Prospective, One-arm, Phase II Clinical Study of Smeitinib Hydrosulfate Capsules for the Treatment of Patients With Type I Neurofibromatosis
Phase: PHASE2
Conditions: Neurofibromatosis 1
Sponsor: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

Clinical study protocol
Project Name: Prospective, single arm, Phase II clinical
study of selmetinib hydrogen sulfate capsules in patients
with neurofibromatosis type I
Sponsor: Sun Yat-sen Memorial Hospital of Sun Yat-sen
University
Version number: V2.0
Version date: 2024.04.17
Project leader: Huang Zhiquan
Scheme signature confirmation:
Compliance Statement
In accordance with the provisions of the Good Clinical Practice for Drug Clinical
Trials and the Administrative Measures for Clinical Studies initiated by Medical
Institutions (Trial) and the Declaration of Helsinki, we promise to carry out this study
according to this protocol. The participants must be trained to conduct the study after
the written approval of the Ethics Committee and the written informed consent of the
subjects, and the protocol revision shall be re-approved again.

1. Protocol abstract (title, brief description of study, study object,
outcome measures, study intervention
*, Sample size, etc., in 300-500
words)
This study focused on patients with neurofibromatosis type I,
currently lacking effective drug therapy and a high recurrence rate after
surgical resection. Hydrosulfate sametinib capsule as a MEK inhibitor,
through selective binding mitogen activated protein kinase (MEK) 1 / 2
protein, can block the regulation of key cells mitogen activated protein
kinase / extracellular signal regulation kinase signaling pathway, can
induce tumor shrinkage, for disease control, surgical radical resection,
reduce postoperative recurrence, reduce complications. This study aims
to provide hydrosulphate seletinib to patients with neurofibromatosis
type I, observe the efficacy of drug treatment, change patients without
surgical
indications
into
indications
for
surgery,
increase
the
proportion of surgical resection and reduce the recurrence rate. In this
study, the objective response rate (ORR) as the main outcome measure, the
range, duration of response (DOR), and progression-free survival (PFS)
as secondary outcome measures to explore the use of surgical resection
rate,
reduction
of
surgical
resection
range
and
postoperative
complications, tumor shrinkage effect, and the stability of efficacy.
2. Introduction (Rereferences should be noted in the introduction)
2.1 Research theoretical basis / background (explain why clinical studies
are conducted from the limitations of disease, standard of treatment and
known treatment, and explain the findings and importance of preclinical,
pharmacological and related studies)
Neurofibromatosis (NF) has been included in the list of rare diseases
in many countries including China, 96% of which are NF 1 subtypes, and
the clinical manifestations of NF 1 are diverse
[1], Involmultiple systems

and can cause serious complications such as airway obstruction, spinal
cord compression and motor dysfunction
[2-4]. Pleexiform neurofibromas (PN)
occur in 30 to 50% of NF 1 patients
[5、6], PN progress fast, accompanied by
serious
appearance
defects,
high
disability,
and
the
risk
of
deterioration
[7-10]. According to the 2023 edition of the multidisciplinary
diagnosis and treatment of type I neurofibromatosis, patients with NF 1
are more likely to have a variety of benign and malignant tumors than the
normal population, including pNF, CNF, MPNST and OPG. Attention should
be paid to the early identification and monitoring of the above tumors.
Neurofibromas with MPNST should have accelerated growth, pain and hard
texture. At the same time, systemic evaluation should be carried out, and
patients with no signs of distant metastasis should undergo early surgical
treatment as far as possible, and patients with distant metastasis can
choose radiotherapy, chemotherapy and targeted therapy.
Neurofibromatosis type I (neurofibromatosis type 1, NF 1) is an
autosomal dominant disorder with 50% of patients with familial and 50%
sporadic mutations. NF 1 gene encodes neurofibromin, downregulates the
activity of Ras-Raf pathway and suppresses cell proliferation; deficiency
in neurofibrosis causes excessive activation of RAS pathway and causes
uncontrolled cell proliferation in NF 1 patients
[5]. At present stage, the
operation is the most commonly used, the main treatment, and neurofibroma
has the characteristics along the nerve root growth, it is difficult to
solve all lesions through surgery, lesions composed of extensive nerve
and vascular tissue and normal tissue, surgical resection difficult and
bleeding, incomplete resection after recurrence as high as 50%.
As a MEK inhibitor, it blocks the mitogen-activated protein kinase
/ extracellular signal-regulated kinase signaling pathway by selectively
binding to the mitogen-activated protein kinase (MEK) 1 / 2 proteins that
regulate key cellular responses
[11-13], And then induce tumor shrinkage,

