Effect of Regional Anaesthesia and General Anaesthesia on Postoperative Delirium in Elderly Patients Undergoing Hip Fracture Surgery: a Multicenter Randomized Controlled Trial.
Phase: NA
Conditions: Post Operative Delirium
Sponsor: Wenzhou Medical University

Study on delirium after hip fracture in elderly patients with local anesthesia and general anesthesia
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Regional or General Anesthesia for Post-operative
Delirium
in
Patients
Undergoing
Hip
Fracture
Surgery
Abbreviations: RAGA-Delirium
Clinical trails No.: NCT02213380
Unit Leader: 01 Second Affiliated Hospital of Wenzhou Medical University
Participants:02 Tongji Hospital, Huazhong University of Science and Technology
03 West China Hospital, Sichuan University
First Affiliated Hospital of Third Military Medical University
(Southwest Hospital)
05 First Affiliated Hospital of Wenzhou Medical University
06 Second Affiliated Hospital of Zhejiang University Medical
College
07 Beijing Jishuitan Hospital
08 First Affiliated Hospital of Nanchang University
09 Second Affiliated Hospital of Anhui Medical University
10 Ningbo Second People's Hospital
11 Taizhou Hospital, Zhejiang Province
12 Lishui People's Hospital
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8 July 2014

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Confidentiality statement
The clinical research thinking, data, and other relevant information in this
document are owned by the Second Affiliated Hospital of Wenzhou Medical
University. We allow the research unit members, the ethics committee, and
other clinical research-related institutions to read. Do not leak this plan without
the consent of the team leader!

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Program summary
Name of study
Prospective, multicenter, large sample, randomized controlled study of
the effect of local and general anesthesia on postoperative delirium in
elderly patients with hip fractures
Purpose of the
study
To evaluate the effect of two anesthetic methods on the incidence and
prognosis of delirium in elderly hip fracture
Clinical trial
units
Clinical trial leader:
Clinical trial
participants:
01 Second Affiliated Hospital of Wenzhou Medical
University
02 Tongji Hospital, Huazhong University of Science
and Technology
03 West China Hospital, Sichuan University
First Affiliated Hospital of Third Military Medical
University (Southwest Hospital)
05 First Affiliated Hospital of Wenzhou Medical
University
06
Second
Affiliated
Hospital
of
Zhejiang
University Medical College
07 Beijing Jishuitan Hospital
08 First Affiliated Hospital of Nanchang University
09 Second Affiliated Hospital of Anhui Medical
University
10 Ningbo Second People's Hospital
11 Taizhou Hospital, Zhejiang Province
12 Lishui People's Hospital
Research Design Prospective, multicenter, large sample, randomized controlled study design
Research
population
Elderly patients with acute hip fractures on one side requiring surgical
treatment
Selection
criteria
1. age greater than or equal to 65
2.ASA Ⅰ~ IV
3. Voluntary signature of informed consent
Exclusion
criteria
Complex 1. injuries: multiple fractures, chest, abdomen, pelvic and sacral
trauma, head trauma, etc
2. contraindications of intraspinal anesthesia: coagulation dysfunction,
thrombocytopenia, intraspinal space-occupying, infection of the puncture
site, etc
3. relative contraindications of general anesthesia: known difficult airway,
malignant hyperthermia, etc
4. nerve block taboo: puncture site infection, peripheral neuropathy, local
anesthetic allergy, etc

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5. have participated in other clinical studies
Research
Groups
1. local anesthesia group (RA group)
2. general anesthesia group (GA group)
Main indicators Incidence of delirium within 7 days after the operation
Secondary
indicators
Type, severity, duration of 1. delirium (DRS-R-98 scale diagnosis);
2. postoperative pain score (pain VAS score);
3. other related complications and outcomes: related complications:
pulmonary infection, myocardial infarction, renal failure, gastrointestinal
bleeding;
4. length of stay;
5. mortality rates during hospitalization and 30 days after surgery;
6. the total cost of hospitalization and anesthesia;
Follow-up for 6 months and 1 year of 7. discharge: incidence, type,
severity, cognitive function, quality of life, mental condition, the mortality
of delirium.
Statistical
analysis
Comparison of incidence of delirium, degree of delirium, type of delirium,
and prognosis of patients
Expected test
progress
2 years

