The Effects and Mechanisms of Short-Term Nutritional Enhancement Combined With Health Education on Clinical Outcomes in Postoperative Patients With Colorectal Cancer: A Multicenter, Open-Label, Randomized Controlled Trial
Phase: NA
Conditions: Colorectal Cancer (Diagnosis), Malnutrition or Risk of Malnutrition
Sponsor: Xiaoqin Luo

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Study Protocol 
Project Name： 
Short-Term Nutritional Enhancement Combined With 
Health Education in Postoperative Colorectal Cancer 
Patients: A Randomized Controlled Trial 
 
 
 
 
 
 
 
 
Study Institution: School of Public Health, Xi’an Jiaotong University 
NCT Number: NCT ID not yet assigned 
Protocol Version and Date: Version 1.0, October 10, 2024 
 
 
 
 
 

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Brief 
Title 
Short-Term Nutritional Enhancement Combined With Health Education in Postoperative 
Colorectal Cancer Patients: A Randomized Controlled Trial 
Official 
Title 
The Effects and Mechanisms of Short-Term Nutritional Enhancement Combined With 
Health Education on Clinical Outcomes in Postoperative Patients With Colorectal Cancer: 
A Multicenter, Open-Label, Randomized Controlled Trial 
Investig
ational 
Product 
N/A 
Clinical 
Phase 
Patients with colorectal cancer staged IIa, IIb, or IIIa without distant metastasis 
 
Study 
Objectiv
es 
Primary Objectives 
1. 
To evaluate the short-term effects of personalized nutritional enhancement 
combined with structured health education on the nutritional status of patients with 
colorectal cancer. 
This will be assessed through a comprehensive set of indicators, including laboratory 
tests, 
anthropometric 
measurements, 
psychological 
evaluations, 
dietary 
assessments, physical activity levels, and sleep patterns. Comparisons will be made 
between intervention and control groups. 
2. 
To determine the long-term impact of nutritional enhancement combined 
with health education on clinical outcomes in colorectal cancer patients. 
This will be evaluated using survival analysis and Cox proportional hazards models 
to examine overall survival, prognosis, and associated prognostic factors. 
Secondary Objectives 
1. 
To improve patients’ quality of life: 
Through nutritional intervention and health education, this study aims to enhance 
the overall quality of life of patients with colorectal cancer, reduce treatment-related 
side effects, and improve psychological well-being. 
2. 
To improve the effectiveness of oncology nutrition education: 
The study will evaluate the positive impact of nutritional education on patients’ 
nutritional status, enhance adherence and engagement with nutrition-related 
interventions, and ensure effective implementation of the intervention protocols. 
Exploratory Objectives 
1. 
To identify potential metabolism-related biomarkers: 
Using integrated metabolomics analyses, the study will investigate metabolic 

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alterations associated with colorectal cancer and aim to discover novel biomarkers 
to support individualized therapy. Specific evaluation metrics include changes in 
metabolite profiles and their correlation with clinical outcomes. 
2. 
To assess the effectiveness of Internet-based health education: 
This objective explores the efficacy of video-based and online platform-delivered 
health education in colorectal cancer patients, compared to traditional education 
formats. Evaluation tools include platform usage analytics and patient feedback 
questionnaires. 
3. 
To assess the effects of nutritional intervention on inflammation and 
immune response: 
By analyzing serum inflammatory markers and immune indicators, the study will 
evaluate the impact of nutritional intervention on systemic inflammation and 
immune function. Specific markers include C-reactive protein (CRP), leukocyte 
count, and cytokine levels. 
 
Study 
Design 
A prospective, multicenter, open-label, randomized controlled clinical trial. 
Study 
Populati
on 
Approximately 360 patients with colorectal cancer will be enrolled. 
 
