Reducing Respiratory Symptoms of Pulmonary Irradiation in Interstitial Lung Disease

Lung Cancer Clinical Trial

— RESPIRE-ILD  

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05986318
• Other study ID #: RESPIRE-ILD
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: May 1, 2024
• Est. completion date: December 31, 2032

Study information

• Verified date: February 2024
• Source: Lawson Health Research Institute
• Contact: David Palma, MD
• Phone: 519-685-8650
• Email: david.palma[@]lhsc.on.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 98
• Est. completion date: December 31, 2032
• Est. primary completion date: July 1, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Interstitial Lung Disease
• Lung Cancer
• Lung Diseases
• Lung Diseases, Interstitial
• Signs and Symptoms, Respiratory

Intervention

Dietary Supplement:
• N-Acetyl cysteine
NAC capsules

Drug:
• Dexamethasone Oral
Dexamethasone tablets

Dietary Supplement:
• N-Acetyl cysteine Placebo
Matching placebo for NAC capsules

Drug:
• Dexamethasone Placebo
Matching placebo for dexamethasone tablets

Radiation:
• Radiation Therapy
All participants will receive radical pulmonary radiation therapy. Conventional techniques or stereotactic ablative radiotherapy will be used.

Locations

Country	Name	City	State
Canada	London Regional Cancer Program, London Health Sciences Centre	London	Ontario
Canada	Centre Hospitalier de l'Universite de Montreal (CHUM)	Montreal	Quebec

Sponsors (3)

Lead Sponsor	Collaborator
Lawson Health Research Institute	Centre Hospitalier de l'Universite de Montreal (CHUM), London Health Sciences Centre

Country where clinical trial is conducted

Canada, 

References & Publications (11)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Rate of Grade 2-5 Dyspnea within 6 Months Post Radiation Measured by the Common Terminology Criteria for Adverse Events (CTCAE) Version 5		Up to 6 months post radiation therapy
Secondary	Patient Scored Dyspnea Measured by Visual Analogue Scale (VAS)	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.	6 weeks, 3, 6, 9, 12,18, 24, 36, 48, and 60 months post radiation therapy
Secondary	Patient Scored Cough Measured by Visual Analogue Scale (VAS)	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.	6 weeks, 3, 6, 9, 12,18, 24, 36, 48, and 60 months post radiation therapy
Secondary	Quality of Life Measured by FACIT.org Functional Assessment of Cancer Therapy - Lung (FACT-L) Questionnaire	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.	6 weeks, 3, 6, 9, 12,18, 24, 36, 48, and 60 months post radiation therapy
Secondary	Quality of Life Measured by EuroQOL Group EQ-5D-5L Questionnaire	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.	6 weeks, 3, 6, 9, 12,18, 24, 36, 48, and 60 months post radiation therapy
Secondary	Local Control as Determined by Radiographic Evidence	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.	9 years
Secondary	Progression Free Survival	Time from enrollment to death from any cause or any progression of disease (local, regional, or distant).	9 years
Secondary	Overall Survival	Time from enrollment to death from any cause .	9 years
Secondary	Cancer Specific Survival	Time from enrollment to death from lung cancer, censored at last follow-up or death from other causes.	9 years
Secondary	Rates of Radiation Treatment Completion		50 months
Secondary	Rates of Study Drug Completion Rates		50 months
Secondary	Rates of Participant Unblinding Related to Adverse Events Development		50 months