Efficacy and Safety of Sapylin Versus Dexamethasone Atomized Inhalation for Concurrent Chemoradiotherapy-Induced Oral Mucositis in Patients With Nasopharyngeal Carcinoma: A Randomized, Parallel, Non-inferiority Clinical Trial
Phase: PHASE3
Conditions: Nasopharyngeal Carcinoma (NPC)
Sponsor: Affiliated Hospital of Guangdong Medical University

Clinical Research Project of Guangdong
Medical University Affiliated Hospital
Project Name
Efficacy and Safety of Sapylin Versus Dexamethasone
Atomized Inhalation for Concurrent Chemoradiotherapy-
Induced Oral Mucositis in Patients With Nasopharyngeal
Carcinoma: A Randomized, Parallel, Non-inferiority
Clinical Trial
Version No.
V1.1
Version Date
July 27, 2022
Principal
Investigator
Luo Haiqing
Contact
Information
Funded Amount
Funding Source
Guangdong
Medical
University
Affiliated
Hospital
Funded
Amount
500,000 RMB

Efficacy and Safety of Sapylin Versus Dexamethasone Atomized
Inhalation
for
Concurrent
Chemoradiotherapy-Induced
Oral
Mucositis
in
Patients
With
Nasopharyngeal
Carcinoma:
A
Randomized, Parallel, Non-inferiority Clinical Trial
Ⅰ. Rationale
1.Background
Nasopharyngeal
carcinoma
(NPC),
an
epithelial
malignancy
originating
from
the
nasopharyngeal mucosa, is one of the common head and neck malignancies. Globally, 70% of new
cases occur in East and Southeast Asia[1]. Nearly 80% of global patients are concentrated in China,
leading to its nickname, "China Cancer". Within China, it is highly prevalent in the southern
regions, especially the Guangdong, Guangxi areas and Hong Kong, hence the common name
"Guangdong Cancer". Currently, radiotherapy is the primary treatment modality for NPC. Seventy
percent of patients are diagnosed at an advanced stage. For Locally Advanced NPC (LA-NPC),
induction chemotherapy combined with Concurrent Chemoradiotherapy (CCRT) is the standard
treatment regimen[1,2]. Since the adoption of induction chemotherapy combined with CCRT for
LA-NPC patients, overall survival rates have improved[3,4]. However, over 20% of LA-NPC
patients still experience treatment failure and have a 5-year survival rate lower than 5 years[5].
Furthermore, during radiotherapy, the radiation causes varying degrees of damage to the normal
tissues adjacent to the tumor. Adverse reactions such as dry mouth and radiation-induced oral
mucositis can reduce patient compliance. In severe cases, these can lead to clinical adverse
outcomes such as reduced radiation dosage, treatment interruption, prolonged hospitalization, or
even life-threatening situations, thereby negatively impacting the efficacy and quality of life
associated with CCRT[6]. The INT0099 trial showed that 37% of patients receiving CCRT
terminated treatment prematurely due to excessive toxicity[7].
Among radiation-induced adverse reactions, radiation-induced oral mucositis (RIOM) occurs in
over 80% of patients undergoing radiotherapy. More than 50% of these patients even develop
Grade 3-4 RIOM[8,9]. Current clinical strategies for the prevention and treatment of RIOM include
oral care, gargling medications, nebulized inhalation drugs, and local application of epidermal
growth factor. Nebulized drug therapy has become an important method in cancer supportive care
due to its ability to increase local drug concentration, decrease blood drug concentration, and
achieve better compliance. MASCC/ISOO, ESMO, and other authoritative guidelines agree that
there is currently no specific drug for the prevention and treatment of RIOM. Treatment focuses
primarily on symptom relief and reducing complications. Epidermal Growth Factor (EGF) and
corticosteroids are recommended. However, the long-term use of corticosteroids increases the risk
of fungal infection and tends to cause radiotherapy interruptions. There is an urgent need for a
highly effective and low-toxicity drug to prevent and treat RIOM. Zhao Weiwei[10] and Chai
Xieli[11], among others, concluded from relevant domestic and international studies that nebulized

inhalation therapy is a non-invasive, highly efficient, and low-side-effect approach in oncology
treatment. However, the application of nebulized Sapylin is currently only reported in lung cancer,
and its nebulized use in CCRT for NPC is rarely reported. Therefore, nebulized drug therapy for
RIOM is one of the current research trends. Nishii et al.[12] found that local application of
corticosteroids can relieve edema, inhibit inflammation, and alleviate patient symptoms. Systemic
use of corticosteroids tends to reduce radiotherapy interruptions but does not decrease the
incidence or severity of RIOM. However, long-term local use of corticosteroids increases the risk
of oral fungal infections[12]. Nebulized traditional Chinese medicines lack multi-center clinical
trials to evaluate their efficacy[13], thus limiting their application in NPC patients. However, a safer
and more effective strategy is currently unavailable. Therefore, finding a drug with high efficacy
and low side effects to improve RIOM in NPC patients and, consequently, enhance CCRT efficacy
is crucial.
Sapylin (Group A streptococcus) is a Biological Response Modifier (BRM) with antitumor
immune effects. Its main component is a lyophilized product of Group A streptococcus treated
with penicillin. It effectively inhibits cancer cell proliferation, significantly enhances immune
function, and increases the activity of various immune cells. It is widely used clinically to boost
the immunity of cancer patients[14,15]. In recent years, Sapylin has been used as an immune
adjuvant in various cancers, such as lung cancer[16-18], breast cancer[19], gastric cancer[20], and
bladder cancer[21]. It has been shown to promote wound healing, enhance the efficacy of
chemotherapy, and inhibit tumor cell proliferation. However, its role in tumor radiotherapy and its
application in NPC patients are rarely reported. Sapylin (OK-432) is considered an adjuvant in
cancer immunotherapy and has proven non-specific immune anti-tumor function. Additionally,
Sapylin is believed to improve pleural fluid osmotic pressure and effectively reduce pleural
effusion in some benign pulmonary diseases. To evaluate the effect of Sapylin on surgical
treatment and immune function regulation in patients with thoracic malignancies, Tian et al.[22]
investigated the clinical data of 71 patients who received Sapylin in the surgical area shortly after
surgery. Local intraoperative application of Sapylin (OK-432) was found to enhance early
postoperative immune function in patients with thoracic malignancies, promote postoperative
recovery, and improve prognosis. This implies it can reduce postoperative chest drainage, shorten
intubation and hospital stay, and decrease patient suffering. The conventional routes of Sapylin
(OK-432) administration are intramuscular and subcutaneous injection, which can cause injection
site pain and fever. Nebulized inhalation of Sapylin is non-invasive, highly efficient, and has low
side effects. Moreover, it can exert its effects in improving RIOM and its antitumor activity by
enhancing cellular immunity. This approach may be a safe and effective method for LA-NPC
patients receiving induction chemotherapy combined with CCRT. This study is the first
prospective, randomized controlled trial to evaluate the incidence rate, severity, efficacy, and
survival analysis of RIOM in NPC patients receiving CCRT combined with nebulized Sapylin
versus CCRT combined with nebulized Dexamethasone. It aims to provide innovative research
evidence for the correct use of Sapylin in LA-NPC patients. This study provides scientific
evidence for a prospective randomized investigation into whether nebulized Sapylin can reduce
the incidence and severity of RIOM in LA-NPC patients.
2. Current Status of Domestic and International Research
(1) Current status of concurrent chemoradiotherapy for locally advanced NPC

