mFOLFOX6 Combined With Citrus Flavonoid Tablets (Aimailang) as Neoadjuvant Therapy for Locally Advanced Rectal Cancer With High YWHAB Expression: A Prospective, Multi-center, Open-Label, Randomized Controlled Phase II Clinical Trial
Phase: PHASE2
Conditions: Rectal Cancer Patients, Rectal Cancer Stage II, Rectal Cancer Stage III
Sponsor: Sixth Affiliated Hospital, Sun Yat-sen University

                                                                                                                                                                          
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Clinical Research Protocol 
 
 
mFOLFOX6 Combined with Citrus Flavonoid Tablets 
(Aimailang) as Neoadjuvant Therapy for Locally 
Advanced Rectal Cancer with High YWHAB  
Expression: A Prospective,Multi-center, Open-Label 
Project Name: 
Randomized Controlled Phase II Clinical Trial 
NCT number： 
NCT07176182 
Version 
Number: 
Version 4.1 
Release Date: 
January 22, 2026 
 
 
 
 The Sixth Affiliated Hospital of Sun Yat-sen University 
 
 Plan Signed and Approved: 

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 Protocol Summary 
Study Title 
mFOLFOX6 Combined with Citrus Flavonoid Tablets (Aimailang) 
as Neoadjuvant Therapy for Locally Advanced Rectal Cancer with 
High YWHAB Expression: A Prospective, Multi-center, Open-
Label, Randomized Controlled Phase II Clinical Trial 
Study Number 
- 
Principal 
Investigator 
Institution 
The Sixth Affiliated Hospital of Sun Yat-sen University 
Study Design 
Prospective, multi-center, open-label, randomized controlled, 
Phase II clinical trial 
Study Population 
Patients with locally advanced rectal cancer (LARC) exhibiting 
high YWHAB expression 
Study Objective 
Primary Objective: 
 Evaluate the proportion of patients with YWHAB-high LARC 
who achieve tumor downstaging to ypTNM stage 0-I after 
undergoing neoadjuvant treatment with the mFOLFOX6 
regimen plus Citrus Flavonoid Tablets (Aimailang). This will 
provide evidence-based support for the efficacy of Citrus 
Flavonoid Tablets (Aimailang) in enhancing the neoadjuvant 
therapeutic effects of the mFOLFOX6 regimen in patients with 
YWHAB-high LARC.   
Secondary Objectives: 
 Efficacy Assessment: Evaluate the pathological complete 
response rate, 3-year DFS, OS, and TRG in patients with 
YWHAB-high LARC receiving neoadjuvant mFOLFOX6 plus 
Citrus Flavonoid Tablets (Aimailang). 
 Safety Assessment: Evaluate the incidence of treatment-
related adverse events (grade 3 or higher) in patients with 

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YWHAB-high LARC receiving neoadjuvant mFOLFOX6 plus 
Citrus flavonoid tablets (Aimailang). 
Primary Endpoints 
Primary Endpoint: 
Tumor downstaging rate (ypTNM stage 0-I) following 
neoadjuvant chemotherapy across treatment groups 
Secondary Endpoint: 
 3-year disease-free survival (DFS) 
 Overall survival (OS) 
 Postoperative tumor regression grade (TRG) 
 Treatment-related adverse reaction rate (grade 3 or higher) 
Inclusion Criteria 
(1) Histopathologically 
diagnosed 
rectal 
adenocarcinoma, 
excluding all other histological types, with concomitant 
hemorrhoids as indicated by colonoscopy reports or clinical 
physical examinations. 
(2) Clinical pathological tumor stage of T3-4 or N+, M0（AJCC 
9th Edition TNM staging, Appendix 1) 
(3) Patients with rectal adenocarcinoma showing high YWHAB 
expression by immunohistochemical staining of tissue 
specimens; 
(4) Age between 18 and 75 years at the time of informed consent 
acquisition; 
(5) Eastern Cooperative Oncology Group (ECOG) performance 
status score of 0-1 (refer to Appendix 3); 
(6) No prior systemic anticancer therapy for rectal cancer, 
including cytotoxic drugs, immune checkpoint inhibitors, 
molecularly targeted therapy, or endocrine therapy; 
(7) Appropriate organ function based on the following laboratory 
values obtained during the screening period: white blood cell 
count ≥3 × 10⁹/L, neutrophil count ≥ 1.5 × 109/L, platelet 

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count ≥75×109/L, serum total bilirubin ≤1.5×upper limit of 
normal (ULN), aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) ≤2.5 ×ULN, serum creatinine ≤
1.5×ULN; 
(8) Female subjects of childbearing potential must have a 
negative serum pregnancy test within 3 days prior to starting 
study medication and must be willing to use a medically 
approved highly effective contraceptive method (e.g., 
intrauterine device, oral contraceptives, or condoms) during 
the study period and for 3 months after the last study drug 
administration; 
(9) Male subjects whose partners are women of childbearing 
potential must use effective contraception during the study 
period and for 3 months after the last study dose; 
(10) The subject has provided informed consent and signed the 
informed consent form, and is willing and able to comply with 
scheduled visits, study treatments, laboratory tests, and other 
trial procedures. 
Exclusion Criteria 
(1) Confirmed distant metastasis by whole-body CT, MR, or PET-
CT (including at least chest, full abdomen, and pelvis); 
(2) Patients with homozygous DPD enzyme deficiency or 
UGT1A1*28 genotype 7/7 as determined by whole-genome 
testing; 
(3) Patients with complete intestinal obstruction, active bleeding, 
or perforation requiring emergency surgery; 
(4) History or concurrent presence of other active malignancies 
(excluding malignancies treated curatively with no recurrence 
for over 5 years or in situ carcinomas amenable to curative 
treatment); 

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(5) Thrombotic or embolic events within 12 months prior to study 
enrollment, such as cerebrovascular accident (including 
transient ischemic attack), pulmonary embolism, or deep vein 
thrombosis; 
(6) Within 12 months prior to study enrollment, occurrence of any 
of the following: myocardial infarction, severe/unstable angina 
pectoris, NYHA Class II or higher heart failure, clinically 
significant supraventricular or ventricular arrhythmias, or 
symptomatic congestive heart failure; 
(7) Systemic antibiotic use for ≥7 days within 4 weeks prior to 
study enrollment, or unexplained fever >38.5 ° C during 
screening/before first dosing (tumor-related fever may be 
acceptable at investigator discretion); 
(8) Major surgery (e.g., laparotomy, thoracotomy, laparoscopic 
organ resection) or severe trauma within 2 months prior to 
study entry (surgical incisions must be fully healed before 
enrollment in this clinical trial); 
(9) Known human immunodeficiency virus (HIV) infection or 
acquired 
immunodeficiency 
syndrome 
(AIDS)-related 
disease; 
(10) Interstitial lung disease, non-infectious pneumonia, or 
uncontrolled systemic diseases (e.g., diabetes, hypertension, 
pulmonary fibrosis, acute pneumonia); 
(11) Untreated active hepatitis (hepatitis B, defined as HBV-DNA 
≥ 500 IU/mL; hepatitis C, defined as HCV-RNA above the 
lower limit of detection of the analytical method) or co-
infection with hepatitis B and C; 
(12) Known or suspected history of allergy to any relevant drugs 
used in the study; 

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(13) Patients deemed unsuitable for participation in this study by 
the investigator. 
Study Drugs 
Oxaliplatin, calcium folinate, 5-fluorouracil, Citrus flavonoid 
tablets (Aimailang) 
Study 
Treatment 
Regimen 
This study is a prospective, multicenter, open-label, randomized 
controlled 
Phase 
II 
clinical 
trial. 
Patients 
diagnosed 
preoperatively with YWHAB-high LARC will be enrolled. They will 
receive neoadjuvant and adjuvant chemotherapy using the 
mFOLFOX6 regimen in combination with Citrus Flavonoid 
Tablets (Aimailang). 
mFOLFOX6 regimen combined with Citrus Flavonoid 
Tablets (Aimailang) × 4-6 cycles preoperatively, with each 
treatment cycle lasting 14 days. Oxaliplatin 85 mg/m² intravenous 
infusion over 180 minutes on Day 1; Folinic acid 400 mg/m² 
intravenous infusion over 120 minutes on Day 1; 5-Fluorouracil 
2400 mg/m², continuous intravenous infusion over 46 hours; with 
or without Citrus Flavonoid Tablets (Aimailang) 500 mg, twice 
daily orally, administered on Days 1–14 of each 14-day 
cycle.Dose adjustments are permitted in this trial. Patients 
experiencing disease progression during neoadjuvant therapy 
will discontinue study treatment and proceed directly to surgery 
or receive treatment according to local guidelines. Surgery may 
also be performed earlier if patients cannot tolerate the planned 
six cycles of neoadjuvant therapy. Any patient who has received 
prior anti-cancer therapy with other regimens before surgery will 
discontinue study treatment and be managed according to the 
appropriate guidelines. Postoperative treatment for subjects in 
both groups will follow clinical practice guidelines: the Chinese 
Guidelines for Diagnosis and Treatment of Colorectal Cancer 