 

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Resea
rch 
Proce
ss 
Participant Enrollment and Study Workflow 
Identify Potential Participants 
↓ 
Confirm Eligibility Criteria 
↓ 
Obtain Informed Consent 
↓ 
Randomization 
→ Intervention Group 
→ Control Group (Standard Care) 
 
Study Arms 
• 
Group A: Nutrition Education + Nutrition Enhancement 
• 
Group B: Nutrition Education Only 
• 
Group C: Nutrition Enhancement Only 
• 
Group D: Basic Nutrition Management (Control) 
 
Follow-up Timeline 
T0, T1, T2, T3, T6, T12 (Baseline and follow-up at months 1, 2, 3, 6, 12), annually up to 5 
years 
 
Sample and Data Collection & Mechanistic Analysis 
Metabolomic Analysis of Key Metabolites in CRC Patients 
• 
Blood sample collection and preservation 
• 
Blood serum untargeted metabolomics analysis 
1. 
Sample pre-processing 
2. 
Serum separation 
3. 
Mass spectrometry analysis 
• 
Blood serum targeted metabolomics analysis 
1. 
Raw data processing 
2. 
Pathway enrichment and differential metabolite screening 
3. 
Identification of non-targeted metabolites 
4. 
Bioinformatics analysis of key metabolites 
o Lipidomic/high-resolution targeted metabolomics 

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o Validation of differential metabolites 
Gut Microbiota and Functional Profiling in CRC Patients 
• 
Fecal sample collection and storage 
• 
Shotgun metagenomic sequencing 
1. 
DNA extraction from fecal samples 
2. 
Library construction and sequencing 
3. 
Taxonomic and functional annotation of metagenomic data 
4. 
KEGG Orthology (KO) annotation 
• 
Microbiome analysis 
o α-diversity analysis 
o β-diversity analysis 
o Taxonomic differential analysis 
o Functional pathway differential analysis 
o Visualization of microbial alterations 
 
Additional Analyses 
• 
Host-related clinical and laboratory parameter analysis 
o Inflammatory markers 
o Nutritional status 
o Physical activity and sleep assessments 
o Biochemical indicators 
o Immune cytokines 
o Clinical endpoints 
o Other disease-related parameters 
 
Integrated Analysis 
• 
Multi-omics and clinical data integration 
• 
Analysis of differences between intervention groups and the control group 
 
Participant Recruitment and Screening Procedures 
Participants will be recruited across multiple hospitals nationwide. Eligible patients will be 
identified by clinical healthcare providers based on the study's inclusion criteria. Research posters 
introducing the study will be distributed to patients. Study staff will follow up with potential 
participants to assess their interest and conduct eligibility screening. Screening may be conducted 

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either in person or via online interviews. Patients who are unable to complete the study, such as those 
planning to become pregnant, will be excluded. Online interviews will not assess adherence at this 
stage. Prior to any study-related measurements during the screening visit, all potential participants 
must provide written informed consent. After eligibility is confirmed, participants will undergo 
baseline assessments and be formally enrolled in the study. Individuals participating in the screening 
visit will not be enrolled unless explicitly authorized by the study investigators. 
Inclu
sion 
Crite
ria 
⚫ 
Signed informed consent 
⚫ 
Age ≥ 18 years 
⚫ 
Pathologically confirmed diagnosis of colon or rectal cancer 
⚫ 
Mentally alert and capable of communication 
⚫ 
Willing to participate in follow-up, with an estimated life expectancy of more than 6 months 
⚫ 
Cancer stage IIa, IIb, or IIIa 
Exclu
sion 
Crite
ria 
⚫ 
Nutritional risk screening score of mPG-SGA < 2 or NRS-2002 < 3 
⚫ 
Diagnosed with AIDS 
⚫ 
History of organ transplantation 
⚫ 
Pregnant or breastfeeding women 
⚫ 
Concurrent participation in another interventional clinical trial 
⚫ 
Inability to care for oneself independently 
⚫ 
Inability to engage in physical activity during the perioperative period 
⚫ 
Severe comorbid conditions (e.g., uncontrolled cardiovascular disease, severe hepatic or renal 
dysfunction) 
⚫ 
Known allergy or intolerance to components of the nutritional supplements used in the study 
Outc
ome 
Meas
ures 
Primary Outcomes 
1. 
Change in Nutritional Status 
The degree of improvement in nutritional status in the intervention groups compared to the 
control group, assessed by laboratory tests, anthropometric analysis, and body composition 
measurements. 
2. 
Improvement in Quality of Life 
Quality of life changes will be assessed through validated questionnaires and psychological 
evaluations, with a focus on physical function, social function, and emotional well-being. 
Secondary Outcomes 
1. 
Survival and Prognosis 
Survival outcomes and prognostic factors will be analyzed using Kaplan-Meier survival 