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Directory
Programme summary......................................................................................3
1.
Background and significance of the study.......................................................6
2.
Research topics................................................................................................9
3.
Purpose of study..............................................................................................9
4.
Research Design.............................................................................................. 9
5.
Case selection..................................................................................................9
5.1
Research population........................................................................................9
5.2
Selection criteria..............................................................................................9
5.3
Exclusion criteria............................................................................................. 9
5.4
Termination criteria.......................................................................................10
5.4.1
Patient standard............................................................................................ 10
5.4.2
Research Standards.......................................................................................10
6.
Random grouping..........................................................................................10
7.
Anaesthesia:.................................................................................................. 11
8.
Main indicators:.............................................................................................12
9.
Secondary indicators:....................................................................................12
10.
Data collection...............................................................................................14
11.
Technical route:............................................................................................. 15
12.
Adverse event reports...................................................................................17
12.1 Adverse events.................................................................................................... 17
12.2 Serious adverse events........................................................................................18
13.
Data management and statistical analysis.................................................... 20
14.
Test management..........................................................................................22
15.
Test quality control........................................................................................19
16.
Data preservation..........................................................................................20
17.
Publication of papers.....................................................................................20
18.
References.....................................................................................................20

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1.
Background and significance of the study
Delirium, also known as acute consciousness disorder, is an acute organic brain
syndrome with attention, feeling, thinking, memory, mental exercise, and sleep
cycle disorders occurring in a short period, characterized by restlessness,
multilingualism, orientation disorders, and unanswered questions. Age (≥65) and hip
fractures are major risk factors for delirium. The incidence of delirium in elderly
inpatients was reported in 14%~56%, while in elderly patients with hip fractures, the
incidence of delirium was 32%~53.3% higher. An incidence of postoperative delirium
was reported in 11.1%~44.8% in elderly patients. The incidence of postoperative
delirium was higher in 20.3%~60.9% in elderly patients with hip fractures.After
delirium occurs, diazepam or psychotic drugs are often needed to increase nursing
requirements and the risk of falling while delaying the time of autonomous activity
and hospital stay and increasing medical costs. During recovery, delirium increases
mortality (figure 1), and disabilitycan also increase the incidence of dementia.
Dysfunction also causes persistent depression or anxiety.
Elderly patients are prone to low-activity delirium, which is not easy to detect
and is easily misdiagnosed as cognitive decline, depression, or dementia.Han results
suggest that low activity type is very common in the emergency department,76% of
which are missed by emergency doctors. Ouimet et al. found that delirium incidence
was 70%, 2/3 of delirium was poor, mortality was higher, and high activity outcome
was generally better, which was closely related to low activity type identification
and misdiagnosis. Mixed delirium (alternate low activity and high activity) is severe,
and cognitive impairment is more severe.However, some studies have suggested
that the prognosis of low active delirium in elderly patients with hip fracture is
higher than that of active delirium. There are many reasons for misdiagnosis or
missed diagnosis of delirium, one of which is that clinicians pay less attention to
delirium and often underestimate the incidence, severity, and delirium outcome. A
British questionnaire found that young doctors lack the basic knowledge of diagnosis
and management of delirium and lack understanding of the prevalence and clinical
significance of delirium. Delirium is traditionally considered a temporary disease, but
there is growing evidence that delirium is often persistent, poor after recovery, and
increases dementia and cognitive impairment.Coler, a systematic review of 18
prospective studies, found continuous delirium common at discharge; the rate is
44.7%, The incidence of delirium was 32.8%,25.6%, and 21% in 1,3 and 6 months
after discharge; poor prognosis in mortality, function, and consciousness in patients
with persistent delirium. Dasgupta's systematic review found, Continuous delirium is

