An Exploratory Randomized, Double-blind, Placebo-controlled Study on Compound Ciwujia Granules in the Treatment of Depression (Heart-Spleen Deficiency Syndrome)
Phase: PHASE4
Conditions: Depression - Major Depressive Disorder, Depression Disorders
Sponsor: Shanghai Mental Health Center

Study protocol （Version 4.0, Date Jul 09,2025） 
 
 
 
 
 
A randomized, double-blind, placebo-controlled 
exploratory study on compound Ciwujia granules 
in the treatment of depression (heart and spleen 
deficiency syndrome) 
   
 
    
Investigator:                  Liu Lanying                    
Department:     Department of Traditional Chinese Medicine    
Sponsor:             Shanghai Mental Health Center            
Funding Source:  Heilongjiang Quanle Pharmaceutical Co., Ltd.  
Version Number:               04                        
Date:                       July 09, 2025                      
 
 

Study protocol （Version 4.0, Date Jul 09,2025） 
 
 
Table of Contents 
 
Researcher Information Form ............................................................................ 1 
Research topic ...................................................................................................... 2 
1 Introduction ....................................................................................................... 2 
1.1 Background .............................................................................................. 2 
2 Research Purpose .............................................................................................. 4 
2.1 Main Purpose ........................................................................................... 4 
2.2 Secondary Purpose ................................................................................... 4 
2.3 Exploratory purpose ................................................................................. 4 
3 Research Design ................................................................................................ 4 
3.1 Types of Experimental Designs ............................................................... 4 
3.2 
Randomization method ........................................................................ 5 
3.3 
Intervention Protocol ............................................................................ 5 
4 Study Subjects ................................................................................................... 6 
4.1 Sample Size .............................................................................................. 6 
4.2 Inclusion Criteria ..................................................................................... 6 
4.3 Exclusion Criteria .................................................................................... 7 
4.4 Withdrawal Criteria .................................................................................. 7 
4.5 Criteria for Study Termination ................................................................. 8 
4.6 Concomitant Medications ........................................................................ 9 
5 Study Procedures and Workflow ................................................................... 10 
5.1 Study Steps and Methods ....................................................................... 10 
5.1.1 Screening/Baseline Phase ........................................................... 10 
5.1.2 Intervention Phase ....................................................................... 11 
5.1.3 Follow-up Phase.......................................................................... 11 
5.2 Study Flowchart ..................................................................................... 12 
6 Clinical Assessments and Measures to Ensure Participant Compliance ... 13 
6.1 Primary Efficacy Endpoint .................................................................... 13 
6.2 Secondary Efficacy Endpoints ............................................................... 13 
6.3 
Study Scales ....................................................................................... 13 
6.3.1 Hamilton Depression Scale-17，HAMD-17 ............................. 13 
6.3.2 TCM Symptom Scale ................................................................ 13 

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6.3.3 Hamilton Anxiety Scale，HAMA............................................. 14 
6.3.4 Clinical Global Impression–Improvement scale (CGI-I) ........ 14 
6.3.5 Pittsburgh Sleep Quality Index (PSQI) ..................................... 14 
6.4 Safety Indicators .................................................................................... 15 
6.5  Measures to Ensure Participant Compliance ...................................... 16 
7 Adverse Events ................................................................................................ 17 
7.1 Adverse Events....................................................................................... 17 
7.1.1 Definition of Adverse Events ...................................................... 17 
7.1.2 Classification of Adverse Events ................................................ 17 
7.1.3 Recording, Reporting, and Management of Adverse Events ...... 17 
8 Drug Management .......................................................................................... 18 
8.1 Investigational Drug............................................................................... 18 
8.2 Dosage and Administration .................................................................... 18 
8.3 Drug Packaging ...................................................................................... 18 
8.4 Drug distribution .................................................................................... 19 
9 Quality Control and Assurance of the Clinical Trial ................................... 19 
10 Data Management and Statistical Analysis Plan........................................ 20 
10.1 Data Management ................................................................................ 20 
10.2 Statistical Analysis ............................................................................... 20 
10.3 Data Traceability Requirements ........................................................... 21 
11 Ethics Requirements ..................................................................................... 21 
11.1 Ethics Committee Review .................................................................... 21 
11.2 Informed Consent ................................................................................. 22 
12 Confidentiality Measures ............................................................................. 22 
13 Trail expected progress ................................................................................. 22 
 
 

Study protocol （Version 4.0, Date Jul 09,2025） 
1 
 
Researcher Information Form 
1.Principal Investigator 
Name 
De-
gree 
Title 
Medical Qualifica-
tion 
GCP Training 
(Yes/No) 
Project 
Role 
Liu Lany-
ing 
Master 
Chief Physi-
cian 
Licensed Clinician 
Yes 
Study Design 
 
2. Study Team Members 
Name 
Institution 
Title 
Medical Qual-
ification 
GCP  
Training 
(Yes/No) 
Project Role 
Li Wei 
Shanghai Mental 
Health Center 
Attending 
Physician 
Licensed  
Clinician 
Yes 
Quality Control 
Li Wangtao 
Shanghai Mental 
Health Center 
Resident 
Physician 
TCM  
Practitioner 
Yes 
Study  
Coordination 
Tian Fei 
Shanghai University 
of Traditional Chi-
nese Medicine 
Resident 
Physician 
TCM  
Practitioner 
No 
Data Pro-
cessing 
Guo Yihan 
Shanghai University 
of Traditional Chi-
nese Medicine 
Resident 
Physician 
TCM  
Practitioner 
Yes 
Sample  
Collection 
Wu Jingjing 
Shanghai Mental 
Health Center 
Attending 
Physician 
TCM  
Practitioner 
Yes 
Intervention 
Implementation 
Xing 
Mengjuan 
Shanghai Mental 
Health Center 
Attending 
Physician 
Licensed  
Clinician 
Yes 
Intervention 
Implementation 
 