Studies over the past 20 years indicate that concurrent chemoradiotherapy (CCRT) plays a crucial
role in the treatment of LA-NPC. Both clinical studies and meta-analyses have confirmed that
induction chemotherapy combined with CCRT offers significant survival benefits compared to
radiotherapy alone, especially for patients with locally advanced disease. A Phase III clinical study
enrolled 284 patients with Stage III and IV NPC without distant metastasis, randomly assigning
them to a radiotherapy-alone group or an induction chemotherapy combined with CCRT group.
The results showed that the locoregional failure rate and distant metastasis rate in the CCRT group
were significantly lower than those in the radiotherapy-alone group. Furthermore, the 5-year
nasopharyngeal failure-free survival rate (89.3%), failure-free survival rate (71.6%), and overall
survival rate (72.3%) in the induction chemotherapy combined with CCRT group were
significantly higher than those in the latter, with only a mild increase in Grade 3/4 acute
toxicities[23]. A Phase III clinical study conducted by Chan et al.[24] reached similar conclusions,
showing that the 5-year OS of the concurrent group was significantly higher than that of the
radiotherapy-alone group, with a hazard ratio for death of 0.71, which further decreased to 0.51 in
the T3-4 subgroup analysis. A meta-analysis comparing induction chemotherapy combined with
CCRT versus radiotherapy alone (including a total of 1608 patients) showed that the relative risks
(RRs) for death at 2, 3, and 5 years in the induction chemotherapy combined with CCRT group
were [0.63, 95% CI (0.50–0.80)], [0.76, 95% CI (0.61–0.93)], and [0.74, 95% CI (0.62–0.89)],
respectively
[25]. Currently, induction chemotherapy combined with CCRT has become the
standard treatment model for LA-NPC. The latest NCCN guidelines recommend induction
chemotherapy combined with CCRT as one of the standard treatment regimens for LA-NPC[26].
However, studies have shown that CCRT is associated with higher toxicity compared to
radiotherapy alone, and these toxicities can reduce patient compliance and treatment efficacy. Liu
et al.[27] comprehensively analyzed 2605 patients across 8 studies and found that in the era of
Intensity-Modulated Radiation Therapy (IMRT), the efficacy of induction chemotherapy
combined with CCRT was comparable to that of induction chemotherapy combined with
radiotherapy alone, but induction chemotherapy combined with CCRT had a higher incidence of
Grade 3/4 toxicities during radiotherapy. Therefore, in the IMRT era, induction chemotherapy
combined with CCRT might be replaced by new treatment mode combinations. Currently, several
ongoing prospective randomized clinical studies are comparing the efficacy of induction
chemotherapy combined with CCRT against other comprehensive treatment modes that do not
utilize induction chemotherapy combined with CCRT under the premise of using IMRT
technology, and the results are eagerly anticipated. Additionally, radiation-induced toxicity
remains one of the primary reasons affecting the therapeutic efficacy and quality of life of LA-
NPC patients; reducing the incidence and severity of toxicity has become an urgent topic in
current research.
(2) Research progress on the treatment of radiation-induced oral mucositis
Due to the high incidence and pathogenesis of RIOM, the Mucositis Study Group of the
Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology
(MASCC/ISOO) released updated clinical practice guidelines for mucositis in 2020[28].
Subsequently, ESMO also updated its guidelines for the prevention and treatment of RIOM[29]. In
China, the Radiation Oncology Branch of the Chinese Medical Association released the Expert
Consensus on Prevention and Treatment Strategies for Radiation-Induced Oral Mucositis in
2019[13]. Clinical practice guidelines and expert consensus believe that: prevention is the priority

for RIOM, with good oral hygiene environment and care being the primary preventive measures;
there is currently no specific drug for the prevention and treatment of RIOM, and treatment mainly
lies in alleviating symptoms and reducing the occurrence of complications. Nutrition support, pain
control, and the prevention and treatment of secondary infections are considered the cornerstones
of RIOM management. The guidelines and consensus list drugs currently used domestically and
internationally for the prevention and treatment of RIOM, such as analgesics, Epidermal Growth
Factor (EGF), corticosteroids, Amifostine, and Leucogen, but analgesics have drawbacks such as
short duration of action and significant side effects. Nishii et al.[12] found that local use of
corticosteroids can reduce edema, inhibit inflammatory responses, and alleviate patient symptoms,
but long-term use increases the risk of oral fungal infections; while systemic use of corticosteroids
has a trend of reducing radiotherapy interruptions, it does not reduce the incidence and severity of
RIOM. Nicolatou-Galitis et al.[30] found that when Amifostine is administered intravenously, there
are side effects such as hypotension, nausea, and infusion-related reactions, whereas subcutaneous
injection 60 minutes before radiotherapy in head and neck cancer patients, although significantly
reducing side effects, lowers efficacy and compliance. Furthermore, due to inconsistent
conclusions across studies and insufficient evidence levels, the guidelines and consensus do not
yet recommend recombinant human granulocyte-macrophage colony-stimulating factor (GM-
CSF), glutamine, and supersaturated calcium phosphate mouthwashes for the prevention of RIOM,
nor do they recommend the local prophylactic use of antibiotics and hormones[13,31,32].
Therefore, the Chinese expert consensus on prevention and treatment strategies for radiation-
induced oral mucositis believes that although much research has been conducted on the prevention
and treatment of RIOM, many prevention and treatment strategies remain controversial due to the
lack of large-scale multicenter randomized controlled trials. It looks forward to carrying out big
data analysis of multicenter symptom management, with a view to discovering more complete risk
factors for RIOM and finding safer and more effective prevention and treatment strategies[33],
thereby improving the efficacy of concurrent chemoradiotherapy in patients with NPC.
(3) Research progress on the role of Sapylin in cancer
Currently, many studies have proven that Sapylin, as an immune adjuvant, has demonstrated
definite efficacy and good prospects in various cancers, such as lung cancer [16-18], breast cancer [19],
gastric cancer[20], and bladder cancer[21]. Xie Chuanhua[16], Zhang Lin[17], Li Xuezhen[18], and
others observed the efficacy of nebulized Sapylin combined with chemotherapy in the treatment of
advanced non-small cell lung cancer (NSCLC) and found that nebulized Sapylin inhalation can
improve chemotherapy efficacy and the body's immune function without obvious side effects.
Yano et al.[31] found through basic in vitro experiments that the cytotoxic effect of OK-432 on lung
cancer cell lines increased in a dose-dependent manner and induced alveolar macrophages to
produce various cytokines, namely IL-1, Tumor Necrosis Factor-α (TNF-α), and IL-6. Based on in
vitro experiments, they subsequently treated 6 patients with bronchioloalveolar carcinoma with
pulmonary metastasis via nebulized OK-432 inhalation and found that no adverse reactions were
observed in any patients, and the production of TNF-α by alveolar macrophages or anti-tumor
cytotoxic activity was enhanced; however, the clinical efficacy of nebulized Sapylin on
bronchioloalveolar carcinoma still requires further study. Zhang[21] et al. treated the lung cancer
cell line A549 with different concentrations of Sapylin and detected the proliferation, apoptosis,
and signaling pathway expression of A549 cells. They found that Sapylin promoted apoptosis in a
dose- and time-dependent manner and inactivated the PI3K/AKT and WNT3a/β-catenin signaling

