Study setting {9}
SPIRIT guidance: Description of study settings (eg, community clinic, academic hospital) and list of countries where data will be collected. Reference to where list of study sites can be obtained.
This clinical trial is being conducted at the multidisciplinary departments of the Kyung Hee University Hospital, Korea. The departments of medical oncology, surgery, clinical pharmacology, psychiatry, nutrition, nuclear medicine, physical medicine, and rehabilitation are involved in patient recruitment and treatment intervention. A specialist from the Department of Sasang Constitutional Medicine of Kyung Hee University Korean Medicine Hospital is also involved in treatment intervention for CAM.
Eligibility criteria {10}
SPIRIT guidance: Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and individuals who will perform the interventions (eg, surgeons, psychotherapists).
The inclusion criteria are as follows: 1) Patients who are diagnosed with recurrent or metastatic solid cancer: gastric, colorectal, pancreatic, biliary tract, and lung. 2) Patients receiving first- or second-line palliative chemotherapy. 3) Eastern Cooperative Oncology Group performance status 0–2. 4) Patients categorized into normal, precachexia, or cachexia by pre-defined stages of CC. Precachexia is defined as weight loss ≤ 5% within the last 6 months, anorexia, and metabolic changes, such as glucose intolerance. Cachexia is defined as weight loss > 5% within the last 6 months or body mass index < 20 and weight loss > 2% within the last 6 months (14). 5) Age ≥ 19 years. 6) Patients who can comply with treatment interventions in the clinical trial at the discretion of the researcher. For example, those who have no restrictions on simple daily exercise, ONS intake, and use of NSAIDs. 7) Patients with adequate organ function. Laboratory findings conducted within one week of the study enrolment should be appropriate for the treatment intervention as well as chemotherapy: total white blood cell ≥ 3,000 mm3, absolute neutrophil count ≥ 1,200 mm3, platelet ≥ 100,000 mm3, haemoglobin ≥ 8.0 g/dL, aspartate transaminase, and alanine transaminase 3 times or less of the upper limit of the reference range, total bilirubin 2 times or less of the upper limit of the reference range, serum creatinine 1.5 times or less of the upper limit of the reference range or estimated glomerular filtration rate calculated by the Cockcroft-Gault equation > 60 mL/min.
Exclusion criteria are as follows:1) Patients who have a history of cardiovascular disease with or without active treatment: congestive heart failure, poorly controlled hypertension ≥ 160 mmHg of systolic blood pressure or 100 mmHg of diastolic blood pressure despite antihypertensive medication, coronary heart disease. 2) Patients with bronchial asthma. 3) Patients who are unable to intake food or medication orally or have considerable difficulty in adequate oral intake: bowel obstruction, uncontrolled active inflammatory bowel disease, and short bowel syndrome. 4) Patients associated with bleeding risk or peptic ulcer disease or contraindication to taking NSAIDs. 5) Patients who have taken MA or progestin analogues within 30 days prior to the study participation. 6) Patients who are taking aspirin or NSAIDs continuously for more than 1 week at the time of the study participation. 7) Patients who are taking anticoagulants.
Prespecified medical oncologists will conduct chemotherapy for each participant and prescribe concomitant interventional drugs (NSAIDs, O3FA, and ONS) during the study period. Psychiatric interventions will be performed by a psychiatrist. The exercise program will be established by a physiatrist, and each individual participant’s exercise therapy will be performed by trained, certified physical therapists. Regular nutritional counseling for participants will be provided by two nutritionists. A certified Korean medical doctor will provide herbal medication as CAM. A nuclear medicine specialist will conduct and interpret dual-energy X-ray absorptiometry (DEXA) for each participant’s study outcomes, although he will not be directly involved in specific treatment intervention. Finally, surveys of patient reported outcomes, including quality of life, will be provided and conducted by medical oncologists and Korean medical doctors who will be the physicians in charge of actual medical management for the participants.
