A Postbiotics Improves the Quality of Life and Nutritional Status in Elderly Hemodialysis Patients
Phase: NA
Conditions: Hemodialysis Complication
Sponsor: Peking University First Hospital

A Postbiotics Improves the Quality of Life and 
Nutritional Status in Elderly Hemodialysis Patients
（Bio-EHD） 
 
Research Program 
 
 
Project Number: Bio-EHD-001 
Version Number: V1.0 
Date: 2023-05-14 
  
 
 
 
 
 
 
Project Source: Horizontal Project 
Sponsor: The Department of Nephrology, Peking University First 
Hospital 
Project Leader: Chen, Yuqing 
Department: The Department of Nephrology, Peking University First 
Hospital 
Telephone: 010-82572254 
Project Execution Time: July, 2023 to July, 2025 
 

 
1
Content 
1.Background ................................................................................................................... 2 
2.Purpose ........................................................................................................................ 6 
3.Methods ....................................................................................................................... 6 
3.1 Design ............................................................................................................................... 6 
3.2 Site for Data Collection ..................................................................................................... 7 
3.3 Population ........................................................................................................................ 7 
    3.3.1 Participation Criteria .................................................................................................. 7 
    3.3.2 The Source and Method of Population Election ........................................................ 8 
    3.3.3 Follow-up ................................................................................................................... 8 
   3.3.3.1 Screening Period (-4th to -2nd week before the randomization) ........................ 9 
       3.3.3.2 Introduction Period (-2nd to 0 week before the randomization)  ..................... 10 
       3.3.3.3 Treatment Period (1st to 12th Week) ................................................................ 11 
       3.3.3.4 Remedial Treatment Period (13th to 24th Week) ............................................. 11 
       3.3.3.5 Termination ........................................................................................................ 12 
3.4 Outcomes ....................................................................................................................... 12 
3.5 Exposure ......................................................................................................................... 13 
3.6 Sample Size ..................................................................................................................... 14 
3.7 Data Management. ......................................................................................................... 15 
3.8 Statistic Analysis. ............................................................................................................ 15 
4.Subject protection ....................................................................................................... 16 
5.Quality Control ........................................................................................................... 18 
6.Schedule ..................................................................................................................... 20 
7.Organization &  Management ...................................................................................... 21 
8.References .................................................................................................................. 21 
9.Appendix .................................................................................................................... 22 

 
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1. Background 
High prevalence of chronic kidney disease (CKD) is a threat to human health, 
and maintenance hemodialysis is an important treatment for ESRD patients. However, 
even after hemodialysis and conventional treatment, CKD patients still often suffer 
from the complications like malnutrition, anemia, calcium and phosphorus 
metabolism disorders, which increase morbidity and mortality rate1-2. How to reduce 
complications and improve prognosis of CKD patients is now a significant issue in 
the prevention and treatment of CKD worldwide. Intestinal flora imbalance has a high 
prevalence in CKD patients and is closely associated with malnutrition, anemia, 
calcium and phosphorus metabolism disorders and other complications, affecting 
patients' quality of life and long-term prognosis3. 
Due to increasing level of uremic toxins, perennial diet control, antibiotic 
application and oral iron, the symbiotic relationship between host and microorganism 
of the CKD patients is broken, which leads to intestinal flora imbalance and manifests 
as a significant decrease in anaerobic probiotics and a significant increase in aerobic 
harmful flora4. Intestinal flora could produce an excess of uremic toxins such as 
indoxyl sulfate (IS), p-cresyl sulfate(PCS), trimethylamine N-oxide(TMAO), 
acetanilide and lipopolysaccharide during the fermentation of proteins and amino 
acids. Physiologically, these enterogenous urotoxins are secreted through renal 
tubules and cleared by the kidneys, however, CKD patients have renal insufficiency, 
and these medium molecular toxins are difficult to be cleared by dialysis, resulting in 
the accumulation of toxins in the blood. A lot of clinical studies show that urotoxins 
not only promote the occurrence and development of CKD but also produce effect on 
anemia, malnutrition, bone-metabolism disorder, cardio- and cerebrovascular 

 
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complications. Because of increasing intestinal urotoxin, damage of intestinal 
mucosal epithelial barrier, delayed intestinal drainage, intestinal mucosa edema and 
ischemia, and the nutrient absorption of CKD patients are reduced. In addition, with a 
low protein diet, CKD patients are prone to malnutrition. Intestinal flora imbalance, 
translocation and accumulation of enterogenous urotoxin and malnutrition can form a 
vicious cycle, leading to poor prognosis of patients6. Current studies show that 
polyamine toxoid can inhibit EPO activity and affect erythropoiesis7. IS and PCS can 
induce osteodystrophy and disordered bone metabolism by several mechanism8, like 
promoting parathyroid hormone resistance, inhibiting osteoclast function and 
osteoblast differentiation. Besides, IS and PCS can accelerate renal fibrosis by 
inhibiting the expression of kidney protective genes (such as Klotho), activating 
renin-angiotensin-aldosterone system, mediating oxidative stress and activating 
inflammatory response9. The increasing plasma TMAO levels can lead to renal 
atherosclerosis10. IS, PCS and TMAO can damage vascular endothelial cells through 
various pathways, promote vascular calcification and atherosclerosis, and lead to 
cardio- and cerebrovascular events11-12. Therefore, preventing intestinal flora 
imbalance and reducing the production and accumulation of urotoxin can provide new 
therapeutic approaches for anemia, malnutrition, disordered bone metabolism and 
other complications in CKD and MHD patients. 
Currently, there are several therapeutic approaches for intestinal flora 
imbalance, including ①High dietary fiber, low animal protein and low fat diet; ②
Toxin adsorbents like activate carbon; ③Fecal transplantation; ④Micro ecological 
preparations like probiotics, prebiotics, synbiotics and postbiotics. CKD and MHD 
patients need to restrict potassium intake, which will inevitably lead to the reduction 
of fructose and cellulose, so that simply diet adjustment has little effect on the 
improvement of CKD. Activate carbon is considered to be an intestinal purifier which 