pathways, suggesting that Sapylin has the effect of inhibiting lung cancer cell proliferation and
promoting apoptosis. In addition, Li Dong et al.[18], through a retrospective analysis of 100 lung
cancer patients with pleural effusion, found that intrapleural perfusion of Sapylin can reduce
malignant pleural effusion, lower the levels of cellular inflammatory factors and tumor markers in
serum and pleural effusion, and alleviate the toxicity of single-agent Cisplatin perfusion
chemotherapy. Kong[19] et al. included 120 patients undergoing modified radical mastectomy for
breast cancer in a prospective continuous cohort study and proved that Sapylin can stimulate the
body to secrete various cytokines and promote wound healing. Studies abroad have also shown
that the in vivo and in vitro application of the streptococcal preparation OK-432 can induce the
production of tumor growth inhibitory factors in human monocytes[32]. Similar to the above results,
Ono et al.[33] found through in vitro cell experiments that the streptococcal preparation can inhibit
nucleic acid synthesis in tumor cells, thereby exerting an anti-tumor effect. Therefore, studying the
effect of Sapylin on patients with NPC and evaluating its safety has important clinical significance.
Previously, through extensive literature review, we found that while Sapylin administered via
traditional methods can reduce malignant pleural effusion and improve immunity in cancer
patients, patients experience reactions such as injection site pain and fever. In contrast, the
nebulized inhalation method is not only safe and effective but also improves the patient's
immunity, inhibits tumor cell proliferation, and enhances the efficacy of tumor chemotherapy
drugs. Furthermore, we have currently collected 32 clinical cases (16 cases in the CCRT + Sapylin
group, 16 cases in the CCRT + Dexamethasone group). The results revealed that nebulized
Sapylin inhalation can improve the efficacy of CCRT and prolong patient survival, improve the
incidence and severity of RIOM in NPC patients, and show no obvious toxic side effects.
However, the application of nebulized Sapylin in cancer treatment is currently only seen in lung
cancer studies both domestically and internationally. Whether its application in NPC patients can
improve the efficacy of concurrent chemoradiotherapy and what its safety profile is like are rarely
reported domestically or internationally and require further research and exploration. Therefore,
we intend to explore the impact of Sapylin on the efficacy of concurrent chemoradiotherapy and
the incidence and severity of RIOM in NPC patients via nebulized inhalation, aiming to find a
highly efficient, low-toxicity method for NPC specialists and patients that can reduce the
occurrence and severity of RIOM and improve the efficacy of CCRT.
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II. Research Content
1. Research Objectives and Significance
1.1 Research Objectives
(1) Primary Objective: The primary objective evaluated will be the incidence and severity of
RIOM.
(2) Secondary Objectives: Secondary objectives include the duration of RIOM, the completion
rate of the planned treatment regimen, the incidence and severity of adverse events as graded by
CTCAE V5.0, as well as changes in body mass index (BMI).
1.2 Research Significance

This study intends to explore the impact of nebulized Sapylin inhalation on the therapeutic
efficacy of CCRT in patients with NPC via nebulized inhalation, observe the effect of nebulized
Sapylin inhalation on the incidence and severity of RIOM, and evaluate the safety of nebulized
Sapylin inhalation. This study aims to find a highly efficient and low-toxicity method for NPC
specialists and patients to reduce the occurrence and severity of RIOM and improve the efficacy of
CCRT.
2. Research Goals and Content
2.1 Research Goals
The purpose of this study is to investigate the effects of atomized inhalation of Sapylin versus
Dexamethasone on the incidence and severity of RIOM, and to further evaluate the safety and
effectiveness of aerosol inhalation of Sapylin and Dexamethasone in NPC patients receiving
CCRT. This study will provide NPC specialists and patients with an efficient and low-toxicity
method to reduce the occurrence and severity of RIOM and improve the efficacy of CCRT.
2.2 Research Content
Under the guidance of Randomized Controlled Trial (RCT) principles, patients will be divided
into an experimental group and a control group. Patients will receive standardized treatment using
the designed clinical treatment protocol, changes in patients' clinical observation indicators during
treatment will be recorded, and follow-up records will be made according to the scheduled time to
collect clinical data. Using statistical methods for comprehensive analysis, the results of this study
will provide scientific research evidence for exploring methods to improve the occurrence and
severity of RIOM and enhance the efficacy of CCRT.
3. Research Protocol
3.1 Study Design Type
Non-inferiority, parallel-design, randomized controlled clinical study.
3.2 Research Methods
(1) Incidence and Severity of RIOM
Guided by the principles of RCT, this study provides scientific research evidence to explore
methods for improving the occurrence and severity of RIOM and enhancing the efficacy of CCRT.
Specialized clinicians will observe whether patients develop RIOM and assess its severity during
daily rounds, recording these in the progress notes. Grading will be performed using the WHO
oral toxicity scale. The incidence and severity of RIOM will be statistically analyzed after the
completion of concurrent chemoradiotherapy.
(2) Duration of Radiation-Induced Oral Mucositis (RIOM)
The duration of Radiation-Induced Oral Mucositis (RIOM) will be calculated from the day of
its initial diagnosis (any grade) until the day it resolves to Grade 0 or baseline level, with this
duration being assessed and documented daily in the medical records by the attending clinician
during ward rounds.
(3) Completion Rate of Treatment Modalities
The completion rate of treatment modalities will be determined by recording the actual

administered dose and number of cycles of concurrent chemoradiation therapy (CCRT) versus the
planned total regimen; this rate is calculated as two ratios: the actual administered dose divided by
the planned total dose, expressed as a percentage, and the actual completed cycles divided by the
planned total cycles, also expressed as a percentage.
(4) Adverse Events (AEs)
All observed adverse events (AEs) will be recorded and graded daily by the clinician based on
patient complaints, physical examination, and laboratory test results, according to the Common
Terminology Criteria for Adverse Events (CTCAE) version 5.0 published by the National Cancer
Institute (NCI).
(5) Change in Body Mass Index (BMI)
Patient height and weight will be measured by the nursing staff at a fixed time using the same
calibrated instrument at two time points—before the initiation of CCRT (baseline) and upon
completion of treatment—with the resulting BMI (kg/m2) difference (post-Treatment BMI-
Baseline BMI) constituting the change in BMI.
3.3 Inclusion and Exclusion Criteria and Sample Size Estimation
(1) Patient Selection: Meeting the diagnostic criteria for NPC; patients who have not yet received
concurrent chemoradiotherapy; meeting the case inclusion and exclusion criteria; patients
voluntarily joining this clinical trial and signing the informed consent form.
(2) Sample Size Estimation: The Delphi method is used to determine the non-inferiority margin of
the observation endpoint. After consulting senior oncology practitioners, we defined an 8%
reduction in the incidence of RIOM as a clinically acceptable non-margin of error. Under the
conditions of test level a=0.05 and test efficacy 1-β=0.9, the proportion of cases in the two groups
is 1:1. Using the module of non-destructiveness Tests for Two Proportions in PASS 15.0 statistical
analysis software, we determined that a sample size of 81 was required per group. Considering a
10% loss to follow-up rate, we estimated that 90 cases would be required in each group, for a total
of 180 cases.
3.4 Randomization Method
This study employs a block randomization method. Random sequences are generated by
independent statistical personnel who are not involved in clinical procedures, utilizing statistical
software. After
patient enrollment, the research personnel access a centralized remote
randomization system to obtain the patient's treatment assignment result, thereby allocating
patients to either the Sapylin group or the Dexamethasone group at a 1:1 ratio. This procedure
ensures the separation of random sequence generation and execution, maximizing the randomness
and concealment of the allocation.
3.5 Clinical Treatment Protocol
(1) Experimental Group
Concurrent
Radiotherapy
Dose:
Nasopharyngeal
primary
tumor
site
(PTVnx):
69.96Gy/2.12Gy/33F; High-risk planning target volume (PTV1): 60.06Gy/1.82Gy/33F; Low-risk

planning
target
volume
(PTV2):
54.12Gy/1.64Gy/33F;
Cervical
lymph
nodes
(PTVnd):
66~69.96Gy/2~2.12Gy/33F; 5 times per week, for a total of 6-7 weeks.
Concurrent Chemotherapy: Cisplatin (80-100 mg/m2, Q3W, 3 times during CCRT); Sapylin: 1
KE/time, nebulized, QD, starting from Day 1 of CCRT until the end of radiotherapy.
(2) Control Group:
Concurrent
Radiotherapy
Dose:
Nasopharyngeal
primary
tumor
site
(PTVnx):
69.96Gy/2.12Gy/33F; High-risk planning target volume (PTV1): 60.06Gy/1.82Gy/33F; Low-risk
planning
target
volume
(PTV2):
54.12Gy/1.64Gy/33F;
Cervical
lymph
nodes
(PTVnd):
66~69.96Gy/2~2.12Gy/33F; 5 times per week, for a total of 6-7 weeks.
Concurrent
Chemotherapy:
Cisplatin
(80-100mg/m2,
Q3W,
3
times
during
CCRT);
Dexamethasone: 10mg/time, nebulized, QD, starting from Day 1 of treatment until the end of
radiotherapy.
3.6 Patient Follow-up
(1) Observation and follow-up personnel will conduct patient follow-up via outpatient visits,
telephone tracking, home visits, etc., to observe and evaluate the patient's RIOM grading, adverse
effects, and weight changes
(2) Follow-up time requirements: The follow-up duration is set at 3 months, with assessments
once a month.
4.Research Design
Study Period
Key Responsibilities
Jul 2022 - Jun 2024
1.Initiate recruitment;
2.Screen
eligible
NPC
cases,
determine
baseline data and collect indicators, perform
randomization, and complete the enrollment of
the expected sample size; it is planned to recruit
90
patients
in
the
2
years
(45
in
the
experimental group, 45 in the control group)
and conduct follow-up observations on these
subjects;
3.Follow up each enrolled case for 1 year;
4.The enrolled cases will proceed according to
the
trial
steps
designed
for
each
group,
including
patient
follow-up,
disease
assessment,
and
indicator
collection
and
follow-up.
Jul 2024 - Jun 2026
1.
Screen
eligible
NPC
cases,
determine
baseline data and collect indicators, perform
randomization, and complete the enrollment of
the expected sample size; it is planned to recruit
90 patients in the second 2 years period (45 in
the experimental group, 45 in the control
group);
2. Follow up each enrolled case for 1 year, and
perform data registration and statistics;
3. The enrolled cases will proceed according to
the
trial
steps
designed
for
each
group,
including
patient
follow-up,
disease
assessment,
and
indicator
collection
and
follow-up.

