Trial objectives and endpoints

The primary objective of this trial is to assess the efficacy of nintedanib in preventing RILI by comparing the incidence of grade 2 or higher radiation pneumonitis according to CTCAE grading between the two groups of patients with unresectable stage II or III NSCLC following CRRT. The secondary objectives of the study included comparing time to radiological lung injury occurrence; pulmonary function changes after radiotherapy; treatment effects in patients with RILI; the efficacy outcomes (OS, PFS, and ORR) in patients with NSCLC; and safety as well as tolerability.

The study focused on clinically meaningful events such as RP occurrence and therapeutic efficacy. Patients reported outcomes included changes in symptoms like shortness of breath, cough, and fatigue, as well as the impact on daily life and overall health status assessment at different time points, which will be compared to baseline. Additionally, lung function (FVC%, FEV1%, DLco%) and HRCT exploratory assessment were evaluated at various time points to compare with the baseline measurements.

Trial design and trial population

This is a prospective, randomized, multicenter, unblinding, control group study aimed at investigating the potential efficacy and safety of nintedanib in preventing RILI in patients with NSCLC undergoing RT. The intervention involves administering nintedanib 1–2 week before CRRT to assess stable blood concentration of the drug at the start of RT. The detailed follow-up program is shown in Fig 1. Fig 2 illustrates the overview of the study procedure.

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Fig 1. Example template of recommended content for the schedule of enrolment, interventions, and assessments.

https://doi.org/10.1371/journal.pone.0356205.g001

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Fig 2. Flowchart of the clinical trial protocol.

NSCLC: Non-small-cell lung cancer; cCRT: Concurrent chemoradiotherapy.

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Eligible participants will be randomised at a 1:1 ratio to the nintedanib group or the control group using a random number generator. Randomization will be stratified by the concurrent chemotherapy regimen, which is categorized into three groups: (1) platinum-based doublet with etoposide; (2) platinum-based doublet with taxanes (docetaxel/paclitaxel); and (3) platinum-based doublet with pemetrexed. Patients receiving vinorelbine will be included in the taxane group due to similar clinical practice patterns and expected sample size considerations. This stratification factor was selected because chemotherapy regimen is one of the strongest predictors of radiation pneumonitis risk, with etoposide-based regimens showing higher pulmonary toxicity compared to pemetrexed-based regimens.

Other potential confounding factors, including radiotherapy planning target volume (PTV), baseline pulmonary function (FVC%/FEV1%), and immunotherapy consolidation (yes/no), will be carefully recorded and adjusted for in the multivariable regression analysis.

Patients diagnosed with unresectable stage II-III NSCLC who comply with trial requirements may qualify to participate in the trial. Non-small cell lung cancer (NSCLC) will be confirmed through histological or cytological examination and is not suitable for surgical removal. The TNM system will be used to classify patients into different stages based on the size of the primary tumor, lymph node involvement, and presence of distant metastasis (the International Association for the Study of Lung Cancer staging manual (8th edition)) [22].

For patients with Stage II NSCLC, eligibility is restricted to those who are medically inoperable or refuse surgery after thorough multidisciplinary discussion. Medical inoperability is defined as the presence of severe comorbidities that preclude surgery, including but not limited to: severe baseline respiratory diseases (e.g., COPD, interstitial lung disease, pulmonary hypertension, et al.), severe cardiac dysfunction (NYHA Class III-IV), or other major medical conditions that contraindicate general anesthesia and surgical resection. Patients with Stage II disease who are surgical candidates but decline surgery after being fully informed of the risks and benefits of both surgical and non-surgical approaches will also be eligible. All Stage II patients will be reviewed by a multidisciplinary team (including a thoracic surgeon, radiation oncologist, and pulmonologist) to confirm inoperability or refusal prior to enrollment.

A total of 66 participants will be enrolled and randomized at 1:1 to nintedanib and control groups through the use of a random number generator. To ensure rigorous allocation concealment, the following standardized procedure will be implemented: potential participants identified in clinical practice will be referred to the study team for formal screening. Upon confirmation of eligibility and completion of informed consent by the study investigators or coordinators, an independent staff member—who is not involved in recruitment or clinical assessments—will assign each enrolled participant to an intervention group. This assignment will be executed through a centralized randomization, which allocates participants according to a pre‑generated sequence.