creating conditions for disease control, surgical resection, reducing
postoperative
recurrence and reducing
complications.
Based
on
the
targeted therapy of selmeetinib capsule, this study monitored the
efficacy of the enrolled patients, so as to verify the effectiveness of
selmeetinib capsule for NF 1 therapy.
2.2 Risk / benefit evaluation
2.2.1 Known potential risks
The potential risks of this study are mainly the adverse reactions
after the use of selmetinib hydrosulphate capsules, the hyperprogression
of tumor treatment caused by the study protocol itself, and the risk of
sudden accidents in the study.
2.2.2 Known potential benefits
The potential benefit of the subjects is the subjects to achieve
partial tumor remission, delay progression, reduce recurrence, and
improve function; Entering the clinical study can get more attention from
researchers and manage the disease changes in time, which is beneficial
to the treatment of the disease.
2.2.3 Potential risk and benefit evaluation
Smetinib Insulphate capsule is indicated for pediatric patients with
neurofibromatosis type I (NF 1) aged 3 years and older with symptomatic,
inoperable plexiform neurofibromas (PN). It was approved to list in China
on April 28,2023, and was included in the medical insurance directory on
December
13,2023. Several guidelines,
consensus
and
diagnosis
and
treatment norms in China recommend selmetinib hydrohydrogen sulfate for
the treatment of NF 1-PN. The most common toxicity of selmetinib sulphate
capsules are grade 1 and 2 gastrointestinal symptoms (nausea, vomiting,
or diarrhea), asymptomatic elevated creatine phosphokinase levels, acnes
rash, and paronychia with good safety and tolerability. Therefore, this

clinical study protocol has a low risk of disease progression and serious
adverse events on the treatment of NF 1
[14、15]. At the same time, in the future
studies, the investigators will pay more attention to the subjects'
systemic condition and tumor treatment condition, and the subjects will
also gain some clinical benefit in this study.
3. Study objective and endpoint (list presentation objective (specific
issues to be addressed), corresponding to the outcome measures)
3.1 Purpose
3.1.1 Main Purpose
The primary objective of this study is to explore the objective
response rate (ORR) of tumors in patients with neurofibromatosis type I
(NF 1).
3.1.2 Secondary Purpose
The secondary objective of this study is to explore the improvement
in
surgical
resectable
range,
duration
of
remission
(DOR),
progression-free survival (PFS) in patients with neurofibromatosis type
I (NF 1) treated with selmeetinib capsules.
3.1.3 Exploratory Purpose
The exploratory purpose of this study is to explore the long-term
efficacy and stability of efficacy in patients with neurofibromatosis
type I (NF 1) treated with selmeetinib capsules.
3.2., study indicators
3.2.1 Main Indicators and Definitions
Objective response rate (ORR): percentage of patients in partial
response after 6 cycles of drug therapy. Partial response was defined as
a 20% reduction in the target neurofibroma volume
from baseline.
Confirmconfirmed partial response was defined as a 3-examinations at 33