Jul 2026 - Jul 2027
1. Statistical analysis, thesis writing, domestic
and international exchange, and promotion
application.
5. Study Subjects
Observe the data of NPC patients with complete clinical and pathological data who underwent
concurrent chemoradiotherapy at the Head and Neck Tumor Ward of the Cancer Hospital of the
Affiliated Hospital of Guangdong Medical University between July 2022 and July 2026.
6. Evaluation Indicators
(1) Primary Evaluation Indicator: Incidence and severity of RIOM.
(2) Secondary Evaluation Indicators: ①Duration of RIOM; ②Rate of completion of treatment
measures; ③Adverse events classified according to CTCAE 5.0; ④Changes in BMI.
Adverse Event (AE) Any untoward medical occurrence in a subject during the clinical trial,
which does not necessarily have a causal relationship with the treatment. An adverse event can be
any unfavorable and unintended sign (including abnormal laboratory findings), symptom, or
temporary illness associated with the use of the drug, whether or not related to the drug.
Serious Adverse Event (SAE) All serious adverse events occurring during the clinical trial
must be recorded in the Serious Adverse Event (SAE) report. The occurrence of any of the
following conditions should be considered a serious adverse event:
①Results in death;
②Is life-threatening;
③Requires inpatient hospitalization or prolongation of existing hospitalization;
④Results in persistent or significant disability/incapacity;
⑤Results in a congenital anomaly or birth defect;
⑥Other.
Causality Assessment of Adverse Events While recording in detail any abnormal symptoms,
signs, laboratory tests, or other special examinations occurring during the clinical study, a
causality assessment should be performed. According to the criteria for adverse reaction/event
analysis, the causality assessment is classified as: 1-Definitely related; 2-Probably related; 3-
Possibly related; 4-Probably unrelated; 5-Definitely unrelated.
①Is there a reasonable temporal relationship between the start of medication and the
appearance of the suspected adverse reaction?
②Does the suspected adverse reaction fit the known adverse reaction profile of the drug? ③
Can the suspected adverse reaction be explained by the effects of concomitant medications, the
patient's clinical condition, or other therapies?
④Does the suspected adverse reaction disappear or alleviate after stopping or reducing the
drug?
⑤Does the same reaction reappear after re-exposure to the suspected drug?
Causality Determination Criteria: Determined sequentially according to the above indicators 1-5.
Causality Determination Table for Adverse Reactions
Judgment
Result
Assessment Indicators
①
②
③
④
⑤
Definitely
Related
＋
＋
－
＋
＋

Probably
Related
＋
＋
－
＋
?
Possibly
Related
＋
＋
＋
±
?
Probably
Unrelated
＋
－
±
±
?
Definitely
Unrelated
－
－
＋
－
－
Remarks: "+" indicates affirmation/positive; "–" indicates negation/negative; "±" indicates
difficult to affirm or deny; "?" indicates unknown/unclear.
The relationship between adverse events (including serious adverse events) and the drug should
be determined whenever possible. If the assessment determines the relationship to be definitely
related, probably related, or possibly related, the event will be considered an adverse reaction
caused by the drug, and its severity will be used to determine if it should be classified as a serious
adverse event.
7. Data Management and Statistical Analysis Plan
(1) Data Management
Original case report forms (CRFs), once data entry and verification are completed as required,
shall be archived and saved in numerical order, and furnished with a retrieval catalog, etc., for
inspection. Electronic data files, including databases, verification programs, analysis programs,
analysis results, code books, and descriptive documents, should be classified and saved, with
multiple backups stored on different disks or storage media, and properly preserved to prevent
damage. All original records shall be preserved for the period stipulated by China's Good Clinical
Practice (GCP).
(2) Statistical Analysis
①General Principles: One-sided tests will be used for superiority tests, while two-sided tests
will be used for other statistical tests. Quantitative indicators will be described using the number
of cases, mean, standard deviation, median, minimum, and maximum. Categorical indicators will
be described using the number of cases and percentages. All statistical analyses will be conducted
using SPSS 26.0 statistical software.
②Statistical Analysis Populations
Full Analysis Set (FAS): Refers to the ideal set of subjects that closely adheres to the intention-
to-treat principle (including all randomized subjects who have received at least one treatment).
This data set is formed by excluding randomized subjects using minimal and reasonable methods.
For example, cases with no follow-up observation data after enrollment (no medication received)
may be excluded. For the estimation of missing values for primary variables, such as case data
where the entire treatment process was not observed, the last observation carried forward (LOCF,
or "carry-forward") method will be used to impute missing trial data. The number of subjects
evaluated for efficacy at the endpoint in each group will remain consistent with the number at the
start of the trial.
Per Protocol Set (PPS): Includes all cases that comply with the trial treatment protocol, have
good compliance (used the trial drug quantity between 80% and 120%), completed the required
fields in the CRF, have measurable primary variables, have no missing baseline variables, and
have no major violations of the trial protocol.
Safety Analysis Set (SS): Includes all enrolled cases that have used the study medication at

least once and have safety records after drug administration. This data set is used for safety
analysis.
In this trial, baseline data will be analyzed using the FAS. Primary efficacy endpoints will be
analyzed simultaneously on the FAS and PPS. Safety evaluation will be conducted using the SS.
③Statistical Analysis Methods
A. Enrollment and Completion Status The enrollment and completion status for each center
will be listed, including whether enrolled cases met the inclusion and exclusion criteria. The actual
number of enrolled cases, excluded cases, and dropped-out cases for each center will be counted
individually, and the FAS, PPS, and SS will be defined.
B. Baseline Balance Analysis Baseline is defined as before radiotherapy (-7 to 0 days). A
comparability analysis of the basic demographic characteristics, general conditions, and baseline
status (pre-treatment) at the time of enrollment will be conducted for the experimental and control
groups. Specifically, quantitative data conforming to a normal distribution will use the
independent samples t-test, quantitative data conforming to a skewed distribution will use non-
parametric tests, ordinal data will use the Kruskal-Wallis test, and categorical data will use the χ2
test or Fisher's exact test.
C. Comparison of Factors Affecting Trial Evaluation
a. Analysis of Concomitant Medication Use The frequency and percentage of concomitant
medication use will be listed for the cases. Group comparison will be performed using the χ2 test
or Fisher's exact test.
b. Analysis of Medication Compliance The frequency and percentage of cases with medication
compliance ＜80%, and ＞120% 、80% ～120% will be listed. Group comparison will be
performed using the χ2 test or Fisher's exact test.
c. Time Exposed to Treatment Treatment duration (days) = Time of last dose – Time of first
dose + 1.
The number of cases, mean, standard deviation, median, minimum, and maximum will be
calculated. Group comparison will be performed using the independent samples t-test or the
Wilcoxon rank-sum test.
8. Study Steps and Technical Route