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(2025 Edition) and the Colorectal Cancer Diagnosis and 
Treatment Guidelines (2025 Edition) established by the Chinese 
Society of Clinical Oncology (CSCO). It is important to note that 
all patients in the control group enrolled in the trial must not take 
Citrus Flavonoid Tablets (Aimailang) without authorization during 
the trial period. If oral administration of this medication is required 
for any reason, the patient should consult their attending 
physician, who will determine whether to substitute another 
medication or discontinue the patient's participation in the trial. 
Determination 
of 
Sample Size 
The primary endpoint of this study was the tumor downstaging 
rate (ypTNM stage 0-I) across treatment groups. Based on our 
center's historical data, the tumor downstaging rate (ypTNM 
stage 0-I) following mFOLFOX6 neoadjuvant chemotherapy 
in patients with LARC was approximately 35%. Among these, 
the tumor downstaging rate in YWHAB-high LARC patients 
(approximately 1/3, n=86) receiving mFOLFOX6 neoadjuvant 
chemotherapy 
was 
around 
25%, 
while 
the 
tumor 
downstaging rate in YWHAB-low LARC patients (approximately 
2/3, n=86) receiving mFOLFOX6 neoadjuvant chemotherapy 
was approximately 43%. Our team's prior single-center, 
prospective, open-label, small-cohort exploratory trial 
revealed that the tumor downstaging rate for YWHAB-high 
LARC 
patients 
receiving 
mFOLFOX6 
neoadjuvant 
chemotherapy was approximately 25.0% (n=20, including 5 
ypTNM stage 0-I patients). The tumor downstaging rate for 
YWHAB-high LARC patients receiving mFOLFOX6 combined 
with Citrus Flavonoid Tablets (Aimailang) neoadjuvant therapy 
was approximately 42.9% (n=28, including 12 ypTNM stage 
0-I patients). The projected tumor downstaging rate for 

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YWHAB-high LARC patients receiving mFOLFOX6 combined 
with Citrus Flavonoid Tablets (Aimailang) neoadjuvant 
chemotherapy is 40%. With a one-sided significance level of 
0.05, test power of 0.8, and a 10% loss to follow-up rate, the 
estimated sample size using PASS V15 software is 236 
patients. 
Criteria 
for 
Discontinuation of 
Study Treatment 
Discontinuation of study treatment does not constitute withdrawal 
from the study. Participants discontinuing study treatment must 
continue to complete all remaining study visits as per the protocol. 
Study drug administration must be discontinued if any of the 
following occur: 
 
The subject requests discontinuation of study medication; 
 
Medical imaging or clinical symptoms indicate disease 
progression; 
 
Pregnancy occurs during the study; 
 
Any clinical adverse event, laboratory abnormality, or other 
medical condition occurs that may no longer benefit the 
subject from continued study treatment; 
 
Significant deterioration in health status rendering continued 
trial participation impossible; 
 
Significant protocol deviations identified post-enrollment, 
such as ineligibility or non-compliance; 
 
Loss to follow-up; 
 
Death of the subject; 
 
Other reasons deemed by the investigator to preclude 
continuation of study treatment. 
Criteria for Study 
Withdrawal 
Subjects may voluntarily withdraw from the trial at any time, or 
may be withdrawn by the investigator or sponsor due to safety 
concerns, behavioral issues, or inability to comply with protocol-

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specified visit schedules or procedures. Withdrawal criteria 
include: 
(1) Withdrawal of informed consent by the subject, refusal of 
further follow-up; 
(2) Occurrence of a clinical adverse event, abnormal laboratory 
findings, or concomitant disease, where the investigator 
determines continued participation is not in the subject's best 
interest; 
(3) Other circumstances deemed necessary for withdrawal by 
the investigator, such as significant protocol violations. 
(4) Death of the subject. 
Efficacy Evaluation 
(1) Tumor downstaging rate (ypTNM stage 0-I): The 
proportion of patients with locally advanced rectal cancer 
who, after receiving mFOLFOX6 or mFOLFOX6 combined 
with citrus flavonoid tablets (Aimailang) neoadjuvant 
chemotherapy, had postoperative pathological staging of 
ypTNM stage 0-I. 
(2) Degrees of Pathological Response: ① Complete Response 
(CR): All target lesions disappear, no new lesions emerge, 
tumor markers return to normal, and this state is maintained 
for at least 4 weeks. ② Partial Response (PR): The sum of 
the maximum diameters of all target lesions decreases by ≥
30%, and this state is maintained for at least 4 weeks. ③ 
Stable disease (SD): Reduction in the sum of the largest 
diameters of target lesions falls short of PR criteria, or 
increase falls short of PD criteria. ④ Progressive disease 
(PD): Increase in the sum of the largest diameters of target 
lesions ≥20%, or emergence of new lesions. 
(3) 3-year DFS: The proportion of subjects who, from study 

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enrollment to the end of the third year, did not experience any 
of the following events: disease progression, macroscopic/ 
microscopic residual tumor at surgical resection, local 
recurrence, distant metastasis, or death from any cause, 
whichever occurs first. 
(4) OS: Time from study enrollment to death from any cause. 
(5) TRG postoperatively: TRG=0 indicates no residual tumor 
cells; TRG=1 indicates a single cell or small cluster of cells; 
TRG=2 indicates residual carcinoma with a connective tissue 
proliferative reaction; TRG=3 indicates minimal evidence of 
tumor response. 
Safety Evaluation 
Treatment-Related Adverse Event Rate (Grade 3 or Higher): In 
antineoplastic drug/ treatment clinical trials, drug-related adverse 
events of Grade 3 or higher determined to be related to drug 
therapy, excluding non-specific infusion reactions. 
Planned Trial Dates 
February 2026 – February 2031 
 
1. Background 
(1) Current Research Status Domestically and Internationally 
Colorectal cancer (CRC) is the third most common malignant tumor worldwide, with 
approximately 1.8 million new cases annually, accounting for about 10% of all new 
malignancies. CRC-related deaths exceed 910,000 [1] . In recent years, both the incidence 
and mortality rates of CRC in China have been on the rise. By 2020, CRC had become the 
second most common malignancy in China, with 550,000 new cases each year, ranking fifth 
in mortality with 280,000 deaths that year [2]. The growing burden of CRC in China highlights 
significant challenges for prevention and control efforts. 
The rectum ends at the upper margin of the functional anal canal, which is defined as 
the palpable superior border of the anal sphincter and the puborectalis muscle of the 
anorectal ring. Rectal cancer refers to malignant lesions occurring in the rectum, located 

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below the imaginary line defined by MRI that extends from the sacral promontory to the 
superior margin of the dentate line. Determining the optimal treatment plan for rectal cancer 
patients is a complex process. Beyond establishing the surgical intent (i.e., curative vs. 
palliative), potential functional outcomes post-treatment must be considered, including the 
maintenance or restoration of normal bowel function, anal continence, and urogenital 
function. This is particularly challenging for patients with low rectal cancer, as achieving 
tumor eradication while minimizing the impact on quality of life presents significant 
difficulties.[3]. Furthermore, compared to colon cancer, rectal cancer patients face a higher 
risk of pelvic recurrence, and locally recurrent rectal cancer is associated with poor prognosis 
[4-6]. 
Current multimodal treatment for stage II or III rectal cancer typically includes 
preoperative fluoropyrimidine-based chemoradiotherapy, total mesorectal excision (TME), 
and postoperative adjuvant chemotherapy [7-8].The FOWARC study conducted at our center 
confirmed that compared to standard preoperative chemoradiotherapy, patients receiving 
mFOLFOX6 neoadjuvant chemotherapy showed no significant differences in tumor 
downstaging rate, DFS, local recurrence rate, or OS. However, the incidence of 
postoperative anastomotic fistula was significantly lower in the mFOLFOX6 neoadjuvant 
chemotherapy group, which also demonstrated superior anal function, effectively improving 
long-term quality of life. This indicates that mFOLFOX6 neoadjuvant chemotherapy can 
partially and selectively replace preoperative chemoradiotherapy, effectively avoiding 
radiotherapy-related adverse reactions without compromising treatment efficacy. The 
relevant research findings have been cited in the NCCN International Guidelines [9-11]. 
Studies indicate that tumor downstaging (ypTNM stage 0-I) is significantly associated with 
improved DFS in patients with locally advanced rectal cancer (LARC) receiving neoadjuvant 
therapy [9-11]. The results of the FOWARC study show that the tumor downstaging rate in 
LARC patients receiving mFOLFOX6 neoadjuvant chemotherapy is approximately 35%. This 
suggests that some patients may not respond effectively to mFOLFOX6 neoadjuvant 
chemotherapy. Identifying and selecting this population of mFOLFOX6-resistant patients, 
along with the potential for combining mFOLFOX6 chemotherapy with targeted therapy using 
relevant drugs, holds promise for improving tumor downstaging rates and prognosis in these 

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patients. 
Dysregulation of the Wnt/ β-catenin signaling pathway is closely associated with the 
initiation and progression of various cancers, particularly playing a significant role in the 
carcinogenesis and progression of CRC [2]. Proteins of the YWHA (14-3-3) family are widely 
expressed in eukaryotic cells, including seven subtypes: 14-3-3β (YWHAB), 14-3-3γ 
(YWHAG), 14-3-3ε (YWHAH), 14-3-3ζ (YWHAZ),14-3-3σ (YWHAS), and 14-3-3τ/θ (YWHAQ) 
[13]. These 14-3-3 isoforms possess highly conserved structures across species, capable of 
forming homodimers and heterodimers. They function as molecular adapters through 
protein-protein interactions [14]. As central hubs in diverse signaling pathways, 14-3-3 
proteins are implicated in numerous cellular processes, including cell cycle regulation, 
protein trafficking, apoptosis, and neuronal plasticity [13-15]. Crucially, dysregulation of 14-3-3 
proteins contributes to various diseases such as cancer, autoimmune disorders, and 
metabolic disorders [13,16].Our preliminary foundational research identified YWHAB (14-3-3β) 
amplification as a key oncogenic somatic copy number variation (CNV)-driven gene, 
associated with poor prognosis in CRC patients, suggesting its potential role as a prognostic 
biomarker. Furthermore, experimental evidence from cellular studies and mouse models 
demonstrates that YWHAB promotes CRC chemotherapy resistance by enhancing 
glycolysis and nucleotide metabolism. Mechanistically, YWHAB interacts with β-TrCP and 
competitively binds β-catenin to β-TrCP, thereby inhibiting β-TrCP-mediated β-catenin 
degradation 
[16], thus promoting CRC progression and chemotherapy resistance. 
Furthermore, through large-scale molecular structure docking and drug binding affinity 
screening, we discovered that the FDA-approved drugs hesperidin and diosmin can 
specifically block the interaction between YWHAB and β-TrCP, significantly enhancing the 
sensitivity of YWHAB-overexpressing CRC organoids and PDX models to FOLFOX therapy. 
Thus, our study elucidates the mechanism of chemotherapy resistance in YWHAB-
overexpressing CRC. YWHAB expression levels serve as a potential biomarker for predicting 
chemotherapy sensitivity in CRC patients, enabling precision chemotherapy. Blocking the 
YWHAB/ β-TrCP/ β-catenin signaling axis holds promise as a key strategy to enhance 
chemotherapy sensitivity in YWHAB-overexpressing CRC patients. 
Flavonoids are a major class of naturally occurring polyphenolic compounds found in 