Who will take informed consent? {26a}
SPIRIT guidance: Who will obtain informed consent or assent from potential trial participants or authorised surrogates, and how (see Item 32).
Medical oncologists who participate as co-investigators in this study will provide informed consent. Patients treated with palliative chemotherapy are potential subjects for this study. If a patient is judged to be potentially eligible, written informed consent is obtained after giving the patient sufficient time to explain the purpose, methods, significance of the study, and the potential risks and benefits.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
SPIRIT guidance: Additional consent provisions for collection and use of participant data and biological specimens in ancillary studies, if applicable.
Not applicable
Interventions
Explanation for the choice of comparators {6b}
SPIRIT guidance: Explanation for choice of comparators.
Participants are randomly assigned to either the “Multimodal Interventional Care” (MIC) group or “Conventional Palliative Care” (CPC) group in a 1:1 ratio.
Intervention description {11a}
SPIRIT guidance: Interventions for each group with sufficient detail to allow replication, including how and when they will be administered.
1. Multimodal Interventional Care (MIC)
1) Intervention with investigational product (IP)
A participant allocated to the MIC group will receive the following medication as IPs for 12 weeks while the palliative chemotherapy continues as planned: NSAID, O3FA, Bojungikki-tang, and ONS. NSAID is provided orally as ibuprofen 200 mg three times a day. O3FA is provided orally at 1000 mg twice a day. Bojungikki-tang is provided orally as 3.75 g twice a day. ONS is in the form of one sachet containing a 200 mL beverage designed for drinking. Each 200 mL ONS contains 9.8 g of protein, 27 g of carbohydrate, 6 g of fat, and 2 g of fiber. The participants will take it twice a day. All prescribed IPs should be taken daily for 12 weeks, unless a participant is intolerable to them. All IPs should be administered to the participants according to the study protocol. To check compliance with the administration of IP, the remaining IPs that the participant could not take will be retrieved at the next visit and the number of remaining medications will be checked.
2) Intervention with a psychiatrist
Type
|
Intervention
|
Psychotherapy
|
General psychotherapy
|
Cognitive behavioral therapy for stress
|
Week 1: stress screening Week 3: talking about cancer, coping with physical symptoms Week 5: finding and changing thoughts causing stress Week 7: learning coping skills or anger management Week 9: coping with physical changes and potential fears
|
Cognitive behavioral therapy for sleep
|
Cognitive behavioral therapy for insomnia
|
Pharmacotherapy
|
Performed when necessary according to the researcher’s clinical decision
|
3) Intervention through exercise by a physiatrist
Type
|
Intervention
|
Warm-up exercise
|
5–10 min: low intensity (< 40 % of VO2Max) or moderate intensity
|
Stretching (ROM exercise)
|
10 mins
|
Conditioning (Training) exercise
|
20–30 mins: aerobic exercise (ergometer or treadmill) Resistance exercise (60%–80% of 1RM, 1 set 10–15 repetition) Flexibility exercise (upper & lower extremity)
|
Cool-down exercise
|
5–10 mins: Low or moderate intensity: cardiovascular & muscle endurance exercise
|
* VO2Max, maximal oxygen consumption; ROM, range of motion; RM, repetition maximum.
4) Others
Participants will receive nutritional counseling four times (baseline, weeks 4, 7, and 13) during the study period by hospital nutrition specialists. Through detailed interviews and counseling, participants can be helped to have their daily meals at home.
2. Conventional Palliative Care (CPC)
Participants assigned to the CPC group will receive their planned chemotherapy with the best supportive care. No additional IP, psychiatric intervention, or exercise will be provided. However, routine nutritional counseling for all patients who are treated with chemotherapy will be provided twice (baseline and week 13) during the study period. In Korea, every patient receiving chemotherapy can be provided with two nutritional counseling sessions under the reimbursement schedule of the Korean National Health Insurance. In addition, at the clinical discretion of the researcher, MA 625 mg once a day can be administered if the participant shows more than grade 2 anorexia or weight loss based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. MA can also be provided to the participant if the subject is categorized as pre-defined precachexia or cachexia.