 
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can effectively reduce the absorption of gastrointestinal toxins in acute poisoning, but 
long-term application can cause gastrointestinal adverse reactions such as nausea and 
vomiting, which causes intestinal peristalsis dysfunction and even intestinal 
obstruction. Fecal transplantation is used to transfer of microbial flora extracted from 
the stool of healthy people into the intestines of patients, but it’s still difficult to 
ensure the long-term stability and safety of the donor stool and find a suitable donor. 
According to current studies, using micro ecological preparations to increase 
probiotics can play a role in prevention and treatment of CKD. 
Probiotics are a kind of active microorganisms which are beneficial to human 
body and can improve the structure of intestinal flora. Studies have confirmed that 
bifidobacterium preparations can effectively bind to human intestinal mucosal 
epithelial cells to build biological barriers after oral entry into the intestine. 
Bifidobacterium can produce extracellular glycosidase to degrade complex 
polysaccharides so that it inhibits pathogenic bacteria significantly13. Lactobacillus 
and bifidobacterium formulations have been shown to reduce PCS and IS levels in 
patients and reduce systemic inflammatory responses14. Moreover, bifidobacterium 
can promote intestinal peristalsis and drainage of intestinal toxic metabolite. 
Prebiotics are organic substances that are not digested and absorbed by the host but 
can promote the proliferation and metabolism of beneficial bacteria in the body. The 
intestinal bifidobacterium can increase significantly when dietary adjustment is 
combined with the intake of prebiotics (such as inulin) 15. Symbiotic is a combination 
of probiotics and prebiotics and it can both supplement probiotics and promote the 
growth and survival of probiotics16. Therefore, the application of micro ecological 
preparation, supplementing probiotics, prebiotics and symbiotics can stimulate and 
regulate intestinal flora, alleviate CKD disease to a certain extent, and improve the 
quality of life of patients, which is of great significance. There are several 

 
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disadvantages of living bacteria components such as high requirement for 
preservation and transportation, potential safety risks, intolerance to stomach acid, 
and non-use with antibiotics. In contrast, inactivated probiotics have their unique 
advantages. Recently, inactivated probiotics preparations attract more and more 
attention and are known as probiotics. Probiotics are those bioactive compounds 
produced by probiotics when they consume prebiotics, including short-chain fatty 
acid, lipolyaccharide, enzyme, exopolysaccharide, cell-free supernatant, inactivated 
probiotic bacteria or cell fragments (e.g. cell wall fragments, bacterial lysates, etc.) 
and other metabolites (e.g. vitamins, amino acids, etc.). Short-chain fatty acids in 
postbiotic are an important energy source for cells and play a vital role in the renewal 
of cells in the intestinal wall. They help to maintain the integrity of the intestinal 
barrier and can be used as an adjunct therapy of inflammatory bowel disease and other 
digestive disorders. Postbiotics can regulate microbiota directly and indirectly and 
inhibit growth of pathogenic microorganism, for example, bacteriocin secreted by 
lactic acid bacteria can inhibit the growth of intestinal pathogens. 
MHD patients have a high incidence of intestinal flora disorders. Malnutrition 
and other complication progression causing by intestinal flora disorders in MHD 
patients currently lacks perfect treatment options, affecting their life quality and 
prognosis, increasing the hospitalization rate and medical costs. In elderly patients, 
malnutrition, intestinal dysfunction, and reduced quality of life are more prominent. 
The purpose of the study is to investigate the effects of exogenous supplementation of 
intestinal probiotic metabolites on life quality, nutrition, intestinal flora and urotoxins 
in elderly MHD patients, and to explore the feasibility and effect of new treatment 
methods. 

 
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2. Purpose 
The purpose of the trial is to explore the effect of exogenous postbiotics supply 
on the quality of life and nutritional status of elderly hemodialysis patients. 
 
3. Method 
3.1 Design 
The study is a multicenter prospective open labeled randomized controlled trial. 
Elderly patients with age ≥65 years and received hemodialysis treatment for more 
than 6 months will be included in the study. After enrollment, the patients will be 
educated about how to keep diet records and then they will be randomly divided into 
group A and group B in a 1:1 ratio. The patients in group A will receive oral 
postbiotics and group B receive placebo. The treatment period is 12 weeks. 
Subsequently, group A ends the trial, and group B enters the remedial treatment 
period, receiving oral postbiotics, and the treatment cycle is 12 weeks. At 0, 12th  and 
24th  week, quality of life score, nutrition evaluation, diet status and gastrointestinal 
symptom score of patients will be evaluated. The stool and serum of patients will be 
collected for intestinal flora and urotoxins IS, PCS and TMAO measurements. The 
improvement of biochemical indicators will be evaluated. The biochemical indicators 
include blood creatinine, urea nitrogen, albumin, prealbumin, hemoglobin, blood 
calcium, blood phosphorus, whole parathyroid hormone, blood potassium, C-reactive 
protein, ferritin, transferrin saturation, et al. During the whole intervention process, 
patients will be encouraged to maintain intake of protein and fiber and keep a diet log. 