3. Sponsor 
Sponsor Name 
 Address 
Shanghai Mental Health Center 
No. 600 Wanping South Road, Xuhui District, Shanghai 
 
4. Study Site 
Shanghai Mental Health Center 
Address: No. 600 Wanping South Road, Xuhui District, Shanghai 
 
 

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Research topic 
A randomized, double-blind, placebo-controlled exploratory study on compound 
Ciwujia granules in the treatment of depression (heart and spleen deficiency syndrome) 
1 Introduction 
1.1 Background 
Major depression disorder (MDD) refers to a type of mood disorder caused by a 
variety of reasons with significant and persistent depressive symptoms as the main clin-
ical feature. Its core symptoms are low mood and loss of interest that are out of propor-
tion to the situation. It can cause patients to lose their social functions and reduce their 
quality of life, and increase the risk of suicide. It is one of the main factors in the global 
burden of disease [1]. The World Health Organization predicts that by 2030, it will rank 
first in the total global burden of human disease. Since 2010, depressive disorder has 
become the second leading cause of years of healthy life lost (YLD) in China [2]. The 
lifetime prevalence of depression in my country is 6.8% [3]. It has a serious impact on 
public health and has brought huge burdens to individuals, families and society. 
Whether during the acute phase, continuation phase, or maintenance phase of 
MDD, clinical guidelines recommend first-line antidepressant medications for adult pa-
tients. Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, paroxetine, 
sertraline, and citalopram, are the most commonly used first-line antidepressants in 
clinical practice. SSRIs exhibit high selectivity for serotonin (5-HT) reuptake inhibition, 
with minimal effects on norepinephrine, dopamine, histamine, and cholinergic neuro-
transmission. They are well absorbed orally, have relatively high bioavailability, good 
tolerability, and favorable adherence, making them suitable for various types of depres-
sion. A large number of randomized controlled trials (RCTs) have demonstrated that 
SSRIs are significantly more effective than placebo in treating depression, and there is 
no significant difference in overall efficacy among different SSRIs. However, approxi-
mately 30%–40% of patients are classified as treatment-resistant due to poor response 
or insensitivity to SSRIs [4]. Moreover, SSRIs are associated with several limitations, 
including delayed onset of action, residual symptoms, and the need for long-term med-
ication. Therefore, there is an urgent need to explore alternative treatment strategies that 
offer a faster onset of effect, better tolerability, improved efficacy, and fewer side effects. 

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In China, many patients with depression either refuse treatment with Western med-
ications or are unable to tolerate them. This presents an opportunity for exploring Tra-
ditional Chinese Medicine (TCM) as an alternative approach to treating depression. In 
TCM, depression falls under the category of “Yu syndrome”, which is considered a type 
of emotional disorder. According to TCM theory, Yu syndrome arises from dysfunction 
of the internal organs and imbalance of Qi, blood, Yin, and Yang. The most commonly 
observed TCM patterns include liver Qi stagnation with spleen deficiency, dual defi-
ciency of the heart and spleen, liver Qi stagnation, and kidney deficiency with liver 
constraint. 
Compound Ciwujia Granules is a proprietary Chinese medicine developed and 
marketed by Heilongjiang Quanle Pharmaceutical Co., Ltd. It is currently approved for 
the treatment of insomnia and other neurological and psychiatric disorders. This formu-
lation consists of two traditional Chinese medicinal herbs: Eleutherococcus senticosus 
and Schisandra chinensis. Eleutherococcus senticosus contains a variety of active 
chemical constituents, including eleutherosides, polysaccharides, carotenoids, syringin, 
isofraxidin glycosides, ethyl galactoside, and lignan diglucosides. These compounds 
have demonstrated pharmacological effects such as anti-fatigue, anti-inflammatory, 
neurotransmitter regulation, and anti-apoptotic activities. Due to these properties, it is 
widely used in the treatment of neurological disorders [5]. Modern studies have shown 
that polysaccharides extracted from Eleutherococcus senticosus exert antidepressant 
effects by modulating neuroinflammation [6]. Schisandra chinensis contains a variety 
of bioactive compounds, including lignans, triterpenoids, sesquiterpenes, essential oils, 
polysaccharides, flavonoids, and organic acids. Among these, lignans are considered 
the primary active constituents. Representative lignan compounds include schisandrol 
A, schisandrin A, and schisandrin B [7]. Modern pharmacological studies have demon-
strated that Schisandra chinensis possesses multiple therapeutic effects, including mod-
ulation of the central nervous system, cardiovascular protection, immune enhancement, 
as well as antibacterial and antimicrobial activities[8]. In TCM, Eleutherococcus senti-
cosus is used to tonify Qi and strengthen the spleen, nourish the kidney, and calm the 
spirit. Schisandra chinensis replenishes Qi, generates body fluids, nourishes the kidney, 
and calms the mind. When used in combination, these two herbs work synergistically 
to tonify both the spleen and kidney, soothe the spirit, and calm the mind. This pairing 

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is especially beneficial in alleviating symptoms associated with the heart-spleen defi-
ciency pattern, such as lack of interest or motivation, general fatigue, poor appetite, 
insomnia, and excessive dreaming. 
To further investigate the clinical efficacy and safety of Compound Ciwujia Gran-
ules in patients with MDD, we have designed a randomized, placebo-controlled clinical 
trial. This study aims to systematically evaluate the therapeutic effects and underlying 
mechanisms of Compound Ciwujia Granules in the onset and progression of MDD, in 
order to provide clinical evidence to support its application in the treatment of depres-
sion. 
2 Research Purpose 
2.1 Main Purpose 
The primary objective of this study is to evaluate the therapeutic efficacy of Com-
pound Ciwujia Granules in the treatment of depression. 
2.2 Secondary Purpose 
1. To evaluate the safety and tolerability of Compound Ciwujia Granules in partici-
pants with depression, as compared to placebo. 
2. To assess the overall clinical efficacy of Compound Ciwujia Granules, as compared 
to placebo, using a Traditional Chinese Medicine (TCM) symptom score scale. 
2.3 Exploratory purpose 
1. To evaluate the efficacy of Compound Ciwujia Granules in improving insomnia 
symptoms associated with depression, as compared to placebo, using the Pittsburgh 
Sleep Quality Index (PSQI). 
2. To assess the effect of Compound Ciwujia Granules on anxiety symptoms comor-
bid with depression, as compared to placebo, using the Hamilton Anxiety Rating 
Scale (HAMA). 
3. To evaluate the impact of Compound Ciwujia Granules on inflammatory levels in 
patients with depression by measuring serum inflammatory cytokines. 
3 Research Design 
3.1 Types of Experimental Designs 
This study is a single-center, randomized, double-blind, placebo-controlled trial 