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associated with hypoactive delirium, Can increase the severity of delirium, Cognitive
impairment, Causes many kinds of complications and so on; Meanwhile, The author
also believes that the existing information can not fully explain this problem .
One of the important medical interference methods in treating patients by
anesthesia surgery is closely related to delirium occurrence and development. There
are few studies on the relationship between anesthesia and delirium, which can
reduce the incidence of delirium. Although simple local anesthesia avoids the
disturbance of general anesthesia to patients' mental state, it has not been
confirmed whether to reduce delirium. Sieber etcShallow sedation (BIS BIS<80)
reduced the incidence and duration of postoperative delirium compared with deep
sedation (BIS<50) in elderly patients with hip fractures. However, at home, Yue
waitedIt was found that general anesthesia with different anesthetic depth and
mode had no significant effect on early delirium incidence in patients with hip
arthroplasty. Tan Gang, China,The results of epidemiological investigation of
postoperative delirium in elderly patients with non-cardiac surgery showed that
general anesthesia was not a risk factor for delirium; the risk factors related to
anesthesia were the occurrence of perioperative hypotension, the use of
scopolamine and pethidine. Abou-Setta etc. The results showed that local nerve
block analgesia did not reduce postoperative delirium incidence. Mouzopoulos andA
randomized controlled study of iliac fascia block and perioperative delirium in hip
fracture showed that iliac fascia block reduced delirium incidence compared with
placebo. Clegg and YoungStudies on different drugs and delirium suggest that
opioids, benzodiazepines, and blood pressure-lowering drugs dihydropyridine can
increase delirium incidence. However, the authors also stress insufficient evidence
to support it. Lonergan etc. A study of ICU patients suggested that lorazepam
increased delirium interval compared with dexmedetomidine. The results did not
suggest that benzodiazepines could be used to treat delirium.
Current Vague Assessment Scale of Consciousness (Confusion Assessment
Method, CAM) It is still the most widely used delirium diagnostic tool for
non-psychiatric specialists. Its items are simple, accurate, and easy to use. It is
widely used in clinical and research. The limitation is that patients with language
disorders can not be assessed, it is difficult to distinguish delirium from dementia,
depression, or other mental illness, and the severity of delirium can not be assessed,
so it is difficult to grasp the fluctuation of the condition dynamically. CAM-ICU scale.
Has been shown to be used to diagnose delirium in patients with severe ICU tracheal
intubation or verbal communication. Its multi-language translations, including
Chinese versions, have also been shown to have high reliability and validity in clinical

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applications. The CAM-ICU scale has been proved to be effective in the diagnosis of
postoperative delirium in the recovery room (PACU) of anesthesiology. The recent
review of delirium emphasizes that patients with delirium should be classified into
exercise subtypes, the severity of delirium should be assessed, and the fluctuation of
delirium should be dynamically monitored, which is beneficial to the diagnosis of
etiology, treatment, cognitive impairment and outcome. At present, there is a
delirium rating scale (Delirium Rating Scale, DRS), delirium rating scale-98 revised
edition (DRS-R-98), memory delirium evaluation scale (Memorial Delirium
Assessment Scale, MDAS) and so on. DRS-R-98 delirium scale. It is considered to be
an effective and credible delirium severity scale; it can be used to distinguish
delirium from other mental disorders such as Alzheimer's disease, schizophrenia,
and depression, to classify delirium and to continuously observe the changes of
delirium patients' condition. The scale has been translated into Chinese and
confirmed to have high reliability and validity.
This study's significance is to observe and compare the effects of general
anesthesia and local anesthesia on delirium and other related complications after
hip fracture in the elderly through prospective, large sample, multicenter and
randomized controlled clinical studies. The following questions are identified:
1)
Is there any difference between general anesthesia and local
anesthesia in the occurrence, severity, attack type, and delirium duration after hip
fracture in the elderly? Which anesthetic method can reduce the incidence of
postoperative delirium?
2)
Is there a difference in the effect of the two anesthetic methods on
postoperative delirium in different older people (elderly, dementia, or delirium)?
3)
Do various factors (hypotension, drugs, pain, etc.) during anesthesia
affect postoperative delirium and extent?
4)
To analyze whether the control of anesthesia can reduce the medical
expenses and related economic benefits caused by delirium.
5)
The relationship between the classification and duration of delirium
and patients' prognosis; does delirium lead to long-term cognitive dysfunction? How
does it affect patients and their families' quality of life? The survival rate in patients
with delirium?

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2.
Research topics
A randomized, controlled, multicenter, prospective study of the effect of local
and general anesthesia on postoperative delirium in elderly patients with hip
fractures
3.
Purpose of the study
To evaluate the effect of two anesthetic methods on the incidence and
prognosis of delirium in elderly hip fracture
4.
Research Design
using prospective, multicenter, large sample, randomized controlled study
design. Randomly enter local anesthesia group or general anesthesia group at 1:1.
According to the domestic literature report of postoperative delirium in elderly
patients, the sample size estimation estimated that postoperative delirium
incidence is about 26. Assuming that postoperative delirium incidence after local
anesthesia is less than 30% of general anesthesia, the calculated sample size is 441
nα= each group. The provisional total sample size is 1000 cases. The sample size can
be adjusted according to the progress of the study and the results in the medium
term.
The number of cases in each center is 100. Because of the central random
system, the number of cases in each center can be automatically adjusted according
to the actual situation of the subjects recruited.
5.
Case selection
5.1 Research population
Elderly patients with acute (≦3 weeks) hip fractures on one side need surgical
treatment.
5.2 Selection criteria
1) Age greater than or equal to 65
2) ASA Ⅰ~ IV
3) Voluntary signature of informed consent
5.3 Exclusion criteria
1)
Compound injury: multiple fractures, chest, abdomen, pelvic and