 
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During the intervention process, the process of hemodialysis and other diagnosis and 
treatment behaviors will be performed according to clinical routine. 
3.2 Site for Data Collection 
The medical history collection, questionnaire, and anthropometric measurements 
of the enrolled patients will be conducted within the first week of the study, and then 
once each week at the 12th and 24th weeks. The questionnaire will be completed by 
specially trained staff. Stool and serum samples will be collected at weeks 0, 12th  and 
24th for intestinal flora and urotoxin determination. The routine biochemical 
indicators of the patients will be collected, including serum creatinine, urea nitrogen, 
albumin, prealbumin, hemoglobin, serum calcium, blood phosphorus, total 
parathyroid hormone, serum potassium, carbon dioxide, C-reactive protein, ferritin, 
transferrin saturation, et al. 
3.3 Population 
3.3.1 Participation Criteria 
Inclusion criteria: 
Investigators must maintain a screening log of all potential study candidates that 
includes limited information about the potential candidate, date, and outcome of the 
screening process (e.g. enrolled into study, reason for ineligibility, or refused to 
participate). After signing an informed consent form, potential patients must meet all 
of the criteria: 
1. Age ≥65 years. 
2. Receiving maintenance hemodialysis therapy for at least 6 months. 
Exclusion criteria: 
The following exclusion criteria must NOT be present for each subject: 

 
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1. Subjects with medical history that might affect oral feeding (e.g. intestinal 
obstruction, gastrointestinal bleeding, acute pancreatitis and accidental inhalation) 
within the last 1 month prior to screening. 
2. Subjects with medical history that might affect gastrointestinal functions (e.g. 
inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), short bowel 
syndrome (SBS), et al.). 
3. Subjects who cannot communicate and collaborate normally. 
3.3.2 The source and method of population selection. 
The study will select the patients who are ≥65 years old and receive long-term 
hemodialysis treatment in the hemodialysis center, and their clinical manifestations 
should meet the eligible criteria. We will communicate with the patients about the 
content and significance of the study, and patients who agree to sign the informed 
consent will finally be included in the study. 
3.3.3 Follow-up.  
        The schedule of follow-up visits is shown in the flowchart below. 
The Study Flowchart 
 
Screening 
period 
Introduction 
Period 
Treatment Period 
 1st to 12th Week 
Remedial Treatment Period 
(Only Group B) 
 13th to 24th Week 
 
Follow-up 1 Follow-up 2 Follow-up 3 Follow-up 4 Follow-up 5 Follow-up 6 Follow-up 7 Follow-up 8 
Follow-up Time Window -4th to -2nd 
week 
-2nd to 0 week 
4th week 
8th week 
12th week 
16th week 
20th week 
24th week 
 Eligibility 
Criteria 
Medical 
History 
√ 
 
 
 
 
 
 
 
Medicine 
Prescription 
√ 
 
 
 
√ 
 
 
√ 
Hemodialysis 
Parameter 
√ 
 
 
 
 
 
 
 
Signature of Informed 
Consent 
√ 
 
 
 
 
 
 
 
Demographic Data 
√ 
 
 
 
 
 
 
 
Kt/V 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
URR 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
3-Day Diet Records 
 
√ 
 
 
√ 
 
 
√ 
Height, Weight, BMI 
 
√ 
 
 
√ 
 
 
√ 
Upper Arm 
 
√ 
 
 
√ 
 
 
√ 

 
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Circumference, Upper 
Arm Skin Fold Thickness 
Grip Strength (Non-
Fistula Side) 
 
√ 
 
 
√ 
 
 
√ 
Abdominal Fat 
 
√ 
 
 
√ 
 
 
√ 
Body Composition 
Analysis (Bioresistive 
Method) 
 
√ 
 
 
√ 
 
 
√ 
Nutritional Scores 
(SGA-7) 
 
√ 
 
 
√ 
 
 
√ 
Life Quality Scores  
(SF-36) 
 
√ 
 
 
√ 
 
 
√ 
Gastrointestinal 
symptoms (GSRS) 
 
√ 
 
 
√ 
 
 
√ 
Enervation Frailty Scale 
(EFS) 
 
√ 
 
 
√ 
 
 
√ 
Pittsburgh Sleep Quality 
Index 
 
√ 
 
 
√ 
 
 
√ 
Scr 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
BUN 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
ALB 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Prealbumin 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Hb 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Ca 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
P 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
iPTH 
 
√ 
 
 
√ 
 
 
√ 
K 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
CO2 Binding Power 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
hs-CRP 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Ferritin 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Transferrin Saturation 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Supply Postbiotics or 
Placebo 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Intestinal Flora 
Determination 
 
√ 
 
 
√ 
 
 
√ 
Urotoxin Determination 
 
√ 
 
 
√ 
 
 
√ 
 
3.3.3.1 Screening Period (-4th to -2nd week before the randomization) 
According to previous study, we will screen the CKD-5HD patients who might 
meet the eligibility criteria. For patients who accept hemodialysis 3 times per week, 
the first follow-up visit of the screening period should be on the first hemodialysis day 
of the week (e.g. Monday or Tuesday). Prior to conducting any study procedures, 
informed consent should be obtained from the patient by the investigator. The patients 
can provide informed consents within 30 days before the screening procedures. 

 
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The following list summarizes the procedures for the screening period: 
 We should record demographic information and medical history. 
 We should record all medications used by the patient within last 4 weeks prior 
to the screening. 
 We should perform a complete physical examination. 
 We should record hemodialysis parameter, including type of vascular access 
route, current dialysis prescription and dry weight. 
 We should record any problem of hemodialysis device, dialyzer and 
hemodialysis line. 
 We should record the most recent URR and spKt/V of patients within last 1 
month prior to the screening. 
 We should review the eligibility criteria. 
 The patients who meet the eligibility criteria after screening period should be 
divided randomly into the treatment group and control group. 
 