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plants [17]. Previous studies have reported that flavonoids exhibit a wide range of therapeutic 
effects, including anti-inflammatory, antioxidant, and anti-hypercholesterolemic activities [18]. 
Hesperidin and diosmin are flavonoids commonly found in citrus fruits. Their molecular 
structures are highly similar, and they are well-known for their antioxidant properties, which 
help protect cells from free radical damage. Research indicates that hesperidin and diosmin 
support heart health by enhancing vascular function and reducing inflammation [18-19]. They 
have also shown benefits for the brain, liver, eyes, and other organs. Hesperidin and diosmin 
have potential therapeutic applications in anti-inflammatory, antioxidant, antitumor, and 
antibacterial treatments [20-22]. Clinical trials and practical applications have confirmed the 
therapeutic effects of hesperidin and diosmin in various diseases, including cardiovascular 
disorders, neurological conditions, type 2 diabetes, venous ulcers, hemorrhoids, metabolic 
dysfunction-associated fatty liver disease, and cancer [23]. Previous studies [23] have 
demonstrated that naringin suppresses the protein expression levels of inducible nitric oxide 
synthase (iNOS), thereby reducing the production of nitric oxide and prostaglandin E2 
(PGE2). Consequently, naringin is considered an inhibitor of cyclooxygenase-2 (COX-2) and 
iNOS, which may explain its anti-tumor and anti-inflammatory properties. A 2022 study 
identified the chemopreventive potential of naringin in 1,2-dimethylhydrazine (DMH)-induced 
colorectal cancer (CRC). In vivo, naringin prevented CRC by modulating the Smad 4 and 
activin A signaling pathways [24]. Another study reported that naringin effectively inhibited the 
incidence of azoxymethane-induced intestinal tumors in mice [25]. Our preliminary work with 
microscale thermophoresis (MST) experiments revealed a strong binding affinity between 
naringin and the YWHAB protein. Both in vitro and in vivo studies demonstrated that naringin 
and diosmin effectively inhibit the interaction between YWHAB and β-TrCP. Animal studies 
further suggest that combining citrus flavonoid tablets (Aimailang, each tablet containing 500 
mg of citrus flavonoids, comprising 90% diosmin and 10% naringin) with FOLFOX 
significantly enhances the inhibitory effect on patient-derived xenograft (PDX) tumors 
compared to FOLFOX monotherapy. The aforementioned in vivo and in vitro experimental 
results confirm that the combination of FOLFOX and Citrus Flavonoid Tablets (Aimailang) 
could serve as a potential treatment regimen for CRC patients with high YWHAB expression. 
However, this requires further validation through prospective clinical trials. 

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Although the therapeutic effects of citrus flavonoid tablets for various diseases have 
been validated in numerous clinical studies and clinical practice, most clinical trials typically 
utilize 300–600 mg of pure hesperidin as an oral supplement. However, hesperidin has low 
bioavailability due to its very low water solubility [21, 26, 27]. After careful consideration, we plan 
to use Citrus Flavonoid Tablets (Aimailang) as a substitute for citrus flavonoids in our clinical 
trials. In clinical practice, Citrus Flavonoid Tablets (Aimailang) are commonly used to treat 
various symptoms associated with venous and lymphatic insufficiency, as well as acute 
hemorrhoidal episodes. In our preliminary basic research, diosmin, naringin, and Citrus 
Flavonoid Tablets (Aimailang) were all found to effectively inhibit the interaction between 
YWHAB and β-TrCP, thereby enhancing the anti-tumor efficacy of FOLFOX. Furthermore, 
Aimailang is already used in clinical practice, and its safety has been well established. 
Therefore, based on our initial foundational research and Aimailang's established safety 
profile, using Aimailang as a naringenin substitute to investigate the neoadjuvant therapeutic 
efficacy of FOLFOX combined with Aimailang in LARC patients with high YWHAB expression 
is both safe and reasonable. 
A common strategy to enhance tumor response in patients with LARC involves 
intensifying neoadjuvant therapy by adding systemic chemotherapy before chemoradiation. 
Results from several Phase II clinical trials indicate [28-31], that administering systemic 
adjuvant chemotherapy prior to chemoradiotherapy can enhance antitumor responses in 
patients with large primary tumors adjacent to the mesorectal fascia. In these trials, the 
proportion of patients achieving a pathological complete response was slightly improved with 
the addition of systemic adjuvant chemotherapy before chemoradiotherapy. In 2004, the 
German CAO/ARO/AIO-94 clinical trial established preoperative fluorouracil infusion 
chemoradiotherapy, total mesorectal excision, and postoperative fluorouracil chemotherapy 
as the standard combination therapy for LARC [2]. In the 2015 CAO/ ARO/ AIO-04 trial [33] 
added oxaliplatin to fluorouracil-based neoadjuvant chemoradiotherapy and adjuvant 
chemotherapy, significantly improving DFS in patients with clinically staged cT3-4 or cN1-2 
rectal cancer. The regimen established by the CAO/ARO/AIO-04 trial is also regarded as a 
new treatment option for patients with LARC. Our center has conducted a series of 
prospective studies in the area of adjuvant and neoadjuvant chemotherapy for LARC, 

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including the FOWARC study. The findings from these studies have been cited multiple times 
in the NCCN guidelines [9-11]. The mFOLFOX6 dual-agent regimen (5-fluorouracil and 
calcium folinic acid combined with oxaliplatin) is a high-intensity chemotherapy protocol and 
one of the first-line treatment options recommended by guidelines such as the NCCN, ESMO, 
and CSCO for advanced CRC. However, it remains unclear whether combining mFOLFOX6 
with Aimelan can enhance treatment efficacy in patients with LARC who exhibit high YWHAB 
expression. Further clinical research is needed to confirm this. 
 
(2) Significance of the Study 
This study aims to conduct a prospective, multi-center, open-label, randomized controlled 
Phase II clinical trial. For patients with LARC, immunohistochemical staining for YWHAB will 
be performed on colonoscopic biopsy specimens to identify those with high YWHAB 
expression. These patients will be randomly assigned to receive neoadjuvant therapy with 
either mFOLFOX6 or mFOLFOX6 combined with citrus flavonoid tablets (Aimailang). After 
completing 4 to 6 cycles of neoadjuvant chemotherapy, participants will undergo a 
preoperative assessment by the attending physician, followed by tumor resection performed 
by a specialized colorectal surgical team. 
Postoperative management for both groups will adhere to clinical practice guidelines, 
including the Chinese Guidelines for the Diagnosis and Treatment of Colorectal Cancer 
(2025 Edition) and the Chinese Society of Clinical Oncology (CSCO) Guidelines for 
Colorectal Cancer Diagnosis and Treatment (2025 Edition). We will evaluate the efficacy of 
mFOLFOX6 combined with citrus flavonoid tablets (Aimailang) as neoadjuvant therapy in 
LARC patients with high YWHAB expression, assessing outcomes such as the proportion of 
patients achieving tumor downstaging, the proportion achieving pathological complete 
response, three-year DFS rate, OS, and TRG, as well as safety in terms of drug-related 
adverse reactions. 
Based on our team's prior research, animal studies, the clinical safety profile of Citrus 
Flavonoid Tablets (Aimailang), and a small-sample prospective exploratory trial of 
mFOLFOX6 combined with Citrus Flavonoid Tablets (Aimailang), this study holds promise 
for improving outcomes for patients with LARC expressing high levels of YWHAB, thereby 

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benefiting a greater number of patients. 
 
2. Study Design and Objectives 
2.1 Overall Study Design 
This study is a prospective, multicenter, open-label, randomized controlled Phase II clinical 
trial exploring the neoadjuvant treatment regimen of mFOLFOX6 combined with Citrus 
Flavonoid Tablets (Aimailang) for locally advanced rectal cancer (LARC) with high YWHAB 
expression. The study design adheres to ethical standards. 
 
2.2 Study Objectives 
Primary Objective 
This study aims to evaluate the proportion of patients achieving tumor downstaging (ypTNM 
stage 0-I) following neoadjuvant treatment with mFOLFOX6 combined with citrus flavonoid 
tablets (Aimailang) in patients with LARC who have high YWHAB expression. The goal is to 
provide evidence supporting the efficacy of Citrus Flavonoid Tablets (Aimailang) in 
enhancing the neoadjuvant therapeutic effect of the mFOLFOX6 regimen in this patient 
population.  
Secondary Objectives 
Efficacy Assessment: Determine the pathological complete response rate, three-year DFS, 
OS, and TRG in patients with LARC expressing high levels of YWHAB who receive 
neoadjuvant mFOLFOX6 combined with Citrus Flavonoid Tablets (Aimailang). 
Safety Assessment: Assess the incidence of treatment-related adverse events (grade 3 
or higher) in patients with LARC expressing high levels of YWHAB who receive neoadjuvant 
mFOLFOX6 combined with Citrus Flavonoid Tablets (Aimailang). 
 