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curves and Cox proportional hazards models to evaluate the impact of nutritional intervention 
on long-term survival and prognosis. 
2. 
Complications and Adverse Effects 
The incidence of treatment-related complications and adverse effects will be compared 
between intervention and control groups to determine whether nutritional intervention reduces 
toxicity or other negative outcomes. 
3. 
Patient Adherence and Effectiveness of Nutrition Education 
Patient adherence to nutritional and educational interventions will be assessed, along with the 
effectiveness of educational videos and counseling in improving nutrition-related knowledge 
and behavioral changes. 
Exploratory Outcomes 
1. 
Gut Microbiota Alterations 
Metagenomic analyses will be used to evaluate the impact of nutritional intervention on gut 
microbial composition and function, and to identify key taxa associated with CRC 
progression. 
2. 
Metabolomic Profiling 
Untargeted serum metabolomics will be performed to assess the effects of nutritional 
intervention on metabolic pathways, aiming to identify novel biomarkers and metabolic 
signatures associated with outcomes. 
3. 
Mechanistic Insights via Single-Cell Analysis 
Single-cell RNA sequencing will be used to investigate how nutritional interventions 
modulate metabolic and immune pathways that influence clinical outcomes, with the goal of 
supporting personalized treatment strategies. 
 
Safet
y and 
Toler
abilit
y 
Para
meter
s 
Primary Safety Parameters 
1. 
Adverse Events (AEs) and Serious Adverse Events (SAEs): 
All AEs and SAEs during the intervention and follow-up phases will be recorded and 
evaluated, including incidence, severity, duration, and potential causal relationship to the 
intervention. 
2. 
Treatment-Related Adverse Reactions: 
Particular attention will be given to gastrointestinal symptoms, metabolic disturbances, and 
psychological burdens potentially associated with nutritional supplementation or health 
education. 
Secondary Safety Parameters 

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1. 
Changes in Laboratory Parameters: 
Regular monitoring of complete blood count, liver and renal function, and electrolyte balance 
will be conducted to assess physiological impacts of the intervention. 
2. 
Vital Signs Monitoring: 
Blood pressure, heart rate, body temperature, and other vital signs will be recorded 
periodically to evaluate the clinical safety of the intervention. 
 
Tolerability Parameters 
1. 
Patient Adherence and Acceptance: 
Adherence and acceptance will be assessed through questionnaires and interviews, capturing 
any discomfort, resistance, or compliance issues experienced during the intervention. 
2. 
Overall Tolerability of the Interventions: 
Clinical observation and patient feedback will be used to evaluate the tolerability of both the 
nutritional supplements and the health education content. 
 
Other 
Para
meter
s 
Disease Characteristics: 
• 
Type and stage of diagnosed tumor (e.g., stage IIa, IIb, or IIIa colorectal cancer) 
• 
Histopathological diagnosis 
• 
Prior cancer treatments (e.g., surgery, radiotherapy, chemotherapy) 
• 
Karnofsky Performance Status (KPS) score 
Laboratory and Anthropometric Data: 
• 
Laboratory parameters: complete blood count, liver function, renal function, 
electrolytes 
• 
Anthropometrics: height, weight, body mass index (BMI), waist circumference, hip 
circumference 
Nutritional Status Assessment: 
• 
Nutritional Risk Screening (NRS-2002) 
• 
Patient-Generated Subjective Global Assessment (mPG-SGA) 
• 
Dietary status using the Simplified Dietary Self-Assessment Tool (SDSAT) 
• 
Physical activity and sleep status (PA tool) 
Quality of Life and Psychological Status: 
• 
Quality of life assessed using the EORTC QLQ-C30 questionnaire 
• 
Anxiety and depression status assessed using the Hospital Anxiety and Depression 
Scale (HAD) 