3.3.3.2 Introduction Period (-2nd to 0 week before the randomization) 
The second follow-up visit should be on the first hemodialysis day of the week 
(e.g. Monday or Tuesday). The following list summarizes the procedures for the 
introduction period: 
 We should record the most recent URR and spKt/V of patients within last 1 
month prior to the randomization. 
 We should record any change of medications after the last follow-up visit. 
 We should record the diet of patients. 
 We should score the rating scales listed in the flowchart above. 
 We should perform the anthropometric measurements listed in the flowchart 
above. 
 We should collect the results of recent routine blood test before dialysis of the 
patient.  
 We should collect the blood and stool samples for urotoxins and intestinal 
flora baseline measurements. 
 The patients will be divided randomly into treatment group and control group. 
Patients in the treatment group will be given oral intestinal flora metabolites 3 
times a day and 1 bag each time. Patients in the control group will be given 
placebo. 
 The therapeutic medications should be supplied. 

 
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3.3.3.3 Treatment Period (1st to 12th Week) 
Follow-up visits are scheduled at every 4 weeks in the treatment period. The 
following list summarizes the procedures for the treatment period: 
 We should ask patients about any adverse events and changes in medication 
after last follow-up visit. 
 We should record any change of dialysis prescription. 
 We should record any problem of hemodialysis device, dialyzer and 
hemodialysis line. 
 We should record the diet of patients in the 12th week. 
 We should score the rating scales in the 12th week. 
 We should perform the anthropometric measurements in the 12th week. 
 We should collect the blood and stool samples for urotoxins and intestinal 
flora measurements in the 12th week. 
 We should collect the results of recent routine blood test before dialysis of the 
patient in the 4th, 8th and 12th week. 
 We should ensure whether the patient has still met the eligibility criteria. If so, 
supply the medicine at the original dose. If not, remove him/her from the 
group. 
 
3.3.3.4 Remedial Treatment Period (13th to 24th Week) 
Group A end the trial and group B enter the remedial treatment period. Follow-
up visits are scheduled at every 4 weeks in the remedial treatment period. The 
following list summarizes the procedures for the remedial treatment period: 
 We should ask patients about any adverse events and changes in medication 
after last follow-up visit. 
 We should record any change of dialysis prescription. 
 We should record any problem of hemodialysis device, dialyzer and 
hemodialysis line. 
 We should record the diet of patients in the 24th week. 
 We should score the rating scales in the 24th week. 
 We should perform the anthropometric measurements in the 24th week. 
 We should collect the blood and stool samples for urotoxins and intestinal 
flora measurements in the 24th week. 

 
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 We should collect the results of recent routine blood test before dialysis of the 
patient in the 16th, 20th and 24th week. 
 We should ensure whether the patient has still met the eligibility criteria. If so, 
supply the medicine at the original dose. If not, remove him/her from the 
group. 
 
3.3.3.5 Termination. 
Patients who complete 24 weeks of follow-up visits are allowed to continue or 
discontinue their medication supply at the end of the study. 
3.4 Outcomes  
3.4.1 Primary Outcome Measure: 
Outcome Measure 
Measure Description 
Time Frame 
Changes of nutritional status 
from the baseline to the end 
of treatment and differences 
between the intervention 
group and the placebo group. 
Nutritional status of the 
patient is defined as the 
results of physical 
examination and SGA-7 
rating scale.  
From the baseline to 
the end of treatment. 
Changes of quality of life 
from the baseline to the end 
of treatment and differences 
between the intervention 
group and the placebo group. 
Quality of life of the patient 
is defined as the scores of 
gastrointestinal symptom 
rating scale (GSRS), kidney 
disease life quality scale 
(TM-SF36) and enervation 
frailty scale (EFS).  
From the baseline to 
the end of treatment. 
3.4.2 Secondary Outcomes: 
Outcome Measure 
Measure Description 
Time Frame 
Changes of enterogenous 
urotoxin level from baseline 
to the end of treatment and 
difference between the 
intervention and placebo 
group. 
Enterogenous urotoxin level 
is defined as the serum level 
of IS, PCS and TMAO. The 
levels of serum IS, PCS and 
TMAO will be measured by 
mass spectrometry.  
From the baseline to 
the end of treatment. 

 
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Changes of intestinal flora 
structure from the baseline to 
the end of treatment, and the 
difference between the 
intervention group and the 
placebo group. 
The structure of intestinal 
flora will be measured by the 
V3-V4 region of 16S rDNA 
with MiSeq PE300 
sequencing platform for high-
throughput analysis and 
described by number of the 
flora.  
From the baseline to 
the end of treatment. 
Changes of routine 
biochemical indicators from 
the baseline to the end of 
treatment, and differences 
between the intervention 
group and the placebo group. 
The routine biochemical 
indicators include serum 
creatinine, urea nitrogen, 
albumin, prealbumin, 
hemoglobin, serum calcium, 
blood phosphorus, total 
parathyroid hormone, serum 
potassium, carbon dioxide, C-
reactive protein, ferritin, 
transferrin saturation.  
From the baseline to 
the end of treatment. 
Changes of dietary intake 
from the baseline to the end 
of treatment, and the diffence 
between the intervention 
group and the placebo group. 
Dietary intakes of the patients 
will be described by the diet 
record.  
From the baseline to 
the end of treatment. 
 