2.3 Study Endpoints 
Primary Endpoint and Definition 
The primary endpoint of this study is the proportion of patients achieving tumor downstaging 
(ypTNM stage 0-I) following neoadjuvant treatment with mFOLFOX6 combined with Citrus 
Flavonoid Tablets (Aimailang) in patients with LARC who have high YWHAB expression. 

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This endpoint measures the tumor downstaging rate (ypTNM stage 0-I) as defined by the 
proportion of LARC patients who reach ypTNM stage 0-I based on postoperative pathological 
staging after receiving neoadjuvant chemotherapy with either mFOLFOX6 or mFOLFOX6 
combined with Citrus Flavonoid Tablets (Aimailang). 
Secondary Endpoints and Definitions: 
(1) Pathological response definitions: ① Complete Response (CR): Disappearance of all 
target lesions with no new lesions and normal tumor markers maintained for ≥4 weeks. 
② Partial Response (PR): ≥30% reduction in the sum of the largest diameters of target 
lesions maintained for ≥4 weeks.③ Stable disease (SD): Reduction in the sum of the 
largest diameters of target lesions not meeting PR criteria, or increase not meeting PD 
criteria. ④ Progression of disease (PD): Increase in the sum of the largest diameters 
of target lesions by ≥20%, or emergence of new lesions. 
(2) 3-Year DFS refers to the proportion of patients who, from the start of randomization to 
the end of the third year, did not experience any of the following events: disease 
progression, macroscopic/microscopic residual tumor at surgery, local recurrence, 
distant metastasis, or death from any cause, whichever occurs first. 
(3) OS is defined as the time from randomization to death from any cause. 
(4) TRG: TRG 0 indicates no residual tumor cells; TRG 1 indicates a single cell or small 
cluster of cells; TRG 2 indicates residual carcinoma with a connective tissue proliferation 
reaction; TRG 3 indicates minimal evidence of tumor response. 
(5) Safety measures, treatment-related adverse reaction rate (Grade 3 or higher): In 
antineoplastic drug/treatment clinical trials, drug-related adverse reactions of Grade 3 
or higher determined to be associated with drug therapy, excluding non-specific infusion 
reactions. 
 
3. Subject Selection and Withdrawal 
3.1 Inclusion Criteria: 
(1) Histopathologically diagnosed rectal adenocarcinoma, excluding all other histological 
types, with concomitant hemorrhoids indicated by colonoscopy report or clinical physical 
examination; 

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(2) Clinical pathological tumor stage of T3-4 or N+, M0; 9th Edition AJCC TNM Staging, 
Appendix 1) 
(3) Patients with rectal cancer whose tissue specimens showed high YWHAB expression 
in immunohistochemical staining; 
(4) Age at informed consent acquisition: 18–75 years; 
(5) Eastern Cooperative Oncology Group (ECOG) performance status score of 0–1 (refer 
to Appendix 3); 
(6) No prior systemic anticancer therapy for rectal cancer, including cytotoxic drugs, 
immune checkpoint inhibitors, molecularly targeted therapy, or endocrine therapy; 
(7) Appropriate organ function based on the following laboratory values obtained during the 
screening period: white blood cell count ≥ 3 × 10⁹/L, neutrophil count ≥ 1.5 × 10⁹/L, 
platelet count ≥ 75 × 10⁹/L, serum total bilirubin ≤ 1.5 × upper limit of normal (ULN), 
aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 2.5 × ULN, 
serum creatinine ≤ 1.5 × ULN; 
(8) Female subjects of childbearing potential must have a negative serum pregnancy test 
within 3 days prior to study drug initiation and must be willing to use a medically 
approved highly effective contraceptive method (e.g., intrauterine device, oral 
contraceptive, or condom) during the study period and for 3 months after the last study 
drug administration; 
(9) Male subjects with female partners of childbearing potential must use effective 
contraception during the study period and for 3 months after the last study dose; 
(10) The subject has provided informed consent and signed the informed consent form, and 
is willing and able to comply with scheduled visits, study treatments, laboratory tests, and 
other trial procedures. 
 
3.2 Exclusion Criteria:    
(1) Confirmed distant metastasis by whole-body CT, MR, or PET-CT (including at least 
chest, full abdomen, and pelvis); 
(2) Patients with homozygous DPD enzyme deficiency or UGT1A1*28 genotype 7/7 as 
determined by whole-genome testing; 

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(3) Patients with complete intestinal obstruction, active bleeding, or perforation requiring 
emergency surgery; 
(4) History or concurrent presence of other active malignancies (excluding malignancies 
treated curatively with no recurrence for over 5 years or in situ carcinomas amenable to 
curative treatment); 
(5) Thrombotic or embolic events within 12 months prior to study enrollment, such as 
cerebrovascular accident (including transient ischemic attack), pulmonary embolism, or 
deep vein thrombosis; 
(6) Within 12 months prior to study enrollment: myocardial infarction, severe/unstable 
angina pectoris, NYHA Class II or higher heart failure, clinically significant 
supraventricular or ventricular arrhythmias, or symptomatic congestive heart failure; 
(7) Systemic antibiotic use for ≥7 days within 4 weeks prior to study enrollment, or 
unexplained fever >38.5°C during screening/before first dosing (tumor-related fever 
may be acceptable at investigator discretion); 
(8) Major surgery (e.g., laparotomy, thoracotomy, laparoscopic organ resection) or severe 
trauma within 2 months prior to study enrollment (surgical incisions must be fully healed 
before enrollment in this clinical trial); 
(9) Known human immunodeficiency virus (HIV) infection or acquired immunodeficiency 
syndrome (AIDS)-related disease; 
(10) Interstitial lung disease, non-infectious pneumonia, or uncontrolled systemic diseases 
(e.g., diabetes, hypertension, pulmonary fibrosis, acute pneumonia); 
(11) Untreated active hepatitis (hepatitis B, defined as HBV-DNA ≥ 500 IU/mL; hepatitis C, 
defined as HCV-RNA above the lower limit of detection of the analytical method) or co-
infection with hepatitis B and C; 
(12) History of known or suspected allergy to any relevant drugs used in the study; 
(13) Patients deemed unsuitable for participation in this study by the investigator. 
 
3.3 Withdrawal Criteria:    
Subjects may voluntarily withdraw from the trial at any time, or may be withdrawn by the 
investigator or sponsor for safety or behavioral reasons, or for failure to comply with protocol-

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required study visit schedules or procedures. Withdrawal criteria include: 
(1) Withdrawal of informed consent by the subject, refusal of further follow-up; 
(2) Occurrence of a clinical adverse event, abnormal laboratory findings, or concomitant 
disease, where the investigator determines continued participation is not in the subject's 
best interest; 
(3) Significant deterioration in health status rendering continued participation impossible; 
(4) Occurrence of pregnancy during the study period; 
(5) Significant protocol deviations identified post-enrollment, such as ineligibility or 
noncompliance; 
(6) Loss to follow-up; 
(7) Death of the subject; 
(8) Other circumstances deemed necessary for withdrawal by the investigator, such as 
significant protocol violations. 
 
4. Study Treatment 
4.1 Study Treatment Assignment (Assignment Method: This section describes the 
assignment method used in the study. If random assignment is employed, we will detail the 
method for generating the random sequence, including the specific randomization technique 
used, any stratification factors considered, and their allocation ratios if applicable. 
Furthermore, we will outline the concealment of random assignment by detailing the 
approach taken to implement the random assignment, such as through central randomization 
or the use of sealed opaque envelopes. Blinding and Unblinding: This section will describe 
who is blinded in the study (e.g., participants, healthcare providers, outcome assessors, and 
data analysts), how the blinding is implemented, and under what circumstances unblinding 
is permitted. Additionally, we will outline the procedures for emergency unblinding that may 
occur during the study.) 
This study utilized block randomization. An independent statistician generated random 
sequences using SAS software, employing block sizes of 4 to ensure randomness and 
objectivity in group assignments. The randomization sequence was completed prior to the 

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trial's initiation and was kept confidential and secure by a third party not involved in clinical 
implementation. Subjects were randomized using a random number table method.The 
random sequence was created by the independent statistician and protected by an individual 
unrelated to the study's execution. Allocation information was sealed in opaque, sequentially 
numbered envelopes, which were opened in order by an independent individual according 
to the enrollment sequence to ensure the independence and unpredictability of the 
randomization process. Researchers gained access to assignment information only after 
subject enrollment. Although this study employed an open-label design in which both 
researchers and subjects were aware of the assignments during the intervention, strict 
allocation concealment was maintained prior to assignment to minimize the risk of selection 
bias.  
This study is a prospective, multi-center, open-label, randomized controlled Phase II 
clinical trial without blinding. It establishes two treatment arms: one for neoadjuvant therapy 
with mFOLFOX6 and another for mFOLFOX6 combined with Citrus Flavonoid Tablets 
(Aimailang). The study plans to collect endoscopic pathological biopsy specimens from 
patients with LARC for YWHAB immunohistochemical testing. Patients with LARC exhibiting 
high YWHAB expression will be identified and randomly assigned to either the mFOLFOX6 
treatment group or the mFOLFOX6 plus Citrus Flavonoid Tablets (Aimailang) treatment 
group for neoadjuvant therapy. The mFOLFOX6 regimen consists of 4 to 6 preoperative 
cycles, with each 14-day cycle including: Oxaliplatin 85 mg/m² administered via intravenous 
infusion over 180 minutes on Day 1; Folinic acid 400 mg/m² given as an intravenous infusion 
over 120 minutes on Day 1; and 5-Fluorouracil 2400 mg/m² delivered as a continuous 
intravenous infusion over 46 hours. For the Citrus Flavonoid Tablets (Aimailang) regimen, 
patients will take 500 mg orally twice daily on Days 1–14 of each 14-day cycle. 
Dose adjustments are permitted in this trial. Patients experiencing disease progression 
during neoadjuvant therapy will discontinue study treatment and either proceed directly to 
surgery or receive treatment according to local guidelines. Surgery may also be performed 
earlier if patients are unable to tolerate the planned 6 cycles of neoadjuvant therapy. Any 
patient receiving another anticancer regimen prior to surgery will discontinue study treatment 
and will be managed in accordance with local guidelines. Postoperative treatment for 