Criteria for discontinuing or modifying allocated interventions {11b}
SPIRIT guidance: Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug dose change in response to harms, participant request, or improving/worsening disease).
Subjects may voluntarily discontinue participation in the study at any time. In addition, the investigator may discontinue the intervention or suspend the subject’s participation in this study at any time according to the following criteria: 1) When a subject requests to discontinue part of the clinical trial treatment during the study period or withdraws consent to participate in this trial. 2) When the investigator decides to drop out of the study because the subject’s continued participation in the study poses a risk that outweighs the potential benefit to the subject. 3) When the subject has taken a drug that is expected to affect the evaluation of the safety and efficacy of the interventions. 4) Violation of inclusion or exclusion criteria.
Strategies to improve adherence to interventions {11c}
SPIRIT guidance: Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence (eg, drug tablet return, laboratory tests).
In this study, especially when assigned to the MIC group, there is a concern that the compliance of the participants might be lowered owing to three kinds of IPs to be taken with multiple and frequent visits to the hospital for exercise intervention. To increase compliance of the participants, trained study coordinators will call the patients before each visit to remind them of the study schedule, and even when they move within the hospital (for example, to the treatment room, laboratory, or exercise therapy room), study coordinators will accompany them directly. To assess drug compliance, the remaining IPs that could not be taken as scheduled will be returned and counted at the next visit.
Relevant concomitant care permitted or prohibited during the trial {11d}
SPIRIT guidance: Relevant concomitant care and interventions that are permitted or prohibited during the trial.
MA is not allowed to the participants allocated to the MIC group. There will be no restrictions on chemotherapy or radiation therapy required for patients during clinical trials.
Provisions for post-trial care {30}
SPIRIT guidance: Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial participation.
When an adverse reaction occurs during the conduct of this clinical trial, the investigators will apply utmost effort to recover the side effect by administering appropriate treatment, and to minimize the financial and social burden on the patient when hospitalization is required because of an adverse reaction directly due to trial participation. Costs for appropriate treatment will be provided even after the clinical trial is completed. The team has joined the insurance compensation scheme for this purpose.
Outcomes {12}
SPIRIT guidance: Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood pressure), analysis metric (eg, change from baseline, final value, time to event), method of aggregation (eg, median, proportion), and time point for each outcome. Explanation of the clinical relevance of chosen efficacy and harm outcomes is strongly recommended.
Primary and secondary outcomes will be measured according to a predefined timeline (Table 1). All measurements for outcome variables will be calculated as changes; values at 5, 7, 9, and 13 weeks - values at 1 week ( baseline value).
Primary outcomes
The primary outcomes of this study are 1) median change ( kg) in LBM, which is defined as the average of the change (kg) from baseline and at weeks 5, 7, 9, and 13 measured by DEXA, and 2) median change (kg) in handgrip strength, which is defined as the average of the change (kg) from baseline and at weeks 5, 7, 9, and 13 measured by a dynamometer.
Secondary outcomes
The secondary outcomes are as follows:
1) Changes (kg) in total body mass, LBM of trunk, LBM of both upper and lower extremities, fat mass from baseline, and at week 13 from DEXA
2) Changes on the anorexia-cachexia scale
The anorexia-cachexia scale will be assessed using the Functional Assessment of Anorexia/Cachexia Treatment (FAACT) version 4, where higher the score, the better is the outcome with a range of 0–156 (15).