3.5 Exposure 
Metabolites of intestinal probiotics are those bioactive compounds produced by 
intestinal bacteria when they consume prebiotics, including short-chain fatty acid, 
lipolyaccharide, enzyme, exopolysaccharide, cell-free supernatant, inactivated 
probiotic bacteria or cell fragments (e.g. cell wall fragments, bacterial lysates, et al) 
and other metabolites (e.g. vitamins, amino acids, et al). Supplying exogenous 

 
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intestinal probiotic metabolites is one of the therapies for intestinal flora disorder. It 
can regulate intestinal flora, improve nutritional status, reduce serum levels of 
urotoxins and improve quality of life. Patients usually need 8-12 weeks to take the 
postbiotic product. Here is the introduction of postbiotic product. 
The Postbiotics used in this study is Yi'en Yuan Honey Fermented Drink, 
which is made from water, edible brown sugar, and honey as raw materials. It is 
fermented by a mixture of plant lactic acid bacteria and coagulating Bacillus, and then 
inactivated at high temperature. The production of the product follows the GB7101 
standard, and no live bacteria or related prohibited ingredients are detected in the 
finished product, which meets the food and beverage standards. According to NJ-
W22070721 Yi'en Yuan Honey Fermented Drink and SH-W23040315 Honey enzyme 
beverage test report, the product includes carbohydrate 4.0-4.7g/100mL, potassium 
about 60.9mg/100mL, phosphorus about 2.8mg/mL. According to the concentration 
shown above, if you consume 150ml of the product a day, you will intake 
carbohydrate 6.0-9.1g, potassium 90mg, phosphorus 4.2mg, which is far lower than 
the daily intake of these substances from the diet and can be used for dialysis and 
diabetic patients. Since its launch in June 2021, no side effects have been reported. 
3.6 Sample Size 
The study is a randomized control trial. There is no previous related published 
study so that it’s an exploratory trial. According to the study of other micro ecological 
preparations, the sample size of each group should be 20. Taking into consideration 
the dropout rate of 20% by the end of the study, a sample size of 30 per group is 
planned for this study. 
 

 
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3.7 Data Management 
The clinical questionnaire is designed by the doctor whose professional position 
is or above the associate director. The clinical data is collected and entered by the 
clinical graduate students participating in the study, while another graduate student 
verifications the data to ensure the reliability and effectiveness. Each subject is coded 
by a unique number for subsequent analysis. The clinical data will be encrypted, 
stored and backed up, and the data analysts should consider of timely updating and 
integrit. The tests involved in the study are routine clinical tests for MHD patients, 
and the relevant clinical departments will perform the data entry and storage. The 
relevant data will be saved by the hemodialysis researchers of the Department of 
Nephrology, Peking University First Hospital. 
The scales involved in the study are commonly used in clinical fields and have 
been widely used in hemodialysis population. The kidney disease quality of life scale 
will be completed by the subjects themselves. 
3.8 Statistical Analysis 
Descriptive statistics for continuous variables will include questionnaire score, 
anthropometric and biochemical indicators, fecal flora structure and urotoxins level. 
They will be expressed as mean ± standard  deviation and median. Analysis of 
categorical variables will include frequency and percentage. 
In analytical statistics, the distribution type of data will be initially considered 
when we determine the reference range, and then we will calculate the unilateral 
lower limit P5. We will compare the distribution of the variables between the normal 
population and the patients in the two groups with Independent t test, Chi-square test 
/Fisher exact test, one-way ANOVA and non-parametric analysis. We will analyze the 
relationship between exposure and outcome with Logistic regression and Cox 

 
16
regression, including univariate and multivariate regression. In multivariate regression 
analysis, the selected variables include important general clinical data, the variables 
clearly associated with the outcome, and the variables analyzed as P < 0.1 in 
univariate regression. 
Statistical analyses will be performed using Statistical Package for Social 
Science (SPSS) for Windows version 23.0 (SPSS Inc. Chicago, IL). Statistical 
mapping will be performed using GraphPad Prism v.8 (La Jolla, CA, USA) and R 
4.1.0 (The R Foundation, Vienna, Austria). Sample size estimation will be performed 
using PASS 2021 (UT, USA). 
P<0.05 is considered statistically significant. All confidence intervals are stated 
at the 95% confidence level. 
4. Subject Protection 
4.1 Subject Benefit 
The study is a crossed randomized control study of metabolites from the gut 
microbiota and every patient enrolled in the study will receive free use of intestinal 
probiotic metabolites. The study will provide the relevant test, nutrition and quality of 
life evaluation free of charge. The examinations in the study are all routine 
examinations in daily clinical work and do not increase the burden of blood collection 
for patients. The only invasive test is venous blood sampling for urotoxins 
measurement, which is carried out according to the routine procedure. The patient 
needs to collect a stool sample for microflora measurement. The other tests and 
evaluations are non-invasive. 

 
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Regular treatment will not be affected for the patients who do not accept the 
study. The privacy information of all patients entering the study will be protected and 
the data will be used in accordance with relevant regulations. 
4.2 Subject Risk 
During the trial, the treatment group will take 150ml of Yi En Yuan honey yeast 
drink each day. The product is made of water, edible brown sugar and honey. It’s 
mixed fermented by plant lactic acid bacteria and Bacillus coagulates and sterilized at 
a high temperature. The product is produced according to GB7101 standard, and there 
is no live bacteria and prohibited ingredients in the product, which meets the food and 
beverage standards. According to NJ-W22070721 Yi En Yuan honey yeast drink and 
SH-W23040315 Honey enzyme beverage test report, the product includes 
carbohydrate 4.0-4.7g/100mL, potassium about 60.9mg/100mL, phosphorus about 
2.8mg/mL. According to the concentration shown above, if you consume 150ml of 
the product a day, you will intake carbohydrate 6.0-9.1g, potassium 90mg, 
phosphorus 4.2mg, which is far lower than the daily intake of these substances from 
the diet and can be used for dialysis and diabetic patients. Since its launch in June 
2021, no side effects have been reported. Patients in the control group will be given 
150ml of placebo each day which is made of water and food coloring.  
Blood samples of the subjects are taken at the same time as routine clinical tests 
without additional samples. The risks are the same as those in daily blood drawing 
tests, including puncture pain, the need for a second puncture when the blood drawing 
is not successful, and a small amount of subcutaneous bleeding caused by poor 
compression after blood drawing. Blood drawing will be performed by experienced 
nurses. The venous blood collection routine will be strictly followed, and after blood 