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patients in both groups will be determined by the investigator, which may include the 
continuation of mFOLFOX6 combined with Citrus Flavonoid Tablets (Aimailang). It is 
important to note that all enrolled patients in the control group must not take Citrus Flavonoid 
Tablets (Aimailang) without authorization during the trial period. If oral administration of this 
medication is necessary for any reason, the patient should consult their primary physician, 
who will decide whether to substitute it with alternative medications or discontinue the 
patient's participation in the trial. 
 
4.2 Dose Adjustment of Study Drug          
 
4.2.1 Protocol for Treatment Discontinuation or Dose Modification 
Adverse events will be continuously monitored during the study treatment, and subjects will 
be instructed to promptly notify their treating physician of any and all adverse events. For 
mild toxicities, dose adjustments or delays may be implemented if the investigator, in 
consultation with the medical monitor or sponsor, determines that this is in the subject's best 
interest. Any dosing interruption may be extended for up to 14 days to allow for recovery 
from toxicity. If recovery to the study's required dosing criteria is not achieved within 14 days, 
the trial will be discontinued. 
 
4.2.2 Criteria for Initiating the Next Treatment Cycle 
Study drug administration may commence only if all criteria listed in the table below are 
confirmed to be met on Day 1 prior to the next treatment cycle. 
 Table 1.1 Criteria for Initiating the Next Treatment Cycle 
Hemoglobin level 
 ≥ 90 g/L 
Neutrophil Count 
≥ 1.5 × 10⁹/L 
Platelet count 
 ≥ 75 × 10⁹/L 
Serum 
total 
bilirubin 
 ≤ 1.5 × UNL 
Aspartate 
aminotransferase 
 ≤ 3×ULN 

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Alanine 
aminotransferase 
 ≤ 3×ULN 
Serum creatinine 
 ≤ 1.5×ULN 
Diarrhea 
 Increase in daily stool frequency of <4 times compared to baseline 
Oral mucositis 
 Only erythema of the mucosa, without patchy ulcers or 
pseudomembrane formation 
Sensory 
Neuropathy 
 Sensory abnormalities or numbness that do not interfere with daily 
activities 
Note: If adverse reactions not listed above occur but delay the initiation of the next 
treatment cycle, the investigator shall determine whether to commence the next 
treatment cycle after the adverse reaction has resolved or improved. 
 
4.2.3 Study Drug Dose Levels 
If medically necessary, dose reductions for oxaliplatin and 5-fluorouracil may be 
implemented according to the criteria outlined in Table 1.2. Each adjustment may only 
decrease by one dose level, and the total number of dose level adjustments throughout the 
study must not exceed two. The fixed dose of leucovorin is 400 mg/m² or 7.5 mg/kg (for a 3-
week regimen). All dose level adjustments must be documented with clear justification. 
 Table 1.2 Study Drug Dose Levels 
Drug Name 
Starting Dose (mg/m²) 
Dose Level-1 
(mg/m²) 
Dose Level-2 
(mg/m²) 
Oxaliplatin 
85 
65 
50 
5-FU 
2400 
2300 
2200 
Citrus Flavonoid 
Tablets (Aimailang) 
Oral, 500mg twice daily  
Oral, 500mg 
QD  
Oral, 250mg QD 
 
4.2.4 Dose Adjustment Criteria 
Dose adjustments should be based on the severity grade (NCI CTCAE version 6.0) and the 
duration of adverse events that occur after administration in the previous treatment cycle. In 

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cases of severe hematologic and hepatic adverse events (excluding liver function impairment 
due to disease progression), the doses of oxaliplatin, 5-FU, and Citrus Flavonoid Tablets 
(Aimailang) should be reduced simultaneously. In instances of severe diarrhea and 
mucositis-related toxicity (excluding vomiting and alopecia), the doses of both 5-FU and 
Citrus Flavonoid Tablets (Aimailang) should also be reduced simultaneously. Refer to Table 
1.3 for further details. 
 Table 1.3 Dose Adjustments for Selected Adverse Events 
Adverse Event 
Severity Grade (NCI CTCAE Version 
6.0) 
Study Drug Dose 
Adjustment 
Neutropenia 
Grade 4 (<0.5 ×10⁹/L) 
Reduce dose level 
by one 
Fever associated with 
neutropenia 
Grade 
3 
or 
higher 
(ANC 
< 
1.0 
×10⁹/L,temperature ≥ 38.5°C) 
Reduce dose level 
by one 
Thrombocytopenia 
Grade 3 or higher (<50×10⁹/L) 
Reduce dose by one 
level 
Aspartate 
aminotransferase 
Grade 3 or higher (>5×ULN) 
Reduce by one dose 
level 
Aspartate 
aminotransferase 
Grade 3 or higher (>5×ULN) 
Reduce by one dose 
level 
Serum total bilirubin 
Grade 3 or higher (>3×ULN) 
Reduce by one dose 
level 
Note: If an adverse event does not meet the criteria for dose reduction but remains 
unresolved by the start of the next treatment cycle and recurs two or more times, the 
dose of the corresponding drug should be reduced by one level in accordance with the 
above guidelines. 
 
Oxaliplatin may cause characteristic neurotoxicity, primarily manifested as sensory 
neuropathy. When such severe adverse events occur, the oxaliplatin dose should be 
reduced independently. The adjustment criteria are detailed in Table 1.4. 

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 Table 1.4 Dose Adjustment for Oxaliplatin-Related Neurotoxicity 
Adverse Event 
Occurrence 
Study Drug Dose 
Adjustment 
Grade 1: Paresthesia 
or hypoesthesia, 
resolving completely 
within 1 week 
Any occurrence 
No adjustment required 
Grade 2: Paresthesia 
or hypoesthesia that 
does not resolve 
completely within 2 
treatment weeks 
Any occurrence 
Reduce dose by one level 
First occurrence 
Discontinue treatment; if 
recovery is expected in the 
next treatment cycle, 
reduce by one dose level 
Grade 3: Paresthesia 
or hypoesthesia with 
functional impairment 
Failure to recover to a Grade 2 
reaction after discontinuation of 
medication 
Permanent discontinuation 
  
4.3 Concomitant Medications and Adjuvant Therapies 
4.3.1 Prohibited Concomitant Medications and Adjuvant Therapies 
No other antitumor therapies are permitted during the study period. This includes 
chemotherapy, molecularly targeted therapy, hormone therapy, immunotherapy, biologic 
therapy, non-palliative radiation therapy, and immunomodulators (such as interferon, 
interleukin-2, and others). 
 
4.3.2 Other Antitumor Therapies and Investigational Medications 
Subjects receiving study treatment will not be allowed to undergo any other antitumor 

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therapies that are not specifically outlined in this study protocol. Other systemic antitumor 
therapies are prohibited.  
  
5. Study Process 
5.1 Screening Period 
Following informed consent, patients enter the screening phase. Endoscopic pathological 
biopsy specimens from LARC patients are collected for YWHAB immunohistochemical 
testing to identify those with high YWHAB expression, which confirms their eligibility for 
inclusion in the study. Laboratory tests and imaging assessments conducted prior to 
obtaining informed consent for routine clinical care may be used if they were performed within 
the specified time window. 
The following screening procedures must be completed within 28 days prior to initiating 
study drug treatment: 
 
Obtain signed informed consent from participants; 
 
Collect demographic data: name, gender, date of birth, height, weight, etc.; 
 
Adverse event collection: Adverse events recorded starting from informed consent 
signing; 
 
Tumor diagnosis: date of pathological confirmation, pathological grade, clinical imaging 
staging (TNM), clinical staging, etc.; 
 
Tumor treatment history; 
 
Imaging studies: Enhanced CT of chest, abdomen, and pelvis; 
 
Perform YWHAB immunohistochemical testing on pathological biopsy specimens from 
colonoscopy. 
 