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• 
Nutrition education compliance and dietary knowledge-attitude-practice (KAP) 
questionnaire 
- 
 
Study 
Arms 
and 
Rand
omiza
tion 
Participants will be coded sequentially according to enrollment order (e.g., 01, 02, 03…). After 
coding, participants will be stratified based on baseline nutritional status and further grouped by 
cancer stage using block randomization. A computer-generated random seed will be used to ensure 
allocation concealment. Participants will then be randomly assigned to one of four arms: 
Group A: Nutritional Enhancement + Health Education 
Participants will receive standard inpatient treatment plus personalized nutritional support based 
on calculated energy and protein requirements, designed by a multidisciplinary nutrition support 
team. Additionally, participants will receive structured health education delivered through short 
videos covering nutrition, physical activity, and psychological support. A dedicated team of experts 
will provide ongoing consultation on nutrition-related issues. 
Group B: Health Education Only 
Participants will receive standard inpatient treatment plus health education. The education 
component consists of short videos addressing nutrition, exercise, and psychological well-being. 
Content is delivered via an online platform, and expert consultation will be available for nutrition-
related questions. 
Group C: Nutritional Enhancement Only 
Participants will receive standard inpatient care along with personalized nutritional support 
designed by the nutrition support team based on individual energy and protein requirements. 
Group D: Basic Nutritional Management (Control Group) 
Participants in this group will receive standard inpatient care without additional nutritional 
support or health education. They will eat according to personal capacity and appetite. No 
individualized nutrition counseling or recommended supplementation will be provided. 
 
Study 
Inter
venti
ons 
and 
Prod
ucts 
Personalized Nutritional Support Program 
The individualized nutritional support plan for colorectal cancer patients will be tailored to each 
participant’s specific nutritional status and clinical needs. The plan will aim for ≥80% of estimated 
energy requirements, ≥80% of protein targets, and 100% of micronutrient requirements. Nutritional 
prescriptions will be developed by a multidisciplinary nutrition support team and adjusted regularly 
to maintain adherence to these targets. 
Health Education Program 

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A digital “Internet Plus” health education platform will be developed and applied to deliver 
structured health education to patients and their families. The platform will include weekly online 
videos, science-based educational articles, and interactive Q&A sessions. Content will cover 
nutrition, physical activity, and psychological support. 
The intervention will last for 12 weeks, structured as follows: 
• 
Weeks 1–4: Intensive education phase, with 6 nutrition videos, 6 exercise videos, 
and 3 psychological support videos released each week 
• 
Weeks 5–12: Maintenance phase, with one routine follow-up per week (online or 
in person) 
• 
Week 12: Comprehensive evaluation at the conclusion of the intervention 
The video content is based on the team’s published book titled "12-Week Cancer Rehabilitation: 
Nutrition, Exercise, and Psychology" (People's Medical Publishing House, ISBN 978-7-117-35805-
7). Selected content from the book has been adapted into the educational materials used in the study. 
Nutrition Monitoring and Evaluation Tools 
Standardized tools will be used to assess and monitor participants’ nutritional status and quality 
of life throughout the intervention. These include: 
• 
Patient-Generated Subjective Global Assessment (mPG-SGA) 
• 
Simplified Dietary Self-Assessment Tool (SDSAT) 
• 
Physical Activity Assessment Tool (PA) 
Biobank and Data Analysis Platform 
Blood serum and tumor tissue samples will be collected and stored to establish a biobank. These 
samples will be analyzed using metagenomic and metabolomic technologies to explore potential 
biological mechanisms and identify novel biomarkers associated with nutritional intervention. 
Clinical Trial Management System 
A dedicated clinical trial management system (CTMS) will be developed and implemented to 
ensure standardized and systematic handling of participant recruitment, randomization, data 
collection, follow-up, and data management. This system is intended to enhance operational 
efficiency and ensure the integrity and quality of research data. 
 