 
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collection we will press effectively to stop bleeding. If the puncture is unsuccessful, 
we will stop the second puncture and we will try again after 24 hours. 
4.3 Confidentiality 
This study mainly collects the required data before and after treatment for 
efficacy observation. Personal datas in the study are confidential. The blood samples 
are routine clinical laboratory items, and all are daily clinical work. The laboratory 
department will handle them according to the routine clinical laboratory. Researchers 
are required to keep the identity of the subjects confidential. Clinical datas and 
records of the subjects will be kept in a locked filing cabinet and will be accessible 
only to the investigator. No personal data is disclosed at publication. There are no 
potential conflicts of interest and no special people involved in this study. The 
personal data of the subjects in the study will be confidential, and their blood samples 
will be coded by a unique number rather than their name. No identifying information 
will be disclosed to anyone other than the researchers, and all researchers are required 
to keep their identities confidential. In order to ensure that the study is carried out in 
accordance with the regulations, members of the government management department 
or the ethics committee can access the personal data of the subjects if necessary, and 
the process will also strictly follow the principle of confidentiality. No personal 
information about any subjects will be disclosed when the results of this study are 
published. 
5. Quality Control 
5.1 Quality Control of Clinical Research Process 
Clinical data collection will be performed by the clinicians. The clinicians 
participating in this study must have received relevant training and understand 

 
19
thoroughly about the objectives and procedures of the research. Besides, they should 
be able to collect high-quality clinical data and biological samples and then pass them 
to the data analysts and laboratory testers after preliminary collation and store. In the 
process, they should ensure the rights and interests of the subjects. Each subject will 
be numbered individually by the clinicians in order to protect their privacy and 
conduct blind analysis. The data of each subject will be verified by two clinicians to 
ensure authenticity and reliability. 
5.2 Laboratory Process 
1）Collection of blood and stool sample: Stool samples will be collected by the 
subjects themselves, and the fresh stool should be 5ml within 2 hours after defecation. 
Blood samples will be collected by the nurses, and 5ml of venous blood before 
dialysis is taken from the subjects on the same day. 
2）Packaging and testing of blood and stool samples: After checking the subject 
number, the specimens will be immediately packaged and stored in the -80 ℃ 
refrigerator. The samples will be tested by professional laboratory technicians. Levels 
of urotoxins will be detected with commercial kits, requiring two multiple holes 
setting up in each sample with four-parameter Logistic regression method to fit the 
standard curve with R2≥0.99. Quality control products will be set up for quality 
control in each test. After preliminary sorting, the test data will be encrypted, stored 
and backed up for the data analyst. 
5.3 Quality Control of Data Management 
Part of the data collection will be carried out by trained nurses, and the entry and 
post-entry verification will be carried out by different personnel. Among the 
observation indicators involved in the study, the clinical laboratory test results will be 
uploaded to the database after completion. The electronic medical record system of 

 
20
the hemodialysis center has a database interface, which can automatically extract and 
export to the document without manual input process. Statistical principles will be 
strictly followed to ensure the authenticity of the results, and the results will be 
interpreted and discussed with the study designers. 
5.4 Training 
The questionnaires and scores involved in the study, such as quality of life and 
malnutrition scores, will produce quantitative assessment data, and the specific 
operation process may affect the results. Therefore, there are specific and complete 
standardized operation procedures for the operation process of the above scales, and   
there are special trainings for researchers involved in the evaluation as well. 
5.5 Supervision Plan 
The person in charge of the study is responsible for the overall coordination of 
the work among various researchers, planning the work progress of clinicians, 
laboratory technicians and data analysts, monitoring the quality and efficiency of their 
work, arranging the transportation and transmission of data and samples, applying for 
relevant research projects and coordinating budgets and funds. Finally, we will assist 
data analysts to interpret the research results, and plan the transformation of scientific 
research results, including patent application, commercial transformation, SCI paper 
writing and publication. 
6. Schedule 
The research schedule is shown below.  
Time 
Work Arrangement 
2023-7 to 2023-10 
Research project application, testing method debugging, personnel training 
and coordination 
2023-11 to 2024-6 
Subject recruitment, clinical data collection and sample testing 
2024-7 to 2025-12 
Data analysis, result interpretation, SCI paper writing 