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sacral trauma, head trauma, etc.
2)
Intravertebral anesthesia contraindications: coagulation dysfunction,
thrombocytopenia, intraspinal space-occupying, puncture site infection,
etc.
3)
relative contraindications of general anesthesia: known difficult airway,
malignant hyperthermia, etc.
4)
Nerve block contraindication: puncture site infection, peripheral
neuropathy, local anesthetic allergy and so on.
5)
Have participated in other clinical studies.
5.4 Termination criteria
5.4.1
Patient standard
5.4.1.1 Subject may withdraw from the study at any time without giving any
explanation and without losing the right to future medical care;
5.4.2
Research Standards
5.4.2.1 Use of drugs in violation of program requirements during observation;
5.4.2.2 Other conditions that may increase the risk of the patient;
5.4.2.3 serious complications occurred during observation.
6.
Random grouping
After obtaining informed consent, all selected patients were randomly
grouped by network or telephone central random system (1∶1):
1)
local anesthesia group (RA group): epidural anesthesia, lumbar
anesthesia, combined spinal anesthesia, nerve block (but the failure
rate is high, not recommended).
2)
General anesthesia group (GA group): general anesthesia + nerve
block, general anesthesia, intraspinal anesthesia, simple general
anesthesia.

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7.
Anesthesia:
Because
of
the
particularity
of
senile
anesthesia,
experienced
anesthesiologists are required to carry out anesthesia. They need to master
nerve block, intraspinal anesthesia, and general anesthesia and be competent
for anesthesia in elderly hip fracture surgery.
1)
Preoperative, intraoperative, and postoperative patients were
prevented from using any sedative drugs other than intravenous
anesthetics (e.g., midazolam, dexmedetomazole, etc.) if surgical
reasons for postoperative use of sedative drugs should be recorded
in detail.
2)
General anesthesia group, propofol or etomidate intravenous
induction, anesthesia should be as simple as possible. Drugs such as
ephedrine, opioids, atropine, and other drugs that have a certain
impact on the spirit of consciousness should be used with clinical
indications and recorded on the CRF table. All-body anesthesia can
be performed before completing the nerve obstruction lag (or
before), laryngeal mask, tracheal intubation, or mask can be passed
through,
mechanical
ventilation,
or
spontaneous
ventilation.
Intraoperative use of intravenous analgesics, inhalation anesthesia
(sevoflurane or isoflurane), or intravenous anesthesia to maintain
general anesthesia. Iliac fascia block "3 in1" block, femoral nerve
block, or posterior lumbar plexus block; single nerve block or a
continuous nerve block can be used.
3)
The local anesthesia group can use nerve block analgesia before
operation
(anterior
femoral
nerve
or
iliac
fascia
block
is
recommended to relieve pain in position) or opioid drugs (avoid
pethidine), and then epidural anesthesia, lumbar anesthesia, or
combined
spinal
anesthesia
puncture.
Do
not
use
sedation
techniques and related adjuvant sedation drugs. If sedative drugs

Study on delirium after hip fracture in elderly patients with local anesthesia and general anesthesia
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are used for surgical or other reasons, please record them in detail.
4)
Intraoperative anesthesia management: if the anesthetic effect of
the local anesthesia group can not complete the operation, the
anesthesiologist can decide to use the drug or change the general
anesthesia and record it in detail. This study does not make any
provision for this situation. The general anesthesia group adjusted
the depth of general anesthesia according to the surgical stimulation.
Blood pressure reduction base value 30% or systolic blood pressure
less than 90 mmHg is hypotension, recommended for vasoactive
drugs or liquid treatment, the anesthesiologist can be appropriate
according to personal experience.
5)
Postoperative analgesia: various analgesia methods can be used
(intravenous, epidural, nerve block sustained or self-controlled
analgesia, or combined with oral medication), but both groups avoid
using any sedative.
Considering the actual situation and the particularity of geriatric anesthesia,
it is estimated that there will be some differences in the implementation of
anesthesia, puncture technique, and intraoperative management among the
research centers and anesthesiologists. The scheme does not provide for these
differences or differences.
8.
Main indicators:
Incidence of delirium within 7 days after surgery (CAM)
9.
Secondary indicators:
1)
Delirium type, severity, duration (diagnosed by DRS-R-98 scale)
2)
Postoperative pain score VAS pain score）
3)
Other related complications and outcomes: related complications:
pulmonary
infection,
myocardial
infarction,
renal
failure,