Study 
Phase
s 
• 
Intervention Phase: 
o Nutritional Enhancement Intervention: Conducted for 14 days post-enrollment 
o Health Education Intervention: Implemented over a 12-week period post-
enrollment 
• 
Follow-Up Phase: 

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o Follow-up assessments will be conducted at 1, 2, 3, 6, and 12 months, annually up to 
5 years after the nutritional enhancement intervention concludes. 
 
Study 
Descr
iption 
This clinical study aims to evaluate whether short-term personalized nutritional support, when 
combined with structured health education, can improve nutritional status, quality of life, and clinical 
outcomes in patients who have undergone surgery for colorectal cancer (CRC). Colorectal cancer is 
one of the most common cancers worldwide, and many patients experience malnutrition and poor 
physical condition during treatment, which can negatively affect recovery and long-term survival. 
In this multicenter, randomized, controlled clinical trial, approximately 360 postoperative CRC 
patients will be enrolled and randomly assigned to one of four groups: (A) nutritional enhancement 
combined with health education, (B) health education alone, (C) nutritional enhancement alone, or 
(D) standard care (control group). Nutritional support will include individualized diet counseling and 
oral nutritional supplements tailored to each patient's needs. Health education will be delivered using 
an “Internet Plus” approach, including weekly educational videos and expert consultations focusing 
on nutrition, physical activity, and mental health. 
The primary objectives are to determine whether these interventions can improve patients' short-
term nutritional status and quality of life. Secondary outcomes include the impact of interventions on 
long-term survival, treatment-related side effects, patient adherence to nutrition recommendations, 
and psychological well-being. 
This study will also investigate the biological mechanisms underlying the clinical effects by 
analyzing changes in the gut microbiome, blood-based metabolic profiles, and immune responses. 
Blood, stool, and tumor tissue samples will be collected and analyzed using advanced techniques, 
including untargeted metabolomics, metagenomics, and single-cell sequencing. 
This trial is designed to provide evidence for the integration of nutritional strategies into routine 
cancer care, and to guide the development of more personalized, effective nutrition-based therapies 
for colorectal cancer patients. Participants will be followed for up to annually up to 5 years to evaluate 
both clinical outcomes and biological markers of response. 
Statis
tical 
Analy
sis 
1. Sample Size 
This study plans to recruit a total of 360 patients with colorectal cancer, who will be randomly 
assigned to four groups, with 90 participants in each group. The sample size was determined based 
on both statistical power considerations and practical feasibility. 
1.1 Sample Size Calculation 
The sample size calculation was based on the following assumptions and parameters: 

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• 
Primary endpoint: improvement in nutritional status (e.g., body weight, body fat, 
muscle mass, and serum protein levels) 
• 
Effect size (δ): 0.3 
• 
Standard deviation between groups (σ): 0.6 
• 
Significance level (α): 0.05 (two-sided) 
• 
Statistical power (1–β): 80% 
Based on the calculation, at least 75 participants per group are required. To account for an 
estimated 20% dropout rate, 90 participants per group will be recruited, totaling 360 participants 
across the four study arms. 
 
2. Interim Analysis 
To ensure ethical and scientific integrity, an interim analysis will be conducted at the midpoint of 
the study. 
• 
Timing: Once all participants have completed the 6-month follow-up 
• 
Scope: Assessment of the primary endpoint (nutritional status improvement), secondary 
endpoints (quality of life, complications, adverse effects), and safety outcomes (adverse 
events and serious adverse events) 
• 
Decision Criteria: Based on the interim results, the study team will determine whether the 
observed effect size or safety profile warrants adjustments in sample size or early termination 
of the trial. If significant treatment effects or safety concerns are identified, protocol 
modifications or study cessation will be considered. 
 