months examinations assessed as partial remission.
3.2.2 Secondary indicators and Definitions
Scope of surgical resection: on the premise of not damaging the
important organs and neurological functions invaded by the tumor, the
proportion of resection can be divided into total resection / near total
resection (90% resection range), subtotal resection (90% resection range
50%), and partial resection (resection range <50%).
Duration of response (DOR): the time between the start of CR or PR
and the first assessment of PD or death from any cause.
Progression-free survival (PFS): the time from the start of treatment
in the trial to tumor progression or death from any cause (whichever occurs
first).
3.2.3, safety indicators
The subject's vital signs, blood routine, liver function, blood
biochemistry, urine routine, stool routine, coagulation function, left
ventricular ejection fraction (LVEF), creatine phosphokinase, vitamin E,
and bleeding risk.
4. study population
4.1 Inclusion criteria
(1) Age≥18 years old
(2) According to the updated NF 1 diagnostic criteria of the National
Institutes of Health (NIH) in 2021,
1
6 or more CALMs:d> 5 mm before puberty or d> 15 mm after
puberty;
2
2
or
more
neurofibromas
of
any
type
or
1
plexiform
neurofibroma;
3
Plaques in the axillary or inguinal area;
4
Optic glioma (OPG);

5
Slit lamp examination of 2 or more Lisch nodules, or optical
coherence tomography (OCT) / imaging of two or more near infrared (NIR)
abnormalities;
6
Characteristic bone lesions, such as sphenoid dysplasia and
anterolateral curvature of the tibia;
7
Pathogenic heterozygous NF 1 variants with allelic variant
scores of 50% in normal tissues (such as leukocytes);
Patients with no parental history and fulfilling 2 or more clinical
characteristics could be diagnosed with NF 1
Parents with a history of 1 or more clinical features can be
diagnosed with NF 1
(3)
Before
enrollment,
a
head
and
neck
surgeon
performed
a
pathological biopsy of the solid tumor to clarify the pathological
diagnosis and exclude the malignant peripheral schwannoma (MPNST)
(4) At least one measurable tumor lesion according to the efficacy
evaluation criteria of solid tumors RECIST 1.1
(5) The tumor infringes on the brain, spine and other important organs,
with no indication for surgical resection
(6) The performance status of the Eastern Cooperative Oncology Group
(Eastern Cooperative Oncology Group, ECOG) was 0-1
(7) Blood routine: white blood cell count (WBC) 3.010
9/ L; Absolute
neutrophil count (ANC) 1.510
9/ L; Platelet (PLT) 10010
9/ L; hemoglobin
level
(HGB)
9.0
g/dL
(no
corresponding
supportive
care,
such
as
transfusion and increased leukocytes within 7 days).
(8) Liver function: 2.5 times aspartate aminotransferase (AST) and
alanine aminotransferase (ALT); albumin (ALB) 30 g / L.
(9) Renal function: serum creatinine 1.5 times ULN or creatinine
clearance (CrCl) 50 mL/min (using the Cockroft / Galt formula); urinary
protein (UPRO) <(+ +), or 24-hour urinary protein <1.0 g.

(10) Cardiac function: blood creatine phosphokinase 200U / L, left
ventricular ejection fraction (LVEF) 50%;
(11) Did not participate in other clinical trials within the previous
30 days;
(12) Patients who voluntarily participate in the project and sign the
informed consent form.
4.2 Exclusion criteria
(1) The patient had abnormal blood index, abnormal liver and kidney
heart function, and cannot tolerate the clinical study process after
multidisciplinary consultation and evaluation
(2) The patient has become a malignant peripheral nerve schwannoma
(MPNST) or has other serious complications such as malignant tumors and
heart disease, or has previously undergone anti-tumor therapy such as
surgery, chemotherapy and radiotherapy
(3) The whole clinical study cannot be completed due to personal,
social and economic reasons
(4) There are previously serious systemic system diseases and the
disease cannot be cured or drug control
(5) Patients who are present in pregnancy
4.3 Lifestyle considerations (lifestyle related restrictions: smoking,
drinking, exercise, diet, etc., and what measures will be taken if the
subject needs drugs, treatments or surgery prohibited in the protocol)
After entering the clinical study, the subject needs a light diet,
food, tobacco, alcohol, and no strenuous exercise. If the subject needs
the medication, treatment or surgery unrelated to the clinical study, the
investigator needs to evaluate the cause of the need for the drug,
treatment and surgical treatment is the cause of the study, additional
treatment due to accident or other reasons, consider the influence of the
treatment on the study, and suggest the subject to receive conventional