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gastrointestinal bleeding;
4)
Hospitalization time
5)
The mortality rate during hospitalization and 30 days after surgery
6)
The total cost of hospitalization and anesthesia.
7)
6 months and 1-year follow-up: incidence, type, severity, the
cognitive function of delirium (mini-mental state examination,
MMSE), quality of life (The MOS 36-item Short-Form Health Survey,
SF-36)Hospital Anxiety and depression scale, HADS mental state),
mortality.
Description:
The incidence of delirium before surgery includes (delirium from admission
to surgery). CAM scale is used for the diagnosis of delirium in the ward; the
CAM-ICU scale is used to diagnose delirium in the intensive care unit, that is,
CAM-ICU is used when the CAM is not available. When there is a contradiction
between the diagnosis obtained by the scale and the psychiatrist's diagnosis,
when there are still differences after consultation, the diagnosis of the
psychiatrist
shall
prevail.
To
prevent
missed
diagnosis,
we
should
communicate with the medical staff in the ward on time. After the patient is
selected, the family member or escort staff should be informed. The
researcher should be informed of the evaluation of delirium when any
abnormal performance of the patient's mood, consciousness, cognition and
so on is found. When postoperative delirium is found, the subject should
communicate with the competent physician and decide on further diagnosis
and treatment if the patient's performance was normal 7 d after the
operation, the visit ended, while the patient with continuous delirium was
followed up until normal or discharged. Delirium patients were assessed by
delirium rating scale 98 revised (DRS-R-98) for type and severity of delirium.
The patient's assessment form was used as evidence of postoperative
delirium and the duration of delirium.

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10.
Data collection
Arrange post-operative delirium assessment and data collection by a fixed
staff member who should not know about the study design and purpose to
reduce the error in the study report, assess the presence, type, severity of
postoperative delirium daily, patient medical records and nurse records are also
used to determine whether delirium occurs for a total of 7 days after surgery
(delirium was observed and discharged). The data collection table is shown in
Table 1. Besides, the mortality, hospitalization time, and discharge department
were recorded. Table 2 summarizes other data to be collected.

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Table 1 Data collected daily. P：days after surgery
Time points
Preoperati
ve
evaluation
P1
P2
P3
P4
P5
P6
P7
Temperature
✼
✼
✼
✼
✼
✼
✼
✼
Blood pressure
✼
✼
✼
✼
✼
✼
✼
✼
Heart rate
✼
✼
✼
✼
✼
✼
✼
✼
Oxygen
saturation
✼
✼
✼
✼
✼
✼
✼
✼
Hemoglobin
✼
✼
✼
✼
✼
✼
✼
✼
Alanine
aminotransferase
✼
✼
✼
✼
✼
✼
✼
✼
Alanine
aminotransferase
✼
✼
✼
✼
✼
✼
✼
✼
Album
✼
✼
✼
✼
✼
✼
✼
✼
Urea nitrogen
✼
✼
✼
✼
✼
✼
✼
✼
Creatinine
✼
✼
✼
✼
✼
✼
✼
✼
PH
✼
✼
✼
✼
✼
✼
✼
✼
PO2
✼
✼
✼
✼
✼
✼
✼
✼
PCO2
✼
✼
✼
✼
✼
✼
✼
✼
HCO3
✼
✼
✼
✼
✼
✼
✼
✼
Na
✼
✼
✼
✼
✼
✼
✼
✼
K
✼
✼
✼
✼
✼
✼
✼
✼
Cl
✼
✼
✼
✼
✼
✼
✼
✼
Delirium CAM or
not
✼
✼
✼
✼
✼
✼
✼
✼
DRS-R-98 of type
and
severity
of
delirium
✼
✼
✼
✼
✼
✼
✼
✼
VAS pain score
✼
✼
✼
✼
✼
✼
✼
✼
Table 2: Other data to be collected
Period
Data
Method
Preoperative
general data
Age, sex, address, type of fracture
History, ASA rating
Cognitive function (MMES)
Medical records
MMSE
Intraoperative
Methods of operation, level of the
surgeon, manner of anesthesia
Anesthesiologist
level,
anesthetic
substance, and dosage
Low blood pressure
Review of medical records
and anesthesia records

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Duration of operation estimated blood
loss
Postoperative
Length of stay, hospitalization costs,
anesthesia
costs,
adverse
events,
mortality
during
hospitalization,30-day
mortality,
withdrawal from the study
Telephone follow-up
6 months and
12
months
later
Whether delirium occurs, type and
severity
Mortality
Quality of life, anxiety or depression
Quality of life scale SF-36,
anxiety
and
depression
scale (HADS)
Review
of
patients'
families