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designed to evaluate the safety and efficacy of Compound Ciwujia Granules in partici-
pants with MDD. 
3.2  Randomization method 
Heilongjiang Quanle Pharmaceutical Co., Ltd. will provide the study medication 
during the trial. The medication boxes contain all drugs required for the treatment pe-
riod, and each box is labeled with a unique identification number. Both the active drug 
and placebo are packaged identically in the study to ensure blinding.The assignment of 
medication numbers to the study drugs is based on a randomized sequence. Eligible 
participants will be randomly assigned in a 1:1 ratio to receive either Compound 
Ciwujia Granules or placebo.A random number generator in a computerized system 
will be used to create the allocation sequence. These random numbers will be sealed in 
sequentially numbered, opaque envelopes. When a participant is enrolled, the corre-
sponding envelope will be opened to reveal the randomization code. This process will 
be conducted by personnel independent of the clinical trial.Investigators will register 
enrolled patients and dispense medication according to the randomization schedule. All 
patients, attending physicians, scale evaluators, prescribing psychiatrists, and statisti-
cians will remain blinded to treatment allocation throughout the study. 
3.3  Intervention Protocol 
Experimental Group: 
Participants will receive Compound Ciwujia Granules, administered twice daily, 
one sachet (8g) each time. The dosing schedule should be relatively fixed, taken half an 
hour after breakfast and dinner, continuously for 56 days. 
Participants who are already taking SSRIs will continue their original dosage and 
frequency as previously prescribed. 
Control Group: 
Participants will receive placebo granules matching Compound Ciwujia Granules 
in appearance and dosage, administered twice daily, one sachet (8g) each time. The 
dosing schedule should be relatively fixed, taken half an hour after breakfast and dinner, 
continuously for 56 days. 
Participants who are already taking SSRIs will continue their original dosage and 
frequency as previously prescribed. 
The treatment duration for both groups is 56 days. Efficacy and safety evaluations 
will be conducted at the end of the treatment course. Throughout the treatment period, 

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patients will be monitored and any side effects or adverse reactions will be documented. 
Participants are required to promptly report any adverse events occurring during or after 
the treatment. 
4 Study Subjects 
The study subjects are patients diagnosed with depressive disorders attending the 
outpatient clinic of Shanghai Mental Health Center. All participants will provide written 
informed consent prior to enrollment. 
4.1 Sample Size 
Based on the guidelines in Determining Sample Size for Pilot Studies in Tradi-
tional Chinese Medicine Clinical Research [9], this study is designed as an exploratory 
pilot trial to test the scientific validity and feasibility of the study design. A total of 60 
participants will be enrolled, with 30 subjects per group. 
4.2 Inclusion Criteria 
1. 
Meet the diagnostic criteria for Major Depressive Disorder according to the DSM-
5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) and the cri-
teria for a depressive episode based on the Mini-International Neuropsychiatric 
Interview (M.I.N.I.). 
2. 
Meet the diagnostic criteria for heart-spleen deficiency syndrome in Traditional 
Chinese Medicine [10], characterized by: 
⚫ 
Primary symptoms: excessive worrying, palpitations, shortness of breath, and 
a sallow complexion; 
⚫ 
Secondary symptoms: dizziness, fatigue, spontaneous sweating, poor appetite, 
loose stools; 
⚫ 
Tongue and pulse: pale and tender tongue with teeth marks on the edges, white 
tongue coating, and a thin weak pulse. 
3. 
Total score on the 17-item Chinese version of the Hamilton Depression Rating 
Scale (HAMD-17) between 8 and 24. 
4. 
Score ≤21 on the Hamilton Anxiety Rating Scale (HAMA). 
5. 
Outpatient men and women aged 18 to 65 years (inclusive). 
6. 
Education level of junior high school or above, capable of completing self-assess-
ment scales. 
7. 
Currently taking a stable dose of a single SSRI medication for at least 6 weeks, 

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with a Clinical Global Impression – Severity of Illness scale (CGI-SI) score ≥4 at 
screening and baseline. 
8. 
Willing to participate voluntarily and provide written informed consent. 
4.3 Exclusion Criteria 
1. 
History or diagnosis of any of the following conditions: depressive disorder related 
to organic mental disorders; clinically significant neurological diseases (including 
epilepsy, encephalopathy); any neurodegenerative diseases; moderate to severe 
head trauma or other neurological conditions potentially affecting central nervous 
system function. 
2. 
Current diagnosis of any DSM-5 mental disorder other than depression, including 
schizophrenia spectrum and other psychotic disorders, bipolar and related disor-
ders, anxiety disorders, obsessive-compulsive and related disorders, somatic symp-
tom and related disorders, substance-related and addictive disorders (except caf-
feine and nicotine), or a positive urine drug screen at screening. 
3. 
History of suicide attempts or, in the investigator’s judgment, current significant 
suicide risk, or any affirmative (“yes”) response to questions 1-5 of the Columbia-
Suicide Severity Rating Scale (C-SSRS). 
4. 
Presence of other serious systemic diseases, or severe cardiac, hepatic, or renal 
insufficiency (including alanine aminotransferase [ALT] or aspartate aminotrans-
ferase [AST] levels greater than 1.5 times the upper limit of normal). 
5. 
Pregnant or breastfeeding women, or women who may become pregnant during 
the study and cannot use effective contraception. 
6. 
Acute or chronic infectious diseases, autoimmune diseases, allergies, cancer, or 
stroke within the past month. 
7. 
Participation in other clinical drug trials within the past month. 
8. 
History of psychosurgery, deep brain stimulation (DBS), or electroconvulsive ther-
apy (ECT). 
4.4 Withdrawal Criteria 
1. 
Participants who experience allergic reactions, severe adverse events, other com-
plications, or special physiological changes, for which the investigator determines 
that study treatment should be discontinued. 
2. 
Participants who, for any reason, are unwilling or unable to continue the clinical 
trial and request withdrawal from the study. 

