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

Sponsor

Lawson Health Research Institute (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05986318

Collaborator

London Health Sciences Centre (Other), Centre Hospitalier de l'Universite de Montreal (CHUM) (Other)

Enrollment

Locations

Arms

109

Anticipated Duration (Months)

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

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	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, we will test the following hypotheses:

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).
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

Anticipated 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

Anticipated Study Start Date :

Dec 1, 2023

Anticipated Primary Completion Date :

Jul 1, 2028

Anticipated Study Completion Date :

Dec 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.	Dietary Supplement: N-Acetyl cysteine NAC capsules Other Names: NAC Drug: Dexamethasone Oral Dexamethasone tablets Other Names: Corticosteroid
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.	Drug: Dexamethasone Oral Dexamethasone tablets Other Names: Corticosteroid Dietary Supplement: N-Acetyl cysteine Placebo Matching placebo for NAC capsules Other Names: NAC Placebo
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.	Dietary Supplement: N-Acetyl cysteine NAC capsules Other Names: NAC Drug: Dexamethasone Placebo Matching placebo for dexamethasone tablets Other Names: Corticosteroid Placebo
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.	Dietary Supplement: N-Acetyl cysteine Placebo Matching placebo for NAC capsules Other Names: NAC Placebo Drug: Dexamethasone Placebo Matching placebo for dexamethasone tablets Other Names: Corticosteroid Placebo

Outcome Measures

Primary Outcome Measures

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 Outcome Measures

Patient Scored Dyspnea Measured by Visual Analogue Scale (VAS) [6 weeks, 3, 6, 9, 12,18, 24, 36, 48, and 60 months post radiation therapy]
Patient Scored Cough Measured by Visual Analogue Scale (VAS) [6 weeks, 3, 6, 9, 12,18, 24, 36, 48, and 60 months post radiation therapy]
Quality of Life Measured by FACIT.org Functional Assessment of Cancer Therapy - Lung (FACT-L) Questionnaire [6 weeks, 3, 6, 9, 12,18, 24, 36, 48, and 60 months post radiation therapy]
Quality of Life Measured by EuroQOL Group EQ-5D-5L Questionnaire [6 weeks, 3, 6, 9, 12,18, 24, 36, 48, and 60 months post radiation therapy]
Local Control as Determined by Radiographic Evidence [9 years]
Progression Free Survival [9 years]
Time from enrollment to death from any cause or any progression of disease (local, regional, or distant).
Overall Survival [9 years]
Time from enrollment to death from any cause .
Cancer Specific Survival [9 years]
Time from enrollment to death from lung cancer, censored at last follow-up or death from other causes.
Rates of Radiation Treatment Completion [50 months]
Rates of Study Drug Completion Rates [50 months]
Rates of Participant Unblinding Related to Adverse Events Development [50 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	State	Country	Postal Code
1	London Regional Cancer Program, London Health Sciences Centre	London	Ontario	Canada	N6A 5W9
2	Centre Hospitalier de l'Universite de Montreal (CHUM)	Montreal	Quebec	Canada	H2X 0A9

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