Study setting {9}
In this study, all participants with stage III-IV of NSCLC who received PD-1 inhibitors treatment and being prescribed ASDs in Changzhou, China from 1 April 2022to 31 December 2023 will be continuously included.
Eligibility criteria {10}
Inclusion criteria
1. Diagnose as NSCLC stage III-IV.
2. Treatment with PD-1 inhibitors.
3. Taking PPIs or H2RA.
4. Age between 18-65 years old.
5. Voluntarily participate in this study and sign an informed consent form.
Exclusion criteria
1. Autoimmune diseases, such as systemic lupus erythematosus (SLE), Sjogren's syndrome (SS), vasculitis, etc.
2. Underlying kidney disease (abnormal urine test, such as urine protein or urine occult blood, or estimated glomerular filtration rate (eGFR) <60ml/min/1.73m2).
3. History of major organ allograft, especially kidney transplantation.
4. History of previous long-term use of PPIs.
5. History of heart failure, uncontrolled angina, severe uncontrolled arrhythmias, or pericardial disease.
6. Infectious diseases, including active hepatitis B or C, syphilis, acquired immune deficiency syndrome (AIDS).
7. Severe infectious diseases.
8. Expected survival time is less than half a year.
9. Psychiatric illness, including clinically defined depression and schizophrenia.
10. Any other conditions that can limit the ability of the patients to participate in the study.
Exiting criteria
The participants are unwilling or unable to continue the study for any reason.
Who will take informed consent? {26a}
All patients informed consent will be signed. The study investigators should protect participants’ privacy and are responsible for the confidentiality of all private information.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
In this study, biological samples of participants will be collected as clinical indicators, which will be used to judge the occurrence of the AKD events. Informed consent form, which informs patients about the aim of biological samples and potential privacy issues, as well as obtaining their consent.
Interventions
Explanation for the choice of comparators {6b}
During the course of receiving PD-1 inhibitors patients developed gastrointestinal discomfort, and are given ASDs therapy by the physician according to the assessment of their condition. The administration of ASDs is based on clinical judgement of responsible physician, no intervention from researcher. To the authors' knowledge, H2RA has not been found to have a similar risk of renal harm. The control group received H2RA treatment and is free to take medicine as directed by their physicians.
Intervention description {11a}
Subjects are assigned to two groups, namely, the intervention group and the control group, in the experimental group, they received PPIs treatment and in the control group, H2RA treatment is given. PPIs treatment group is defined as using oral or intravenous PPIs (including omeprazole, pantoprazole, lansoprazole, rabeprazole, esomeprazole, etc.) at least once within 30 days before and after receiving PD-1 inhibitor treatment as recorded in the medical advice of electronic medical record information system.
Criteria for discontinuing or modifying allocated interventions {11b}
In the following situations, subjects that have been enrolled but have not completed the clinical protocol should be deemed dropouts:
1. Patients withdrew from the trial on their own.
2. Lost to follow-up.
3. The study physician think that subjects are unable to perform the experiment because of some diseases.
Strategies to improve adherence to interventions {11c}
During the study, researchers should make every effort to make the subjects complete the whole research. Whatever the reason, participants have the right to withdraw from the study at any time. This clinical study will pay for the relevant examination expenses (including blood routine, liver and kidney function) and transportation subsidies (transportation expenses in the city of Changzhou) during participation in this study.
Relevant concomitant care permitted or prohibited during the trial {11d}
During the trial, other drugs affecting renal function can be used according to the doctor’s advice. If used, detailed records are required.
Provisions for post-trial care {30}
There are no expected harms resulting from the trial. After this trial, the subjects can be informed of the relevant experimental conclusions, and the indications and side effects of routine drug use can be publicized.
Outcomes {12}
The endpoint of our study is defined as AKD during the treatment of PD-1 inhibitor. AKD: kidney injury within 3 months, including AKI (increased serum creatinine ≥ 50% within 7 days, or increased serum creatinine ≥ 26.5μmol/l within 48 hours, or oliguria), or GFR < 60ml/min/1.73m2 within 3 months, or decreased GFR ≥ 35%, or increased Scr > 50% [21].
Participant timeline {13}
The participant timeline is presented in Table 1.