treatment after withdrawal and seal the subject data.
4.4 Screening failures (definition of screening failures and how to
process screening failed subjects)
Screening failure refers to the recruitment of subjects who failed
to
meet
the
inclusion
criteria
or
the
exclusion
criteria
after
multidisciplinary
evaluation.
The
study
will
inform
the
multidisciplinary consultation and give the current best treatment
advice.
4.5 Recruitment and retention strategy (how to recruit subjects (location,
method,
expected
number
of
people......);
How
to
retain
subjects
(multiple contact information, incentive); such as involving vulnerable
groups: reason + safeguard measures; if having compensation or incentive
measures: object, quantity, form, time, etc.)
This study will take offline, combining online recruiting subjects,
offline main location for sun Yat-sen memorial hospital
oral and
maxillofacial surgery, including but not limited to posters, leaflets,
lectures and other forms to attract more subjects, each interested
patients on-site registration, leave contact information and continue to
one-on-one explanation. If the subject is in financial difficulties, the
investigator team will assist the subject in providing assistance with
the charity fund application to reduce the financial burden of the
subject.
5. research design
5.1 Overall design (including assumptions, type, etc.)
This
study
hypothesized
selmetinib
hydrosulphate
capsules
for
neurofibromatosis type I, including improving the resectable range of
surgery, shrinkage, delaying progression, reducing recurrence, and
improving function. A prospective, single-arm, phase study design is

estimated to improve the resectable range of NF 1 surgery, with objective
response rate (ORR) in 40%, duration (DOR) in more than 30% of patients,
and progression-free survival (PFS) in more than 12 months in 90% of
patients.
5.2 Study design process
5.2.1 Study the specific implementation process
This study started from the recruitment of subjects, with clinical
diagnosis, definite diagnosis by pathological biopsy, primary screening
according to inclusion criteria, and exclusion criteria, and enrollment
after signed informed consent. Patients evaluated as no indication for
surgical resection and treated with selmetinib hydrosulphate capsules.
Based on individualized patient body surface area (BSA), oral selmetinib
hydrosulphate capsules daily (20-50mg bid) were evaluated for shrinkage
efficacy, ORR and surgical resection after 6 cycles.
Interview
Screen
ing
period
Drug 6 cycles
Surgery /
continued
medication /
follow-up
V1
V2
V3
V4
V5
V 6
V 7
V 8
V9
Follow-up time
1 Day
before
enroll
ment
And
1
cycle
after
V 1
And 1
cycle
after
V 2
And 1
cycle
after
V 3
Cycle
1
after
V4
And 1
cycle
after
V 5
And 1
cycle
after
V 6
For 3
cycles
after
V 7
For 3
cycles
after
V 8
Signed the
informed
consent form
√
Inclusion /
exclusion
criteria
√
Demographic
data
√
medical
history
√
√
√
√
ECOG grade
√
√
√
√
√
√
√
√
√
check-up
√
√
√
√
√
√
√
√
√

5.3 Methods to reduce bias (e. g., randomization, blindness, matching
method, etc.)
The end of this study was defined as the last subject who completed the
last follow-up or was lost to follow-up or died
5.4 Definition of end of study (e. g. last subject completes last
follow-up)
5.5 Statistical analysis
5.5.1 Sample size and calculation basis
The estimated sample size was based on the objective response rate.
The study hypothesis is that selmetinib sulphate capsule has shrinkage
effect on NF 1. The study parameters are set: α =0.025 (one side),
vital sign
√
√
√
√
√
√
√
√
√
electrocardiog
ram
√
√
√
√
routine blood
test
√
√
√
√
√
√
√
√
Blood
biochemical
√
√
√
√
√
√
√
√
Liver, kidney,
and heart
function
√
√
√
√
√
√
√
√
coagulation
function
√
√
√
√
√
√
√
√
Heart
ultrasound
√
√
√
√
Pathological
biopsy
√
Infectious
disease
examination
(hepatitis B,
hepatitis C,
HIV, syphilis)
√
Imaging
examination
√
√
√
√
complication
And adverse
event
assessment
√
√
√
√
√
√
√

