The Safety and Effectiveness Study of Prebiotics and Probiotics in the Intervention of Obesity in Children With Prader-Willi Syndrome
Phase: NA
Conditions: Prader-Willi Syndrome
Sponsor: Children's Hospital of Fudan University

 
 
 
 
Research protocol 
(Version No.: Version 2.0 Version date: 2023.01.05) 
 
 
 
 
Safety and effectiveness of prebiotics and probiotics in 
intervention of obesity in children with Prader-Willi syndrome 
 
Children’s Hospital of Fudan University 
Main researcher: Lu Wei 
 

1. Background 
Prader-Willi syndrome (PWS) is a rare genetic disease with a wide range 
of clinical manifestations, including changes in body composition, excessive 
appetite and serious behavioral problems [1]. The combination of low energy 
consumption and high energy intake is considered to be the most common 
cause of hereditary obesity [2-4]. The clinical symptoms of PWS vary with age 
and present different nutritional stages. In infancy, it is characterized by weak 
sucking and feeding difficulties, and in early childhood, it gradually transits to 
lack of satiety, morbid obesity and related complications caused by gluttony, 
which are the most common causes of poor prognosis and death of PWS [5-
8]. At present, there are no effective drugs to help control appetite, and 
obesity treatment drugs such as weight-loss drugs are not suitable for children, 
and the use of gastric volume reduction surgery for PWS is still controversial. 
Therefore, how to effectively control the appetite of children, avoid or reduce 
the occurrence and severity of obesity, and reduce the occurrence of related 
complications has become the most serious challenge for PWS treatment. 
In recent years, more and more evidence shows that intestinal flora is 
closely related to the occurrence of obesity, and is considered as an important 
participant in the development of obesity and metabolic diseases [9,10] and 
mental health disorders including depression, anxiety and social behavior [11-
13]. Probiotics, as a kind of microorganism that can improve the changes of 
intestinal micro-ecology, has been proved to improve biochemical indicators 
such as blood lipids in obese people. Several animal bifidobacteria 
subspecies and lactic acid bacteria strains have been proved to improve the 
risk factors of cardiac metabolism in adult obese patients by reducing central 
obesity and insulin resistance [14~16]. Specifically, the strain CECT 8145 
(BPL1) was initially identified as an effective probiotics, which reduced fat 
deposition in the high-throughput screening of Cryptostrongylus elegans [17]. 
In this organism, BPL1 targets both energy homeostasis and tryptophan 
metabolism [17]. It is an important regulator of central nervous system 
processes, including satiety, anxiety and depression [13, 18]. Research on 
intestinal microbiota of PWS patients found that 17 children and adolescents 
with PWS were given low-calorie diet intervention in hospital, and the changes 
in intestinal microbiota directly contributed to improving obesity and metabolic 
health [19]. Olsen et al. studied the intestinal microbiota of 17 adult PWS 
subjects and the matched group of non-hereditary obesity, and concluded that 
intestinal bacteria play a positive role in insulin sensitivity [20]. The recently 
reported intestinal microbiota associated with obesity in PWS children found 
changes similar to those in simple obesity [21], while Peng et al.'s research 
suggested that there were some differences in intestinal bacterial and fungal 
communities in PWS children compared with the control group [22]. 

Since carrying out molecular genetic diagnosis of PWS, our hospital has 
successively carried out a national multi-center study on "early screening and 
intervention of PWS"; Set up PWS special clinic; Establish PWS Club of 
Pediatric Hospital Affiliated to Fudan University; Carry out special research on 
PWS MDT and special disease cohort; In 2018, it initiated the establishment 
of the "China Prad Willi syndrome clinical standardized diagnosis and 
treatment cooperation alliance", and took the lead in carrying out the national 
multi-center study of "Phase III clinical trial to evaluate the efficacy and safety 
of recombinant human growth hormone injection in the treatment of PWS" in 
China, and assisted the domestic growth hormone product to obtain the first 
approval of PWS treatment indications on June 30, 2022. So far, hundreds of 
cases have been accumulated, and long-term follow-up monitoring and 
multidisciplinary comprehensive management have been carried out, and rich 
clinical diagnosis and treatment, drug clinical trials and multi-center research 
experience have been accumulated. 
 