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3. 
Participants who do not explicitly request withdrawal but discontinue medication 
and assessments, resulting in loss to follow-up. 
4. 
Participants who become unblinded during the study. 
5. 
Participants who become pregnant. 
The investigator should also consider withdrawal based on the participant’s spe-
cific condition in the following situations: 
⚫ Participants who develop serious drug-related hepatic or renal toxicity as judged 
by the investigator. 
⚫ Participants who experience other serious adverse events that require hospitaliza-
tion or prolonged hospitalization. If these events do not impact safety and efficacy 
evaluations, withdrawal may not be necessary. 
⚫ Participants who develop comorbidities, complications, or special physiological 
changes that may render continued participation inappropriate. 
⚫ Participants who use prohibited medications or treatments as specified in the study 
protocol. 
For participants who withdraw or drop out, investigators should attempt to main-
tain contact by home visits, scheduled follow-ups, telephone calls, or letters. The last 
date of medication use should be recorded, and as many assessment items as possible 
should be completed. For those withdrawing due to allergic reactions, adverse events, 
or treatment failure, investigators should provide appropriate medical care based on the 
participant’s condition. 
The reasons for withdrawal must be documented in the participant’s medical rec-
ords, case report forms (CRF), and electronic case report forms (eCRF). 
4.5 Criteria for Study Termination 
1. 
Study termination refers to the premature cessation of the entire clinical trial before 
its planned completion. The primary purpose of terminating a study is to protect 
participant rights, ensure research quality, and avoid unnecessary economic losses. 
The criteria for study termination include: 
2. 
Serious safety issues arise during the study, requiring immediate termination of the 
trial. 
3. 
It becomes evident during the study that the investigational product lacks practical 
value, warranting termination to avoid delaying effective treatment for participants 
and to prevent unnecessary economic loss. 

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4. 
Significant flaws are identified in the clinical trial protocol that impede the assess-
ment of the drug’s efficacy, or major deviations occur during implementation that 
make continued evaluation of the product’s effects unfeasible. 
5. 
The sponsor requests termination due to financial, administrative, or other reasons. 
6. 
The National Medical Products Administration (NMPA) mandates the termination 
of the study for any reason. 
4.6 Concomitant Medications 
All concomitant medications or treatments used by participants from the time of 
signing the informed consent until the end of the follow-up period must be recorded, 
except for the investigational product. Common intravenous solvents such as sodium 
chloride injection or glucose injection do not need to be documented. Medications used 
solely for examinations, skin tests, or wound dressings are also exempt from recording. 
Investigators should request participants to bring all medications and medication con-
tainers they are currently using to each follow-up visit. Concomitant medications will 
be reviewed and documented in detail in the original medical records, including the 
generic name (or name of other therapies), dosage and administration, start date, and 
indication (or reason for use). 
4.6.1 Permitted Concomitant Medications or Treatments 
During the treatment period, aside from the originally prescribed SSRI medication 
and the investigational drug, the use of other medications should be minimized when-
ever possible. If the investigator determines that additional treatment is necessary for 
the participant’s condition and does not interfere with the study medication, appropriate 
therapies or treatments may be administered based on clinical judgment (excluding 
medications or treatments prohibited by the study protocol). 
New-generation non-benzodiazepine hypnotics (including zolpidem, zopiclone, 
eszopiclone, and zaleplon) may be taken before bedtime, with a cumulative duration 
not exceeding two weeks. 
For participants receiving long-term treatment for chronic somatic diseases, the 
type and dosage of medications should be kept as stable as possible throughout the trial. 
4.6.2 Prohibited Concomitant Medications or Treatments 
During the entire study period, the use of any medications or treatments that may 
affect the efficacy and safety evaluation of the investigational product is strictly pro-
hibited. Specifically: 
⚫ The use of any antidepressant medications other than the investigational drug is 

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prohibited, including but not limited to monoamine oxidase inhibitors (MAOIs), 
serotonin-norepinephrine reuptake inhibitors (SNRIs), and any traditional Chinese 
medicine or proprietary Chinese medicine with antidepressant effects. 
⚫ The use of benzodiazepine-class sedative-hypnotics, all anxiolytics, all antipsy-
chotics, mood stabilizers, and similar central nervous system drugs is prohibited 
during the study. 
5 Study Procedures and Workflow 
5.1 Study Steps and Methods 
5.1.1 Screening/Baseline Phase 
During this visit, the following activities will be completed: 
1. 
The investigator explains the study details, and the participant signs the informed 
consent form. 
2. 
The investigator confirms the participant’s eligibility according to inclusion and ex-
clusion criteria. 
3. 
Collection of basic participant information, physical measurements, and vital signs 
assessment. 
4. 
Demographic information: name, sex, phone number, ethnicity, age, occupation, etc. 
5. 
Physical measurements: height, weight. 
6. 
Vital signs: temperature (T), heart rate (HR), respiration rate (R), blood pressure 
(BP), etc. 
7. 
Medical history, including past illnesses, medication history, personal history, and 
current illness. 
8. 
Administration of questionnaires/scales to the participant: 
1) 17-item Hamilton Depression Rating Scale (HAMD-17); 
2) Traditional Chinese Medicine symptom score scale; 
3) Hamilton Anxiety Rating Scale (HAMA); 
4) Pittsburgh Sleep Quality Index (PSQI); 
5) Clinical Global Impression – Improvement scale (CGI-I); 
6) Columbia-Suicide Severity Rating Scale (C-SSRS). 
9. 
Serum inflammatory marker testing: collection of 5 ml fasting venous blood to 
measure serum levels of C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-
1β (IL-1β), and tumor necrosis factor-α (TNF-α) using enzyme-linked immuno-
sorbent assay (ELISA). 