Power=90%. Based on the results of relevant study or pre-test, the
objective response rate (ORR) is expected to reach 40%, 29 cases were
calculated using PASS 15.0 software, and considering 10% shedding rate,
33 subjects should be included.
5.5。2 Data analysis set (e. g. full analysis set, compliance protocol
set, safety analysis set)
Statistical analysis will be performed using the SAS statistical
software
(V.9.4, SAS
Institute)
Statistical
analysis
software
for
calculation,
if
no
special
instructions,
the
main
indicators
use
one-sided test, control the first class error α is 0.025, the remaining
indicators use two-sided test, one class error is α =0.05. To calculate
confidence intervals, calculate two-sided 95% confidence intervals if not
otherwise specified.
(1) Full analysis set (full analysis set, FAS): consisting of all
subjects who received at least one drug / treatment and obtained efficacy
assessment. This dataset was derived from all subjects after removing
subjects in the least and reasonable way.
(2) Safety analysis set (safety analysis set, SS): a population
treated at least once / once and having at least one safety evaluation
data. In the safety analysis, all patients will be analyzed by the actual
drug drug group.
(3) Compliance with the protocol set (per-protocal set, PPS): all
concomitant medications that met the trial protocol and did not use the
impact effectiveness evaluation, good medication compliance (between 80%
and 120%), excluded subjects who had major protocol violations and were
judged to have a significant impact on the results. All protocol
deviations excluding subjects from the compliant protocol set will be
described in detail in the Statistical Analysis Plan (SAP) and completed
prior to data lock.

5.3 5 Statistical analysis plan
Data description of statistical analysis, analysis method of primary /
secondary indicators / safety indicators, statistical school positive
method, control of bias, stratification / subgroup / sensitivity analysis,
etc
Demographic, and other baseline characteristics
Based on the analysis of FAS set, the demographic data, medical
history, vital signs and other baseline data were statistically described,
where the measurement data (age, BMI, XX, etc.) gave mean, SD, minimum,
maximum, median, and gave frequency and corresponding percentage for
count data (gender, XXX, etc.).
Analysis of efficacy indicators
(1) Main efficacy indicators
Point estimates for the main evaluation index (ORR) and estimated
two-sided 95% confidence intervals using the Clopper-Pearson exact
probability method. If the lower limit of the 97.5% confidence interval
was less than the ORR rate of the historical control, the efficacy was
considered better than the historical control.
(2) Secondary efficacy indicators: analysis using FAS and PPS
analysis sets. For survival metrics, the digit survival time and its
two-sided 95% confidence intervals were calculated. For the rate of each
index, point estimates were performed and two-sided 95% confidence
intervals were estimated using the Clopper-Pearson exact probability
method. For the continuity index, the mean and two-sided 95% confidence
intervals were calculated based on the normal distribution method,
otherwise
the
median
and
two-sided
95%
confidence
intervals
were
calculated based on the percentile method.
Safety index analysis

The SS set was used to provide a statistical description of the
incidence of adverse events / serious adverse events and adverse reactions,
and to list the details of the occurrence of each adverse event in each
subject, including the type and severity of adverse events. Evaluation
of laboratory indicators, vital signs, electrocardiogram and other safety
related indicators, compare and evaluate the changes before and after
treatment, and give a statistical description of the clinical evaluation
(normal, abnormal without clinical significance, abnormal with clinical
significance, not checked) before and after treatment.
Principles of handling missing / deletion / follow-up data
LOCF (last observation carried forward), that is, the main index data
is not observed at the last time; the secondary indicators and safety
indicators are not filled.
6. Research intervention
*
6.1 Study intervention content (description of intervention content,
implementation steps, dose and route of intervention drug, frequency of
intervention, product of test group and control group, etc.)
All
patients
received
oral
selmetinib
hydrosulphate
capsules
(20-50mg bid) daily for 30 days for 6 cycles on patient body surface area
(BSA).
6.2 Preparation / handling / storage / responsibilities (allocation plan
for the drug and control article when the intervention is drug)
Use of a medication must be recorded in the patient's medical record
and in the appropriate location of the CRF. After the enrollment of the
subjects and at the 1st and 2nd months of follow-up, the executive nurse
shall receive the corresponding number of drugs at the drug administrator,
and the remaining drugs and packaging boxes shall be returned to the drug