Table 1 outlines the specific criteria for inclusion, exclusion, and withdrawal in the study. Participants meeting the eligibility criteria should provide written informed and commit to actively taking part in and finishing the study, along with all necessary follow-up procedures. Before the commencement of the trial, all participants are required to undergo a series of examinations and counseling sessions within a timeframe of 1–2 weeks. These procedures are mandatory for each patient.

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Table 1. Key eligibility criteria for the trial.

https://doi.org/10.1371/journal.pone.0356205.t001

We will employ a multi-center design and conduct comprehensive start-up training for all site teams to ensure full protocol comprehension, supported by a clear enrollment flowchart for streamlined screening. Recruitment progress, screen failure rates, and reasons will be monitored weekly/monthly to enable timely strategy adjustments and ensure target sample size attainment.

This study was registered on April 16, 2025, at the Chinese Clinical Trial Registry (No. ChiCTR2500100845). The authors confirm that all ongoing and related trials for this drug/intervention are registered. This study entered the study phase and subjects began to be enrolled on 01/05/2025 and concluded on 30/10/2027.

Data collection methods

The Case Report Form (CRF) was used as the main data collection tool in this study. The design of the CRF form was rigorously planned and contained multiple sections that comprehensively covered the subject’s basic information, enrollment information, course of treatment, signs and symptoms, examination and test results, and health-related questionnaires. The specific structure of the CRF form is as follows:

• Basic information: Record the subjects’ name, age, gender, contact information and other basic information.
• Enrollment information: Record the enrollment time, enrollment criteria, exclusion criteria, etc. of the subjects.
• Tumor molecular characteristics: Record the driver mutation status (including but not limited to EGFR, ALK, ROS1, KRAS) if available from routine clinical testing. This information will be collected as exploratory variables for safety analyses.
• Treatment information: Record the specific treatment program received by the subject, including the name of the drug, dosage, treatment cycle and so on.
• Symptoms and signs: Record any symptoms and signs that the subject experienced during the study period, including the severity and duration of the symptoms.
• Examination and test results: Record all relevant laboratory tests and imaging results.
• Health-related questionnaires: Record the results of health-related questionnaires completed by the subjects, including quality of life assessment, psychological status assessment, etc.

The CRF form was filled out offline, by trained researchers at each follow-up visit. To ensure the accuracy and completeness of the data, the researchers recorded the subjects’ information in detail during the follow-up visits and collected the CRF forms immediately after the follow-up visits. All CRF forms were double-checked within 24 hours of completion to ensure the accuracy and completeness of the data.

During the data entry phase, data in the CRF tables were imported into the study database by manual entry. During the entry process, each piece of data was entered by two independent data entry clerks and cross-validated to minimize entry errors. After data entry was completed, the data management team performed further quality control of the database, including data cleansing, logic checking, and consistency validation to ensure the accuracy and completeness of all data.

Multiple imputation using chained equations will be performed under the missing at random (MAR) assumption, with 20 imputed datasets created based on baseline characteristics and observed outcome data. Sensitivity analyses will be conducted to assess the robustness of results under different missing data assumptions, including best-case and worst-case scenarios. Complete case analysis will be presented as a secondary analysis.

For outliers, they are identified through visualization tools (e.g., box-and-line diagrams) and the values are removed or corrected as appropriate. In addition, data are regularly checked for completeness, consistency and scope to ensure data quality. All data processing was documented in detail so that other researchers could replicate the research process. Through these measures, this study ensured the high quality of the data and the reliability of the findings.

Screening and baseline assessments

Each participant must undergo designated medical examinations and counseling within a two-week period before the trial commences.

• The baseline characteristics of the patients include gender, age, smoking status, and underlying diseases as well as the treatments, with a focus on respiratory conditions like chronic obstructive pulmonary disease (COPD) and interstitial lung diseases (ILDs).
• Lung cancer characteristics, including its anatomical site, dimensions, and TNM classification.
• Tumor molecular characteristics: Driver mutation status (EGFR, ALK, ROS1, KRAS, etc.) will be recorded if available from prior routine testing. This information will be used for exploratory analyses of potential associations between mutation status and RILI risk, as well as to document any prior or subsequent exposure to targeted therapies (TKIs) that may influence pneumonitis risk.
• Physical assessments include height, weight, vital signs, and respiratory status, with particular emphasis on auscultation for crackles.
• Blood tests, including complete blood count (CBC), serum biochemistry, coagulation function, C-reactive protein, and blood sedimentation.
• Chest CT and pulmonary function assessment.