reference 
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2. Kimonis V.E., Tamura R., Gold J.A., Patel N., Surampalli A., Manazir J., Miller J.L., 
Roof E., Dykens E., Butler M.G., et al. Early Diagnosis in Prader-Willi Syndrome 
Reduces Obesity and Associated Co-Morbidities. Genes. 2019; 10:898. doi: 
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of the probiotic Bifidobacterium animalis subsp. lactis CECT 8145 on anthropometric 
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Chen Y., Karoly E.D., Ramón D., Genovés S. Probiotic Strain Bifidobacterium 
animalis subsp. lactis CECT 8145 Reduces Fat Content and Modulates Lipid 
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18. O’Mahony S.M., Clarke G., Borre Y.E., Dinan T.G., Cryan J.F. Serotonin, 
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Ouyang H., et al. Dietary Modulation of Gut Microbiota Contributes to Alleviation of 
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10.1016/j.ebiom.2015.07.007.  
20. Olsson L.M., Poitou C., Tremaroli V., Coupaye M., Aron-Wisnewsky J., Backhed 
F., Clement K., Caesar R. Gut microbiota of obese subjects with Prader-Willi 
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10.1136/gutjnl-2019-319322.  
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Ibáñez L., Ramon-Krauel M., Lerin C. Specific Dietary Components and Gut 
Microbiota Composition are Associated with Obesity in Children and Adolescents 
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Madsen K.L., Walter J., Tun H.M., et al. The Gut Microbiota Profile in Children with 
Prader-Willi Syndrome. Genes. 2020; 11:904. doi: 10.3390/genes11080904.  
 
 
2. Research purpose 
 
This study aims to explore the new method and potential mechanism of 
PWS treatment by observing the safety and effectiveness of prebiotics and 
probiotics in the intervention of obesity in children with PWS. 
 

3. Research overview 
3.1 Overall research and design 
It is planned to carry out a 12-week randomized, single-blind, parallel 
controlled, and efficacy test single-center clinical intervention trial. The trial 
plan screened 60 PWS obese patients (3-10 years old) who met the 
enrollment criteria and were divided into three groups. At the time of 
enrollment, the subjects were randomly assigned to different groups 
according to the block randomization method. 
 
⚫ Group A: probiotics 2g × 2/day; 
⚫ Group B: probiotics 2g × 2/day+prebiotics 25g × 2/day; 
⚫ Group C: control group (food with equal energy and no functional 
ingredients) 
The intervention products comply with the Food Safety Law of the People's 
Republic of China, the probiotic solid beverage of GB/T 29602 standard, and 
the food grade inulin extract prebiotics of GB/T 19883 standard. 
3.2 Study population 
PWS obese children aged 3-10 years. 
3.2.1 Selection criteria 
1)Pre-adolescent children with Prader Willi syndrome which were definitely 
diagnosed by gene testing. 
2)Consistent with the diagnostic criteria for obesity. 
3)Not participate in other research projects at present or three months before 
the research; 
4)Agree to participate in the test and obtain the consent of their parents; 
voluntarily be the subjects and sign the informed consent form. 
3.2.2 Exclusion criteria 
1)Losing weight in ways other than the intervention measures of this project, 
such as taking weight loss drugs or known drugs that cause weight change; 
2)Use antibiotics within 1 month before the study and lasted for 3 days or 
more; 
3)Use probiotics within 1 month before the study and lasted for 3 days or 
more; 

4)Complicated with liver and renal insufficiency (alanine aminotransferase and 
serum creatinine indexes exceed 2 times the upper limit of the normal value 
set by the hospital); 
5)Have gastrointestinal diseases affecting food digestion and absorption 
(such as severe diarrhea, constipation, severe gastrointestinal inflammation, 
active gastrointestinal ulcer, acute cholecystitis, etc.); severe diarrhea refers 
to watery stool 3 or more times a day and lasts for 3 or more days. severe 
constipation refers to defecation 2 or less times a week with difficulty in 
defecation; 
6)Surgery was performed within 1 year before the study (except for 
appendicitis and hernia surgery); 
7)Have hepatitis B, active tuberculosis, AIDS and other infectious diseases; 
8)Those who are suffering from mental illness and are taking psychotropic 
drugs such as antidepressants. 
3.2.3 Withdrawal criteria 
1)The tested children have serious violations of the study plan, such as taking 
weight loss drugs, and stopping the trial intervention plan on their own for a 
long time; 
2)Other clinical events, such as fracture and trauma, sudden disease 
requiring surgery, cannot continue to be tested; 
3)Subjects were absent for two consecutive times in three test visits; 
4)If the subject and his caregiver withdraw their informed consent and request 
to withdraw from the study, the case record in this study is active termination, 
and all clinical data cannot be used for statistical analysis. 
3.2.4 Test completion criteria 
Subjects completed all protocols of the study. 
3.2.5 Number of subjects and grouping method 
Sixty eligible subjects were divided into three groups at a ratio of 1:1:1. At 
the time of enrollment, the subjects were randomly assigned to different 
groups according to the block randomization method. The randomization 
scheme was generated by the statisticians using SAS 9.4 statistical software. 
 