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11.
Adverse event reports
11.1 Adverse events
11.1.1 Definition of adverse events and reactions
Adverse events (Adverse Event, AE) refer to any adverse symptoms, abnormal signs,
and abnormal laboratory results after the intervention study, whether there is a
causal relationship with the intervention. Any adverse events, including those
provided by the subjects voluntarily or obtained through inquiry by the researcher or
by physical examination, laboratory examination, or other examination methods,
should be recorded on the CRF and actively handled, followed closely until remission
or condition is stable.
Adverse reactions (Adverse Drug Reaction, ADR): harmful, rather than desirable,
results in a causal relationship with drug use during the normal application of the drug
at the prescribed dose.
11.1.2 Records of adverse events
(1) All adverse events must be tracked, and the researcher must record them in the
corresponding section of the case report form and record the adverse events in
detail.
(2) Adverse event content: name of symptom or sign or diagnostic name of disease
or laboratory examination of an indicator abnormality.
(3) Date of onset of adverse events: date of the first occurrence of AE or related
symptoms AE subjects.
(4) End date of adverse events: date of cessation of AE or AE-related symptoms. If
the AE still exists, do not fill in the end date.
(5) Evaluation of the severity of adverse events
Mild: symptoms and signs present, but can tolerate, generally without
treatment
Moderate: Symptoms or signs cause discomfort, daily activities are limited,
appropriate treatment can be taken

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Severe: no ability to work and daily activities, need active treatment
(6) Measures taken :discontinuation of the relevant medication or treatment ; use
of therapeutic measures; and no measures are taken.
(7) Result of adverse events: persistence, improvement, mitigation
(8) Evaluation of the correlation between adverse events and anesthesia:
Five-level evaluation criteria:
Positive correlation: adverse events appear under a reasonable time order after
anesthesia;
The anesthetic method used to explain adverse events is more reasonable than other
causes;
The pattern of adverse events is consistent with the pattern of adverse reactions
caused by such anesthesia.
Maybe relevant: adverse events appear under the reasonable time order after
anesthesia;
The use of anesthesia to explain adverse events is more reasonable than other causes;
but do not rule out other reasons.
It may not be relevant: the occurrence of adverse events does not conform to the
reasonable time order after anesthesia; (Other causes may cause adverse events, but
the possibility of anesthesia can not be ruled out;None: The possibility of adverse
events resulting from or excluding from anesthesia by other causes);
Can not be determined: the occurrence of adverse events does not conform to the
reasonable time order after anesthesia; However, it is impossible to determine
whether it is related to anesthesia, nor can it be explained by other reasons.
11.2 Serious adverse events
11.2.1 Definition of serious adverse events (SAE)
In the course of clinical trials, such events as hospitalization, prolonged
hospitalization, disability, affecting working ability, endangering life or death, causing
congenital malformation, etc.
11.2.2 Serious adverse event handling process

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When serious adverse events occur, we should make every effort to rescue and
actively take various measures to avoid permanent damage. The SAE researcher must
notify the applicant, clinical trial organization, ethics committee by telephone or fax
within 24 hours from the beginning of the trial to the observation period, and fill in
the section of the case report form on serious adverse events. SAE's medical
information should also be reported to the applicant after 24 hours.
11.2.3 Reporting procedures for serious adverse events
(1) Applicant: Second Affiliated Hospital of Wenzhou Medical University
(2) Clinical Trial Institution/Ethical Committee of the Unit Leader
Second Affiliated Hospital of Wenzhou Medical University
Tel :057788002990 Fax :057788002925
11.2.4 Responsibilities of severe adverse events researcher
When a severe adverse event occurs, the researcher should actively take
appropriate medical measures, carry out rescue treatment, and notify the above
responsible person by telephone or fax within 24 hours.
11.2.6 Responsibility of applicants for serious adverse events
Assist researchers to report serious adverse events and take necessary measures
to ensure the safety of subjects.
11.2.7 Responsibility of the Inspector for Serious Adverse Events
Assist researchers to report serious adverse events and take necessary measures
to ensure the safety of subjects.
11.3 Adverse reactions recorded in (CRF) of the case report form
All adverse reactions should be recorded in the case report form (CRF) adverse
events.