(Optional) Determine KRAS mutations in tumor tissue:Exon 3 codons 59 and 61, Exon 
4 codons 117 and 146; NRAS exon 2 codons 12 and 13, Exon 3 codons 59 and 61, 
Exon 4 codons 117 and 146; and BRAF V600E gene status; 
 
(Optional) Tumor tissue MMR/MSI testing; 
 
 
The following screening should be completed within 7 days prior to initiating study drug 
administration: 
 
Body weight and ECOG performance status; 

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 
Vital signs: pulse, respiratory rate, temperature, and blood pressure; 
 
Comprehensive physical examination: general condition, head and neck, skin, lymph 
nodes, eyes, ears, nose, throat, mouth, respiratory system, cardiovascular system, 
abdomen, genitourinary system, musculoskeletal system, nervous system, and mental 
status; 
 
Complete blood count: red blood cell count, hemoglobin, platelet count, white blood cell 
count, neutrophil count, and lymphocyte differential; 
 
Urinalysis: Leukocytes, erythrocytes, proteinuria; if proteinuria ≥ 2+, add 24-hour urine 
protein quantification; 
 
Blood Biochemistry: Alanine Transaminase (ALT), Aspartate Transaminase (AST), 
Gamma-Glutamyl Transferase (γ-GT), Total Bilirubin (TBIL), Direct Bilirubin (DBIL), 
Alkaline Phosphatase (AKP), Blood Urea Nitrogen (BUN) or Urea (BUN preferred),Total 
Protein (TP), Albumin (ALB), Creatinine (Cr), Glucose (GLU), K+, Na+, Ca2+, Mg2+, 
Cl-; 
 
Tumor-associated markers; 
 
Coagulation function: Activated partial thromboplastin time (APTT), Prothrombin time 
(PT), Thrombin time (TT), Fibrinogen (FIB), International Normalized Ratio (INR); 
 
12-lead electrocardiogram: Pay attention to QT, QTc, and P-R intervals. If abnormalities 
are present, additional relevant tests may be performed at the investigator's discretion; 
 
Echocardiogram: Must include assessment of left ventricular ejection fraction (LVEF); 
 
Pregnancy test: For women of childbearing potential, using serum pregnancy testing. 
 
5.2 Treatment Period 
The treatment period extends from the administration of the subject's first dose until the 
conclusion of study treatment. The first study dose should be administered as close as 
possible to the time when screening examinations confirm eligibility criteria. All examinations 
and assessments (except for imaging studies) should be completed within 3 days prior to the 
first dose. For laboratory tests conducted on Day 1 of Cycle 1 (including complete blood 
count, urinalysis, fecal occult blood test, blood biochemistry, coagulation function, and 
thyroid function) and the electrocardiogram (ECG), repetition is not required if corresponding 

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baseline tests were performed within 7 days prior to the first dose. The following 
assessments should be completed prior to each study treatment administration: 
Body weight and ECOG performance status; 
Vital signs; 
 
Physical examination; 
 
Complete blood count: red blood cell count, hemoglobin, platelet count, white blood cell 
count, neutrophil count, and lymphocyte differential count; 
 
Blood biochemistry: alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
gamma-glutamyl transpeptidase (γ-GT), total bilirubin (TBIL), direct bilirubin (DBIL), 
alkaline phosphatase (AKP), blood urea nitrogen (BUN) or urea (preferably BUN),Total 
Protein (TP), Albumin (ALB), Creatinine (Cr), Glucose (GLU), K+, Na+, Ca2+, Mg2+, 
Cl-; 
 
Urinalysis: White blood cells, red blood cells, proteinuria; if proteinuria ≥ 2+, add 24-
hour urine protein quantification; 
 
Coagulation function: Activated partial thromboplastin time (APTT), Prothrombin time 
(PT), Thrombin time (TT), Fibrinogen (FIB), International Normalized Ratio (INR); 
 
Tumor markers; 
 
12-lead electrocardiogram: Pay attention to QT, QTc, and P-R intervals. If abnormalities 
are present, additional relevant tests may be performed at the investigator's discretion; 
 
Adverse event recording; 
 
Imaging evaluation: Conducted after completion of 6 cycles and 12 cycles of adjuvant 
mFOLFOX6 chemotherapy. Includes contrast-enhanced chest/abdominal/pelvic CT and 
pelvic MRI. Unplanned imaging may be performed for any subject suspected of disease 
progression during treatment (e.g., worsening symptoms). 
 
5.3 Treatment Completion/Study Exit Visit 
Upon completion of study treatment or study withdrawal, subjects require relevant 
assessments and examinations. The following items should be performed: 
 
Body weight and ECOG performance status; 
 
Vital signs: pulse, respiratory rate, temperature, and blood pressure; 

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 
Comprehensive physical examination: general condition, head and face, skin, lymph 
nodes, eyes, ears, nose, throat, mouth, respiratory system, cardiovascular system, 
abdomen, genitourinary system, musculoskeletal system, nervous system, and mental 
status; 
 
Complete blood count: red blood cell count, hemoglobin, platelet count, white blood cell 
count, neutrophil count, and lymphocyte differential; 
 
Urinalysis: Leukocytes, erythrocytes, proteinuria; if proteinuria ≥ 2+, add 24-hour urine 
protein quantification; 
 
Blood Biochemistry: Alanine Transaminase (ALT), Aspartate Transaminase (AST), 
Gamma-Glutamyl Transferase (γ-GT), Total Bilirubin (TBIL), Direct Bilirubin (DBIL), 
Alkaline Phosphatase (AKP), Blood Urea Nitrogen (BUN) or Urea (BUN preferred),Total 
Protein (TP), Albumin (ALB), Creatinine (Cr), Glucose (GLU), K+, Na+, Ca2+, Mg2+, Cl-; 
 
Tumor-associated markers; 
 
Coagulation function: Activated partial thromboplastin time (APTT), Prothrombin time 
(PT), Thrombin time (TT), Fibrinogen (FIB), International Normalized Ratio (INR); 
 
12-lead electrocardiogram: Pay attention to QT, QTc, and P-R intervals. If abnormalities 
are present, additional relevant tests may be performed at the investigator's discretion; 
 
Adverse events should be recorded. 
 
5.4 Follow-up Period 
Survival follow-up continues until the subject's death, loss to follow-up, withdrawal of 
informed consent with refusal to provide further information, or termination of the study by 
the sponsor. During this period, one follow-up visit should be conducted every three months 
via telephone or other effective means to collect survival information and details on 
subsequent antitumor therapy. If the subject initiates new antitumor treatment, record the 
treatment regimen along with the start and end dates. 
For subjects without radiographic evidence of disease progression, imaging 
assessments should continue at the frequency specified in this study until any of the following 
occurs: disease progression, death, loss to follow-up, withdrawal of informed consent with 
refusal to provide further information, initiation of other antitumor therapy, or termination of 

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the study by the sponsor. Efforts should be made to obtain radiographic evidence of disease 
progression for these subjects. 
 
6. Efficacy Evaluation 
6.1 Efficacy Parameters: 
The primary efficacy endpoint of this study is the proportion of patients achieving tumor 
downstaging (ypTNM stage 0-I) across treatment groups. Secondary efficacy endpoints 
include the proportion of patients achieving pathological complete response, 3-year DFS, 
OS, and TRG. 
 
6.2 Efficacy Evaluation Criteria: 
This study primarily evaluates the proportion of patients achieving tumor downstaging 
(ypTNM 0-I stage) following neoadjuvant mFOLFOX6 plus Citrus Flavonoid Tablets 
(Aimailang) in patients with LARC expressing high YWHAB. 
(1) Tumor downstaging rate (ypTNM stage 0-I): The proportion of patients with 
LARC who, after receiving mFOLFOX6 or mFOLFOX6 combined with citrus flavonoid 
tablets (Aimailang) neoadjuvant chemotherapy, achieved a postoperative 
pathological stage of ypTNM 0-I stage. 
(2) Pathological response definitions are as follows: ① Complete Response (CR): 
Disappearance of all target lesions with no new lesions and normal tumor markers 
maintained for at least 4 weeks. ② Partial Response (PR): ≥30% reduction in the 
sum of the largest diameters of target lesions maintained for at least 4 weeks.③ Stable 
disease (SD): Reduction in the sum of the maximum diameters of target lesions not 
meeting PR criteria, or increase not meeting PD criteria. ④ Progression of disease 
(PD): Increase in the sum of the maximum diameters of target lesions ≥20%, or 
emergence of new lesions. Subjects for whom the primary endpoint was not collected 
were included in the denominator of this ratio but excluded from the numerator. 
(3) When determining DFS, clinical deterioration occurring in the absence of conclusive 
evidence of disease progression according to RECIST version 1.1 does not constitute 
disease progression. For deceased subjects without prior reported progression, 

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progression is deemed to have occurred on the date of death. Subjects who neither 
experienced disease progression nor death will be censored at the date of their last 
evaluable tumor assessment. An independent central imaging review service provider 
will receive all images from the study center and assess disease progression according 
to RECIST 1.1 criteria. 
(4) Survival data recording and assessment: Disease status and survival are monitored 
every 3 months after treatment completion or study withdrawal via telephone follow-up 
until death, loss to follow-up, withdrawal of informed consent with refusal to provide 
further information, or sponsor-initiated study termination. 
(5) TRG: TRG =0 indicates no residual tumor cells; TRG =1 indicates a single cell or small 
cluster of cells; TRG =2 indicates residual cancer with a connective tissue proliferation 
reaction; TRG =3 indicates minimal evidence of tumor response. 
 
7. Safety Evaluation 
7.1 Safety Parameters 
Safety parameters in this study include clinical symptoms, vital signs, physical examinations, 
and laboratory tests (such as complete blood count, blood biochemistry, coagulation function, 
etc.). Adverse events were evaluated in accordance with the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (Version 6.0) (NCI CTCAE Version 6.0) 
(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm), 
which 
encompasses type, incidence, severity, onset and resolution times, seriousness, relationship 
to study treatment, and outcome. 
 
7.2 Definition of Adverse Events 
An adverse event is any unfavorable medical occurrence in a patient or clinical research 
subject following drug administration, not necessarily related causally to the treatment. 
Therefore, adverse events may include any adverse or unexpected signs (including 
abnormal laboratory findings) and symptoms, or diseases temporally associated with the 
use of a medical product, regardless of whether they are considered related to the study 
drug. They include, but are not limited to, the following: 

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  Exacerbation of pre-existing medical conditions/diseases (including worsening of 
symptoms, signs, or laboratory abnormalities); 
 Any new adverse medical condition (including symptoms, signs, or newly diagnosed 
diseases); 
Abnormal laboratory values or results of clinical significance. 
 