9. Data Confidentiality Plan
All records related to the subject's identity shall be kept confidential, and these materials will
not be made public beyond the scope permitted by relevant laws and/or regulations. The subject's
name will not be provided to the sponsor. Only the subject's number and initials of the name will
be recorded on the case report form. If the subject's name appears in any other document (e.g.,
pathology reports), it must be redacted before providing copies of the documents to the sponsor.
Study reports stored on computers must comply with local data protection laws. Patients will be

notified in writing that representatives of the sponsor, Ethics Committee/Institutional Review
Board, or drug regulatory authorities may review their medical records to verify the information
collected. All personal information involved in the review will be kept strictly confidential and
will comply with local data protection laws. If the study results are published, the patient's
personal identity will remain confidential. The investigator will retain a list to verify patient
records.
III. Study Participant Recruitment
1. Inclusion Criteria
(1) stage III-IVa NPC (AJCC 8th edition) diagnosed via pathology in a tertiary hospital;
(2) no previous radiotherapy, chemotherapy, surgery, immunization, or targeted therapy;
(3) Karnofsky Performance Status score ≥80;
(4) intact and normal oral mucosa before treatment;
(5) age 18–75 years;
(6) voluntary participation and provision of informed consent in person;
(7) routine blood examination: white blood cell count ≥4.0×109/L, hemoglobin ≥100g/L,
neutrophil count ≥1.5×109/L, and platelet count ≥100×109/L;
(8) biochemical examination: total bilirubin ≤1.5×the upper limit of the normal range (ULN),
alanine aminotransferase and aspartate aminotransferase ≤2×ULN, and estimated glomerular
filtration rate ≥60 mL/min.
2. Exclusion Criteria
(1) with other malignant tumors in the past or present and/or distant metastasis during treatment;
(2) who have undergone surgery, chemoradiotherapy, and targeted immunotherapy;
(3) with a history of asthma, rash, urticaria, and other allergic diseases;
(4) with a history of autoimmune diseases, connective tissue diseases, and diabetes mellitus that
significantly affect the healing of the oral mucosa;
(5) with concomitant diseases, such as heart disease, kidney disease, and acute infectious
diseases, which are judged by the investigator to seriously endanger the safety of patients or
affect the completion of the study;
(6) who are breastfeeding, pregnant, or planning to become pregnant during the study;
(7) with known allergies to the therapeutic agents and penicillin used in the trial;
(8) with mental or nervous system diseases or poor compliance will be excluded from the
study.
3. Withdrawal and Termination Criteria
3.1 Withdrawal determined by the investigator
Withdrawal determined by the investigator refers to situations where it is inappropriate for an
already enrolled patient to continue the trial, and the investigator decides to withdraw the patient
from the trial:
①The patient is unsuitable to continue receiving the trial treatment;
②The patient has poor compliance;
③Occurrence of a serious adverse event or emergency unblinding in the trial;
④Use of protocol-prohibited medications during the trial.

3.2 Subject initiated withdrawal
In accordance with the informed consent form, the subject has the right to withdraw from the
trial midway. A subject is also considered "withdrawn" if they do not explicitly request to
withdraw but are lost to follow-up by no longer receiving medication and testing. The reason for
withdrawal should be ascertained and recorded whenever possible. Examples include: feeling the
treatment is ineffective; finding certain adverse reactions intolerable; having commitments
preventing continuation of the clinical study; economic factors; or being lost to follow-up without
stating a reason. Regardless of the reason, the case report form for the withdrawn patient should be
retained.
3.3 Handling of Dropouts
When a patient drops out, the investigator must fill in the reason for dropout in the CRF. They
should contact the patient whenever possible, complete all feasible assessment items, and fill in
the end-of-treatment follow-up record form, recording the time of the last dose if possible. For
dropouts due to an adverse event that is ultimately judged to be related to the study drug following
follow-up, this must be recorded in the CRF and the sponsor notified. No replacement cases are
needed for dropouts.
3.4 Criteria for Case Exclusion
①Case selection does not meet the inclusion criteria;
②The trial medication was never used;
③No data exists after randomization or major indicators are missing, or the data is obviously
incomplete;
④Use of medications prohibited by the trial protocol, making efficacy evaluation impossible.
4. Duration of Participation (Time per session and total time)
This study is expected to last 5 years, including an 48-month enrollment period. Each patient
will be followed up for 12 months after stopping treatment.
(1) Planned date for enrollment of the first patient: July 30, 2022.
(2) Planned date for enrollment of the last patient: July 1, 2026.
(3) Planned date for the last patient's exit or trial conclusion: July 1, 2027.
(4) Estimated report date: July 20, 2027.
(5) Follow-up duration: 12 months; Primary endpoint: Incidence and severity of RIOM;
Secondary endpoints: ①Duration of RIOM; ②Rate of completion of treatment measures;
③Adverse events classified according to CTCAE 5.0; ④Changes in BMI
Follow-up frequency: The follow-up period is 1 year; The first follow-up is 1 month after
concurrent chemoradiotherapy; thereafter, follow-up visits are every 3 months. RIOM incidence
rate, severe RIOM incidence rate, ORR, and PFS.
5. Recruitment Process (Including recruitment procedure and start time,
recruitment materials, expected number of recruits)
(1) Patient selection: Meeting the diagnostic criteria for NPC; patients who have not yet
received concurrent chemoradiotherapy; meeting the inclusion and exclusion criteria; patients
voluntarily joining this clinical trial and signing the informed consent form.
(2) Expected number of recruits: The Delphi method is used to determine the non-inferiority
margin of the observation endpoint. After consulting senior oncology practitioners, we defined an

8% reduction in the incidence of RIOM as a clinically acceptable non-margin of error. Under the
conditions of test level a=0.05 and test efficacy 1-β=0.9, the proportion of cases in the two groups
is 1:1. Using the module of non-destructiveness Tests for Two Proportions in PASS 15.0 statistical
analysis software, we determined that a sample size of 81 was required per group. Considering a
10% loss to follow-up rate, we estimated that 90 cases would be required in each group, for a total
of 180 cases.
(3) Planned date for enrollment of the first patient: July 30, 2022; Planned date for enrollment
of the last patient: July 1, 2026; Planned date for the last patient's exit or trial conclusion: July 1,
2027.
IV. Risk/Benefit Assessment
1. Benefits (Individual and Societal Benefits)
This study intends to explore the impact of nebulized Sapylin inhalation on the therapeutic
efficacy of CCRT in patients with NPC via nebulized inhalation, observe the effect of nebulized
Sapylin inhalation on the incidence and severity of RIOM, and evaluate the safety of nebulized
Sapylin inhalation. This study aims to find a highly efficient and low-toxicity method for NPC
specialists and patients to reduce the occurrence and severity of RIOM and improve the efficacy of
CCRT.
2. Risks
(1) Efficacy and adverse reaction risks;
(2) Time risk;
(3) Policy risk;
(4) Personnel risk.
Mitigation Measures: Flexibility (high variability); diverse services; low cost; shortened
research time; expanded research resources; and the ability to adapt to and meet strict GCP
requirements, etc.
3. Protection of Special Populations (Women, children, the elderly, and other
special populations such as incarcerated individuals, etc., risk and protection)
The study population for this project consists of NPC patients aged 18-75. The research
personnel will conduct risk assessment for women, the elderly, and other special populations, and
implement corresponding risk protection measures.
V. Ethical Issues in the Study
1. Ethics Approval
This clinical trial has followed the Declaration of Helsinki and China's relevant clinical trial
research norms and regulations. The implementation of this trial protocol has been approved by
the Ethics Committee of the principal clinical research unit prior to the start of the trial.
2. Informed Consent
Before any patient is selected for this study, the investigator must fully and comprehensively
introduce the study's objectives, procedures, and possible risks to the patient's family members or
their designated representatives in written form. Patients and their family members should be
informed that they have the right to withdraw from the study at any time. A written Patient