 
21
7. Organization & Management 
The organization and management of the study is shown below.  
Participating Institutions and 
Responsible Persons 
Responsibility 
Chen Yuqing (Peking 
University First Hospital) 
Overall planning of the project, application for scientific 
research projects, personnel training and coordination, 
preservation of biological samples, data collation and analysis, 
interpretation and discussion of results 
Wan Xin (Nanjing First 
Hospital) 
Subject recruitment, clinical research, clinical data and sample 
collection 
Wang Hui (Taiyuan Central 
Hospital) 
Subject recruitment, clinical research, clinical data and sample 
collection 
Shen Yulan (Beijing Miyun 
District Hospital) 
Subject recruitment, clinical research, clinical data and sample 
collection 
8. References 
1. Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker S, Plattner B, SaranR, Wang AY, 
Yang CW: Chronic kidney disease: Global dimension and perspectives. Lancet 382: 
260–272, 2013. 
2. Foley RN, Parfrey PS, Sarnak MJ: Clinical epidemiology of cardiovascular disease 
in chronic renal disease. Am J Kidney Dis 32[Suppl 3]: S112–S119, 1998. 
3. Aronov PA, Luo FJ-G, Plummer NS, Quan Z, Holmes S, Hostetter TH, Meyer TW: 
Colonic contribution to uremic solutes. J Am Soc Nephrol 22: 1769–1776, 2011. 
4. Ramezani A, Raj DS. The gut microbiome, kidney disease, and targeted 
interventions. J Am Soc Nephrol. 2014;25(4):657-670. 
5. Gibson SA, McFarlan C, Hay S, Macfarlane GT. Significance of microflora in 
proteolysis in the colon. Appl Environ Microbiol. 1989;55(3):679-683. 
6. Org E, Blum Y, Kasela S, et al. Relationships between gut microbiota, plasma 
metabolites, and metabolic syndrome traits in the metsim cohort[J]. Genome Biology, 
2017, 18(1):70. 
7. Yoshida K ，Yoneda T ，Kimura S ，et a1.Polyamines as an inhibitor 
onerythmpoiesis of hemodialysis patients by in vitro bioassay using the fetal mouse 
liver assay[J].Ther Apher Dial，2006，10(3):267-272. 
8. Yang C Y , Tarng D C. Diet, gut microbiome and indoxyl sulphate in chronic 
kidney disease patients[J]. Nephrology, 2018, 23:16-20. 
9. Esmeralda C R, Raul F P, Raquel E, et al. Impact of altered intestinal microbiota on 
chronic kidney disease progression[J]. Toxins, 2018, 10(7):300. 

 
22
10. Shafi T, Powe N R, Meyer T W, et al. Trimethylamine n-oxide and cardiovascular 
events in hemodialysis patients[J]. Journal of the American Society of Nephrology, 
2017, 28(1):321-331. 
11. Shafi T, Powe N R, Meyer T W, et al. Trimethylamine n-oxide and cardiovascular 
events in hemodialysis patients[J]. Journal of the American Society of Nephrology, 
2017, 28(1):321-331. 
12. Meijers B K I, Kerckhoven S V, Verbeke K, et al. The uremic retention solute p-
cresyl sulfate and markers of endothelial damage[J]. American Journal of Kidney 
Diseases, 2009, 54(5):891-901. 
13. Takayama F, Taki K, Niwa T. Bifidobacterium in gastro-resistant seamless 
capsule reduces serum levels of indoxyl sulfate in patients on hemodialysis[J]. 
American Journal of Kidney Diseases, 2003, 41(3): S142-S145. 
14. Gómez -Guzmán M, Toral M, Romero M, et al.An tihypertensive effects of 
probiotics Lactobacillus strains in spontaneously hypertensive rats [J]. Molecular 
Nutrition & Food Research, 2015, 59(11):2326-2336. 
15. Meijers B K I, Vicky D P, Kristin V, et al. p-Cresyl sulfate serum concentrations 
in haemodialysis patients are reduced by the prebiotic oligofructose-enriched inulin. 
Nephrol Dial Transplant,2010, 25(1):219–224. 
16. Iwashita Y, Ohya M, Yashiro M, Sonou T, Kawakami K, Nakashima Y, Yano T, 
Iwashita Y, Mima T, Negi S, Kubo K, Tomoda K, Odamaki T, Shigematsu T. Dietary 
Changes Involving Bifidobacterium longum and Other Nutrients Delays Chronic 
Kidney Disease Progression [J]. Am J Nephrol, 2018, 47(5): 325-32. 
 
 
9. Appendix  
9.1 Appendix A. SGA 7 Scale  
SGA 7 Scale：6-7 points are classified as very mild malnutrition to good nutrition; 3-
5 points are classified as mild to moderate malnutrition; 1-2 points are classified as 
severe malnutrition. 
 
Subjective Comprehensive Nutrition Assessment Form 
Items 
Instructions 
Score 

 
23
Change of Weight 
(Measured in % compared to 
the weight 6 months earlier) 
Dry weight 6 months ago:     Kg 
Dry weight 2 months ago:     Kg 
Current dry weight:      Kg 
+5% is normal 
7 points: Body weight stable without change 
6 points: There is a recent trend of weight loss 
>5 to 10% indicates a potential problem 
5 points: Weight loss of 5 to 6% 
4 points: Weight loss of 7-8% 
3 points: Weight loss >10% 
>10% indicates serious problems 
2 points: Weight loss, recent tendency to stabilize or slight change 
1 point: Sustained weight loss 
 
Diet 
Based on daily intake of the 
patients and evaluate whether it 
meets the dietary recommendations 
7 points: Normal amount 
6 points: Decreased in recent days, but usually moderate 
5 points: Continuous reduction, but moderate 
4 points: Continue to decrease, sometimes moderate and sometimes not 
3 points: Continued to decrease, but not a moderate amount 
2 points: Continued to decrease, mostly very little food 
1 point: Continued to decrease, but very little food 
 
Gastrointestinal 
Symptoms 
Loss of appetite, nausea, 
vomiting, diarrhea, etc. 
The frequency and duration of 
symptoms. 
7 points: Asymptomatic 
6 points: Symptoms are rare 
5 points: One or more symptoms occur, but not daily 
4 points: Appear more than one per day 
3 points: Most symptoms appear daily 
2 points: A day with almost all symptoms 
1 point: Daily occurrence of all symptoms 
 