3.3 Test drug 
Group A: probiotics 2g × 2/day; 
Group B: probiotics 2g × 2/day+prebiotics 25g × 2/day; 
Group C: control group (food with equal energy and no functional ingredients) 
 
Interventions are probiotic solid drinks in accordance with the Food Safety 
Law of the People's Republic of China and the GB/T 29602 standard, and 
prebiotics (strawberry dietary fiber jelly) in food grade inulin extract in 
accordance with the GB/T 19883 standard, which are provided free of charge 
by the research center with self-raised funds. 
 
Table 1. Nutritional composition of probiotics 
project 
Every 100g 
Nutrient reference 
value% 
energy 
1312 kJ 
16% 
protein 
4.1 g 
7% 
Fat 
0 g 
0% 
carbohydrate 
58.5 g 
20% 
dietary fiber 
30.1 g 
120% 
sodium 
60 mg 
3% 
 
Table 2. Nutritional composition of prebiotics (strawberry dietary fiber jelly) 
project 
Every 100g 
Nutrient reference 
value% 
energy 
448 kJ 
6% 
protein 
0 g 
0% 
Fat 
0 g 
0% 
carbohydrate 
17.2 g 
6% 
dietary fiber 
19.5 g 
78% 
sodium 
93 mg 
5% 
 
3.4 Research steps and methods 
① Research steps 
⚫ Intervention group (group A): from day 0: ① Sabijian ® Probiotic solid 
beverage 2g × 2/day oral; ② Accept the dietitian's diet and lifestyle 
recommendations. The dietitian collects the daily diet and exercise 
information of the subjects through the WeChat widget, and gives the 
corresponding personalized diet and exercise suggestions to the subjects 
according to the Diet Guide for Chinese School-age Children; 
⚫ Intervention group (group B): from day 0: ① probiotics solid beverage 2g 
× 2/day+prebiotic dietary fiber jelly 25g × 2/day oral; ② Accept the 
dietitian's diet and lifestyle recommendations. The dietitian collects the 

daily diet and exercise information of the subjects through the WeChat 
widget, and gives the corresponding personalized diet and exercise 
suggestions to the subjects according to the Diet Guide for Chinese 
School-age Children; 
⚫ Control group (group C): healthy diet guidance was given only in the 0, 4 
and 8 weeks (three times). 
 
② Indicator detection 
Use intervention food twice a day (30 minutes before meals). At the same 
time, they accept the daily diet content management and exercise prescription 
management of dietitians. The following tests were performed on the 0th, 4th 
and 12th week after enrollment: 
⚫ Main outcome measures: weight, height and BMI, BMI - SDS, waist 
circumference, body composition (body fat), and stool macrogene 
sequencing; 
⚫ Secondary indicators: ① fasting triglyceride, total cholesterol, low density 
lipoprotein (LDL) and high density lipoprotein (HDL) - cholesterol levels, 
fasting glucose, insulin and hemoglobin A1c (HbA1c) concentrations, 
insulin resistance index (HOMA-IR), blood pressure; ② Psychological 
behavior scale; ③ Clinical Trial Hyperappetite Questionnaire (HQ-CT); ④ 
Gastrointestinal symptoms (constipation, diarrhea, abdominal pain, 
excessive flatulence, bloody stool, nausea, dysphagia, anorexia, 
dyspepsia and acid reflux); ⑤ Stool frequency, stool form, etc. 
 
The trial was observed for a total of 12 weeks, and there were 3 clinical 
follow-up test time points, which were weeks 0, 4 and 12. After the start of 
treatment, stage obesity assessment was conducted every 2 weeks in the first 
12 weeks until the end of the study. In addition to the baseline, the time 
window of each visit is ± 3 days (based on the baseline). 
 
 
4. Observation of adverse events 
4.1 Definition of adverse events 
4.1.1 Definition 
Adverse events: adverse medical events occurred after patients or 
subjects involved in human trials received a drug (or product), but not 
necessarily related to treatment. 
Serious adverse events: during the clinical trial, such events as 
hospitalization, prolonged hospitalization, disability, impact on work ability, 
life-threatening or death, and congenital malformation occurred. 