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10. Safety assessments including: 
1) Electrocardiogram (ECG); 
2) Complete blood count (CBC): red blood cells (RBC), white blood cells (WBC), 
hemoglobin (Hb), platelets (PLT); 
3) Urinalysis: white blood cells (WBC), protein (PRO); 
4) Liver function tests: alanine aminotransferase (ALT), aspartate aminotransfer-
ase (AST), total bilirubin (TBIL), direct bilirubin (DBIL); 
5) Renal function tests: blood urea nitrogen (BUN), serum creatinine (Scr); 
6) Pregnancy test. 
11. Dispensing of the investigational medication. 
12. Scheduling of the next visit. 
5.1.2 Intervention Phase 
The intervention phase lasts 8 weeks, with visits every 4 weeks, totaling 2 visits. 
At each visit, the following procedures will be completed: 
1. 
Vital signs assessment: temperature (T), heart rate (HR), respiration rate (R), blood 
pressure (BP), etc. 
2. 
Administration of questionnaires/scales: 
1) 17-item Hamilton Depression Rating Scale (HAMD-17); 
2) Traditional Chinese Medicine symptom score scale; 
3) Hamilton Anxiety Rating Scale (HAMA); 
4) Pittsburgh Sleep Quality Index (PSQI); 
5) Columbia-Suicide Severity Rating Scale (C-SSRS); 
6) Treatment Emergent Symptom Scale (TESS). 
3. 
Dispensing of investigational medication. 
4. 
Collection of used investigational medication and packaging. 
5. 
Recording of adverse events. 
6. 
Scheduling the next visit. 
7. 
At the week 8 visit, participants will undergo serum inflammatory marker testing 
and safety assessments, identical to those conducted at baseline. 
5.1.3 Follow-up Phase 
During the follow-up visit, the following assessments will be conducted: 
1. 
Administration of questionnaires/scales: 
1) 17-item Hamilton Depression Rating Scale (HAMD-17); 
2) Traditional Chinese Medicine symptom score scale; 

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3) Hamilton Anxiety Rating Scale (HAMA); 
4) Pittsburgh Sleep Quality Index (PSQI); 
5) Columbia-Suicide Severity Rating Scale (C-SSRS); 
6) Treatment Emergent Symptom Scale (TESS). 
5.2 Study Flowchart 
 
Figure 1. Study Flowchart 
5.3 Research Schedule 
Table1 Research Schedule 
Stages 
Screening 
period 
Baseline 
Treatment 
period 
4 weeks after 
treatment 
Visits 
V1 
V2 
V3 
V4 
V5 
Visits time 
W1 
W1 
W4 
W8 
W12 
Sign informed consent form 
X 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
Medical history collection 
X 
 
 
 
 
Randomization 
 
X 
 
 
 

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Demographic data 
X 
 
 
 
 
Laboratory testing 
X 
 
 
X 
 
Scale testing 
 
X 
X 
X 
X 
6 Clinical Assessments and Measures to Ensure Participant Compli-
ance 
6.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the change in HAMD-17 score from baseline to 
the end of treatment at Day 56 (Week 8). The percentage reduction in HAMD-17 score 
after treatment is calculated as follows: Reduction rate = (Baseline HAMD-17 score – 
Week 8 HAMD-17 score) / Baseline HAMD-17 score. A reduction rate of ≥50% is 
considered clinically effective. 
6.2 Secondary Efficacy Endpoints 
Secondary efficacy will be assessed by: Improvement of TCM syndrome scores 
using the TCM symptom scale; Improvement of anxiety symptoms assessed by the 
Hamilton Anxiety Rating Scale (HAMA); Improvement of insomnia measured by the 
Pittsburgh Sleep Quality Index (PSQI); Improvement in overall function evaluated by 
the Clinical Global Impression (CGI) scale. Additionally, changes in serum inflamma-
tory markers will be observed to evaluate the anti-inflammatory effects of Compound 
Ciwujia Granules. 
6.3 Study Scales 
6.3.1 Hamilton Depression Scale-17，HAMD-17 
The Hamilton Depression Rating Scale-17 (HAMD-17) is one of the most commonly 
used clinician-administered scales for assessing depressive states in psychiatric practice. 
Previous studies have demonstrated that the scale has good reliability and validity. The 
scale uses a 5-point scoring system to evaluate the severity of depressive symptoms, 
with higher total scores indicating more severe depression. A total score above 24 indi-
cates severe depression; a score above 17 indicates mild to moderate depression; and a 
score below 7 indicates absence of depressive symptoms. 
6.3.2 TCM Symptom Scale 
In clinical trials, this scale is used to dynamically monitor changes in patients’ 