3) Changes in quality of life
The quality of life will be assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 version 3 (16). Questions 1 to 28 use a 4-point scale. The scale scores from 1 to 4: 1 (“Not at all”), 2 (“A little”), 3 (“Quite a bit”), and 4 (“Very much”). Half points are not allowed. The range is 3. For the raw score, fewer points were considered to have a better outcome. The subsequent questions 29 and 30 use a 7-point scale. The scale scores from 1 to 7: 1 (“Very poor”) to 7 (“Excellent”). Half points are not allowed. The range is 6. The raw score needs to be calculated using mean values. Subsequently, a linear transformation is performed to be comparable. More points were considered to have better outcomes. Finally, the rate of toxicity with clinical significance and possible relationship to either study intervention will be obtained based on CTCAE v5.0.
4) Changes in spleen Qi deficiency questionnaire
The spleen Qi deficiency questionnaire is a validated questionnaire that includes 11 questionnaires (17,18). Each item is measured on a 5-point Likert scale, which is as follows: 0 indicates not at all or not applicable; 1 indicates a little applicable; 2 indicates moderately applicable; 3 indicates quite applicable; and 4 indicates extremely applicable. The cut-off value is 43.18 (spleen qi deficiency >43.18 and nonspleen qi deficiency (≤ 43.18).
Table 1. Timeline for outcome measurements
Time schedule
|
W1
|
W2
|
W3
|
W4
|
W5
|
W6
|
W7
|
W8
|
W9
|
W10
|
W11
|
W12
|
W13
|
Primary
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Total LBM1
|
✓
|
|
|
|
✓
|
|
✓
|
|
✓
|
|
|
|
✓
|
Handgrip strength
|
✓
|
|
|
|
✓
|
|
✓
|
|
✓
|
|
|
|
✓
|
Secondary
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Anorexia-cachexia scale
|
✓
|
|
|
|
✓
|
|
|
|
✓
|
|
|
|
✓
|
EORTC QLQ C-302
|
✓
|
|
|
|
✓
|
|
|
|
✓
|
|
|
|
✓
|
SQDQ3
|
✓
|
|
|
|
✓
|
|
|
|
✓
|
|
|
|
✓
|
1 Total lean body mass (LBM) and other secondary variables (total body mass, LBM of the trunk, LBM of both upper and lower extremities, and fat mass) will be measured using dual-energy X-ray absorptiometry.
2 European Organisation for Research and Treatment of Cancer quality of life questionnaire C-30
3 Spleen Qi deficiency pattern questionnaire
Participant timeline {13}
SPIRIT guidance: Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for participants. A schematic diagram is highly recommended (see figure at http://www.spirit-statement.org/publications-downloads/).
Sample size {14}
SPIRIT guidance: Estimated number of participants needed to achieve study objectives and how it was determined, including clinical and statistical assumptions supporting any sample size calculations.
A sample size of 100 subjects was calculated for comparison of handgrip strength between the MIC and CPC arms with the following conditions: two-sided type I error at 0.5, power of 90%, and 1:1 allocation of MIC versus CPC arm. Only the standard deviation (SD) of handgrip strength was used because the SD of handgrip strength was larger than that of LBM. A total sample size of 112 subjects was calculated after considering a 10% dropout rate.
Recruitment {15}
SPIRIT guidance: Strategies for achieving adequate participant enrolment to reach target sample size.
Physicians from the Department of Surgery or Medical Oncology are designated as co-investigators to screen all potentially eligible patients, even if they visit our institute for the first time.
Assignment of interventions: allocation
Sequence generation {16a}
SPIRIT guidance: Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any factors for stratification. To reduce predictability of a random sequence, details of any planned restriction (eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants or assign interventions.
Concealment mechanism {16b}
SPIRIT guidance: Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned.
The independent statistician will not be allowed to contact the subjects, and this statistician will generate a randomization list using SAS, version 9.4 (Cary, NC). The randomization list will be prepared using a simple randomization procedure in a pre-determined computer with restricted access using a secure password. Eligible subjects will be randomly assigned by an independent statistician.