Informed Consent Form (included as an appendix to the protocol) must be provided to every
patient and family member before enrollment. The investigator must obtain informed consent
before any patient or family member enters the study, and the informed consent form must be
retained as a clinical trial document for inspection.
VI. Annual Plan
Study Period
Key Responsibilities
Jul 2022 - Jun 2024
1.Initiate recruitment;
2.Screen
eligible
NPC
cases,
determine
baseline data and collect indicators, perform
randomization, and complete the enrollment of
the expected sample size; it is planned to recruit
90
patients
in
the
2
years
(45
in
the
experimental group, 45 in the control group)
and conduct follow-up observations on these
subjects;
3.Follow up each enrolled case for 1 year;
4.The enrolled cases will proceed according to
the
trial
steps
designed
for
each
group,
including
patient
follow-up,
disease
assessment,
and
indicator
collection
and
follow-up.
Jul 2024 - Jun 2026
1.
Screen
eligible
NPC
cases,
determine
baseline data and collect indicators, perform
randomization, and complete the enrollment of
the expected sample size; it is planned to recruit
90 patients in the second 2 years period (45 in
the experimental group, 45 in the control
group);
2. Follow up each enrolled case for 1 year, and
perform data registration and statistics;
3. The enrolled cases will proceed according to
the
trial
steps
designed
for
each
group,
including
patient
follow-up,
disease
assessment,
and
indicator
collection
and
follow-up.
Jul 2026 - Jul 2027
1. Statistical analysis, thesis writing, domestic
and international exchange, and promotion
application.
VII. Assessment Indicators
The primary assessment indicator is the incidence and severity of RIOM. The secondary
assessment indicators are: (1) duration of RIOM, (2) rate of completion of treatment measures, (3)
adverse events classified according to CTCAE 5.0, and (4) changes in BMI.
VIII. Preliminary Research Foundation and Working Conditions
The research team conducted a retrospective study on 32 NPC (NPC) patients from 2016 to
2019. The study observed the effect of nebulized Sapylin and Dexamethasone on the incidence
rate of RIOM (radiation-induced oral mucositis) and the efficacy of CCRT (Concurrent

Chemoradiotherapy) during concurrent chemoradiotherapy. Results showed: The CCRT combined
with nebulized Sapylin group had a lower incidence rate of RIOM and Grade III-IV RIOM
compared to the CCRT combined with nebulized Dexamethasone group (43.75% vs 68.75%) and
(12.5% vs ≥31.3%), respectively. Furthermore, the CCRT combined with nebulized Sapylin group
was superior to the CCRT combined with nebulized Dexamethasone group in terms of objective
response rate (ORR) (87.5% vs 62.5%), median overall survival (OS) (53.7M vs 46.4M), and
median progression-free survival (PFS) (27M vs 23M). Moreover, comparison of the efficacy and
survival analysis between the CCRT combined with nebulized Sapylin group and the CCRT
combined with nebulized Dexamethasone group revealed that the nebulized Sapylin inhalation
group showed a trend toward reducing the incidence rate of Grade III-IV RIOM and enhancing
CCRT efficacy in NPC patients, with no obvious toxic side effects observed. Therefore, this
project will conduct a non-inferiority, parallel-design, randomized controlled study of nebulized
Sapylin versus nebulized Dexamethasone for the prevention and treatment of radiation-induced
oral mucositis in NPC.
(I) Research Methods
1. Study Subjects
Data of NPC patients with complete clinical and pathological data who underwent concurrent
chemoradiotherapy at the Head and Neck Tumor Ward of the Cancer Hospital of the Affiliated
Hospital of Guangdong Medical University between May 2016 and December 2019 were
observed.
1.1 Inclusion Criteria:
(1) stage III-IVa NPC (AJCC 8th edition) diagnosed via pathology in a tertiary hospital;
(2) no previous radiotherapy, chemotherapy, surgery, immunization, or targeted therapy;
(3) Karnofsky Performance Status score ≥80;
(4) intact and normal oral mucosa before treatment;
(5) age 18–75 years;
(6) voluntary participation and provision of informed consent in person;
(7) routine blood examination: white blood cell count ≥4.0×109/L, hemoglobin ≥100g/L,
neutrophil count ≥1.5×109/L, and platelet count ≥100×109/L;
(8) biochemical examination: total bilirubin ≤1.5×the upper limit of the normal range (ULN),
alanine aminotransferase and aspartate aminotransferase ≤2×ULN, and estimated glomerular
filtration rate ≥60 mL/min.
1.2 Exclusion Criteria
(1) with other malignant tumors in the past or present and/or distant metastasis during
treatment;
(2) who have undergone surgery, chemoradiotherapy, and targeted immunotherapy;
(3) with a history of asthma, rash, urticaria, and other allergic diseases;
(4) with a history of autoimmune diseases, connective tissue diseases, and diabetes mellitus
that significantly affect the healing of the oral mucosa;
(5) with concomitant diseases, such as heart disease, kidney disease, and acute infectious
diseases, which are judged by the investigator to seriously endanger the safety of patients or
affect the completion of the study;
(6) who are breastfeeding, pregnant, or planning to become pregnant during the study;
(7) with known allergies to the therapeutic agents and penicillin used in the trial;
(8) with mental or nervous system diseases or poor compliance will be excluded from the
study.
2. Treatment Methods: NPC patients will undergo CCRT, divided into the CCRT combined with
nebulized Sapylin group and the CCRT combined with nebulized Dexamethasone group.
2.1 CCRT combined with nebulized Sapylin group:
Concurrent
Radiotherapy
Dose:
Nasopharyngeal
primary
tumor
site
(PTVnx):
69.96Gy/2.12Gy/33F; High-risk planning target volume (PTV1): 60.06Gy/1.82Gy/33F; Low-risk
planning target volume (PTV2): 54.12Gy/1.64Gy/33F; Cervical lymph nodes (PTVnd): 66 ~
69.96Gy/2 ~ 2.12Gy/33F; 5 times per week, for a total of 6-7 weeks.
Concurrent Chemotherapy: Cisplatin (80-100mg/m2, Q3W, 3 times during CCRT); Sapylin: 1
KE/time, nebulized, QD, starting from Day 1 of CCRT until the end of radiotherapy.
2.2 CCRT combined with nebulized Dexamethasone group:
Concurrent
Radiotherapy
Dose:
Nasopharyngeal
primary
tumor
site
(PTVnx):

69.96Gy/2.12Gy/33F; High-risk planning target volume (PTV1): 60.06Gy/1.82Gy/33F; Low-risk
planning target volume (PTV2): 54.12Gy/1.64Gy/33F; Cervical lymph nodes (PTVnd): 66 ~
69.96Gy/2 ~ 2.12Gy/33F; 5 times per week, for a total of 6-7 weeks.
Concurrent
Chemotherapy:
Cisplatin
(80-100mg/m2,
Q3W,
3
times
during
CCRT);
Dexamethasone: 10mg/time, nebulized, QD, starting from Day 1 of treatment until the end of
radiotherapy.
3. Observation Indicators: The primary observation indicator is the RIOM incidence rate. The
secondary observation indicators are: Grade III-IV RIOM incidence rate; RIOM onset time and
duration; assessment of adverse reactions, ORR, and PFS for both regimens.
4. Statistical Methods
①General Principles: One-sided tests will be used for superiority tests, while two-sided tests
will be used for other statistical tests. Quantitative indicators will be described using the number
of cases, mean, standard deviation, median, minimum, and maximum. Categorical indicators will
be described using the number of cases and percentages. All statistical analyses will be conducted
using SPSS 26.0 statistical software.
②Statistical Analysis Populations:
Full Analysis Set (FAS): Refers to the ideal set of subjects that closely adheres to the intention-
to-treat principle. It includes all randomized subjects who have received at least one treatment.
The number of subjects evaluated for efficacy at the endpoint in each group will remain consistent
with the number at the start of the trial.
Per Protocol Set (PPS): Includes all cases that comply with the trial treatment protocol, have
good compliance (used the trial drug quantity between 80% and 120%), completed the required
fields in the CRF, have measurable primary variables, have no missing baseline variables, and
have no major violations of the trial protocol.
Safety Analysis Set (SS): Includes all enrolled cases that have used the study medication at
least once and have safety records after drug administration. This data set is used for safety
analysis.
In this trial, baseline data will be analyzed using the FAS. Primary efficacy endpoints will be
analyzed simultaneously on the FAS and PPS. Safety evaluation will be conducted using the SS.
(II) Preliminary Research Work
1. Clinical and Pathological Features of NPC Patients Receiving Chemotherapy:
A retrospective study reviewed 32 NPC patients with complete clinical and pathological data
who underwent concurrent chemoradiotherapy at the Head and Neck Tumor Ward of the Cancer
Hospital of the Affiliated Hospital of Guangdong Medical University between May 2016 and
December 2019. NPC patients were predominantly male (63.8%), with an average age of 51±15
years. The pathological types of NPC were mainly undifferentiated non-keratinizing carcinoma
(90.2%) and differentiated non-keratinizing carcinoma (6.35%). The vast majority of NPC patients
were TNM stage III-IVa.
2. Observation of treatment efficacy, prognosis, RIOM incidence, and severity in NPC patients:
Table 1 Efficacy and Survival Analysis of CCRT combined with Nebulized Sapylin Group versus CCRT combined
with Nebulized Dexamethasone Group in the Treatment of Locally Advanced NPC
Group
N
PR+CR
PD
Median OS
(months)
Median
PFS
(months)​
CCRT + Sapylin Neb.
16
14
1
53.7M
27M
CCRT +
Dexamethasone Neb.
16
0
3
46.4M
23M
CCRT: Concurrent Chemoradiotherapy 、PR: Partial Remission/Response 、CR: Complete
Remission/Response 、PD: Progressive Disease 、OS: Overall Survival 、PFS: Progression-Free
Survival