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TCM syndromes before and after treatment (e.g., changes in total scores), providing 
scientific evidence for the efficacy of traditional Chinese medicine. The scale is devel-
oped based on the efficacy evaluation criteria outlined in the Guiding Principles for 
Clinical Research on New Traditional Chinese Medicines issued by the National Health 
Commission and the Guidelines for Integrated Traditional Chinese and Western Medi-
cine Diagnosis and Treatment of Depression published by the Chinese Medical Asso-
ciation. 
6.3.3 Hamilton Anxiety Scale，HAMA 
The Hamilton Anxiety Rating Scale (HAMA) is a clinician-administered scale used to 
assess the severity of anxiety symptoms in patients with neurosis and other disorders. 
Previous studies have demonstrated good reliability and validity of this scale. Accord-
ing to the assessment criteria provided by the Chinese Psychiatric Scale Cooperative 
Group, a total score above 29 indicates severe anxiety; above 21 indicates definite sig-
nificant anxiety; above 14 indicates definite anxiety; above 7 suggests possible anxiety; 
and below 7 indicates no anxiety symptoms. In previous research, a cutoff score of 14 
is often used. Higher total scores represent more severe anxiety symptoms. 
6.3.4 Clinical Global Impression–Improvement scale (CGI-I) 
The Clinical Global Impression–Improvement scale (CGI-I) is a patient self-rated scale 
using an 8-point scoring system ranging from 0 to 7. The participant evaluates their 
current condition compared to the baseline at enrollment. The score interpretation is as 
follows: 
0 – Not assessed; 
1 – Very much improved; 
2 – Much improved; 
3 – Minimally improved; 
4 – No change; 
5 – Minimally worse; 
6 – Moderately worse; 
7 – Very much worse. 
6.3.5 Pittsburgh Sleep Quality Index (PSQI)  
The Pittsburgh Sleep Quality Index (PSQI) is a patient self-rated questionnaire 
assessing sleep quality. It is simple to administer and demonstrates good reliability and 
validity. The scale uses a 0 to 3 scoring system, with a total score range from 0 to 21. 

Study protocol （Version 4.0, Date Jul 09,2025） 
15 
 
Higher scores indicate poorer sleep quality. 
6.4 Safety Indicators 
Safety assessments will be conducted at Weeks 4 and 8. 
Safety and tolerability will be evaluated through adverse event (AE) reports, physical 
examinations, electrocardiograms (ECG), vital signs, and clinically significant changes 
in laboratory test results. 
1) Vital Signs and Physical Measurements (Height and Weight) 
According to the study assessment schedule and medical necessity, seated vital 
signs (temperature, blood pressure, and pulse rate) as well as height and weight will be 
recorded during scheduled visits. 
2) Electrocardiogram (ECG) 
A 12-lead ECG will be recorded at scheduled visits per the study assessment plan 
or as medically indicated. 
3) Physical Examination 
Participants will undergo a comprehensive physical examination as specified in 
the study assessment schedule. The examination should include at least the following 
areas: HEENT (head, eyes, ears, nose, and throat), neck, lymph nodes, lungs, cardio-
vascular system, abdomen, skin, and musculoskeletal system. The assessment will be 
conducted by the principal investigator or a medically qualified designee. If a partici-
pant discontinues the study for any reason, an attempt should be made to perform a final 
physical examination. Physical examinations may also be performed at any time based 
on the investigator’s judgment. 
4)  Laboratory Assessments 
On Day 1 (baseline) and at Week 8 of treatment, 5 ml of venous blood and 10 ml 
of urine will be collected from participants for laboratory tests. The laboratory assess-
ments will include the following: 
1) Hematology: Hemoglobin, hematocrit, platelets, complete blood count (CBC) 
with differential, and absolute neutrophil count; 
2) Blood Biochemistry: Sodium, potassium, chloride, calcium, alanine ami-
notransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogen-
ase (LDH), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), 
phosphorus, bicarbonate, total protein, albumin, total bilirubin, glucose, cre-
atinine, blood urea nitrogen (BUN), and uric acid; 
3)  Urinalysis: At scheduled visits according to the study assessment schedule 

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and medical necessity, tests will include pH, specific gravity, ketones, nitrites, 
urobilinogen, leukocyte esterase, protein, glucose, and occult blood. If blood, 
protein, or leukocytes are positive, microscopic examination will be per-
formed to further evaluate abnormal results; 
4)  Pregnancy Testing: Serum pregnancy tests will be conducted at baseline and 
scheduled follow-ups in the central laboratory as per the study assessment 
schedule. Urine pregnancy tests will be performed at the study center prior to 
dosing, at baseline, and at subsequent scheduled visits according to the as-
sessment plan or at the investigator’s discretion. 
Any laboratory test results outside the normal reference ranges must be brought to 
the attention of the study physician (investigator or sub-investigator). The investigator 
will determine the clinical significance of abnormal values. If necessary, repeat labora-
tory testing may be conducted. 
5)  Columbia-Suicide Severity Rating Scale (C-SSRS) 
The Columbia-Suicide Severity Rating Scale (C-SSRS) is an assessment tool used to 
evaluate suicidal ideation and behavior [11]. This tool uses a series of simple, easy-to-
understand questions that anyone can answer to assess an individual's risk of suicide. 
The responses help the user determine whether a person is at risk for suicide, evaluate 
the severity and immediacy of that risk, and measure the level of support the person 
requires. 
If the investigator determines that a participant is at risk of suicide or self-harm, 
appropriate measures must be taken to ensure the participant's safety and obtain a men-
tal health evaluation. The participant must be immediately withdrawn from the study. 
6) Treatment Emergent Symptom Scale (TESS) 
The Treatment Emergent Symptom Scale (TESS) was developed by the U.S. Na-
tional Institute of Mental Health in 1973 to assess adverse reactions experienced by 
patients during treatment. Each adverse symptom is evaluated based on severity, its 
relationship to the medication, and any measures taken. The scale includes an overall 
severity rating (TESS-A) and an individual distress rating (TESS-B), with lower scores 
indicating better tolerance [12]. 
6.5  Measures to Ensure Participant Compliance 
Regular contact and communication with participants will be maintained. Physical 
examinations and scale assessments will be conducted periodically. Additionally, health 
consultations, health education sessions, group fitness, or wellness activities will be 