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12.
Data management and statistical analysis
12.1 Input of case report form and completion of original record form
This study adopts an electronic case report form; researchers should input in
time to ensure accurate content and timely summary. The paper original record
form is used to record the study's relevant data, generally should not be altered, if
there is an error that needs to be modified, it should sign at the modification
place and sign the date of modification. The completed original record form
should be entered immediately into the electronic medical record report form.
12.2 Data entry and modification
12.2.1 Source file definitions
The source file is the first-hand information of clinical trial data recording. This
clinical study's source documents refer to the research medical records, informed
consent, physical and chemical examination reports, drug management documents,
quality inspection documents, etc.
12.2.2 Data recording and reporting
Any observation and inspection results in the study should be recorded in the
source file in a timely, accurate, complete, standardized, and true manner.
Changes to source files and source data must be sufficiently substantiated.
Otherwise, the first judgment (a record) shall prevail.
Data reporting uses a network-based "electronic CRF and data management
system. "
Data entry: independent double timely input.
The advantages of electronic CRF and data management system: to ensure that
the organizer can grasp the dynamic of each center test in time; to facilitate the
quality controller to review and question the data of each center in time through
the network platform, to improve the working efficiency and reduce the cost of
quality control; to set the data rules and ensure the quality of the data through the
network CRF,; to input the CRF data from each center to help each center find

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problems in time and correct them, and to export the data entered by the center
for academic papers with the permission of the team leader; After the completion
of the test, faster and more accurate completion of the statistical analysis report.
12.2.3 Data verification requirements
The Data Monitoring Committee will conduct a mid-term evaluation of the research
data, monitor the data, and hold occasional meetings to evaluate the research
data's security and effectiveness.
During site inspection (SDV), clinical research institutions shall provide
convenience and consult in prescribed places.
Data audit method: the inspector logs in the data monitoring end of the
electronic CRF and data management system in each center and uses the online
method to confirm the inconsistent data input. 100% check the consistency of
electronic CRF data with source data such as research medical records.
The reference of source documents should follow hospital medical documents'
regulations and the regulations of archives of drug clinical research institutions.
12.2.4 Requirements for Data Questions and Answers
Issue of questions: questions issued in logical checks and questions issued
during SDV are regularly logged into the system by the CRC- data entry officer, and
the organization's questions are downloaded to generate a data clarification table
(DCF).
Question answering: the CRC- data entry staff will DCF the corresponding
researcher to answer questions; the data is modified on the DCF, DCF saved as the
source file.
Online update: CRC- data entry will answer questions on the DCF online data
update.
Solution: the inspector SDV, the DCF, checks its authenticity and rationality; the
project data manager verifies the answer data," confirms the correct, "or" issues a
new question "when there is still a problem or a new problem. The question is
deemed to be resolved.

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Data entry is the responsibility of the designated data administrator. In order to
ensure the accuracy of the data, two data administrators should independently
input and proofread.
The data manager will question the case report form (DRQ) questions and send
questions to the researcher through the clinical inspector. The researcher should
answer and return them as soon as possible. The data manager will modify, confirm,
and input the data according to the researcher's answer and issue the DRQ. again if
necessary
12.3 Data locking
After confirming that the established database is correct, the data is locked by
the principal researcher, the applicant, and the statistical analyst. Locked data files
are no longer changed in principle.
Statistical analysis
12.4.1 Analysis of data sets
(1) Total Analysis Set (FAS): A collection of all cases randomly enrolled and
treated with at least one trial drug.
When analyzing the main curative effect index, the FAS concentration's missing
value is processed by carrying the results observed at the last time point to the
current (LOCF) method.
An Available Case Analysis principle is used to deal with the missing value in
the analysis of secondary efficacy index, general condition, and safety.
(2) Conformity with program set (PPS): a collection of cases that meet the
inclusion criteria and complete treatment in accordance with the provisions of the
trial program, i.e., cases that meet the trial program, have good compliance, have
not taken banned drugs, and have completed the evaluation of effectiveness (at
least primary efficacy), if any.
(3) Security data set (SAS): at least one treatment and actual data recorded
with a safety indicator evaluation.

