A Multicenter, Randomized, Double-blinded, Placebo-controlled Phase III Trial to Evaluate the Efficacy and Safety of Liraglutide on Body Weight Loss in Obese and Overweight Patients
Phase: PHASE3
Conditions: Obese, Overweight
Sponsor: Shanghai Zhongshan Hospital

 
 
Clinical Trial Protocol 
 
A multicenter, randomized, double-blinded, placebo-controlled phase III clinical 
study to evaluate the efficacy and safety of Liraglutide Injection in the intervention 
of obese or overweight adult patients with associated metabolic abnormalities 
 
Protocol No.: JSWB-LRG2020-301 
Clinical phase: III 
Drug name: Liraglutide Injection 
 
 
 
 
Sponsor 
Wanbang Biopharmaceuticals 
No.6 Yangshan Road, Jinshanqiao Economic Zone, Xuzhou-221004, Jiangsu Province, China. 
 
Document version number/version date: V1.0/March 26, 2020 
 
Confidentiality Claim 
The information herein contains exclusive or confidential trade secrets and business information, which can only be 
disclosed when required by applicable laws or regulations. In any case, the person to whom the information is given 
must be informed that the information is proprietary or confidential and may not be further disclosed by them. These 
restrictions on disclosure also apply to all future information provided to you that is marked as proprietary or 
confidential. 
 
 

Protocol Summary 
Investigation
al drug 
Liraglutide Injection 
Registration classification Biology - Class 7 
Study title 
A multicenter, randomized, double-blinded, placebo-controlled phase III clinical 
study to evaluate the efficacy and safety of Liraglutide Injection in the intervention 
of obese or overweight adult patients with associated metabolic abnormalities 
Clinical 
study 
approval No. 
CXSL1900149 
Sponsor 
Wanbang Biopharmaceuticals 
Trial site 
Zhongshan Hospital, Fudan University 
PI: 
Professor Xiaoying Li 
Trial phase 
III 
Study 
objective 
Primary study objective 
To evaluate the body weight loss effect of Liraglutide Injection compared with 
placebo in obese or overweight adult patients with related metabolic abnormalities 
(hypertension, dyslipidemia or type 2 diabetes). 
Secondary study objective: 
⚫ 
To observe the effect of Liraglutide Injection on waist circumference, blood 
pressure, blood lipid, blood glucose and other metabolic index and quality of 
life compared with placebo; 
⚫ 
To evaluate the safety and tolerance of Liraglutide Injection. 
Trial design 
This is a multicenter, randomized, double-blind, placebo-controlled phase III clinical 
trial. The total study duration will be about 34~36 weeks, including a 2-week 
screening period, a 6~8-week dosage adjustment period, a 24-week stable treatment 
period and a 2-week safety follow-up period. Subjects with obesity or overweight 
with related metabolic disorders will be subcutaneously injected with 3.0 mg 
Liraglutide Injection or placebo every day. Changes in body weight from baseline 
for Liraglutide Injection will be compared with placebo at the end of treatment. In 
the course of the trial, the subjects will be weighed on an empty stomach and blood 
samples will be collected according to the protocol, and the efficacy and 
safety will be evaluated. All subjects will be given medication on the basis of 
reduced calorie diet guidance (reduced by about 500 kcal/day) and increased 
physical exercise. 

 
Subject 
population 
Obese or overweight adult patients with associated metabolic abnormalities 
Sample size 
Total 291 subjects will be enrolled as planned, and about 414 subjects will be included 
in the study as expected considering the dropouts. 
Inclusion 
criteria 
1) 
Those voluntarily participating and signing the ICF. 
2) 
Those aged 18-70 years old (including 18 and 70 years old), without restriction 
on male and female 
3) 
Those failing to control their body weight in previous diet therapy alone. 
4) 
Those voluntarily following the medication, diet and exercise requirements 
decided by the investigators. 
5) 
Those with a stable body weight (patient reported body weight change < 5 kg) in 
last 3 months. 
6) 
Those with BMI ≥ 30 kg/m2 (obese) or BMI ≥ 27 kg/m2 (overweight) 
accompanied by at least one treated or untreated related metabolic abnormality 
(hypertension, dyslipidemia, type 2 diabetes). Those with untreated hypertension 
defined as SBP ≥ 140 mmHg or DBP ≥ 90 mmHg; untreated dyslipidemia 
defined as LDL-C ≥ 4.1 mmol/L, TG ≥ 1.7 mmol/L, TC ≥ 5.7 mmol/L or HDL-
C < 1.0 mmol/L in male and < 1.3 mmol/L in female. 
7) 
Those with type 2 diabetes should additionally meet the following inclusion 
criteria: 
a) 
Those diagnosed as type 2 diabetes according to WHO (1999) Diagnostic 
and Classification Criteria at the time of screening; 
b) 
Those receiving diet and exercise therapy alone, or receivig metformin, 
sulfonylureas, glycosidase inhibitors and glinides alone or in combination 
on the basis of diet and exercise therapy, with their treatment remaining 
stable at least 3 months before screening (with original documents such as 
prescriptions provided); 
c) 
Those with HbA1c of 7.0-10.0% (inclusive); 
d) 
Those with FPG < 13.3 mmol/L (240 mg/dL). 
Exclusion 
criteria 
Subjects who meet one of the following exclusion criteria will be excluded. 
1) 
Those with type 1 diabetes or secondary diabetes. 
Liraglutide  
Subcutaneous injection 
Placebo  Subcutaneous 
injection 
Reduce 500 Kcal calories daily and increase physical 
i i
Scree
ning
Rando
m
2 
weeks 
6-8 
weeks 
24 
weeks 
2 
weeks 
Screening 
 