Figure 1 Survival Analysis of CCRT combined with Nebulized Sapylin Group versus CCRT combined with
Nebulized Dexamethasone Group in the Treatment of Locally Advanced NPC.
Table 2 Grading of Toxic/Adverse Reactions (CTCAE Version 5) in CCRT combined with Nebulized Sapylin Group
versus CCRT combined with Nebulized Dexamethasone Group in the Treatment of Locally Advanced NPC.
Adverse
Event
CCRT + Sapylin Neb.
CCRT + Dexamethasone Neb.
0
Ⅰ
Ⅱ
Ⅲ
Ⅳ
0
Ⅰ
Ⅱ
Ⅲ
Ⅳ
Anemia
2
4
7
3
0
1
3
7
5
0
White
blood cell
decreased
4
4
6
2
0
4
3
5
4
0
Neutrophil
count
decreased
16
0
0
0
0
12
0
4
0
0
Platelet
count
decreased
15
0
1
0
0
12
2
1
1
0
Weight
loss
0
8
8
0
0
1
6
6
3
0
Vomiting
5
6
5
0
0
2
4
6
3
1
Nausea
5
8
3
0
0
3
5
5
3
0
RIOM
9
1
4
2
0
5
2
4
3
2
The results from Table 1 show that the treatment response rate in the CCRT combined with
nebulized Sapylin inhalation group was higher than in the Dexamethasone group, suggesting that
nebulized Sapylin inhalation can improve the efficacy of CCRT and prolong patient OS. The
results from Table 2 show that a comparison of common adverse reactions between the two groups
suggests that the CCRT combined with nebulized Sapylin inhalation group can reduce the
incidence and severity of RIOM, and can reduce overall adverse reactions.
(III) Conclusion
1.The combined use of nebulized Sapylin during concurrent chemoradiotherapy in NPC patients
reduces the incidence and severity of radiation-induced oral mucositis.
2.The combined use of nebulized Sapylin during concurrent chemoradiotherapy using Cisplatin as
the main chemotherapy regimen in NPC patients shows a trend toward improving the efficacy of
chemoradiotherapy
and prolonging
patient
survival
compared
to
the
use
of
nebulized
Dexamethasone.
IX. Other Issues to be Explained

1. Form of Publication of Results and Authorship Arrangements
All data and results obtained from this study, as well as all intellectual property rights, belong to
the sponsor. The sponsor may utilize these materials in various forms. At the same time,
researchers may use the data obtained from this study independently for scientific purposes, but
must consult with the sponsor and obtain the sponsor's written consent before publication. The
sponsor acknowledges the right of the investigator to publish the study results after the study is
completed. The research results will be published in the form of a paper. It is expected that 1 paper
will be published in an SCI-indexed or Chinese scientific and technological core professional
journal, 2 master's students will be trained, and relevant academic achievements will be shared
and reported at relevant academic conferences.
2. Other Issues to be Explained
The first affiliation for authorship shall be the Affiliated Hospital of Guangdong Medical
University, and the intellectual property rights belong to the Affiliated Hospital of Guangdong
Medical University.
X. Investigator Information Table
1. Principal Investigator
Name
Telephone Number
Email Address
Haiqing Luo
13729196345
hqluo@126.com
Project
Secretary:
Donghong
Yang ；Contact
Number:
15812356223 ；Email ：
ydh192@sina.com
2. Project Team Members (including Principal Investigator)
Name
Affiliation
Degree
Title
Project Task
Assignment
Ethics
Training
GCP
Training
Haiqing
Luo
Affiliated
Hospital of
Guangdong
Medical
University
Ph.D.
Chief
Physician,
Associate
Professor
Overall
Responsibility,
Project Design,
Implementation
Guidance
Received
Received
Xuesong
Chen
Affiliated
Hospital of
Guangdong
Medical
University
Bachelor's
Degree
Chief
Physician
Project
Implementation
Monitoring
Received
Received
Liren Hu
Affiliated
Hospital of
Guangdong
Medical
University
Bachelor's
Degree
Associate
Professor
Statistical
analysis of
patient survival
data
Received
Received
Jiayuan
Wu
Affiliated
Hospital of
Guangdong
Medical
University
Master's
Degree
Deputy
Chief
Physician
Patient follow-
up, data
statistics
Received
Received
Donghong
Yang
Affiliated
Hospital of
Guangdong
Medical
University
Master's
Degree
Deputy
Chief
Physician
Project
Secretary
Received
Received
Guihua Yi
Affiliated
Hospital of
Master's
Student
None
Case enrollment
and screening
Received
Received

Guangdong
Medical
University
Qianbing
Luo
Affiliated
Hospital of
Guangdong
Medical
University
Master's
Student
None
Filling out the
patient CRF
Received
Received
Ningxin
Huang
Affiliated
Hospital of
Guangdong
Medical
University
Master's
Student
None
Filling out the
patient CRF
Received
Received
Haifeng
Tang
Affiliated
Hospital of
Guangdong
Medical
University
Master's
Student
None
Patient follow-
up, data
statistics
Received
Received
Jiaqi He
Affiliated
Hospital of
Guangdong
Medical
University
Master's
Student
None
Manuscript
writing
Received
Received
XI. Appendices
(1) Appendix 1: NPC TNM Staging Criteria (AJCC 8th)
(2) Appendix 2: Radiation Therapy Oncology Group (RTOG) Grading Criteria for Acute
Radiation Morbidity of Mucosa
(3) Appendix 3: CTCAE Version 5 Adverse Event Grading Criteria (Partial Content)
(4) Appendix 4: Performance Status Rating Scale (Karnofsky Score)
(5) Appendix 5: Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
Applicant's Commitment and Signature: I guarantee the authenticity of the application
content. If funding is obtained, I will fulfill the responsibilities of the principal, strictly abide by
the relevant regulations such as the institutional and national GCP principles, effectively ensure
the time dedicated to the research, earnestly carry out the work, submit relevant materials on, and
consciously perform annual summaries and final reports. I will assume full responsibility for any
false reporting or violation of regulations.
Appendix 1: NPC TNM Staging Criteria (AJCC 8th)
Regional Lymph Node (N) Staging
TX​
Primary tumor cannot be assessed
T0​
No evidence of primary tumor
T1​
Tumor confined to the nasopharynx, or extends to oropharynx and/or nasal cavity without
parapharyngeal involvement.
T2​
Tumor with extension to parapharyngeal space.