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12.4.2 Content of statistical analysis
The main analysis includes:
(1) Distribution of cases between the two groups: Comparing total abscission
rate and abscission rate due to adverse events.
(2) Comparability analysis: Comparison of demographic data and other
baseline indicators to measure comparability between the two groups.
(3) Compliance analysis: To compare whether the two groups of patients were
using the test drugs on time and on time, and the drugs that were not banned in
the unused regimen.
(4) Validity analysis: both PP and ITT analyzed the main efficacy indicators;
since this study is a multicenter clinical trial, the effects of central effect and
baseline on efficacy indicators should be considered.
The incidence of delirium was compared by chi-square test, chi-square test,
CMH chi-square test, delirium exacerbation analysis, H analysis of data consistent
with normal distribution; otherwise, H test, single-factor analysis of delirium
aggravation, The data that do not conform to normal distribution are tested by rank
sum test or Kruskal-Wallis test (H test).
(6) Safety analysis: First of all, according to the requirements of the correlation
of adverse reactions, the list describes the adverse events and adverse reactions in
the two groups (including the number of cases of various adverse events, the
number of cases of "normally abnormal" before and after the test and the rate of
variation). The adverse reactions were statistically analyzed by the chi-square test.
12.4.3 Statistical analysis methodology
Metrological data: First, the normal test is carried out, and the methods of
t-test, pairing t-test, variance analysis, covariance analysis are used for those that
conform to a normal distribution, and rank-sum test, paired rank-sum test, H test
and so on are used for the data that do not conform to normal distribution.
Numbering data: using calibration chi-square test, Fisher accurate test, etc.;
grade data using Ridit analysis, CMH method.

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(3) Multi-center analysis of comprehensive efficacy: counting data using CMH
method; measurement data using covariance analysis.
All the statistical tests were bilateral, and the P-value was less than or equal to
0.05.
12.4.4 Data management and statistical analysis software
1. Data management and statistical analysis software
Beijing Baiaozhi Information Technology Co., Ltd. clinical research integrated
information platform (www.bioknow.net), using double independent input, check
the correct statistical analysis. The statistical analysis adopts SAS9.13 software
programming analysis.
(2) Setting of parameters in statistical analysis
The bilateral test (two-side test) was used for all hypothesis tests, and the α=
was 0.05. P ≤0.05, the reliability of all confidence intervals was 95.
13. Test management
13.1 Programme compliance
The approved plan shall carry out the test, and any deviations from the plan
shall be recorded.
13.2 Programme changes
13.2.1 Subject to the Ethics Committee's approval, this program shall be subject
to developing a "program modification specification ", signed by the lead
researcher. The proposal may be amended only with the consent of the applicant;
13.2.2 The program shall be amended and submitted to the Ethics Committee for
approval before implementation;
13.2.3 Any person participating in the test shall follow the GCP principle and shall
not violate the program. In the event of a breach of the program, it shall be
recorded in the original record sheet.
13.3 Case report form (eCRF)

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13.3.1 eCRF; completed by the researcher according to original records
13.3.2 Timely, accurate, complete, and reliable data recording;
13.3.3 The eCRF form shall be reviewed by the heads of the centers upon completion;
14.
Test quality control
14.1 After the start-up of the project, the centers will hold in-hospital start-up
meetings to train the pilot program, delirium assessment scale, and eCRF form;
14.2 Inclusion of cases in strict accordance with inclusion/exclusion criteria;
14.3 Both the applicant and the researcher shall implement a quality control and
quality assurance system for clinical trials using standard operating procedures in the
program:
a)
(a) The recording and preservation of raw materials must meet the GCP
requirements;
b)
The laboratory must have inspection qualification to ensure that the inspection
results are correct and reliable and can be properly preserved in the database;
c)
All observations and findings should be verified to ensure the reliability of the
data. Ensure that the conclusions of clinical trials are derived from raw data and
that quality control must be used at each stage of data processing;
d)
The applicant will monitor the research center on-site or by telephone during the
middle and end of the study, when the sub-research center begins to be selected.
e)
The designated researcher shall be responsible for formulating and implementing
the test rules;
f)
(b) Prior to the experiment, all the participants were trained in programs,
operations, and GCP;
g)
Participants in the test should strictly abide by the provisions of the program,
according to the procedures can not be arbitrarily changed;
h)
Designate statisticians to be responsible for the statistical processing of
comprehensive data;
i)
The original records shall be kept by a particular person and kept in each
sub-research center after the test.

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15.
Data preservation
According to the Clinical Trial Management Standard, the researcher should keep
the clinical trial data until 5 years after the clinical trial.
16.
Publication of papers
All research participants shall strictly keep confidential all information provided
by the second Affiliated Hospital of Wenzhou Medical University, and at the same
time require other participants and ethics committees to take the same
confidentiality measures, without written permission, Information shall not be
leaked to others.
The researcher and the applicant own all the data and results of this
experiment. The researcher may not publish himself without the consent of the
applicant. The applicant reserves the right to sign the paper. The applicant unit is
the unit to which the project results belong.