Dosage 
adjustment 
3.0 mg/d stable treatment 
 
Safety follow-
up 
 

2) 
Those with acute metabolic complications such as diabetic ketoacidosis or 
hyperglycemia (coma) within 6 months before screening. 
3) 
Those with 2 or more severe hypoglycemia events (hypoglycemia with severe 
cognitive impairment and need other measures to help them recover) without 
obvious inducement within 3 months before screening. 
4) 
Those receiving GLP-1 receptor agonist, DPP-4 inhibitors, SGLT-2 inhibitor, or 
insulin therapy within 3 months prior to screening. 
5) 
Those with obesity caused by endocrine diseases such as Cushing's syndrome. 
6) 
Patients taking drugs that can significantly increase weight in the 3 months before 
screening, including systemic glucocorticoid (except cumulative or continuous 
use of less than 14 days). 
7) 
Those using OTC weight-loss drugs or appetite inhibitors (including traditional 
Chinese medicine as weight-loss drugs) within 1 month before screening, or use 
prescription weight-loss drugs (such as fentanyl, sibutramine, orlistat) or lipid 
dissolving injection (such as fat dissolving needle) within 3 months before 
screening. 
8) 
Those with binge eating behavior in the past, that is, eating a large amount of food 
in a short period of time with a sense of loss of control. 
9) 
Those who have treated or plan to treat obesity (during the trial) with surgery or 
body weight loss devices. 
10) Those with a past or family history of MTC (grandparents, parents, siblings), or 
those whose genetic diseases are prone to induce MTC and MEN2. 
11) Those with thyroid nodules of unknown etiology at the time of screening which 
is considered clinically significant by the investigator (calcitonin is more than 50 
pg/ml, which is only allowed to be retested once). 
12) Those with a past history or found to have hyperthyroidism or hypothyroidism or 
subclinical hypothyroidism at the time of screening [TSH > 6 mIU/L]. 
13) Those with history of pancreatic cancer, acute or chronic pancreatitis, or with 
acute or chronic pancreatitis at the time of screening, or having blood amylase or 
lipase ≥ 3 times ULN. 
14) Those with acute gallbladder disease (cholecystitis, gallstone) more than 2 times 
in 1 year before screening. 
15) Those with MDD, anxiety disorder or other mental illnesses or with the PHQ-9 
score ≥ 15 at screening 
16) Those with the following cardiovascular and cerebrovascular diseases within 6 
months before screening: decompensated cardiac insufficiency (NYHA Class III-
IV), UA or AMI, CVA or stroke. 
17) Those with a history of heart valve replacement, CABG or other PTCA including 
percutaneous coronary intervention. 
18) Those who fail to control their blood pressure effectively, with SBP ≥ 160 mmHg 
or DBP ≥ 100 mmHg. 
19) Those with a history of malignancy in the past 5 years, not including cervical 
epithelial carcinoma, squamous cell carcinoma or basal cell carcinoma of skin 
that have been clinically cured within 5 years. 
20) Those with known proliferative retinopathy or maculopathy. 
21) Those with a history of major surgical operations (intrathoracic, intracranial, 
intraperitoneal, etc.) within 6 months, or planning to perform operations that may 
interfere with the completion or compliance of the study. 
22) Those with a history of organ transplantation. 
23) Those with ADIS or syphilis at the time of screening, or whose serum virological 
test shows hepatitis C virus antibody or hepatitis B surface antigen and hepatitis 
B core antibody are positive at the time of screening. 
24) Those with AST or ALT > 3.0-fold ULN, or total bilirubin > 2.0-fold ULN at the 
time of screening. 
25) Those with eGFR < 60 mL/min/1.73 m2 at the time of screening. 
26) Those with a history of drug abuse (heavy and repeated use of dependent drugs 
or substances not related to medical purposes, including addictive and habitual 