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organized to ensure timely feedback of relevant information during the trial period. 
7 Adverse Events 
7.1 Adverse Events 
7.1.1 Definition of Adverse Events 
An adverse event (AE) refers to any unfavorable medical occurrence in a patient 
or clinical trial participant who has received a pharmaceutical product or treatment, 
which does not necessarily have a causal relationship with the treatment. 
A serious adverse event (SAE) refers to any adverse event occurring during a clin-
ical trial that results in hospitalization or prolongation of existing hospitalization, disa-
bility, impairment of work capacity, life-threatening conditions, death, or congenital 
abnormalities. 
7.1.2 Classification of Adverse Events 
Mild: The participant can tolerate the event; it does not affect treatment and re-
quires no special intervention. It has no impact on the participant’s recovery. 
Moderate: The event is difficult for the participant to tolerate and requires special 
intervention. It has a direct impact on the participant’s recovery. 
Severe: The event is life-threatening, causes death or disability, and requires im-
mediate emergency treatment. 
7.1.3 Recording, Reporting, and Management of Adverse Events 
Recording of Adverse Events: During the trial, adverse events (AEs) must be ac-
curately recorded on the adverse event case report forms, including the time of onset, 
severity, duration, interventions taken, and outcomes. Any clinically significant abnor-
mal laboratory results, vital signs, electrocardiograms (ECGs), or other examination 
findings should be documented by the investigator or sub-investigator in the “Pre-ex-
isting Conditions and Study Adverse Events” section of the case report form (CRF). If 
a clinically significant diagnosis can be made, it should be recorded as an adverse event. 
For findings without a clear diagnosis, the clinical significance will be determined by 
the investigator, and findings deemed clinically significant will be recorded as adverse 
events. 
Reporting of Adverse Events: Upon discovery of a serious adverse event (SAE), 
the investigator must report it to the designated personnel approved by the principal 

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investigator (PI) within 24 hours. Initial reporting is by telephone, followed immedi-
ately by submission of a completed SAE report form specific to this study. SAEs in-
clude but are not limited to: death; hospitalization or prolonged hospitalization; life-
threatening conditions (imminent risk of death); persistent or significant disability or 
incapacity; congenital anomalies or birth defects; or any event the investigator deems 
significant for any reason. 
Management of Adverse Events: Any serious adverse reaction occurring during 
the trial must be promptly managed to ensure participant safety and immediately re-
ported to the institutional ethics committee. The investigator should complete the “Se-
rious Adverse Event Report Form” and notify the contact persons listed in the informed 
consent form (ICF) with phone numbers. All adverse events must be followed up with 
detailed documentation of management and outcomes until resolved or the condition is 
stabilized. For abnormal laboratory results, follow-up should continue until values re-
turn to normal. Follow-up methods may include hospitalization, outpatient visits, home 
visits, phone calls, or correspondence, depending on the severity of the adverse reaction. 
If participants sustain injury related to the study, appropriate compensation should be 
provided. 
8 Drug Management 
8.1 Investigational Drug 
The investigational drug and placebo are provided by Heilongjiang Quanle Phar-
maceutical Co., Ltd. and meet quality standards. Storage conditions: Store in a cool, 
dry, and dark place, out of reach of children. 
8.2 Dosage and Administration 
Compound Eleutherococcus Senticosus Granules (Marketing Authorization Holder: 
Heilongjiang Quanle Pharmaceutical Co., Ltd., Drug Approval Number: Z20025148, 
Batch Number: 20220301): Main components are Eleutherococcus senticosus extract 
and Schisandra chinensis extract. Oral administration, one sachet (8g) per dose, twice 
daily. Treatment duration is 8 weeks. 
Placebo for Compound Eleutherococcus Senticosus Granules: same as above (de-
tails omitted). 
8.3 Drug Packaging 
The investigational drugs are packaged in boxes. The labels on the boxes include 

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information such as drug number, quantity, specifications, dosage instructions, storage 
conditions, and precautions. 
8.4 Drug distribution 
The investigational drugs are centrally stored by the clinical department and man-
aged by a drug administrator who is not directly involved in the clinical trial. The ad-
ministrator is responsible for the storage, dispensing, collection, record-keeping, and 
return or retrieval of the investigational drugs. After a participant is enrolled, the drug 
administrator dispenses the medication according to the drug number assigned by the 
participant’s randomization code. The investigational drug is dispensed at the start of 
medication and any remaining drugs, empty boxes, and empty sachets are collected at 
each visit or the final visit. 
Storage of Investigational Drugs: A management system for investigational drugs 
during the trial period is established. The drugs are stored in a dedicated cabinet in a 
well-ventilated, dry, and temperature-controlled environment, and are managed uni-
formly by the drug administrator. 
9 Quality Control and Assurance of the Clinical Trial 
Researchers must fulfill their respective responsibilities and strictly follow the 
clinical trial protocol, using standard operating procedures (SOPs) to ensure the imple-
mentation of quality control (QC) and quality assurance (QA) systems for the clinical 
trial. All observations and findings during the trial must be verified, and quality control 
must be conducted at every stage of data processing to ensure data completeness, accu-
racy, authenticity, and reliability. 
Study Monitoring: Project member Li Wei will conduct regular monitoring 
throughout the research progress. The monitor must ensure that the clinical facilities at 
the study site meet the requirements, that researchers adhere to the trial protocol and 
accurately record trial results. During each monitoring visit, the monitor must also re-
view participant documentation and ensure every participant has signed the informed 
consent form. All study procedures are governed by standardized operating procedures. 
Research Staff Qualifications: Researchers must be physicians trained in clinical 
trials and work under the guidance of senior professionals. 
Scale Consistency Testing: Consistency testing will be conducted on the primary 
cognitive function and symptom evaluation scales. 
Symptom Quality Control: This study uses an integrated Traditional Chinese and 