4.1.2 Degree 
Mild: the subject can tolerate, does not affect the treatment, does not 
need special treatment, and has no impact on the subject's rehabilitation. 
Moderate: the subject is intolerable and needs special treatment, which 
has a direct impact on the rehabilitation of the subject. 
Severe: endangering the life of the subject, causing death or disability, 
requiring immediate emergency treatment. 
4.2 Recording and reporting of adverse events 
This study will record the adverse events occurred during the study and 
any clinically relevant changes, and evaluate whether there is any correlation 
with the application of experimental drugs; And immediately take measures to 
correct and ensure the safety and interests of the subjects. The recorder shall 
sign and date it, and file it with the source file and submit it to the clinical 
research center (CRU) in the hospital. 
Subjects may have clinical adverse events during treatment. Once 
adverse events (including important adverse events) occur, the occurrence 
time, clinical manifestation, treatment process and duration, outcome and 
relationship with the test drug (or test product) shall be recorded in detail on 
the case report form. In case of serious adverse events, fill in the form of 
serious adverse events and report to the sponsor, clinical medical ethics 
branch, relevant management departments and health administrative 
departments within 24 hours. 
4.3 Risk prevention and treatment 
The following risk minimization measures are taken in this study to ensure 
that the potential benefits of research participation exceed the relevant risks. 
1. The application of prebiotics and probiotics in this study is based on the 
overlapping 
administration 
of 
the 
original 
PWS 
multidisciplinary 
comprehensive management. The study participants still maintain the original 
treatment plan during the study process, and the treatment risk is low. 
2. Take the following measures to reduce potential risks. 
(1) People younger than 3 years old were not included in this study. 
Compared with older children, liver and kidney functions of younger children 
are prone to damage, and the risk of adverse reactions is higher. Therefore, 
children under 3 years of age are not included in this study. 
(2) The dosage selection of prebiotics and probiotics in this study is based on 
the product manual and previous studies, and no obvious adverse reactions 

have been observed. 
 
5. Statistical analysis 
5.1 Sample size estimation 
According to the main outcome index BMI, the sample size was estimated 
by using the inter-group parallel control design of measurement data. 
According to the BMI distribution of normal children and adolescents and 
previous clinical studies on PWS, the average BMI of PWS patients with 
obesity in Hefei is 22 kg/m2, and the standard deviation of BMI is 2.0 kg/m2 
α= Under the assumption of 0.05 and 80% statistical efficiency, the sample 
size required to detect the 10% difference in the mean BMI before and after 
the intervention (BMI reduction of 2.0 kg/m2) is at least 16 subjects in each 
group. According to the 1:1:1 distribution of three groups of samples, 48 
children were needed. In consideration of the factors of sample separation 
during the study, it is proposed to enroll 20 children in each group, with a total 
of 75 children recruited. 
5.2 Statistics and analysis of research data 
⚫ All statistical tests are double-sided tests. A P value less than or equal to 
0.05 will be considered statistically significant. 
⚫ The description of quantitative indicators will calculate the mean, standard 
deviation, median, minimum and maximum, and the classification 
indicators will describe the number of cases and percentage of each type. 
⚫ Enrollment and completion: summarize the number of enrollees and 
completion, and list the shedding cases. Describe the demographic 
characteristics (age, height, weight, vital signs, etc.), medical history, 
family history, etc. of the patient. The comparison of the three groups of 
general conditions will be analyzed by appropriate methods according to 
the type of indicators. The group t test or Wilcoxon rank sum test will be 
used for the comparison of quantitative data between groups, the chi-
square test or accurate probability method will be used for classification 
data, and Wilcoxon rank sum test or CMH will be used for grade data- χ 2 
Inspection. 
 
6. Research on relevant ethical issues 
6.1 Review by the Ethics Committee 
This study will fully inform participants and their legal representatives of 
the risks and requirements of this study, and will provide participants and their 
legal representatives with any new information that may affect their continued 
participation in decision-making during the study. Only participants and legal 

representatives who fully understand the risks, benefits and potential adverse 
events of this study and voluntarily provide consent will be included in this 
study. 
The protocol, written informed consent and data directly related to the 
subjects were submitted to the Clinical Medical Ethics Branch, and the study 
was officially conducted after obtaining the written approval of the Clinical 
Medical Ethics Branch. Submit the annual research report to the Clinical 
Medical Ethics Branch every year. 
Inform the Clinical Medical Ethics Branch in writing when the study is 
suspended and/or completed; Report all changes in the research work (such 
as the revision of the protocol and/or the number of informed consent) to the 
Ethics Committee in a timely manner, and implement these changes after 
obtaining the approval of the Clinical Medical Ethics Branch. 
6.2 Informed consent 
6.2.1 Procedures for obtaining informed consent 
The researcher must provide the subject or his legal representative with 
an easy-to-understand informed consent form approved by the Clinical 
Medical Ethics Branch, and give the subject or his legal representative 
sufficient time to consider the study. The subject shall not be included in the 
group until the signed written informed consent form is obtained from the 
subject. During the participants' participation, all updated informed consent 
forms and written information will be provided to the subjects. The informed 
consent form shall be kept for future reference as an important document 
involving human trials. 
7. Confidentiality measures 
The results of the research through this project may be published in the 
magazine, but we will keep the information of the subject confidential 
according to the requirements of the law, and the personal information of the 
subject will not be disclosed unless required by the relevant laws. When 
necessary, the government administrative department, the Clinical Medical 
Ethics Branch and its relevant personnel can access the data of the subjects 
according to the regulations. 
 

