Drug-Related Side Effects and Adverse Reactions, Immune Checkpoint Inhibitor-Related Pneumonitis, Neoplasms
Conditions
Keywords
Immune checkpoint inhibitor, Pneumonitis, Immune-related adverse events, Glucocorticoids, Spirulina, Bifidobacterium, Grape seed proanthocyanidin, Ganoderma spore oil, Antioxidant
Brief summary
This is a prospective, single-center, open-label, randomized controlled clinical trial evaluating whether the addition of a nutritional therapy regimen (Spirulina-Bifidobacterium capsules, fish oil-grape seed-blueberry soft capsules, and Ganoderma spore oil) to standard glucocorticoid therapy improves outcomes in patients with Grade 3-4 immune checkpoint inhibitor-related pneumonitis (CIP), compared with standard glucocorticoid therapy alone. A total of 60 patients with malignancies who develop Grade 3-4 CIP (per CTCAE v5.0) after at least one cycle of immune checkpoint inhibitor therapy will be randomized 1:1 to the experimental or control arm. The primary endpoints are time to pneumonitis downgrading and the proportion of patients achieving downgrading at 3 months.
Detailed description
BACKGROUND: Immune checkpoint inhibitor-related pneumonitis (CIP) accounts for the largest proportion of fatal immune-related adverse events. Approximately 30% of patients respond poorly to corticosteroid therapy, and long-term high-dose steroids increase the risk of secondary infection. Oxidative stress plays a key role in pulmonary fibrosis. The investigational nutritional products have demonstrated antioxidant and immunomodulatory properties in preclinical and clinical studies. OBJECTIVES: Primary: To evaluate the efficacy of nutritional therapy combined with glucocorticoids versus glucocorticoids alone in treating CIP, as measured by time to pneumonitis downgrading and the 3-month downgrading rate. Secondary: To evaluate safety (AE/SAE incidence, severity), total steroid dose and duration, and changes in 6-minute walk distance (6MWD), modified Medical Research Council dyspnea scale (mMRC), St George's Respiratory Questionnaire (SGRQ), and Leicester Cough Questionnaire (LCQ). Exploratory: To analyze the relationship between treatment response and changes in T-cell subsets, inflammatory cytokines (IL-1 beta, IL-6, IL-10), KL-6, ALC, CD4+ Th1/Th17, Tregs, NLR, AEC, and gut microbiome. STUDY DESIGN: Sixty eligible participants will be randomized 1:1 to: * Experimental arm: Spirulina-Bifidobacterium capsules 1080 mg twice daily orally, fish oil-grape seed-blueberry soft capsules 1200 mg twice daily orally, and Ganoderma spore oil 800 mg twice daily orally, plus methylprednisolone (dose and tapering per investigator assessment, referencing NCCN Guidelines 2025 v1). * Control arm: Matching placebo orally plus methylprednisolone (per NCCN Guidelines 2025 v1), tapered until symptoms and imaging improve and then discontinued. Pneumonitis imaging (chest X-ray or CT) will be assessed at baseline and on Days 3, 7, 14, 28, 42, and 56, and at 2-3 months post-treatment, with additional imaging as clinically indicated. Pneumonitis grade will be determined by an Independent Radiologic Review Committee (IRRC) blinded to treatment allocation. PARTICIPANTS: Adults 18-75 years of age with histologically or cytologically confirmed malignancy, who have received at least one cycle of immune checkpoint inhibitor therapy, and who develop Grade 3-4 CIP per CTCAE v5.0 and radiologic grading. FOLLOW-UP: All participants will be followed for 2 years or until death, with contacts every 90 (plus or minus 7) days.
Interventions
DIETARY_SUPPLEMENTSpirulina-Bifidobacterium capsule
1080 mg orally twice daily, from randomization until pneumonitis resolution, intolerance, or death.
DIETARY_SUPPLEMENTFish oil-grape seed-blueberry soft capsule
1200 mg orally twice daily, from randomization until pneumonitis resolution, intolerance, or death.
DIETARY_SUPPLEMENTGanoderma spore oil
800 mg orally twice daily, from randomization until pneumonitis resolution, intolerance, or death.
DRUGMethylprednisolone
Dose and tapering schedule per investigator assessment, referencing NCCN Guidelines 2025 version 1 for immune-related pneumonitis, continued until clinical and radiologic improvement and then tapered to discontinuation.
OTHERMatching placebo
Oral placebo capsules identical in appearance, color, shape, size, odor, taste, packaging, label, route, and dosing frequency to the investigational nutritional products, administered to maintain blinding and control for non-specific effects.
Sponsors
Guangzhou Institute of Respiratory Disease
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Masking description
The control arm receives matching placebo capsules identical in appearance, color, shape, size, odor, taste, packaging, label, route, and dosing frequency to the investigational nutritional products. Pneumonitis imaging is assessed by an Independent Radiologic Review Committee blinded to treatment allocation.
Intervention model description
Eligible participants are randomized 1:1 to either the nutritional therapy plus glucocorticoid arm or the glucocorticoid-only (matching placebo) arm. Stratification factors: tumor type and CIP grade (3 vs 4).
