Nutritional + Usual Corticosteroids Randomized Trial for Immune-Related pneumoniA - Therapeutic Utilization Evaluation

A Single-Center, Open-Label, Randomized Controlled Clinical Trial Comparing Nutritional Therapy (Spirulina-Bifidobacterium Capsules, Fish Oil-Grape Seed-Blueberry Soft Capsules, and Ganoderma Spore Oil) Combined With Standard Glucocorticoid Regimen Versus Standard Glucocorticoid Regimen Alone in the Treatment of Immune Checkpoint Inhibitor-Related Pneumonitis

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Neoplasms; Drug-Related Side Effects and Adverse Reactions; Immune Checkpoint Inhibitor-Related Pneumonitis
• Intervention / Treatment: Dietary supplement: Spirulina-Bifidobacterium capsule; Dietary supplement: Fish oil-grape seed-blueberry soft capsule; Dietary supplement: Ganoderma spore oil; Drug: Methylprednisolone; Other: Matching placebo

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.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Fei Wang; Phone Number: +86 18355293991; Email: doctorlzk@163.com

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510120
      • The First Affiliated Hospital of Guangzhou Medical University, Department of Pulmonary Oncology
      • Principal Investigator: Chengzhi Zhou, MD
      • Contact: Fei Wang; Phone Number: +86 18355293991; Email: doctorlzk@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nutritional Therapy Plus Glucocorticoid; Participants receive Spirulina-Bifidobacterium capsules 1080 mg orally twice daily, fish oil-grape seed-blueberry soft capsules 1200 mg orally twice daily, and Ganoderma spore oil 800 mg orally twice daily, in addition to methylprednisolone administered per investigator assessment (referencing NCCN Guidelines 2025 v1), until pneumonitis resolution, intolerance, or death.	Dietary supplement: Spirulina-Bifidobacterium capsule; 1080 mg orally twice daily, from randomization until pneumonitis resolution, intolerance, or death.; Dietary supplement: Fish oil-grape seed-blueberry soft capsule; 1200 mg orally twice daily, from randomization until pneumonitis resolution, intolerance, or death.; Dietary supplement: Ganoderma spore oil; 800 mg orally twice daily, from randomization until pneumonitis resolution, intolerance, or death.; Drug: Methylprednisolone; 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.
Placebo Comparator: Placebo Plus Glucocorticoid; Participants receive matching placebo capsules (identical in appearance, color, shape, size, odor, taste, packaging, label, route, and dosing frequency to the investigational nutritional products) in addition to methylprednisolone administered per investigator assessment (referencing NCCN Guidelines 2025 v1), tapered until symptoms and imaging improve and then discontinued.	Drug: Methylprednisolone; 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.; Other: Matching 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to immune-related pneumonitis downgrading	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.	From randomization until first IRRC-confirmed pneumonitis grade reduction of at least 1 grade, assessed up to 6 months
Proportion of participants with pneumonitis downgrading at 3 months	Proportion of participants in each arm with an IRRC-confirmed reduction of at least 1 pneumonitis grade from baseline within 3 months after randomization.	3 months (plus or minus 7 days) after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in 6-minute walk distance (6MWD)	Distance (meters) walked in 6 minutes on a flat, hard surface, measured according to a standardized protocol by trained personnel.	Baseline, Day 28, Day 56, Month 2-3
Change from baseline in modified Medical Research Council (mMRC) dyspnea scale	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.	Baseline, Day 28, Day 56, Month 2-3
Change from baseline in St George's Respiratory Questionnaire (SGRQ) total score	Validated Chinese version of SGRQ; total score ranges 0-100, higher scores indicate worse respiratory-related quality of life.	Baseline, Day 28, Day 56, Month 2-3
Change from baseline in Leicester Cough Questionnaire (LCQ) score	Validated Chinese version of LCQ; total score ranges 3-21, higher scores indicate better cough-related quality of life.	Baseline, Day 28, Day 56, Month 2-3
Total cumulative corticosteroid dose	Total cumulative glucocorticoid dose used for CIP, expressed in methylprednisolone-equivalent milligrams.	From randomization to end of corticosteroid treatment, up to approximately 6 months
Duration of corticosteroid treatment	Total number of days on glucocorticoid therapy for CIP, from initiation to final discontinuation.	From randomization to end of corticosteroid treatment, up to approximately 6 months
Incidence of adverse events, treatment-related adverse events, and serious adverse events	Incidence, severity (CTCAE v5.0), and relationship to study treatment of all AEs, TRAEs, and SAEs.	From randomization through 30 days after last dose; SAEs collected through 90 days after last dose

Other Outcome Measures

Outcome Measure	Time Frame
Change in serum KL-6 (Krebs von den Lungen-6)	Baseline, Day 28, Day 56, Month 2-3
Change in serum inflammatory cytokines (IL-1 beta, IL-6, IL-10)	Baseline, Day 28, Day 56, Month 2-3
Change in immune cell subsets (ALC, CD4+ Th1/Th17, Tregs, NLR, AEC)	Baseline, Day 28, Day 56, Month 2-3

Collaborators and Investigators

• Sponsor: Guangzhou Institute of Respiratory Disease
• Investigators: Principal Investigator: Chengzhi Zhou, MD, The First Affiliated Hospital of Guangzhou Medical University

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): October 1, 2029

Study Registration Dates

• First Submitted: April 21, 2026
• First Submitted That Met QC Criteria: April 21, 2026
• First Posted (Actual): April 28, 2026

Study Record Updates

• Last Update Posted (Actual): May 26, 2026
• Last Update Submitted That Met QC Criteria: May 21, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Glucocorticoids; Bifidobacterium; Immune checkpoint inhibitor; Antioxidant; Immune-related adverse events; Spirulina; Pneumonitis; Grape seed proanthocyanidin; Ganoderma spore oil
• Additional Relevant MeSH Terms: Respiratory Tract Infections; Infections; Respiratory Tract Diseases; Lung Diseases; Chemically-Induced Disorders; Neoplasms; Pneumonia; Drug-Related Side Effects and Adverse Reactions; Polycyclic Compounds; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Pregnadienetriols; Prednisolone; Methylprednisolone
• Other Study ID Numbers: CROC-Edinburgh001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: The decision regarding sharing of individual participant data has not yet been made. A plan will be provided before publication of study results.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No