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Western medicine scale for depressive symptoms syndrome differentiation, which has 
demonstrated good reliability and validity. 
During the entire study, the research team will hold weekly coordination meetings 
to discuss project progress and plan subsequent steps. 
Reducing Placebo Effect Bias: The placebo and investigational drug are identical 
in appearance (shape, color), smell, taste, and packaging, prepared and coded by Hei-
longjiang Quanle Pharmaceutical Co., Ltd. Neither researchers nor participants can pre-
dict group assignment. At the end of the study, a blinding efficacy assessment will be 
conducted with participants and researchers. If a significant placebo effect is detected, 
the possible reasons will be analyzed and discussed, and the effect size difference be-
tween placebo and investigational groups will be reported. 
10 Data Management and Statistical Analysis Plan 
10.1 Data Management 
This study uses EpiData 3.1 for data entry, implementing double data entry and 
verification. 
1. EpiData Database Construction: The data manager will construct the database based 
on the study protocol and case report forms. 
2. Data Entry: Clinical researchers or designated data entry personnel (clinical coor-
dinators) will promptly and accurately enter data from the case report forms into 
EpiData. EpiData is not considered the original record; its content originates from 
the case report forms and study visit manuals. 
3. Data Locking and Export:After each participant completes the trial and the data is 
verified by the monitor, the data manager will lock the data. During the trial, locked 
data can be exported in real time for interim analysis as needed. After all partici-
pants’ trial data are locked, the data manager will export the data to the designated 
database for final statistical analysis by statisticians. 
10.2 Statistical Analysis 
The study data will be analyzed using SPSS version 23.0 software. Categorical 
variables will be presented as counts and percentages [n (%)], and comparisons between 
groups will be performed using the Chi-square (χ²) test. Continuous variables that fol-
low a normal distribution will be expressed as mean ± standard deviation (mean ± SD); 
those that do not follow a normal distribution will be presented as median (minimum, 

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maximum) [Median (min, max)]. If the data meet the assumptions of normality and 
homogeneity of variance, one-way analysis of variance (ANOVA) will be used for 
group comparisons. When statistically significant differences are detected, the Least 
Significant Difference (LSD) method will be applied for pairwise comparisons between 
groups. If the data do not meet normality or homogeneity of variance assumptions, the 
non-parametric Kruskal-Wallis H test will be used for multiple independent samples. If 
significant differences are found, the Games-Howell test will be used for pairwise com-
parisons. A p-value less than 0.05 (P < 0.05) will be considered statistically significant. 
10.3 Data Traceability Requirements 
The data collection for this study is managed by the Shanghai Mental Health Cen-
ter. It is required to ensure the authenticity, completeness, and confidentiality of the 
clinical trial data. The data management process must comply with relevant regulations 
to guarantee the traceability of clinical trial data. 
Researchers should truthfully, thoroughly, and carefully complete all questionnaire 
items as per the requirements, ensuring that the content is accurate and reliable. All 
observations and findings in the study must be verified to ensure that all conclusions 
are based on original data. After the questionnaires are completed and reviewed by the 
principal investigator, they will be securely stored by designated personnel in a locked 
cabinet within the research office. All procedures are documented. The safekeeping of 
research files, data processing, and related test results are managed by designated staff. 
11 Ethics Requirements 
11.1 Ethics Committee Review 
The study protocol, written informed consent form, and materials directly related 
to participants must be submitted to the Ethics Committee of Shanghai Mental Health 
Center. The study may only commence after receiving written approval from this Ethics 
Committee. Researchers must submit an annual progress report to the Ethics Committee 
of Shanghai Mental Health Center at least once a year (if applicable). Upon study ter-
mination and/or completion, researchers must notify the Ethics Committee of Shanghai 
Mental Health Center in writing. Researchers must promptly report any changes occur-
ring during the study (such as amendments to the protocol and/or informed consent 
documents) to the Ethics Committee. Such changes must not be implemented before 
receiving approval from the Ethics Committee, except when changes are necessary to 

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eliminate obvious and immediate risks to participants. In such cases, the Ethics Com-
mittee of Shanghai Mental Health Center will be informed accordingly. 
11.2 Informed Consent 
Researchers must provide participants or their legal guardians with an informed 
consent form that is easy to understand and approved by the Ethics Committee of 
Shanghai Mental Health Center. Participants or their legal guardians should be given 
sufficient time to consider participation in the study. Participants must not be enrolled 
before obtaining their signed written informed consent. During the participant’s in-
volvement in the study, all updated versions of the informed consent form and related 
written information will be provided to the participant. The informed consent form shall 
be retained as an important document related to human subject research for future ref-
erence. 
12 Confidentiality Measures 
The results of this study may be published in academic journals; however, partic-
ipant information will be kept confidential in accordance with legal requirements. Ex-
cept when required by applicable laws, participants’ personal information will not be 
disclosed. When necessary, government regulatory authorities and the Ethics Commit-
tee of Shanghai Mental Health Center, as well as relevant personnel, may review par-
ticipant records as per regulations. 
13 Trail expected progress 
Annual Annual Project Plan and Objectives 
2025 
Annual 
 
Quarter 2: Complete literature review and manuscript writing; Obtain ethical 
approval; Register the clinical trial. 
Quarter 3: Enroll and randomly assign 20 eligible patients; Conduct interven-
tion and follow-up visits. 
Quarter 4: Enroll and randomly assign another 20 eligible patients; Conduct 
intervention and follow-up visits. 
Node goals: Complete enrollment, intervention, and evaluation of 40 study par-
ticipants 
 

Study protocol （Version 4.0, Date Jul 09,2025） 
23 
 
2026 
Annual 
 
 
Quarter 1: Enroll and randomly assign 20 eligible patients; Conduct interven-
tion and follow-up visits. 
Quarter 2: Summarize and clean data; Perform data analysis; Write and submit 
manuscript; Prepare research summary report; Complete project defense and 
closure. 
Node goals: Complete data organization, project defense, and project closure. 
 
 

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24 
 
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