v1.0                                   Dec 8, 2022          
1 
Informed consent 
(Legal guardian version) 
Clinical trial name: Safety and effectiveness of prebiotics and probiotics in 
intervention of obesity in children with Pradville syndrome 
Main investigator: Lu Wei, Department of Endocrine Genetics and Metabolism, 
Pediatric Hospital Affiliated to Fudan University 
Dear parent or legal guardian: 
Your child will be invited to participate in a study. This informed consent 
form provides some information to help you and your child decide whether to 
participate in the study. Please read carefully. If you have any questions, please 
ask the researcher in charge of the study. 
1. What is the research background and purpose of this study 
Prader-Willi syndrome (PWS) is one of the main genetic causes of morbid 
obesity in children. The clinical symptoms change with age, presenting different 
nutritional stages, and gradually transiting to lack of satiety in early childhood, 
morbid obesity and related complications caused by overeating, which are the 
most common causes of poor prognosis and death of PWS. At present, there 
are no effective drugs to help control appetite, and obesity treatment drugs 
such as weight-loss drugs are not suitable for children, and the use of gastric 
volume reduction surgery for PWS is still controversial. Therefore, how to 
effectively control the appetite of children, avoid or reduce the occurrence and 
severity of obesity, and reduce the occurrence of related complications has 
become the most serious challenge for PWS treatment. 
In recent years, more and more evidence has shown that intestinal 
microflora is closely related to the occurrence of obesity, and probiotics, as a 
kind of microorganism that can improve the changes of intestinal micro-ecology, 
has been proved to improve the blood lipids and other biochemical indicators 
of obese people. Our previous 16s rRNA sequencing results of fecal bacteria 
in PWS and normal control children suggest that the diversity of intestinal flora 
in PWS children is significantly reduced, the beneficial bacteria producing short 
chain fatty acids such as Faecalibacterium, Blautia, Prevotella, etc. are 
significantly decreased, and the opportunistic pathogenic bacteria such as 
Streptococcus, Escherichia-Shigella, Klebsiella, etc. are increased, suggesting 
that intestinal flora may play a role in the occurrence and development of 
obesity in PWS. 
Therefore, the purpose of this study is to observe the safety and 
effectiveness of prebiotics and probiotics in the intervention of obesity in 
children with PWS, and explore new methods and potential mechanisms of 
PWS treatment. 
2. How was the study conducted? 
It will take about 12 weeks for your child to participate in and complete the 
study. The study will be carried out in a research center of the Pediatric Hospital 
affiliated to Fudan University. There will be 60 patients enrolled in the study, and 
the research center will recruit at least 75 patients. 

v1.0                                   Dec 8, 2022          
2 
⚫ Research content: 
Potential benefits of  
probiotics and prebiotics on body mass index, glucose 
and lipid metabolism and intestinal flora composition of PWS obese subjects. 
This study selected obese PWS patients as the study object, and compared 
probiotics, probiotics combined with probiotics (inulin) and placebo to explore 
the effects of probiotics combined with probiotics (inulin) on body mass index, 
glucose and lipid metabolism and intestinal flora composition of PWS patients 
with obesity. 
⚫ Study design: 
This study is a 12-week randomized, single-blind, parallel controlled, and 
clinical intervention test with excellent effect. To evaluate the potential benefits 
of probiotics and prebiotics on body mass index, glycolipid metabolism and 
intestinal flora composition of PWS patients with obesity. Sixty eligible subjects 
were divided into three groups at a ratio of 1:1:1. At the time of enrollment, the 
subjects were randomly assigned to different groups according to the way of 
block randomization: 
 
Intervention group (group A): from day 0: ① probiotics powder 2g × 
2/day oral; ② Accept the dietitian's diet and lifestyle recommendations. The 
dietitian collects the daily diet and exercise information of the subjects through 
the WeChat widget, and gives the corresponding personalized diet and 
exercise suggestions to the subjects according to the Diet Guide for Chinese 
School-age Children; 
 
Intervention group (group B): from day 0: ① probiotics powder 2g × 
2/day+prebiotic dietary fiber jelly 25g × 2/day oral; ② Accept the dietitian's diet 
and lifestyle recommendations. The dietitian collects the daily diet and exercise 
information of the subjects through the WeChat widget, and gives the 
corresponding personalized diet and exercise suggestions to the subjects 
according to the Diet Guide for Chinese School-age Children; 
 