drugs, causing physical and mental dependence) in 5 years before screening and 
alcohol dependence (long-term heavy drinking, causing physical and mental 
dependence, male drinking more than 14 units of alcohol per week, and female 
drinking more than 7 units per week) (1 unit alcohol = 360 mL beer or 45 mL 
spirits with 40% alcohol content or 150 mL wine)]. 
27) Female who are known to be pregnant (determined by pregnancy test at the 
time of screening) or who are breast-feeding or who plan a pregnancy during 
the study and are unwilling to take effective contraceptive measures (including 
partners). 
28) Those participating in other intervention clinical trials within 3 months prior to 
screening. 
29) Those known to be allergic to GLP-1 receptor agonist. 
30) Those with any serious systemic diseases as determined by the investigator, or 
other diseases as believed by the investigator to be possible to interfere with the 
results of this study or abnormal laboratory tests with clinical significance. 
31) Those who, according to the opinion of investigators, are not suitable to 
participate in clinical trials, including those who are physically or psychologically 
unable to comply with the protocol. 
Stratified 
standard 
Based on stratified randomization, stratifying factors included baseline BMI < 30 kg/m2 
and ≥ 30 kg/m2，presence and absence of type 2 diabetes. The number of enrolled 
patients with type 2 diabetes should not exceed 17% of the total number. 
Rescue 
therapy 
criteria 
If the fasting blood glucose of patients with type 2 diabetes exceeds the following 
standard (at least 2 times, one of which should be fasting venous blood glucose), the 
combination of hypoglycemic drugs can be gradually increased to the maximum 
prescription dose. If the blood glucose is still out of control, other hypoglycemic 
treatments (metformin, sulfonylureas, glycosidase inhibitors or glinides) permitted by 
this protocol should be allowed to be increased, which will determined by the 
investigator. 
⚫ 
Baseline - Week 6: FPG > 13.3 mmol/L (240 mg/dL) 
⚫ 
Week 7~Week 30: FPG > 11.1 mmol/L (200 mg/dL) 
Rescue therapy will affect the evaluation of body weight and response indicators, so the 
body weight and blood glucose efficacy analysis will only include the measured values 
before rescue therapy. 
Administrati
on regimen 
Investigational drug: Liraglutide Injection (BID), by subcutaneous injection, with the 
injection site to be at the abdomen, thigh or upper arm as selected. Dosage adjustment 
is not required when injection site and injection time change. The initial dose of 
Liraglutide Injection should be 0.6 mg per day. The dose escalation protocol should be 
based on the table below to reduce the likelihood of gastrointestinal symptoms. At Week 
7, the dose should be increased to 3.0 mg per day. A subject failing to tolerate the target 
dose of 3.0 mg may try the dose of 2.4 mg and try to increase the dose to 3.0 mg again 
within 2 weeks. If the subject is still unable to tolerate such dose (3.0 mg), the drug must 
be discontinued and the treatment must be terminated. 
Control drug: placebo, which should be used as above. 
Dose increment protocol for the investigational drug 
Week 
Daily dose 
Week 1 
0.6 mg 
Week 2 
1.2 mg 
Weeks 3~4 
1.8 mg 
Weeks 5~6 
2.4 mg 
Week 7 
3.0 mg 
Study cycle 
Screening period: 2 weeks 
Treatment period: 30~32 weeks (about 6~8 weeks of dosage adjustment period, 24 
weeks of stable treatment period)  
Safety follow-up period: 2 weeks 

The study cycle will be about 34~36 weeks. 
Response 
evaluation 
indicator 
Primary endpoint: 
1) 
The percentage of body weight loss from baseline at the end of treatment; 
2) 
The proportion of subjects whose body weight will decrease by ≥ 5% from 
baseline level at the end of treatment;  
Secondary endpoint: 
1) 
Changes in waist circumference of the subjects at the end of treatment; 
2) 
Changes in blood pressure level (diastolic pressure and systolic pressure) and 
pulse of the subjects at the end of treatment; 
3) 
The changes in blood lipid levels (triglyceride, total cholesterol, low density 
lipoprotein cholesterol, and high density lipoprotein cholesterol) of the subjects 
at the end of treatment; 
4) 
The change of blood glucose level (insulin, fasting blood-glucose) of the subjects 
at the end of treatment; 
5) 
The changes in HbA1c of patients with type 2 diabetes at the end of treatment; 
6) 
The absolute body weight loss of the subjects at the end of treatment; 
7) 
The proportion of subjects with body weight loss > 10% at the end of treatment; 
8) 
Effect of changes in body weight of the patients to the IWQOL-lite at the end of 
treatment 
Response 
evaluation 
criteria 
The product can be considered to be effective in body weight control when the 
following conditions are met simultaneously after 30-32 weeks of treatment: 
 
The difference in mean body weight loss between the experimental group and the 
placebo group is at least 5%, and the difference is statistically significant. 
 