3. Analysis Populations 
Three analytical datasets will be established for data evaluation: 
• 
Full Analysis Set (FAS): Includes all randomized participants who received at least one 
intervention. Analysis will follow the Intention-to-Treat (ITT) principle. 
• 
Per Protocol Set (PPS): Includes participants who strictly adhered to the study protocol and 
completed all scheduled visits and interventions. Used to evaluate the true efficacy of the 
interventions. 
• 
Safety Analysis Set (SAS): Includes all participants who received at least one intervention 
and have available safety data. Used to assess the safety and tolerability of the interventions. 

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4. Descriptive Statistics 
Descriptive statistics will summarize and present: 
• 
Demographic characteristics: age, sex, marital status, education, occupation 
• 
Baseline characteristics: body weight, mPG-SGA score, quality of life scores 
• 
Intervention data: weight changes at each visit, laboratory results, questionnaire responses 
Statistical methods will include means, standard deviations, medians, interquartile ranges, 
frequencies, and percentages as appropriate. 
 
5. Statistical Methods for Data Analysis 
Statistical methods will be selected based on the objectives and types of data collected: 
• 
Primary Endpoint Analysis: Repeated Measures ANOVA will be used to assess changes in 
nutritional status across time points and between groups. Kaplan-Meier survival analysis and 
Cox proportional hazards models will be applied to evaluate overall survival and progression-
free survival. 
• 
Secondary Endpoint Analysis: Multivariate regression analysis will be used to explore 
factors influencing quality of life, complications, and adverse effects. Categorical variables 
between groups will be compared using chi-square tests or Fisher’s exact tests. 
• 
Exploratory Endpoint Analysis: Bioinformatic tools will be used to analyze gut microbiota 
and metabolomics data. Principal component analysis (PCA) and clustering methods will be 
used to identify metabolic features and potential biomarkers. 
• 
Safety Analysis: Descriptive statistics and proportion comparisons will be applied to analyze 
the incidence of adverse events and serious adverse events. Logistic regression will be used 
to assess predictors of safety outcomes. 
• 
Data Handling and Missing Data: Multiple imputation will be employed to address missing 
data and ensure robustness of results. 
 
Princ
ipal 
Inves
tigato
r 
Team 
The study will be conducted by the team of Professor Xiaoqin Luo at the School of Public 
Health, Xi’an Jiaotong University. 
 

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Appendix 1: Roles and Responsibilities 
 
PRIMARY PROTOCOL DEVELOPMENT TEAM 
Name 
Title 
Role in the Study  
Xiaoqin Luo 
Professor 
Study design, protocol drafting and 
revision 
Hexiang Yang 
 
Study design, protocol drafting and 
revision 
Haige Cao 
 
Statistical analysis planning, protocol 
revision 
Yaxin Yu 
 
Protocol review and revision 
 
 
Study Oversight Committee 
The research team led by Professor Xiaoqin Luo at Xi’an Jiaotong University will establish the following 
committee to monitor the progress of the study and oversee data quality and integrity. 
Data Review and Monitoring Committee 
 
Position 
Role 
CS Researcher / Chief Scientist 
Chair / Lead Presenter 
CS Manager 
Committee Member 
Data Manager 
Committee Member 
Biostatistician 
Committee Member 
Statistical Programmer 
Committee Member 
Medical Monitor 
Committee Member 
Senior Methodology Lead 
Committee Member 
Scientist 
Committee Member 
 
 
 

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Appendix 2: Study Schedule of Events 
Variable 
SV 
Folllow-up 
1th 
month 
2th 
month 
3th 
month 
6th 
month 
1year 
Every 
year until 
the 
tenth 
year 
Demographic 
information 
√ 
 
 
 
 
 
 
Disease status 
√ 
 
 
 
 
 
 
KPS Scoring 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Laboratory 
examination 
√ 
 
 
 
 
 
 
Anthropometry 
√ 
 
 
 
 
 
 
Nutrition 
survey 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
EORTC QLQ 
C30 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Hospital 
anxiety and 
expression scale 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Nutrition-
Supply 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
SDSAT 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
PA 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
KAP 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Adverse Event 
Recording 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Short-Term 
Clinical Outcome 
 
√ 
√ 
√ 
√ 
√ 
√