Control group (group C): healthy diet guidance was given only in the 0, 4 
and 8 weeks (three times). 
Weight, height, blood pressure, BMI, BMI - SDS, waist circumference, body 
composition (body fat), and fecal macrogene sequencing were performed 
 
before treatment (0W) and at the 4th week (4Ws) and 12th week (12Ws) of 
treatment respectively; Glycolipid metabolism and other indicators: fasting 
triglyceride, total cholesterol, low density lipoprotein (LDL) and high density 
lipoprotein (HDL) - cholesterol levels, fasting glucose, insulin and hemoglobin 
A1c (HbA1c) concentrations, insulin resistance index (HOMA-IR). 
 
The trial was observed for a total of 12 weeks, and there were 3 clinical 
follow-up test time points, which were weeks 0, 4 and 12. After the treatment, 
the stage obesity assessment was conducted every 2 weeks until the end of 
the study. In addition to the baseline, the time window of each visit is ± 3 days 
(based on the baseline). 
⚫ Test termination criteria for subjects: 
 
In case of one of the following conditions, the test process should be 
stopped: 

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3 
 Serious adverse events occur and have certain relationship with the test 
product; 
 The tested children have serious violations of the study plan, such as taking 
weight loss drugs, and stopping the trial intervention plan on their own for 
a long time; 
 Other clinical events, such as fracture and trauma, sudden disease 
requiring surgery, cannot continue to be tested; 
 Subjects were absent for two consecutive times in three test visits; 
 If the children and their caregivers withdraw their informed consent and 
request to withdraw from the study, the case record in this study is an active 
termination, and all clinical data cannot be used for statistical analysis. 
 
3. Does my child have other treatment options? 
This study is a superimposed treatment plan based on the original PWS 
multidisciplinary comprehensive management. No matter which group you are 
assigned to, the original treatment plan will continue. If the research results 
show that the treatment effect is not good, there are other clinical research 
programs, such as new long-acting glucagon-like peptide-1 (GLP-1) analogues 
or stomach volume reduction surgery, traditional Chinese medicine and so on, 
which can be considered. Please discuss these and other possible options with 
your doctor. 
 
4. What does my child need to do in the study? 
You need to provide true information about your medical history and current 
physical condition; Tell the research doctor about any discomfort of your child 
during this study; It is necessary to take your child to the clinic for follow-up and 
complete relevant examinations according to the scheduled time. 
 
5. What are the risks and adverse reactions of my child participating in 
this study? 
⚫ Treatment risk: The application of prebiotics and probiotics, the intervention 
drug of the researcher, is the superimposed administration based on the 
original PWS multidisciplinary comprehensive management. Therefore, the 
study participants still maintained the original treatment plan during the 
study, and the treatment risk was low. 
⚫ Adverse reactions: Sabijian was used in the experiment ® Probiotic solid 
beverage and Sabijian ® Strawberry dietary fiber is a food-grade health 
care product that has been marketed. Generally, there will be no adverse 
reactions when consumed in the appropriate range, such as Sabijian ® 
Excessive strawberry dietary fiber may cause gastrointestinal symptoms 
such as diarrhea, abdominal distension and excessive intestinal exhaust. 
In the course of drug application, we will closely observe and monitor the 
situation of children. In case of any discomfort, new changes in the 
condition of the subject, or any unexpected situation in the study, whether 
related to drugs or not, the parents should contact the subject's primary 
doctor in time, and the doctor will make judgment and medical treatment. If 
any test-related damage occurs due to participation in the test, the subject 

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4 
will receive timely treatment and corresponding compensation. 
⚫ In terms of blood sample collection: no additional blood sample is required 
for this study. 
 
6. What are the benefits of this study for my children? 
The application of prebiotics and probiotics in this study is based on the 
superimposed 
administration 
of 
the 
original 
PWS 
multidisciplinary 
comprehensive management. Therefore, no matter which group the study 
participants are assigned to, the original treatment plan will remain unchanged 
during the study, and will benefit from the treatment. If you are in the trial drug 
group, the trial drug may better improve your obesity and metabolic disorders, 
but we cannot guarantee this. In addition, the relevant information of this study 
will help to obtain important information about PWS obese children, and your 
participation will bring benefits to children suffering from the same pain in the 
future. 
 
7. Will you be paid for participating in the research? 
You will not receive any remuneration for participating in this experiment 
or this study. We will provide probiotics and prebiotic intervention drugs and 
intestinal flora detection related to this study for free. 
 