Implementation {16c}
SPIRIT guidance: Who will generate the allocation sequence, who will enrol participants, and who will assign participants to interventions
If a patient is determined to enroll by a medical oncologist according to the protocol, the information (screening number, alphabetical initials) for this subject will be provided to the independent statistician. This statistician will assign the enrolled patient to one of the two arms (MIC or CPC) based on the predetermined randomization list. The results of the assignment will be provided to investigators and clinical staff using e-mail, just before the start of week 1.
Assignment of interventions: Blinding
Who will be blinded {17a}
SPIRIT guidance: Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome assessors, data analysts), and how.
This is an open-label study. Blinding is not possible because of the nature of each intervention. However, the person in charge of computed sequencing randomization is independent of the study team and will not know who the participants assigned to each group are.
Procedure for unblinding if needed {17b}
SPIRIT guidance: If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant’s allocated intervention during the trial.
This study is not blinded to either the participants or investigators.
Data collection and management
Plans for assessment and collection of outcomes {18a}
SPIRIT guidance: Plans for assessment and collection of outcome, baseline, and other trial data, including any related processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known. Reference to where data collection forms can be found, if not in the protocol.
Primary and secondary outcomes will be collected according to a predefined timeline (Table 1). The data for outcome variables (total LBM from DEXA, handgrip strength, survey questionnaires for the anorexia-cachexia scale, EORTC quality of life), and the other data for clinical laboratory data or AEs will be primarily collected on the electronic medical reporting system of Kyung Hee University Hospital, which will be reviewed to enter into the electronic data capture tools of REDCap, hosted at Kyung Hee University. Data entry operators should be trained before data collection (19,20).
Plans to promote participant retention and complete follow-up {18b}
SPIRIT guidance: Plans to promote participant retention and complete follow-up, including list of any outcome data to be collected for participants who discontinue or deviate from intervention protocols.
All the research teams, including the principal investigator, medical oncologist, and other staff, will have regular meetings to inspect subjects’ compliance and IP accountability at each visit and withdrawal reasons for the subject. In particular, the staff who will contact subjects will communicate their discomfort related to the subject’s compliance, and medical oncologists and dietitians will try to alleviate expected problems for subjects, such as abdominal discomfort and dyspepsia, which can be a hurdle to participate and complete the current study.
Data management {19}
SPIRIT guidance: Plans for data entry, coding, security, and storage, including any related processes to promote data quality (eg, double data entry; range checks for data values). Reference to where details of data management procedures can be found, if not in the protocol.
Data collection will be performed according to the protocol. These data are stored and managed in the REDCap system (19,20). All data will be entered by two pre-determined staff. The quality of data will be regularly assessed by the staff and managers of the REDCap system. The developed electronic CRF in the REDCap system will automatically announce missing values and errors for values outside the predefined range. In addition, the manager will regularly export clinical data from the system to maintain data quality.
Confidentiality {27}
SPIRIT guidance: How personal information about potential and enrolled participants will be collected, shared, and maintained in order to protect confidentiality before, during, and after the trial.
All records that could identify the participants will be kept confidential. All documents related to this study, such as the patient’s information or treatment in detail, will be recorded and classified by the subject identification code (subject study number and alphabetical initials) rather than the subject’s name to protect the subject’s privacy and confidentiality. Even when the results of the clinical trial are published, the identity of the participants will be kept confidential, and only the subject’s study number or initials will be recorded when individual data of the subject is to be published or reported.
Clinical trial monitoring personnel and inspectors can view a subject’s medical records to verify the collected information. At this time, the exposed subject’s information will be handled under strict confidentiality, and the investigator will inform the subject of this fact.
Kyung Hee University Hospital will preserve and maintain the security of all data and records related to the conduct of this clinical study. The person responsible for the management and storage of the trial-related documents is the principal investigator, and access is limited to the person in charge of the study. After reporting the study results to the Institutional Review Board (IRB) of Kyung Hee University Hospital after completing the study, informed consent forms and other documents related to the study will be preserved for 3 years in accordance with the Bioethics and Safety Act in Korea.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
SPIRIT guidance: Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in the current trial and for future use in ancillary studies, if applicable.