Investigational product

The investigatory medication, nintedanib, in capsules will be supplied by CSPC NBP Pharmaceutical Co., Ltd. Each capsule consists of 150 mg of the active ingredient. The prescribed dosage is 150 mg per administration, taken twice daily. The capsules should be ingested with food and water to minimize gastrointestinal side effects associated with nintedanib. It is important to swallow the whole capsule without chewing or crushing it due to the bitter taste of the product. Diarrhea is another prevalent adverse event that can be managed using traditional antidiarrheal drugs. If the adverse events persist or are intolerable, the dosage will be temporarily lowered to 100 mg per dose, twice daily until the participant can tolerate the symptoms. This approach aims to mitigate the occurrence of adverse events while ensuring the participant’s comfort and safety.

The initial administration will occur 1–2 weeks before CCRT to establish a consistent drug concentration in the bloodstream during treatment and maintain it for a duration of 12 weeks. The first dosing phase ends at week 12. From weeks 13–24, treatment will follow the principle of patient voluntarism, allowing participants to decide whether to continue or discontinue nintedanib based on their tolerance and preference. This voluntary period was designed to accommodate patient autonomy and reflect real-world clinical practice, given the lack of established evidence on the optimal duration of prophylactic nintedanib in this setting. Of note, the primary endpoint (incidence of grade ≥2 RILI) is assessed within 6 months after radiotherapy initiation, with the voluntary period commencing at week 12; therefore, the primary outcome is determined largely before the voluntary period begins.

The decision to discontinue drug treatment lies with the physician, who may do so based on the circumstances. Nintedanib therapy will be ceased permanently if severe adverse events occur, such as liver dysfunction, jaundice, severe hypersensitivity, and photosensitivity. It is important to be cautious when prescribing nintedanib to patients with mild hepatic impairment (Child-Pugh A) [23]. The recommended dosage for these individuals is 100 mg twice daily, with doses spaced approximately 12 hours apart, and should be taken with food.

Anti-tumor therapy

Following the guideline recommendations, patients participating in this study will receive an anti-tumor treatment regimen that combines concurrent chemoradiotherapy with immunotherapy. Anti-tumor treatments are as follows.

Radiotherapy

Definition related to tumor target area: outlining in CT simulation scan, outlining the target area and organs at risk. Gross tumor volume-primary tumor (GTVp) is the primary lung tumor after induction therapy. Gross Tumor Volume-Lymph Node (GTVnd) is the metastatic lymph node. The CTV includes the GTVp and the GTVnd externally placed 5 mm and includes the ipsilateral hilar as well as the mediastinal lymphatic drainage area that is involved before the induction therapy. On top of the above CTV, 5 mm of externalization was used to form the planning target volume (PTV). 5 mm of externalization of GTVp + GTVnd was used to form planning gross target volume (PGTV). The target area needed to be reviewed and modified for approval by at least one supervising physician and above senior physician. Tumor target area prescription dose: 95% PTV 60Gy/2Gy/30F. Critical organ limits: bilateral lung V20 < 28%, bilateral lung mean dose (MLD) <17 Gy; spinal cord PRV maximum dose (Dmax) <45 Gy; esophageal mean dose (Dmean) ≤34 Gy; cardiac V30 < 40%, V40 < 30.

Chemotherapy and immunotherapy

Two cycles of chemotherapy administered every 3 weeks (Q3W) are required to include either cisplatin or carboplatin, along with one of the specified agents such as etoposide, vinorelbine, a taxane (docetaxel/paclitaxel), pemetrexed. The study proposes the use of immunoconsolidation therapy as a viable treatment option to improve the anti-cancer response in patients after completing chemoradiotherapy. This therapy will be administered within 90 days post-chemoradiotherapy to target the adapted population.

Evaluation and Intervention in RP

Additional treatments

Additional interventions include the management of hormonal side effects, particularly in cases of high-dose hormone therapy. Additionally, proton pump inhibitors are utilized to safeguard the stomach lining while undergoing treatment. Supplementation with calcium and vitamin D is recommended for patients on extended glucocorticoid therapy to reduce the likelihood of developing osteoporosis. These treatments aim to address the potential adverse effects of hormonal therapy, minimize gastric damage, and reduce the risk of bone-related complications in patients undergoing glucocorticoid treatment.