Regional Lymph Node (N) Staging
T3​
Tumor involves bony structures of skull base and/or paranasal sinuses.
T4​
Tumor with intracranial extension and/or involvement of cranial nerves, hypopharynx,
orbit, parotid gland, and/or extensive soft tissue infiltration beyond the lateral surface of
the lateral pterygoid muscle.
Primary Tumor (T) Staging
Nx​
Regional lymph nodes cannot be assessed
N0​
No regional lymph node metastasis
N1​
Unilateral metastasis in cervical lymph node(s), ≤6 cm in greatest dimension, above the
caudal border of cricoid cartilage, and/or unilateral or bilateral retropharyngeal lymph
node(s), ≤6 cm in greatest dimension.
N2​
Bilateral metastasis in cervical lymph node(s), ≤6 cm in greatest dimension, above the
caudal border of cricoid cartilage.
N3​
Metastasis in a lymph node(s) > 6 cm in greatest dimension and/or extension below the
caudal border of cricoid cartilage.
Distant Metastasis (M) Staging
M0​
No distant metastasis
M1​
Distant metastasis
NPC TNM Staging
Stage
T
N
M
0
Tis
N0
M0
I
T1
N0
M0
II
T0, T1
N1
M0
II
T0～2
N0 ~ 1
M0
III
T2
N2
M0

NPC TNM Staging
Stage
T
N
M
III
T0 ~ T2
N0 ~ 2
M0
IVa
T3
N0 ~ 3
M0
IVa
T4
N3
M0
IVb
Any T
Any N
M1
Appendix 2: Radiation Therapy Oncology Group (RTOG) Grading Criteria for
Acute Radiation Morbidity of Mucosa
0
Ⅰ
Ⅱ
Ⅲ
Ⅳ
Mucosal
appearance
No change
over
baseline
Erythema
Patchy
mucositis、
With
inflammatory
sero-
sanguinous
discharge
Confluent
fibrinous
mucositis
Ulceration、
Hemorrhage、
Necrosis
Pain level
No change
over
baseline
Mild pain
Moderate pain
Severe pain
Pain
management
No change
over
baseline
No analgesic
required
Analgesic
required
Requiring
narcotic
analgesic
Appendix 3: CTCAE Version 5 Adverse Event Grading Criteria (Partial Content)
Adverse
Event
Grade
1
2
3
4
5
HGB
＜LLN-
10.0g/dL
＜LLN-
6.2mmol/L
＜LLN-
100g/L
＜10.0－
8.0g/dL
＜6.2－
4.9mmol/L
＜100－
80g/L
＜8.0－
6.5g/dL
＜4.9－
4.0mmol/L
＜80－65g/L
＜6.5g/dL
＜4.0mmol/L
＜65g/L
Death
WBC
＜LLN-
3000/mm3
＜LLN-
3.0×109 /L
＜3000-2000/
mm3
＜3.0－
2.0×109 /L
＜2000-1000/
mm3
＜2.0－
1.0×109 /L
＜1000/ mm3
＜1.0×109 /L
Death
PLT
＜LLN-
75,000/mm3
＜LLN-
75.0×109 /L
＜75,000-
50,000/mm3
＜75.0－
50.0×109 /L
＜50,000－
25,000/mm3
＜50.0－
25.0×109 /L
＜
25,000/mm3
＜25.0×10 9
/L
Death
Nausea
Loss of
appetite
without
Decreased
oral intake;
no significant
Inadequate
oral caloric or
fluid intake;
Life-
threatening
consequences
Death

alteration in
eating habits
weight loss,
dehydration,
or
malnutrition;
requires
intravenous
(IV) fluids for
< 24 hours
requires IV
fluids, tube
feeding, or
TPN (Total
Parenteral
Nutrition) for
≥24 hours
Episodes
1-2 episodes
in 24 hours
(separated by
5 minutes)
3-5 episodes
in 24 hours
(separated by
5 minutes)
≥6 episodes in
24 hours;
requires
nasogastric
tube feeding,
total parenteral
nutrition
(TPN), or
hospitalization
Life-
threatening
consequences;
requires
urgent
intervention
Death
Diarrhea
Increase of <4
stools per day
over baseline;
mild increase
in ostomy
output
compared to
baseline
Increase of 4-
6 stools per
day over
baseline;
moderate
increase in
ostomy
output
compared to
baseline
Increase of ≥7
stools per day
over baseline;
incontinence;
requires
hospitalization;
marked
increase in
ostomy output
compared to
baseline;
limiting
instrumental
activities of
daily living
Life-
threatening
consequences;
requires
urgent
intervention
Death
Oral
Mucositis
Asymptomatic
or mild
symptoms;
intervention
not indicated
Moderate
pain; not
interfering
with oral
intake;
modified diet
indicated
Severe pain;
interfering
with oral
intake
Life-
threatening
consequences;
urgent
intervention
indicated
Death
Appendix 4: Performance Status Rating Scale (Karnofsky Score)
Score
Performance Status
100​
Normal, no complaints; no evidence of disease.
90
Able to carry on normal activity; minor signs or symptoms of disease.
80​
Normal activity with effort; some signs or symptoms of disease.
70​
Cares for self; unable to carry on normal activity or to do active work.
60​
Requires occasional assistance but is able to care for most personal
needs.

Score
Performance Status
50​
Requires considerable assistance and frequent medical care.
40​
Disabled; requires special care and assistance.
30​
Severely disabled; hospital admission is indicated although death not
imminent.
20​
Very sick; hospital admission necessary; active supportive treatment
necessary.
10​
Moribund; fatal processes progressing rapidly.
0
Dead.
Note 1:​
A higher score indicates a better performance status and a greater ability to tolerate the
side effects of treatment, thereby increasing the likelihood that the patient can undergo aggressive
therapy. Conversely, a lower score indicates a poorer performance status. If the score falls below
70, many effective anti-tumor treatments may not be feasible.
Note 2:​
This scale is adapted from the original table developed in 1948 by Dr. Karnofsky and Dr.
Burchenal for the objective assessment of chemotherapy efficacy.
Appendix 5: Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
Therapeutic Response
Complete remission (CR)
Disappearance of all target lesions, no new
lesions, and normalization of tumor marker
levels, maintained for at least 4 weeks.
Partial remission (PR)
At least a 30% decrease in the sum of the
longest diameters of target lesions, maintained
for at least 4 weeks.
Stable disease (SD)
The change in the sum of the longest diameters
of target lesions does not meet the criteria for
either PR or Progressive Disease (PD).
Progressive disease (PD)
At least a 20% increase in the sum of the
longest diameters of target lesions compared to
the smallest sum recorded, or the appearance of
one or more new lesions.
Measurable Lesions: Lesions that can be measured in diameter using clinical or imaging methods,
according to the RECIST criteria. For example, intrapulmonary lesions ≥10mm on chest X-ray,
≥20mm on conventional CT or MRI scan, or ≥10mm in diameter on helical CT scan.
Evaluable Lesions: Includes unidimensionally measurable lesions, masses with unclear
boundaries, small lesions whose diameter cannot be measured (such as miliary or patchy lesions in
the lung), lesions whose diameters are both less than ≥10mm, and masses whose diameter is less
than the scanning interval, etc.
Non-Evaluable Lesions: Includes osteoblastic metastases, pleural effusion, ascites, pericardial
effusion, lymphangitis carcinomatosa in the lung, and previously irradiated lesions without
progression.
Notes:

①Changes in slice thickness of CT or MRI scans may affect the measurement and detection of
new lesions. The standard should be 5mm thin-slice CT. To reduce detection error, imaging should
be performed before and after treatment, whenever possible, using the same equipment, the same
examination method, and marked by tumor diameter.
②Enrolled patients must have at least one bidimensionally measurable lesion. If there are
multiple measurable lesions in the head and neck but not all can be evaluated, up to 3 lesions may
be selected for evaluation before enrollment, and the rest should be observed as evaluable lesions.
③The lesion status determined before drug administration, and the method of its evaluation,
will be applied throughout the entire trial process for efficacy assessment and cannot be changed.
④Lesion measurement should be performed using unified technical methods. Each evaluation
should be compared with the baseline measurements taken at enrollment, and the best response
should be recorded. Cases where efficacy is difficult to evaluate should be handed over to the
clinical lead unit for comprehensive evaluation by an independent expert panel.