Table 1
Time schedule of enrollment, interventions, and assessments
|
STUDY PERIOD
|
|
Enrolment
|
Allocation
|
Intervention period
|
Close-out
|
TIMEPOINT
|
0
|
0
|
t1
|
t2
|
t3
|
t6
|
t21
|
Trial months
|
-1
|
0
|
1
|
2
|
3
|
6
|
21
|
ENROLMENT
|
|
|
|
|
|
|
|
Eligibility screen
|
X
|
|
|
|
|
|
|
Demographic characteristic
|
X
|
|
|
|
|
|
|
Randomization
|
X
|
|
|
|
|
|
|
Informed consent
|
|
X
|
|
|
|
|
|
INTERVENTIONS
|
|
|
|
|
|
|
|
PPIs group
|
|
|
|
|
|
|
|
H2RA group
|
|
|
|
|
|
|
|
ASSESSMENTS
|
|
|
|
|
|
|
|
Blood routine test
|
X
|
|
|
X
|
|
X
|
|
Liver function
|
X
|
|
|
X
|
|
X
|
|
Renal function
|
X
|
|
|
X
|
|
X
|
|
Urine routine test
|
X
|
|
|
X
|
|
X
|
|
The occurrence of AKD
|
X
|
|
|
|
|
X
|
X
|
Sample size {14}
According to the results of small sample size in our center, the incidence of AKD in the control group (PD-1 inhibitor + H2RA) was estimated to be about 18%, and that in the intervention group (PD-1 inhibitor + PPIs) was about 32%. The sample size calculations are derived from Power Analysis and Sample Size (PASS) software where the alpha and minimum required power is fixed at 0.05 and higher than 0.80 respectively. Finally, 190 cases in PPIs group and 190 cases in H2RA group are needed in our study.
Recruitment {15}
Three hundred and eighty participants with stage III-IV of NSCLC who received PD-1 inhibitors treatment in Changzhou, China from 1 April 2022 to 31 December 2022 will be continuously included.
Assignment of interventions: allocation
Sequence generation {16a}
The subjects who meet the eligibility criteria will be assigned to each group following the randomization schedule generated by an independent statistician using the statistical analysis system (SAS).
Concealment mechanism {16b}
The generated sequences will be placed in serialized, opaque, sealed envelopes (to ensure concealment of allocation from the evaluators).
Implementation {16c}
The randomisation list will be sealed in opaque sealed envelopes with continuous numbers. Envelopes will be stored in a locked cabinet and will only be opened by the practitioner to assign participants to the experimental or controlled group only after obtaining informed consent and eligibility screening. The opened envelope will again be stored separately in another cabinet with locks and managed by a dedicated research assistant.
Assignment of interventions: blinding
Who will be blinded {17a}
In this trial, participant blindness cannot be achieved because informed consent is required for inclusion and grouping of subjects. In addition, it is impossible for practitioners involved in the treatment process to achieve blindness. After all, practitioners need to make professional judgments to adjust the treatment plan. However, data analysts and outcome assessors are not involved in PPIs treatment management and are unaware of grouping.
Procedure for unblinding if needed {17b}
Unblinding will only be allowed under emergencies such as the incidence of serious adverse effects.
Data collection and management
Plans for assessment and collection of outcomes {18a}
We conduct baseline surveys through the electronic medical record system of our hospital, including basic individual information and clinical indicators.
Basic information
- Demographic information: age, sex, race, height, weight.
- Information about diseases: history of disease (including cardiovascular and cerebrovascular diseases, smoking and drinking history, diabetes, hypertension).
- Information about drugs: chemotherapy drugs (such as cisplatin, vinorelbine, paclitaxel, carboplatin, pemetrexed, etc.), epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) (such as gefitinib, erlotinib, afatinib, orhitinib, etc.), PPIs, H2RA, angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor block (ARB), non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics (especially nephrotoxic drugs), and contrast agents.
Clinically indicators
- Blood tests: white blood cells, red blood cells, hemoglobin, platelets, lymphocytes, alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, serum creatinine (Scr), blood urea nitrogen (BUN), uric acid (UA), and C-reactive protein (CRP).
- Urine test: urine protein, urine occult blood, urine white blood cells, urine red blood cells.
Plans to promote participant retention and complete follow-up {18b}
All participants will sign informed consent forms. The consent form will describe the study and its objectives, potential benefits and risks, indicate that participants are free to withdraw at any time and safeguards will be taken to maintain confidentiality of data. During 12 weeks of PD-1 inhibitor treatment, blood and urine tests will be examined before each course of treatment (21 ± 3 days). After 12 weeks of PD-1 inhibitor treatment, the follow-up time will be extended to 12 ± 1 weeks. In addition, the information about drug use at each stage will be recorded. Of course, if there is a decrease in urine volume (< 400 ml/d), edema, nausea, vomiting, unplanned hospital visits are required.
Data management {19}
The electronic data capture (EDC) system is used for data collection, and EpiData entry is also used for the double-key data entry and the program control of the data entry. The monitors ensure that the data recorded in the case report form (CRF) are consistent with the source files and that the entire research process conforms to the approved scheme.
Confidentiality {27}
All patients’ data are kept confidential and not disclosed. The organizers were equipped with clinical research coordinator (CRC) and clinical research associate (CRA), which will be mainly used for quality control (QC) and supervision of the inclusion of research subjects, selection of treatment schemes, laboratory index detection and other aspects.
Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
After signing the informed consent form, the baseline blood sample and urine sample of the patient will be obtained. During the follow-up period, the changes of blood routine, liver and kidney function, urine routine and CRP will be used as evaluation indexes to judge the occurrence of AKD events. Blood and urine samples are properly stored at -80 ℃ and not used by any other means than this study. Meanwhile, existing and further sample specific studies will be carried out with the approval of the Ethics Committee. If there are any remaining research specimens, biological specimens will be allowed for future research.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
Analyses were conducted using SPSS. All data were first checked for normality of distribution using the Kolmogorov-Smirnov test. Normally distributed data are presented as the mean ± standard deviation. Non-normally distributed data are represented as the median (inter-quartile range). The comparison of continuous variables uses Welch's t-test or Kruskall-Wallis test, depending on the distribution of data. Chi-square test is used to compared categorical data. In observational studies, it is difficult to guarantee the credibility of test results due to data bias and confounding variables for various reasons. We use univariate logistic regression models to initially determine which factors might have an impact on outcomes. Second, multivariate logistic regression models are established to assess potential confounding factors and reveal adjusted RR, and to adjust the confounding factors. In addition, we use propensity score matching to further estimate the incidence of AKD while accounting for covariate imbalances in populations. First, logsitic regression model is established to estimate propensity score according to the independent variable (AKD incidence) converted into dependent variable and the control variables (age, sex, hypertension, diabetes, cancer stage etc.) converted into independent variables. Select the nearest neighbor matching method to match the propensity score in a 1:1 ratio, and finally the balance groups of PPIs users and H2RA users are obtained. The Kaplan-Meier method and the log-rank test were used to estimate the survival rate of patients. A two-sided p value of <0.05 was considered to indicate statistical significance.
Interim analyses {21b}
There are no interim analyses planned.
Methods for additional analyses (e.g., subgroup analyses) {20b}
Patient characteristics of interest that might potentially influence the results. Possible confounding factors, such as age, cancer stage, disease history and medication history will be identified and summarised at baseline. Details are as follows.
- Age: 18-50 or 50-65 years old.
- Cancer stage: stage III or IV (refer to NCCN Guidelines for Non-Small Cell Lung Cancer in 2021, Fourth Edition).
- Diabetes: yes or no (refer to 2021 ADA Guidelines-Updates in T2DM Care).
- Hypertension: yes or No (refer to 2018 Chinese Guidelines for Prevention and Treatment of Hypertension).
- Medications with possible risks of AKD: yes or no (including ACEI / ARB, NSAIDs, contrast agents, aminoglycosides, etc.).
We may perform subgroup analysis based on the relevant age, sex, and cancer stage according to the above confounding factors.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
Participants with missing primary outcome data are excluded.
Plans to give access to the full protocol, participant level data, and statistical code {31c}
The datasets analyzed during the current study are available from the corresponding author on reasonable request.
Oversight and monitoring
Composition of the coordinating center and trial steering committee {5d}
The organizers were equipped with CRC and CRA, which will be mainly used for QC and supervision of the inclusion of research subjects, selection of treatment schemes, laboratory index detection and other aspects. There are several CRCs at each study center. Study coordinators play a role in coordination and study management. At the start-up meeting of clinical trials, all participants who are preparing to be authorized need to attend the training of the start-up meeting and carry out special training for relevant personnel according to the authorized authority.
Composition of the data monitoring committee, its role and reporting structure {21a}
The data security and monitoring board (DSMB) is composed of researchers from the Department of Oncology and Nephrology of the Third Affiliated Hospital of Soochow University. Members should have professional knowledge in medicine, pharmacy and health statistics, and be familiar with relevant laws and regulations of clinical trials. The Committee monitors the eligibility, integrity, security and validity of the research center data through the EDC system.
Adverse event reporting and harms {22}
All AEs will be recorded throughout the study period. We define AEs as any hospitalization behavior related to treatment. Researchers will determine whether AEs occur by following up subjects or inquiring by electronic medical record information system. We divide the severity of AEs into ‘general AEs (GAEs)’ and ‘severe AEs (SAEs)’.
GAEs: No special reports are required, but they need to be recorded in CRF. The DSMB and institutional review board (IRB) will review them in regular meetings.
SAEs: Fill in the SAE report form within 24 hours, send it to the project leader in PDF form, and then submit it to the data monitoring committee (DMC). The risk is assessed by DSMB, and finally the hospital ethics committee makes decision.
When it is not appropriate to rate the severity of AEs, we judge them as unexpected AEs (UAEs), and divide them into ‘possibly related to research intervention’, ‘possibly not related to research intervention’, and ‘definitely not related to research intervention’.
Possibly related to research intervention: report within 24 hours.
Possibly not related to research intervention: report within 5 working days.
Definitely not related to research intervention: report within 10 working days.
Frequency and plans for auditing trial conduct {23}
The supervisor meet monthly to ensure that the study is being conducted in accordance with the study protocol.
Plans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees) {25}
All changes to the study will be notified to the Ethics Committee of Soochow University. Non-material changes will be recorded and archived. If the modification involves or affects participants in any way, they will be informed of the change. If necessary, additional consent will be requested and registered. In addition, the online test registry will be updated accordingly.
Dissemination plans {31a}
The findings will be disseminated in conferences and peer-reviewed publications, and hope to attract the attention of oncologists, nephrologists and other peers. Our study findings will have significant implications for AKD prevention and control in the PD-1 inhibitor-treated patients with NSCLC.