7.3 Definition of Serious Adverse Events 
A serious adverse event is any adverse medical condition occurring at any dose that meets 
one of the following criteria: 
  Fatality (resulting in death; note: death is an outcome, not an event); 
  Life-threatening (Life-threatening means the patient is at immediate risk of death at 
the time of the event, not a hypothetical risk of death if the event were more severe); 
  Requiring hospitalization or prolonging hospitalization; 
  Causing permanent or severe disability/functional impairment; 
  Congenital anomaly or birth defect; 
  Medically significant or requiring intervention to prevent any of the above 
consequences. 
Tumor progression or worsening during the study (including new metastatic sites and death 
due to disease progression) should be evaluated as part of efficacy assessment and should 
not be reported as an adverse event or serious adverse event.  
 
7.4 Definition of Serious Adverse Events 
Disease progression is defined as the worsening of the subject's condition related to the 
study indication. This includes both imaging progression and the progression of clinical 
symptoms or signs. The emergence of new metastatic lesions relative to the primary tumor 
or the progression of existing metastatic lesions is also considered disease progression. 
Events leading to life-threatening conditions, requiring hospitalization or prolonged 
hospitalization, causing permanent or severe disability, functional impairment, affecting 
work capacity, or resulting in congenital anomalies or birth defects due to symptoms and 
signs of disease progression should not be reported as serious adverse events. However, 

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death resulting from symptoms and signs of disease progression must be reported as a 
serious adverse event (SAE). 
 
7.5 Classification of Adverse Events and Serious Adverse Events 
7.5.1 Criteria for Assessing Adverse Event Severity: 
Adverse event severity will be graded using NCI CTCAE version 6.0 and reported in detail 
as required on the CRF. For adverse events not included in NCI CTCAE version 6.0, the 
following five-level grading system will be applied:  
 
Mild: No clinical symptoms or only mild clinical symptoms; only clinical or laboratory 
abnormalities; no treatment required. 
 
Moderate: Requires minor, local, or non-invasive treatment; age-appropriate limitations 
in activities of daily living, such as use of assistive devices. 
 
Severe: Significant illness or medically serious symptoms not immediately life-
threatening; leading to hospitalization or prolonged hospitalization; resulting in disability; 
limiting activities of daily living. 
 
Life-threatening: Immediate risk to life requiring urgent treatment. 
 
Death: Death related to the adverse event. 
 
7.5.2 Assessment of the Relationship Between Adverse Events and Study Treatment 
The following criteria should be used to assess the relationship between an adverse event 
and treatment: 
 
Very Likely Related (must meet the first three criteria): This category indicates adverse 
events that are considered highly likely to be related to the investigational drug. An 
adverse event may be classified as 'very likely related' if it meets the following criteria: 
1. 
The occurrence of the adverse event has a reasonable temporal relationship with the 
administration of the drug. 
2. 
The adverse event cannot be reasonably attributed to the patient's known medical 
condition, environmental or toxicological factors, or other treatments administered. 
3. 
The adverse reaction resolves or diminishes after the discontinuation or reduction of 
the dose. However, there are important exceptions where certain drug-related adverse 

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reactions may persist even after discontinuation, such as (1) bone marrow suppression 
and (2) tardive dyskinesia. 
4. 
The adverse event fits the pattern of suspected drug reactions. 
5. 
The adverse event recurs upon re-administration. 
 
Possibly Related (requires the first two criteria): This category includes adverse events 
that are unlikely to be related to the administration of the investigational drug but cannot 
be definitively ruled out. An adverse event may be classified as 'possibly related' if it 
meets the following criteria: 
1. 
The occurrence of the adverse event is reasonably timed with the administration of the 
drug. 
2. 
The adverse reaction may be attributed to the patient's disease state, environmental 
or toxic factors, or other concurrent treatments the patient is receiving. 
3. 
The adverse event corresponds to the anticipated pattern of reactions associated with 
the suspected drug. 
 
Possibly Unrelated (must fulfill the first two criteria): This category applies to adverse 
events that meet the following criteria: 
1. 
The occurrence of the adverse event does not exhibit a reasonable temporal 
relationship with the administration of the drug.  
2. 
The adverse event can be clearly attributed to the patient's disease state, 
environmental or toxic factors, or other concurrent treatments the patient is undergoing. 
3. 
The adverse event does not align with the anticipated pattern of reactions associated 
with the suspected drug.  
4. 
The adverse event does not recur or exacerbate upon re-administration of the drug. 
 
Irrelevant: This category encompasses adverse events that are clearly and 
unequivocally determined to be solely attributable to external factors (such as 
underlying disease, environmental influences, etc.) and that do not fulfill the criteria for 
drug-relatedness as defined in the categories of 'Possibly Irrelevant,' 'Possibly 
Related,' or 'Likely Related.' 
 
7.5.3. Laboratory Abnormalities 

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Laboratory test results will be documented on the Laboratory Test Data page of the Case 
Report Form (CRF). The study monitor will continuously review the entries in the CRF. Any 
laboratory test abnormality that meets the criteria for a Serious Adverse Event (SAE) should 
be reported immediately using the SAE reporting form and additionally recorded as an 
Adverse Event (AE) in the CRF. 
Laboratory test abnormalities are not required to be reported as Adverse Events (AEs) 
on the Adverse Event page of the Case Report Form (CRF) unless they fulfill any of the 
following criteria: 
 
They are accompanied by clinical manifestations; 
 
This necessitates a modification of the study medication, which may include dose 
adjustment, temporary interruption, or permanent discontinuation. 
 
This requires modification of concomitant therapy, which may include the addition of 
appropriate treatments, discontinuation of concomitant therapies or medications, or 
other adjustments. 
 
The investigator considers it to be medically significant (the investigator shall determine 
whether an isolated laboratory test abnormality can be classified as an Adverse Event 
(AE) based on scientific and medical judgment). 
 
7.6 Follow-up and Reporting of Adverse Events 
7.6.1 Collection and Follow-up of Adverse Events/Serious Adverse Events: 
The adverse event collection period commences upon the subject's signature on the 
informed consent form and concludes 30 days after the administration of the final study 
dose. 
The collection period for Serious Adverse Events (SAEs) commences upon the 
subject's signature on the informed consent form. For SAEs determined to be unrelated to 
the study drug, collection continues until 90 days after the last administration of the study 
dose or until the initiation of new antitumor therapy, whichever occurs first. Subsequently, 
only SAEs related to the study drug will be collected. 
Adverse Events (AEs) and Serious Adverse Events (SAEs) are monitored until 
resolution, improvement to baseline or a severity of ≤ Grade 1, stabilization, or a 

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reasonable explanation for their cessation (e.g., loss to follow-up, death), with the best 
possible outcome documented whenever feasible. Investigators should inquire about any 
AEs and SAEs that have occurred since the previous visit at each follow-up appointment 
and promptly provide follow-up information as requested by the sponsor in response to 
queries. 
 
7.6.2 Reporting of Serious Adverse Events: 
Throughout the study period, irrespective of the treatment administered, any Serious 
Adverse Event (SAE) or serious laboratory abnormality must be documented by the 
investigator on the Adverse Event Report Form and the CFDA Serious Adverse Event 
Report Form. Such events must be reported to the designated contact person within 24 
hours of their identification: 
Serious Adverse Event Reporting Contact:  
Principal Investigator Contact:  
Email:  
Address:  
The Serious Injury Event (SIE) reporting contact must fax the investigator-signed SIE 
report to the lead institution within one business day of receiving it from the investigator. 
This process must adhere to the International Council for Harmonisation (ICH) guidelines 
for the management of safety data in clinical trials, including definitions and standards for 
expedited reporting. 
 
7.6.3 Reporting of Non-Serious Adverse Events: 
With the exception of specific adverse events, all other non-serious adverse events should 
be documented by the investigator on the adverse event page of the Case Report Form 
(CRF) in a retrievable format. The collection period for adverse events for each patient 
extends from the date of informed consent signature to 30 days following the administration 
of the last dose. The minimum requirements for documentation on the Adverse Event Form 
(AEF) include: subject identification, the drug involved, duration of the event, onset date, 
and assessment of causality. 

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7.6.4 Follow-up for Abnormal Laboratory Findings 
In the event of clinically relevant unexplained laboratory abnormalities, repeat testing should 
be conducted immediately, with monitoring continued until the values normalize and/or a 
reasonable explanation for the abnormality is identified. If a clear explanation becomes 
available, it should be documented in the Case Report Form (CRF). 
 
7.6.5 Pregnancy Reporting 
Pregnancy must be strictly prohibited during the study period. If a female subject becomes 
pregnant during the study, study treatment must be terminated immediately, and the 
investigator must be notified without delay. Additionally, pregnancies occurring within six 
months following the completion of study treatment must also be reported to the investigator. 
All male subjects must utilize effective contraception during the study and for six 
months following the completion of the study. If a male subject's partner becomes pregnant 
during the study or within six months after the conclusion of treatment, this must be reported 
to both the investigator and the sponsor. The investigator is required to report all 
pregnancies to the sponsor within 24 hours using the Clinical Trial Pregnancy Report Form. 
Pregnancy events should be monitored until 30 days following the termination of the 
pregnancy. Pregnancy events encompass spontaneous or induced abortions, details of 
delivery, neonatal birth defects or congenital anomalies, fetal malformations and 
abnormalities in stillbirths, as well as maternal and neonatal complications. Reporting 
timelines and follow-up visits should adhere to the protocol for Serious Adverse Events 
(SAEs). 
Investigators should provide counsel to patients regarding the risks associated with the 
continuation of pregnancy and potential effects on the fetus. Patients should remain under 
observation until the completion of the pregnancy. Information regarding pregnancy 
outcomes must be reported to the sponsor. 
 