8. What fees do I need to pay to participate in this study? 
Participation in this research project will not increase your additional 
expenses. Your child will participate in this research, and all other relevant 
inspection items are routine outpatient follow-up inspection items except for the 
detection of fecal intestinal flora during the research process. You will not pay 
any additional fees for participating in this research project. 
9. What if my child is injured during the study? 
If your child is injured during the study or has adverse events during 
medication, please contact your research doctor, and your child will receive 
timely treatment; For any injury that has a causal relationship with the study or 
the trial drug, the sponsor will bear the medical expenses and give you 
corresponding economic compensation according to the relevant national 
laws and regulations. 
 
10. Will I keep my child's information confidential? 
During the study, we will collect your child's medical history information, 
laboratory and imaging examination results, and follow-up information. To 
ensure privacy, we will code some of your information, and your personal 
identifier (such as name, date of birth, address) will be replaced by a code 
(unique patient number), so that no one can determine your identity. All data 
are kept in the hands of the main researchers, and stored in the clinical research 
center for 3 years, and then destroyed. The biological samples collected during 
the study period are kept in the hands of the main researchers, in the clinical 
research center for 3 years, and then destroyed. Except for this study, you will 

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5 
not use this information again in the future. 
The results of the research through this project may be published in 
medical journals, but we will keep your research records confidential according 
to legal requirements. The personal information of the research subjects will be 
strictly confidential, and your personal information will not be disclosed unless 
required by relevant laws. If necessary, the government management 
department, the hospital ethics committee and other relevant researchers can 
access your data according to regulations. 
 
11. Does my child have to participate in this study? 
Whether to participate in the study depends entirely on your and your 
child's willingness. You and your child can refuse to participate in the study, or 
withdraw from the study at any time during the course of the study, which will 
not affect the relationship between you and the doctor, nor will it affect the loss 
of medical treatment or other benefits to your child. 
If your child needs other treatment, or your child does not comply with the 
study plan, or has test-related injury or for any other reason, the study physician 
can terminate your child's participation in the study. 
 
12. If I have questions, who should I contact? 
If you have any questions or concerns about this study, you can consult 
the doctor in charge of this study: Lu Wei. The contact number is 021-64933281. 
If you have any questions about the right to participate in this study, please 
consult the Ethics Committee of the Pediatric Hospital affiliated to Fudan 
University, Tel: 021-64931221, Working hours: 8:00-11:30 a.m., 1:30-5:00 p.m. 
on weekdays.

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Informed consent form (signature page) 
I have read and understood the information in this informed consent. I have 
had the opportunity to ask questions and am satisfied with the answers to all 
questions. I have been given enough time and opportunity to ask about the 
details of the study and consider whether to participate in the study. I 
volunteered my child to participate in this study. Signing this informed consent 
does not mean that I will waive any of my legal rights. 
I have been informed that I will receive a signed copy of this document. 
 
Name of the tested child (in block letters):___________________ 
 
Name of legal guardian (in block letters):__________________ 
 
Signature of legal guardian:__________________________ Relationship with 
children:_________________ 
Signature date: Contact number:___________________ 
 
 
Statement of informed consent acquirer: 
I confirm that I have explained the details of this study to the subject's 
guardian, including their rights, possible benefits and risks, and have given 
them a signed copy of the informed consent form. 
Name of informed consent recipient_____________________ 
Signature of informed consent acquirer_____________________ 
Signature 
date_________________________ 
 
Contact 
number______________________ 
 
 

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Dec 08, 2022  
 
Informed consent 
(Written notice version for minors ≥ 8 years old) 
You will be asked whether you are willing to assist in the research of a new 
type of treatment drug for obesity in PWS. Before you participate in the study, 
you need to discuss with your parents/guardians, and the doctor or nurse will 
explain the study to you and answer all your questions. If there are any 
problems, you can contact the research doctor at any time. 
1. What is the research background and purpose of this study 
PWS often develops into severe obesity due to uncontrollable appetite, 
lack of exercise ability and amount of exercise, and obesity related 
complications such as diabetes, metabolic syndrome, etc. slowly appear. If 
effective treatment cannot be carried out in time, bad consequences will occur. 
Probiotic solid beverage and prebiotic dietary fiber jelly are food-grade health 
products, which can help us reduce food intake, regulate the bacteria in the 
intestines, and help us lose weight. Our main purpose of this study is to observe 
the safety and effectiveness of prebiotics and probiotics on obesity in children 
with PWS, and to find new methods for PWS treatment. 
2. What will I encounter if I participate in this study? 
In the process of participating in this study, you need to come to the hospital 
with your father or mother or other family members to visit the doctor three times. 
During the outpatient visit, the doctor will ask you about the drugs you are taking, 
as well as your daily diet and exercise, and will carry out the same physical 
measurement and blood test as the previous regular follow-up, and at the same 
time, you need to cooperate to take some fresh stool. Finally, the doctor will call 
you for a follow-up. 
3. Is there anything in the research that makes me feel uncomfortable, 
scared or uncomfortable? 
During the course of the study, you may experience some side effects, 
which may cause you to suffer from loss of appetite, poor appetite and other 
discomfort. 
You may also have other feelings. In the process of participating in the 
study, when you feel unwell or take any medicine, you must inform your parents 
or your life. You or your parents can call the doctor at any time. 
4. Will it help me to participate in the research? 
Participation in this study is expected to improve your obesity and metabolic 
disorder, but we cannot guarantee it. Your participation will certainly help 
children with the same disease as you. 
5. Do I have to participate in this research? 
You do not have to participate in this study. You can continue to use your 