administrator. If the drug is found or damaged during the preparation
process, this box of drugs should not be used, the damaged drugs shall
be treated as empty bottles, and other undamaged drugs shall be returned
to the drug administrator together with the packaging box. The study
center shall be responsible for the management of test drugs, including
receiving, distribution, counting and recovery. The investigator shall
ensure that the test drug is stored in a safe, independent and locked place
at the study site and that the storage conditions shall meet the storage
requirements of the test drug. No one can be contacted without the consent
of the investigator. Empty boxes shall be stored and managed as the test
drug.
6.3 Study Intervention Compliance (How to maintain, evaluate, and verify
study compliance)
After each medication, the subject should be required to return to
the study center for review, and the compliance of the study can be
verified according to the subject's review. During the late follow-up,
the study team members must conduct a telephone follow-up communication
with the subject and reasonably arrange the review visit.
6.4 Concomitant therapy (permitted adjuvant medication, complementary /
replacement therapy)
If the subject has hypertension, diabetes, coronary heart disease and
other diseases that need long-term drug control, the investigator and the
relevant specialist should evaluate the impact of the disease and the
relevant study protocol and determine the dose and duration of adjuvant
medication.
6.4.1 Rescue (drug, treatment methods, relevant records......）
The life hazards during the implementation of the clinical study
protocol should be implemented in accordance with the clinical rescue plan,
such as cardiopulmonary resuscitation, emergency airway management,

emergency surgical treatment, relevant records during hospitalization
should be recorded in the medical record system, after discharge should
be recorded in the adverse event record form, and the investigator should
analyze whether the rescue causes are related to the study and discuss
and discuss synchronously in the rescue records.
7.
Discontinuation
of
the
study
intervention
/
subject
discontinuation and withdrawal
*
7.1 Study Intervention discontinuation (reasons / criteria: such as how
many adverse events occurred, length of study discontinuation, how data
were collected during discontinuation and how to reactivate the study
intervention, whether follow-up was continued during discontinuation)
If the Grade 5 adverse event of CTCAE 5.0 standard reaches 10% of the
number of subjects, the study should be discontinued, and the drug safety
of the study protocol should be discussed to determine whether to adjust
the dose of drugs in the study protocol, continue the follow-up during
the study suspension, and maintain the follow-up record of the original
subject.
7.2 Subjects discontinuation / withdrawal from the study (possible reason
for subject discontinuation; involving implantable device, discuss how
to remove / replace, obtain alternative materials, later contact with the
subject, etc.)
When
the
subject
stops
or
withdraws
from
the
study
due
to
dissatisfaction with the treatment effect of the study plan or his own
economic reasons, he should actively communicate with the subject,
encourage the subject to actively treat and help them apply for public
welfare funds to complete the treatment. If the subject clearly withdraws,
the investigator can continue to complete the follow-up without the study
intervention.

7.3 Loss to follow-up (measures to reduce and reduce missing data due to
loss to follow-up)
The investigator should keep the contact information of multiple subjects
and the contact information of the family members after the subjects are
enrolled. The investigator should actively contact the subjects by phone
after leaving the hospital, timely understand the condition and arrange
the subject to the hospital in advance for the next stage of treatment.
8. Adverse events and unexpected events
Adverse events (AEs) are adverse medical events occurring after the
subject receives treatment, but they are not necessarily causally related
to the treatment. An adverse event can be any adverse and unexpected signs
(including
abnormal
laboratory
findings),
symptoms,
or
illness
associated to the use of treatment, regardless of relation to treatment.
It includes, but is not limited to,:
(1) the exacerbation of the preexisting disease before the use of the
study treatment measures;
(2) The frequency or severity of existing episodes before the use of
study treatment;
(3) Abnormal changes detected or diagnosed after the use of the study
treatment measures, although such abnormal changes may have existed
before the treatment;
(4) deterioration of disease or symptoms that persisted before the
study.
Causal relationship between adverse events and treatment measures:
In the trial, the investigator should make a comprehensive analysis
according to the specific situation of adverse events and the past history,
concomitant diseases and concomitant medication to judge the relationship
between adverse events and treatment measures. The relationship between