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Voluntary participation with full understanding of the study and signed informed consent form. 2. Age 18 to 75 years (inclusive) on the day of informed consent signing. 3. Histologically or cytologically confirmed malignancy. 4. Received at least one cycle of immune checkpoint inhibitor therapy. 5. Grade 3-4 immune-related pneumonitis (per CTCAE v5.0 and radiologic grading). 6. ECOG performance status 0-2, with expected survival of more than 3 months. 7. Adequate organ function based on laboratory results (without transfusion, apheresis, erythropoietin, or granulocyte colony-stimulating factor support within 14 days before the first dose). Women of childbearing potential must have a negative serum pregnancy test within 7 days before first dose.
Exclusion criteria
1. Severe cardiac, cerebrovascular, renal, hematologic, or other serious systemic disease, including: NYHA Class III-IV heart failure; acute myocardial infarction or unstable angina within 6 months; severe post-stroke functional impairment (mRS greater than or equal to 3); progressive neurodegenerative disease; Child-Pugh Class B or C liver disease or acute liver failure; CKD stage 4-5 (eGFR less than 30 mL/min/1.73 m2) or requiring dialysis; absolute neutrophil count less than 1.5 x 10\^9/L, platelet count less than 50 x 10\^9/L, or Grade 3 or higher anemia (Hb less than 8 g/dL). 2. Severe allergic constitution or contraindications to the study treatment. 3. Significant psychiatric or psychological disorder, or doubts about the treatment plan. 4. Investigator judgment that the patient is unsuitable for the trial (e.g., poor follow-up adherence, refusal of supportive care). 5. Use of anti-tumor traditional Chinese medicine within 14 days before first dose. 6. History of or active inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis). 7. Severe acute or chronic infection. 8. Known alcohol or drug abuse history. 9. Pregnancy or breastfeeding. 10. Use of antibiotics, probiotic food, or microecological preparations within 2 weeks before enrollment. 11. Prior treatment-related lung injury: (a) targeted-therapy-related pulmonary toxicity (prior EGFR-TKI, ALK inhibitor, VEGF inhibitor, or antibody-drug conjugate causing interstitial lung disease or pneumonitis that has not fully resolved, with radiologic fibrosis or persistent functional impairment); (b) thoracic radiation-related lung injury (radiation pneumonitis or radiation fibrosis with irreversible CT findings). 12. Use of another investigational drug within 28 days before first dose that, per investigator judgment, would interfere with evaluation of study treatment. 13. Gastrointestinal disorder precluding oral administration.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to immune-related pneumonitis downgrading | From randomization until first IRRC-confirmed pneumonitis grade reduction of at least 1 grade, assessed up to 6 months | Time from randomization to the first imaging assessment, confirmed by the Independent Radiologic Review Committee, showing a reduction of at least 1 grade in pneumonitis severity compared with baseline, per CTCAE v5.0 and radiologic grading. |
| Proportion of participants with pneumonitis downgrading at 3 months | 3 months (plus or minus 7 days) after randomization | Proportion of participants in each arm with an IRRC-confirmed reduction of at least 1 pneumonitis grade from baseline within 3 months after randomization. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline in 6-minute walk distance (6MWD) | Baseline, Day 28, Day 56, Month 2-3 | Distance (meters) walked in 6 minutes on a flat, hard surface, measured according to a standardized protocol by trained personnel. |
| Change from baseline in modified Medical Research Council (mMRC) dyspnea scale | Baseline, Day 28, Day 56, Month 2-3 | Self-reported dyspnea severity on the 0-4 mMRC scale, where 0 indicates no dyspnea except with strenuous exercise and 4 indicates dyspnea too severe to leave the house. |
| Change from baseline in St George's Respiratory Questionnaire (SGRQ) total score | Baseline, Day 28, Day 56, Month 2-3 | Validated Chinese version of SGRQ; total score ranges 0-100, higher scores indicate worse respiratory-related quality of life. |
| Change from baseline in Leicester Cough Questionnaire (LCQ) score | Baseline, Day 28, Day 56, Month 2-3 | Validated Chinese version of LCQ; total score ranges 3-21, higher scores indicate better cough-related quality of life. |
| Total cumulative corticosteroid dose | From randomization to end of corticosteroid treatment, up to approximately 6 months | Total cumulative glucocorticoid dose used for CIP, expressed in methylprednisolone-equivalent milligrams. |
| Duration of corticosteroid treatment | From randomization to end of corticosteroid treatment, up to approximately 6 months | Total number of days on glucocorticoid therapy for CIP, from initiation to final discontinuation. |
| Incidence of adverse events, treatment-related adverse events, and serious adverse events | From randomization through 30 days after last dose; SAEs collected through 90 days after last dose | Incidence, severity (CTCAE v5.0), and relationship to study treatment of all AEs, TRAEs, and SAEs. |
Countries
China
Contacts
CONTACTFei Wang
PRINCIPAL_INVESTIGATORChengzhi Zhou, MD
The First Affiliated Hospital of Guangzhou Medical University
Outcome results
None listed