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Dec 08, 2022  
 
conventional medicine or ask your doctor to give other treatment drugs. After 
participating in this study, you can also withdraw from the study at any time if 
you change your mind. Whether you participate in this study or not, your doctor 
will give you the best medical care. 
6、 If I have questions, who should I contact? 
If you have any questions or concerns about this study, you can consult 
the doctor in charge of this study: Lu Wei. The contact number is 64933281. If 
you have any questions about the right to participate in this study, please 
consult the Ethics Committee of the Pediatric Hospital affiliated to Fudan 
University, Tel: 021-64931221, Working hours: 8:00-11:30 a.m., 1:30-5:00 p.m. 
on weekdays. 
 
 
 
 

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Dec 08, 2022  
 
Informed consent form (signature page) 
 
The doctor has explained this information to me in detail, and I have also 
asked the doctor about the words and expressions I don't understand. I 
understand that participation in this study is voluntary. After consideration, I am 
willing to participate in this study and cooperate with the doctor's diagnosis, 
treatment and follow-up. In case of any discomfort, I will notify my 
parents/guardian or doctor in time. 
I understand that I can stop this study at any time, and the doctor will help 
me with other treatments. 
 
Name of child subject in block letters:                Date of birth:          
Signature of child subject:                        Date:            
 
 
Doctor's statement 
I confirm that I have explained the details of this trial to the patient, including 
their rights, possible benefits and risks, and have given them a signed copy of 
the informed consent form. 
 
Signature of informed consent interview doctor (researcher):             
Date of signature:                 Tel.:                   
 
 
 
 
 
 
 
 
 

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Dec 8, 2022 
Informed consent 
(<8 years old minor oral notice version) 
Hello, children: 
PWS often develops into severe obesity due to uncontrollable appetite, 
lack of exercise ability and amount of exercise, and obesity related 
complications such as diabetes, metabolic syndrome, etc. slowly appear. If 
effective treatment cannot be carried out in time, bad consequences will occur. 
Probiotic solid beverage and prebiotic dietary fiber jelly are food-grade health 
products, which can help us reduce food intake, regulate the bacteria in the 
intestines, and help us lose weight. Our main purpose of this study is to observe 
the safety and effectiveness of prebiotics and probiotics on obesity in children 
with PWS, and to find new methods for PWS treatment. 
1. What do I need to do if I participate in the research? 
If you try this new therapeutic drug, we will take care of you very carefully 
and carry out some tests on you. This is clinical research. You can ask your 
parents and doctors to help you decide whether to participate in this study. 
During your participation in this study, the doctor will ask you about the drugs 
you are taking, as well as your daily diet and exercise. You need to come to the 
hospital with your father or mother or other family members to visit the doctor 
three times, and the doctor will call you for a follow-up. If you want to participate 
in this study, we will also ask your father or mother if they agree. 
2. Is there anything in the research that makes me feel uncomfortable, 
scared or uncomfortable? 
We hope that therapeutic drugs can help you feel better, but sometimes 
therapeutic drugs may make you feel a little uncomfortable. So if you feel sick, 
you should tell your father or mother, or tell the doctor or nurse. We will take 
good care of you and make your uncomfortable feeling better soon. During the 
test, you may encounter the same situation as you used to see a doctor: (For 
example, the doctor or nurse will use a needle to draw blood from you (arm). It 
may hurt a little. Your arm may have red spots or bruises.) 
3. Will it help me to participate in this research? 
You may become better, such as weight control and obesity reduction, but 
we can't guarantee it. Your participation may help children with the same 
disease as you. 
4. Is participation in this study voluntary? 
No matter whether you choose to participate or not, no one will be angry. 
If you don't want to, you can not participate in this study. If you agree to 
participate in this study now and do not want to participate in it later, you can 
still stop participating in this study. Even if you don't want to participate in this 
study, your doctor will still take care of you.