The storage of specimens for current or future studies is not planned. All laboratory evaluations are to be performed as a blood or urine test for routine medical purposes (i.e., scheduled chemotherapy). The exceptions are plasma levels of interleukin-2, interleukin-6, and pre-albumin, which are not essential for routine clinical practice. Blood tests will be performed three times (screening, week 6, and week 13) with 5 mL of whole blood each time. No genetic or molecular analyses are planned.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
SPIRIT guidance: Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the statistical analysis plan can be found, if not in the protocol.
All data will be analyzed using SAS (version 9.4; SAS Institute Inc., Cary, NC). Primary and secondary outcomes will be described using descriptive statistics, and the assumptions of normality will be tested for all the outcome variables to apply appropriate statistical methods: parametric (two-sample t-test) or non-parametric (Wilcoxon rank sum test) method. All the outcome variables will be calculated as the change or % change from the baseline measurement, [value at pre-defined schedule (5, 6, 9, and 13 weeks) - value at 1 week] or [value at pre-defined schedule (5, 6, 9, and 13 weeks) - value at 1 week]/value at 1 week. Two primary outcomes, change in handgrip strength or change in lean body mass, will be analyzed using multiple comparison procedures (Bonferroni, Holm–Bonferroni) to control the family wise error rate.
Interim analyses {21b}
SPIRIT guidance: Description of any interim analyses and stopping guidelines, including who will have access to these interim results and make the final decision to terminate the trial.
Interim analysis is not planned for this study.
Methods for additional analyses (e.g. subgroup analyses) {20b}
SPIRIT guidance: Methods for any additional analyses (eg, subgroup and adjusted analyses).
Primary and secondary outcome values will be analyzed using an analysis of covariance (ANCOVA) model, adjusting for each measurement baseline as a covariate. In addition, subgroup analysis will be performed according to categorical variables such as sex or body mass index. In addition, the changes or % changes for the primary or secondary outcomes collected within each time point will be compared using a paired t-test or Wilcoxon signed-rank test between the MIC and CPC groups.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
SPIRIT guidance: Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any statistical methods to handle missing data (eg, multiple imputation).
Data for protocol non-adherence will be dealt with according to the statistical concept of intention-to-treat principle, which will prevent or minimize bias in the statistical analysis. Missing data will be handled based on the International Conference on Harmonization guidelines (ICH E9), entitled Statistical Principles for Clinical Trials. We will analyze the mechanism for the missing data to be handled with suitable methods (e.g., single imputation or multiple imputation, etc.) (21).
Plans to give access to the full protocol, participant level-data and statistical code {31c}
SPIRIT guidance: Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical code.
The full protocol will be available upon request to investigators.
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
Trials guidance: Provide information on the composition, roles and responsibilities of the coordinating centre and trial steering committee and all groups providing day to day support for the trial. There will always be a group running the trial day-to-day and providing organisational support and knowing how often they will meet, plus information on other committees providing oversight such as a Trial Steering Committee, and how often they will meet over the course of the trial, is what we need for item 5d. We do not need names of staff.
SPIRIT guidance: Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint adjudication committee, data management team, and other individuals or groups overseeing the trial, if applicable (see Item 21a for data monitoring committee).
Not applicable
Composition of the data monitoring committee, its role and reporting structure {21a}
SPIRIT guidance: Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of whether it is independent from the sponsor and competing interests; and reference to where further details about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not needed.
Based on the standard operating procedure of the IRB of Kyung Hee University Hospital, researchers are required to operate the data monitoring committee if the risk category is 3 (moderate risk without benefit) or higher according to the risk/benefit ratio assessment during the initial review of this study protocol. As this protocol was judged to be category 2 (more than minimal risk with possible benefit), a data monitoring committee was not mandatory.