8. Safety Evaluation 
8.1 Analysis Population 

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 
Informed Consent Set (ICS): All subjects who signed an informed consent form will be 
included in this analysis set. 
 
Intention-to-Treat (ITT) Set: All randomized patients are included according to the ITT 
principle and analyzed according to the group they were assigned to at randomization. 
This set is the primary analysis set for efficacy endpoints. 
 
Full Analysis Set (FAS): All subjects enrolled and receiving at least one dose of study 
drug, determined according to the ITT principle. In FAS analyses, subjects are 
analyzed according to their assigned group at enrollment (regardless of the actual drug 
treatment received). 
 
Per-Protocol Set (PPS): Patients in the ITT set who did not experience major protocol 
deviations affecting efficacy assessment. The PPS population is used for sensitivity 
analyses of primary and key secondary efficacy endpoints. 
 
Safety Set (SS): Includes all subjects who received at least one dose of study drug. 
The SS is the primary population for safety analyses. 
 
8.2 General Analysis 
Quantitative data are summarized using the mean, standard deviation, median, maximum, 
and minimum values. Categorical data are summarized using frequency and percentage. 
For time-to-event data, Kaplan-Meier estimates are employed to calculate survival rates 
and generate survival curves. When applicable, survival curves are plotted, and the overall 
95% confidence interval for the median survival time is estimated. 
 
8.3 Efficacy Analysis and Statistical Methods 
For each treatment group, the proportion of patients achieving tumor downstaging (ypTNM 
stage 0-I), the proportion of participants with a pathological complete response, and the 
tumor regression grade (TRG) were analyzed using means and standard deviations. For 
three-year disease-free survival and overall survival, Kaplan-Meier survival curves were 
constructed, and the Brookmeyer-Crowley method was utilized to calculate the 95% 
confidence interval for the median survival time. The Log-rank test was employed to 
compare intergroup differences and to estimate hazard ratios (HR) for each endpoint based 

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on Cox proportional hazards models. Additionally, the influence of factors other than 
treatment on differences in the endpoints was explored. Furthermore, the number and 
percentage of events occurring for each endpoint, as well as the number and percentage 
of censored cases, were calculated and categorized according to the reasons for censoring. 
 
8.4 Safety Analysis and Statistical Methods 
The safety analysis will be conducted based on the safety set and will be confined to 
descriptive statistical summaries, which will include, but not be limited to, the following 
aspects. A detailed analysis will be outlined in the statistical analysis plan. 
 
Summary of adverse events (all-cause and treatment-related); 
 
Incidence and severity of adverse events (all-cause and treatment-related); 
 
Summary of details for serious adverse events; 
 
Analysis of adverse event causality; 
 
Occurrence 
of 
abnormalities 
in 
laboratory 
parameters, 
vital 
signs, 
and 
electrocardiogram data. 
The safety analysis will primarily utilize descriptive statistical summaries derived from 
the safety set. 
This study will utilize the Medical Dictionary for Regulatory Activities (MedDRA) to code 
adverse events. All adverse events occurring during the treatment period, including drug-
related adverse events, serious adverse events, and drug-related serious adverse events, 
will be summarized according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 6.0, utilizing the worst grade. Laboratory parameters collected during the 
study period will also be summarized in accordance with CTCAE version 6.0 based on the 
worst grade. 
 
8.5 Sample Size Determination 
The primary endpoint of this study was the tumor downstaging rate (ypTNM stage 0-I) across 
the various treatment groups. Based on our center's historical data, the tumor downstaging 
rate (ypTNM stage 0-I) following mFOLFOX6 neoadjuvant chemotherapy in patients with 
LARC is approximately 35%. Among these, the tumor downstaging rate in patients with high 

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expression of YWHAB (approximately one-third, n=86) receiving mFOLFOX6 neoadjuvant 
chemotherapy was approximately 25%, while the tumor downstaging rate in patients with 
low expression of YWHAB (approximately two-thirds, n=86) receiving the same treatment 
was approximately 42.9%. Our team’s previous single-center, prospective, open-label 
exploratory trial revealed a tumor downstaging rate of approximately 25.0% for YWHAB high-
expression rectal cancer patients receiving mFOLFOX6 neoadjuvant chemotherapy (n=20, 
including 5 patients with ypTNM stage 0-I). For YWHAB-high LARC patients receiving 
mFOLFOX6 combined with Aimailang neoadjuvant therapy, the tumor downstaging rate was 
approximately 42.9% (n=28, including 12 patients with ypTNM stage 0-I). The projected 
tumor downstaging rate for YWHAB-high patients receiving mFOLFOX6 combined with 
Citrus Flavonoid Tablets (Aimailang) in neoadjuvant chemotherapy is estimated to be 40%. 
The one-sided significance level is set at 0.05, the statistical power is 0.8, and the anticipated 
loss to follow-up rate is 10%. Using PASS V15 software, the estimated sample size required 
for this study is 236 patients. 
 
9. Ethical Considerations 
9.1 Local Regulations/Helsinki Declaration 
Investigators must ensure that the study is conducted in full compliance with the principles 
of the Declaration of Helsinki and the legal and regulatory requirements of the study site to 
achieve maximum protection for participants. The study must adhere rigorously to the 
principles outlined in the International Council for Harmonisation (ICH) Tripartite Guideline 
titled 'Guidance on Good Clinical Practice' (January 1997), or comply with local regulations 
that offer greater protection for subjects. In countries with Good Clinical Practice (GCP) 
requirements, researchers will strictly adhere to the relevant provisions. 
 
9.2 Good Clinical Practice 
This study will be conducted in accordance with the ethical principles outlined in the ICH 
Good Clinical Practice (GCP) guidelines. The study will be implemented as per the approved 
study protocol. The study protocol and any amendments, along with the informed consent 
form for participants, will receive prior approval or favorable review from the Institutional 

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41
Review Board/Independent Ethics Committee (IRB/IEC) before the initiation of the study. All 
serious violations must be reported immediately to the sponsor and the principal investigator. 
A serious violation is defined as a breach of GCP principles and requirements related to the 
study or protocol that may affect, or significantly affect, the safety, physical or mental health 
of study subjects, or the scientific validity of the study. Personnel involved in this study shall 
possess qualifications through education, training, and experience pertinent to their assigned 
duties. Individuals who have been subject to sanctions or who have demonstrated scientific 
misconduct or deception shall not participate in this study. Regulations and procedures will 
be implemented to ensure the integrity of all aspects of the study. 
 
9.3 Institutional Review Board/Independent Ethics Committee 
Prior to the initiation of the study, the investigator must obtain written and dated approval or 
favorable opinion documents from the Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) for the study protocol, informed consent form, and any other written 
materials provided to participants.  
The investigator or sponsor shall also submit a copy of the investigator's brochure or 
product description to the IRB/IEC, along with any updated information intended for the 
participants. Additionally, the investigator or sponsor is responsible for providing the IRB/IEC 
with relevant reports, updates, and any other information as mandated by regulatory 
requirements or institutional procedures. 
 
9.4 Informed Consent 
The investigator must ensure that the subject or his/her legally authorized representative (for 
subjects unable to sign the informed consent form personally) is clear and fully informed 
about the purpose of the trial, potential risks, and other key issues related to the clinical trial 
in which he/she is voluntarily participating.Prior to participation in this clinical study, each 
subject or their legal representative must voluntarily sign a written informed consent form, 
including consent for any screening procedures conducted to determine eligibility criteria. 
The investigator or designated personnel must explain to subjects their right to refuse 
participation or withdraw from the study at any time for any reason. 

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The rights, safety, and health of participants are the most important considerations for 
the investigator and should take precedence over the scientific and societal value of the 
research. 
 
10. Data Collection, Management, and Quality Assurance 
Study data will be recorded via CRFs, which will be transcribed from paper source 
documents by the study site. The study monitor will verify and cross-check CRFs against the 
investigator's records (source document verification) to ensure data collection accuracy and 
reliability. Source document verification will be performed for all patients observed at each 
participating site. Discrepancy reports will be generated accordingly and provided to the 
study site for investigator resolution.Additionally, CRF data will undergo ongoing review to 
ensure medical and scientific plausibility. 
 
11. Case Report Form 
The investigator shall ensure the accuracy, completeness, and timeliness of data reported 
to the sponsor in the CRF and all required reports. 
 
12. Confidentiality of Trial Documents and Subject Records 
Investigators must ensure that subject anonymity is maintained and prevent unauthorized 
parties from learning their identities. In CRFs or other documents submitted to the sponsor, 
subjects should be identified by an identification code rather than their names. Investigators 
should maintain a subject enrollment record displaying the code, name, and address. Certain 
documents, such as the subject's signed written informed consent and the subject enrollment 
record, should be kept strictly confidential at all times. 
 
13. Conditions for Protocol Amendments 
Protocol amendments may only be made following consultation between an appropriate 
representative of the sponsor and the investigator. Amendments should be drafted by a 
sponsor representative and evaluated and approved in advance by another qualified 
individual from the sponsor. All protocol amendments must be submitted to the relevant 

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ethics committee for information or approval in accordance with local procedures and 
regulations. Approval must be obtained before any changes are implemented. 
 
14. Conditions for Study Termination 
The sponsor and investigators retain the right to terminate the trial at any time. If necessary, 
both parties may arrange for the implementation of this procedure based on the specific 
circumstances of the study after review and consultation. Upon termination of the study, the 
investigator shall give full consideration to protecting the interests of the subjects. 
 
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