Symptomatic patients with grade 2 and 3–4 radiation pneumonitis (RP) are at risk of developing pulmonary infections. In cases where infection is suspected, empirical anti-infective therapy is administered. Short-term administration of low-dose sulphonamide is recommended for preventing Pneumocystis carinii infections in high-risk populations, particularly in patients receiving high-dose hormones. These approaches aim to prevent and manage infections in vulnerable patients with RP. Symptomatic treatment involving antitussive and sputum medications is appropriate for patients with significant symptoms. Oxygen therapy is provided to patients experiencing hypoxia to increase the oxygen levels in the blood. Patients presenting with airway obstruction undergo nebulization to widen and moisten the airway. This treatment aims to improve airflow and alleviate symptoms associated with airway constriction.

Post-treatment

The follow-up period will be half year. All participants will be followed up 1 month after radiotherapy and every 3 months thereafter, or as needed clinically. Routine follow-up will include the assessment of clinical symptoms and quality of life assessment, blood test, chest CT, pulmonary function evaluation. Also, the tumor’s disease status is assessed during follow-up visits, specifically at the end of radiotherapy, the thirth month, and sixth month. These time points are of particular interest for evaluation. The 1-year time point serves as an additional observation period for data collection. The data collected at the 1-year time point will be comparable to that collected at the 6th month time point. This additional time point allows for further insights to be gathered regarding the study outcomes.

Assessments

George’s Questionnaire and the Health Status Questionnaire SF-36 were used to assess the health status of the subjects [26]. The symptoms and the impact of symptoms on daily life will be evaluated using the Patient’s Overall Impression of Disease Severity questionnaire (see as supl. materials) [27]. Imaging assessment of both radiation pneumonitis (RP) and the effectiveness of tumor therapy is crucial in this study.

Spirometry measurements will be performed according to ATS/ERS 2019 guidelines [28]. Force vital capacity (FVC) and carbon monoxide diffusion capacity (DLCO) will be assessed using standardized spirometry equipment at sites. FVC is deemed stable if the results fluctuate within ± 5% of the baseline level. An increase of more than 5% indicates improvement, while a decrease of more than 5% indicates deterioration. In the context of DLCO measurements, stability is defined as a variation of less than ± 10% from the baseline value. Improvement is noted when there is an increase of more than 10%, whereas deterioration is observed with a decrease of more than 10%.

Safety parameters mainly include the assessment of adverse events and safety laboratory parameters. The main focus of our study is on the gastrointestinal adverse reactions associated with nintedanib, such as diarrhea, nausea, vomiting, abdominal pain, decreased appetite, weight loss, and increased levels of liver enzymes. These reactions have been reported in published literature and are of particular interest in patients receiving nintedanib.

Endpoints

The primary endpoint is the incidence of grade 2 or higher RP in the full analysis set and per-protocol set. Diagnosis and grading of RP will be confirmed after review by multidisciplinary senior physicians, including a radiation oncologist, a pulmonologist, and a radiologist. Medical history, physical parameters, chest CT scans, and previous radiotherapy will be evaluated at follow-up during study visits (Fig 1). RILI will be scored based on the CTCAE V.5.0 classifying symptoms and imaging findings will be used to classify into five grades (Table 2) [29] and the grade will be scored at the maximal level in cases who experience RILI. The case demonstrates that RILI will be managed according to the procedure described earlier.

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Table 2. Incidence and grading criteria of radiation pneumonitis.

https://doi.org/10.1371/journal.pone.0356205.t002

The progression from radiotherapy to the onset of RP will be recorded. The severity of RP and treatment outcomes will be assessed through symptom evaluation, imaging tests, and lung function measurements. A comparative analysis will be performed between the treatment group and the control group to assess the impact of investigational medicine on oncological treatment efficacy. Tolerability of treatments and occurrence of adverse drug reactions will also be compared between the two groups.

Ethical approval

This study was approved by the Ethics Committee of the First Hospital of Zhangjiakou (No. 2024-IIT-007–03), Beijing Cancer Hospital (No. 2024YJZ166), Cancer Hospital Chinese Academy of Medical Sciences (No. 24/578–4858). Participants who meet the eligibility criteria have provided written informed consent and committed to actively take part in and complete the study, including all required follow-up procedures.