Adverse event reporting and harms {22}
SPIRIT guidance: Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse events and other unintended effects of trial interventions or trial conduct.
Safety profiles including AEs will be checked and collected at every visit for chemotherapy. All AEs are standardized according to the CTCAE v5.0. In the case of dropout participants, safety profiles before dropout should be included in the safety analysis. The causal relationship between adverse events and interventions is determined in accordance with the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) causality assessment (22,23).
Frequency and plans for auditing trial conduct {23}
SPIRIT guidance: Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent from investigators and the sponsor.
The Kyung Hee University Hospital’s Human Research Protection Program (HRPP) system is comprised of the institutional leadership, HRPP manager, audit team, research compliance officer, quality improvement team, institutional review board, office for human research protection, and IRB steering committee (committee of conflict of interest). The IRB works with the HRPP to conduct a study site-visit audit and monitoring. Routine audits are conducted annually between March and November every year. Before conducting the audit, the auditor should carefully review the written plan for the audit target, consent form, and documents submitted to the IRB, and establish detailed audit plans. The auditor assigns an audit number to each audit according to the order of execution of the audit. The audit number shall be prepared as “Year-Audit Type + Audit Order.” At an audit initiation meeting, an auditor explains the purpose, scope, and procedure of the audit to the investigator and receives research-related documents. Based on the predefined “Study Site Visit Checklist for Kyung Hee University,” the auditor shall inspect the data that may affect the reliability and integrity of the trial, such as documents related to consent of the participants (such as consent form), suitability of the target (selected/exclusion criterion), records related to administration/application of medicines/medical devices, and items to be evaluated for primary validity/safety of the research. The auditor may secure a copy of the evidence, if necessary. A closing meeting of the audit shall be attended by an investigator in charge of the research, including a principal investigator, and an auditor who conducted the related audit of the research. The auditor shall conduct an interview with the person in charge of the relevant task at the closing meeting of the audit to check whether the findings are true. In addition, major findings and suggestions are explained verbally, and the audit results should be discussed. The auditor may reflect modifications in the audit results based on the details discussed with the investigator. If there are any lost, incomplete, or incorrect data, an investigator may submit the data to an auditor within 3 days of the audit. The auditor may check the submitted data and reflect the results of the discussion in the audit results. The auditor shall record the list of documents reviewed during the audit and the discussion with the investigators in the “Study Site Visit Checklist for Kyung Hee University.” Of note, all the processes are completely independent of the investigators and the sponsor of this study. The IRB and HRPP of Kyung Hee University Hospital are accredited by the Association for the Accreditation of Human Research Protection Programs, Inc. (AAHRPP).
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
SPIRIT guidance: Plans for communicating important protocol modifications (eg, changes to eligibility criteria, outcomes, analyses) to relevant parties (eg, investigators, REC/IRBs, trial participants, trial registries, journals, regulators).
In the event of alterations, the amended study protocol should be submitted to the IRB for review. A report of amendments made to the previously approved study protocol is requested for submission. In the report, the following items are to be included: 1) description and explanation of amendments made, 2) reason for making amendments, 3) any AEs that occurred under the original research protocol, and 4) expected AEs owing to the amendments. Because this clinical trial is conducted after obtaining approval from the Ministry of Food and Drug Safety of Korea, the amended study protocol and related documents are necessary to confirm whether the Minister of Food and Drug Safety approved the change. However, changes that do not significantly affect the safety of the subjects or the reliability of the test results can be waived.
Dissemination plans {31a}
SPIRIT guidance: Plans for investigators and sponsor to communicate trial results to participants, healthcare professionals, the public, and other relevant groups (eg, via publication, reporting in results databases, or other data sharing arrangements), including any publication restrictions.
The study results will be published in a peer-reviewed journal. Before that, the abstract of the results can be presented at an academic conference.