Han DH, Yoo IeR, Kang JH, Hong SH. Interstitial Lung Change in Pre-radiation Therapy Computed Tomography Is a Risk Factor for Severe Radiation Pneumonitis. Cancer Res Treat. 2015 Oct;47(4):676-86. doi: 10.4143/crt.2014.180. Epub 2015 Feb 13.

Yamaguchi S, Ohguri T, Matsuki Y, Yahara K, Oki H, Imada H, Narisada H, Korogi Y. Radiotherapy for thoracic tumors: association between subclinical interstitial lung disease and fatal radiation pneumonitis. Int J Clin Oncol. 2015 Feb;20(1):45-52. doi: 10.1007/s10147-014-0679-1. Epub 2014 Mar 11.

• Responsible Party: David Palma, Principal Investigator, Lawson Health Research Institute
• ClinicalTrials.gov Identifier: NCT05986318
• Other Study ID Numbers: RESPIRE-ILD
• First Posted: August 14, 2023
• Last Update Posted: February 29, 2024
• Last Verified: February 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by David Palma, Lawson Health Research Institute:

Pulmonary Irradiation; Radiation Therapy; N-Acetyl Cysteine; Dexamethasone; Radiation Pneumonitis

Additional relevant MeSH terms:

Lung Diseases; Lung Diseases, Interstitial; Signs and Symptoms, Respiratory; Respiratory Tract Diseases; Acetylcysteine; Dexamethasone; Dexamethasone acetate; BB 1101; N-monoacetylcystine; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antiviral Agents; Anti-Infective Agents; Expectorants; Respiratory System Agents; Free Radical Scavengers; Antioxidants; Protective Agents