Statistical analysis and determination of sample size

Sample size calculation

Based on published literature, the incidence of grade ≥2 radiation pneumonitis in patients receiving concurrent chemoradiotherapy for locally advanced NSCLC is approximately 20% in the control group. We hypothesize that nintedanib prophylaxis will reduce this incidence to 5% in the treatment group. Using a two-sided χ² test with α = 0.05 and power = 80%, a sample size of 58 patients per group would be required. Accounting for a 10% dropout rate, we plan to enroll 66 patients in total (33 per group).

Statistical analysis of the population

• Full Analysis Set (FAS): including all subjects who were randomised into the group. And those who have taken the drug at least once and have at least one follow-up record.
• Per-Protocol Set (PPS): all the cases that complied with the trial protocol, completed the visit plan, had good adherence, did not use prohibited drugs during the trial, completed the CRF and complied with the visit window, and the efficacy of the cases was statistically analysed.
• Safety Analysis Set (SS): All the cases that used the study drug at least once and have the safety evaluation data after the use of the drug constitute the safety dataset of this study. This data set was used to evaluate the safety of this study.

Data collection and management

The research assistant will gather all clinical data and document it thoroughly in the predetermined electronic database. This process ensures accurate and comprehensive recording of clinical information for research purposes. The written informed consent forms will be securely stored in a designated location, with restricted access only granted to researchers handling the research data. This protocol ensures that confidentiality and data security are maintained throughout the research process.

To ensure participant retention and complete follow-up, we will implement multiple participant-centered support measures, including flexible visit scheduling, dedicated personnel for regular contact, and reminder systems. Even if participants discontinue the intervention, we will continue to collect key outcome data—such as primary efficacy endpoints, serious adverse events, survival status, and reasons for discontinuation—through alternative means such as telephone follow-up.

The final trial dataset will be accessible to the principal investigators, study statisticians, and relevant personnel directly involved in the analysis and reporting of this study. Additionally, access will be granted to regulatory authorities and the ethics committee for their respective oversight functions.

Dissemination

The results will be shared at international academic conferences and published in peer-reviewed journals. Authorship will be granted to those who make substantial contributions to the conception/design, acquisition/analysis/interpretation of data, drafting or critical revision of the manuscript, and final approval of the version to be published.

Patient and public involvement

Patients and the general public do not play a role in designing, executing, or measuring outcomes in the study.

Limitations

Our research has several limitations.

First, the unblinded trial design, while convenient, is susceptible to bias and subject expectancy effects, which may influence the reporting and interpretation of adverse events, as well as patient satisfaction and adherence. Patient-reported outcomes should be interpreted with particular caution given the open-label design.

Second, the sample size calculation assumed a 10% dropout rate. Should dropout exceed this, the study may be underpowered. Any positive findings will require confirmation in a larger, blinded, multicenter trial.

Third, the voluntary dosing period (weeks 13–24) introduces heterogeneity in drug exposure. However, the primary endpoint is assessed within six months of radiotherapy initiation, largely before this period begins. For secondary outcomes beyond week 12, sensitivity analyses stratified by actual treatment duration (≤12 weeks vs. > 12 weeks) will be conducted to account for exposure variability.

Fourth, the inclusion of multiple chemotherapy regimens and immunotherapy consolidation reflects real-world practice but may introduce confounding bias. We addressed this by stratifying randomization by chemotherapy regimen and adjusting for relevant covariates (immunotherapy consolidation, PTV, baseline pulmonary function) in the analyses. Nonetheless, residual confounding cannot be fully excluded, and subgroup analyses should be interpreted cautiously given the limited sample size.

Fifth, the absence of a centralized independent imaging core laboratory for RILI assessment is a limitation. To mitigate this, rigorous quality control measures were implemented as described in the Methods section. Future studies with larger sample sizes should incorporate centralized blinded review to enhance reliability.

Sixth, driver mutation status will be collected when available from routine testing, but this study is not powered to detect differences in RILI risk based on mutation status or prior TKI exposure. These data will be used for exploratory analyses and hypothesis generation only; definitive conclusions regarding interactions between mutation status, targeted therapy, and nintedanib’s preventive effect cannot be drawn. Future studies with larger samples and prospective molecular data collection are needed.