The proportion of subjects losing more than 5% of their body weight from 
baseline in the experimental group should be at least 35%, which should be about 
2 times as much as that in the placebo group. In addition to that, the difference 
between the two groups should be statistically significant. 
Safety 
evaluation 
index 
It is used to evaluate the safety and immunogenicity of the investigational drug 
following subcutaneous injection. 
⚫ 
Incidence rate of AEs, AEs during treatment, serious and non-SAEs 
⚫ 
Incidence rate of gastrointestinal reactions: including nausea, diarrhea, vomiting, 
constipation, abdominal pain and dyspepsia 
⚫ 
Incidence rate of hypoglycemic events: proportion of subjects and incidence rate 
of hypoglycemic events in each category 
⚫ 
Early withdrawal due to AEs: including stopping treatment due to nausea and 
vomiting 
⚫ 
Changes in vital signs 
⚫ 
Changes in physical examination 
⚫ 
Changes in 12 lead ECG 
⚫ 
Changes in clinical laboratory examination parameters (blood routine, urine 
routine, blood biochemistry (liver function, kidney function, TSH, calcitonin, 
amylase, lipase, etc.)) 
⚫ 
Changes in PHQ-9 
⚫ 
Incidence rate of Liraglutide antibody 

Sample size 
calculation 
According to the statistical requirements of placebo-controlled superiority trial, the 
main reponse indicator of this study is the mean weight loss percentage of subjects 
compared with baseline at the end of treatment and the proportion of subjects with body 
weight loss ≥ 5% at the end of treatment, and the two indicators will be the synergistic 
response indicators. 
According to the response evaluation criteria, the product can be considered effective 
for body weight control if the following two conditions are met simultaneously at the 
end of treatment: 
response indicator (1) The difference in mean body weight loss between the 
experimental group and the placebo group should be at least 5%, with the difference to 
be statistically significant. With the bilateral test α=0.05 and the power as 90% and 
without considering the shedding, the random proportion of experimental group: 
placebo group is 2:1, the required sample size is 102 cases in the experimental group 
and 51 cases in the placebo group, with a total sample size of 153 cases 
Response indicator (2) The proportion of subjects with body weight loss ≥ 5% from 
baseline in the experimental group should be at least 35%, which is about 2 times the 
body weight loss rate of subjects in the placebo group, with the difference between the 
two groups to be statistically significant. With the bilateral test α= 0.05 and the power 
as 90% and without considering the shedding, the random proportion of experimental 
group: placebo group is 2:1, the required sample size is 194 cases in the experimental 
group and 97 cases in the placebo group, with a total sample size of 291 cases. 
According to the above response evaluation criteria, the above 2 response indicators 
should be met at the same time in order to succeed in the trial. Therefore, 291 cases of 
the larger sample size required to achieve statistical significance of the 2 indicators are 
taken as the effective sample size required for the synergistic response indicator. Taking 
into account the shedding factors, it is estimated that about 414 subjects will be included 
according to the 30% shedding rate. 
Statistical 
analysis 
The software of SAS 9.4 or above will be used for analysis. The safety data set will be 
used for safety analysis, and the data from the full analysis set and the per protocol set 
will be used for the analysis of efficacy. The analysis of the primary endpoint will be 
based on the full analysis set. 
 Collaborative main evaluation indicator of the study 1: The percentage of subjects 
in the experimental group who lost body weight compared with baseline at the end of 
treatment. Superiority test hypothesis 1: 
⚫ 
H0:The difference in the mean change in body weight between the Liraglutide 
Injection group and the placebo group at the end of treatment compared with the 
baseline period is < 5%; 
⚫ 
H1:The difference between the Liraglutide Injection group and the placebo group 
at the end of treatment compared with baseline body weight change was ≥ 5%. 
Collaborative main evaluation indicator of the study 2: The proportion of subjects 
whose body weights decrease by ≥ 5% from baseline at the end of treatment. Superiority 
test hypothesis 2: 
⚫ 
H0:The proportion of subjects who lost more than 5% of their body weight from 
baseline is less than 35% in the experimental group, or the proportion of subjects 
in the experimental group lost body weight 2 times as much as that in the placebo 
group, or there is no statistical significant difference between the two groups. 
⚫ 
H1: The proportion of subjects with body weight loss ≥ 5% from baseline in the 
experimental group is greater than or equal to 35%, which is 2 times as much as 
that in the placebo group, and there is a statistical significant difference between 
the two groups. 
The above two statistical test hypotheses are based on two-sided test, and at the 
significance level of α= 0.05, the two collaborative primary endpoints should reach 
statistical significance at the same time. 
The safety evaluation indexes include physical examination, vital signs, 
electrocardiogram, laboratory examination, immunogenicity, mental health assessment 
and AEs. The immunogenicity evaluation indicator is the incidence rate of Liraglutide 
antibody.