adverse events and treatment measures is divided as "definitely related,
most likely related, likely related, possibly unrelated and unrelated".
None: Adverse events were not associated with treatment measures.
Probably unrelated: The occurrence of adverse events is more likely
related to other factors such as medication or concomitant
Disease, or the timing of the event suggests that it is unlikely to
be causally related to treatment measures.
Possible concern: Adverse events may be caused by therapeutic
measures. Cannot exclude whether it may be caused by other
Factors, such as: medication conditions or concomitant diseases. The
occurrence of adverse events and treatment measures have a reasonable time
order, and the causal relationship between events and treatment measures
cannot be excluded.
It is likely that: adverse events may be caused by treatment measures.
There is a reasonable temporal sequence of event occurrence and treatment
measures.
Positive concern: The type of adverse event has been identified as
treatment and no other reason
Explanation, such as: medication status and concomitant diseases. The
timing of the event strongly suggests causality.
The adverse event severity criteria can be according to the CTCAE
5.0 (US Department of Health and Human Services). Beyond the above
criteria list, refer to the following criteria:
Mild: Symptoms or signs but tolerable.
Moderate; discomfort enough to interfere with normal life.
Severe: Normal activities are already impossible.
All information about adverse events, whether mentioned by the
patient, found by the investigator, or found by physical examination,
laboratory examination, etc., should be recorded on the study medical

record and case report form. During the trial, the time, duration,
symptoms, signs, severity, measures taken, outcome and relationship
assessment of adverse events should be carefully observed and recorded,
and the trial should be appropriately followed up.
Possible adverse events include: medication-related complications;
procedure-related
complications;
and
related
complications
after
withdrawal.
The investigator should use medical terms / concepts to record AEs
or SAEs. Its type, degree, occurrence time, duration, treatment measures,
treatment are recorded in detail. The association of the combination of
complications and medication with the study treatment was evaluated. All
AEs (including SAEs) should be recorded on the Adverse Event Form for the
CRF. Any patient who is treated must be evaluated for toxicity. The
occurrence of any adverse events (AEs) should be graded according to the
NCI Common AE classification criteria (NCI-CTCAE version 5.0).
9. Data collection and management
9.1 Case report form / electronic data records
Prior to the study start, the Redcap electronic database / EDC
database was established based on the content of the paper version of the
case report form.
9.2
Data
management
(data
collection
form,
data
storage
carrier:
electronic / paper, data integrity inspection, database establishment
method, data management system, data quality detection method, definition
of data lock library, etc.)
The original data should be uniformly recorded in the study medical
records. According to the content of the study medical record, the case
report form can be completed in the electronic database to ensure the
integrity and accuracy of the information. In order to ensure the accuracy

of the data, the researcher should conduct self-examination no less than
twice a year, regularly appoint personnel to the sub-center for project
quality control, and accept the examination by the hospital and school
management departments. If the data registered in the case report form
/ electronic database are inconsistent with the original records (study
medical records), the investigator shall organize timely verification of
the data, modify the wrong part according to the requirements of GCP
regulations, and make corresponding explanations if necessary.
10. Ethics requirements
This study complied with the provisions of Good Clinical Practice
and the Administration of Investigator-Initiated Clinical Studies (Trial)
and the Declaration of Helsinki. This study will be conducted only before
the ethics committee of the trial. In the course of the study, the revised
protocol must be resubmitted to the Ethics Committee for review, and the
investigator must wait until the consent of the Ethics Committee before
implementing the new protocol.
Each enrolled patient must sign an informed consent form. Copies of
the informed consent form and contact information of the investigator and
the ethics committee must be provided to the requested patients
*. This
study will collect the clinical data and personal information of the
research subjects for scientific research, which will involve the privacy
rights of the patients. The study participants and the data analysts
signed a confidentiality agreement not to disclose the personal patient
information and disease-related information to any individuals and
institutions unrelated to the study. The collected patient data should
be managed to prevent personal privacy leakage.

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