Ability of Daily Living 
(Compared to 6 months ago) 
Work, family, social 
7 points: General condition 
6 points: Worse than average, but not related to nutritional status 
3-4-5 points: Worse than average, but related to nutritional status 
2 points: Bedridden or wheelchair, related to nutritional status but can 
perform simple activities 
1 point: bedridden, related to nutritional status but unable to perform 
simple activities 
 
Metabolic Stress 
7-6 points: Only ESRD or (and) well-controlled DM 
4-5 points: DM with infection/fever/peritonitis/poor control 
1-2-3 points: Serious diseases such as ulcerative colitis with diarrhea 
 
Physical Examination 
Measure muscle layer and fat 
layer 
1 point (sunken) - 7 points(full) fat: eyelids/triceps/biceps 
1 point (bone protrusion) - 7 points (bone not easily seen) 
Muscles: temples/scapula/clavicle/ribs/jaws and interphalanges of 
palms/quadriceps/knees 
1 point (severe edema) -7 points (no edema) : Edema of fibula or ankle 
 
Total 
Do not average; Overall nutritional status and clinical experience are 
evaluated to range from 1 to 7 points. 
 
 
The result is shown as follows: 
Items 
Score 
Change of Weight 
 
Diet 
 
Gastrointestinal Symptoms 
 
Ability of Daily Living 
 
Metabolic Stress 
 
Physical Examination 
Fat 
 
Muscle  
Edema  
Total 
 
 
Physical Examination of Fat and Muscle: 
Fat: Eyelids, triceps, biceps. 1 point is classified as sunken; 7 points are classified as 
full. 

 
24
Muscle: temples, scapula, clavicle, ribs, jaws and interphalanges of palms, quadriceps, 
and knees. 1 point is classified as bone protrusion; 7 points are classified as bone not 
easy seen. 
Researchers should give an overall score (from 1 to 7) refer to the combination of fat 
and muscle assessment and the final average should be rounded. 
 
Change of Weight of 6 Months: 
Body weight stable without change: 7 points. 
Weight loss less than 3%: 6 points. 
Weight loss of 3-5%: 5 points. 
Weight loss of 5-7%: 4 points. 
Weight loss of 7-10%: 3 points. 
Weight loss of 10-15%: 2 points. 
Weight loss more than 15%: 1 point. 
 
9.2 Appendix B. Kidney Disease Quality of Life Scale（TM-SF36） 
1. Generally speaking, do you think your health status is: 
Superb 
Very good 
Good 
Normal 
Terrible 
1 
2 
3 
4 
5 
The following items are about the activities you may do during the day. Does your current state of health limit your 
ability to do these activities? If so, how much? 
 
Yes, limited a lot. 
Yes, limited a little. 
No, not limited at all. 
2. Moderate 
activities, such as 
moving the table, 
sweeping the floor, 
playing badminton 
or swimming 
1 
2 
3 
3. Climbing a few 
flights of stairs 
1 
2 
3 
During the past 4 weeks, did you have any of the following problems while working or performing daily activities 
due to your health condition? 
 
Yes 
No 
4. Doing less than 
wish 
1 
2 
5. Limited ability in 
working and daily 
activities. 
1 
2 
In the past 4 weeks, did you have any of the following problems while working or performing daily activities due to 
emotional condition, such as feeling depressed or anxious? 
 
Yes 
No 
6. Doing less than 
wish 
1 
2 
7. Not as carefully 
as the past in daily 
work or activities. 
1 
2 
8. In the past 4 weeks, how much did the pain interfere with your normal work, including working outdoors and 
housework? 
Not at all 
A little 
Moderate 
Severe 
Extreme 

 
25
1 
2 
3 
4 
5 
These questions are related to your feelings and life over the past 4 weeks. For each question, please give an answer. 
 
All time 
Most of time 
Many time 
Sometime 
Seldom 
Never 
9. Do you feel 
peaceful? 
1 
2 
3 
4 
5 
6 
10. Do you feel 
energetic? 
1 
2 
3 
4 
5 
6 
11. Do you feel 
depressed? 
1 
2 
3 
4 
5 
6 
12. During the past 4 weeks, how many times did your physical health or emotional problems interfere with your 
social activities (e.g. visiting friends)? 
All time 
Most of time 
Sometime 
Seldom 
Never 
1 
2 
3 
4 
5 
About your kidney disease, how much are these following statements true or untrue to you? 
 
Definitely true 
Mostly true 
Don’t know 
Mostly untrue 
Definitely untrue 
13. My kidney 
disease interferes too 
much with my life. 
1 
2 
3 
4 
5 
14. I waste too much 
time to coping with 
my kidney. 
1 
2 
3 
4 
5 
15. I’m depressed 
about coping with my 
kidney. 
1 
2 
3 
4 
5 
16. I think I’m the 
burden of my family. 
1 
2 
3 
4 
5 
During the past 4 weeks, how much were you troubled by any of the following? 
 
No trouble 
Little trouble 
Moderate 
Heavy trouble 
Extreme trouble 
17. Muscle soreness 
 
 
 
 
 
18. Chest pain 
 
 
 
 
 
19. Cramp 
 
 
 
 
 
20. Cutaneous seizure 
 
 
 
 
 
21. Dry skin 
 
 
 
 
 
22. Tachypnea 
 
 
 
 
 
23. Giddy 
 
 
 
 
 
24. No appetite 
 
 
 
 
 
25. Fatigued 
 
 
 
 
 
26. Numbness of 
hands and feet 
 
 
 
 
 
27. Vomiting or 
stomachache 
 
 
 
 
 
28. Is there any 
problem with the 
vascular site where 
you inserted the 
catheter? 
 
 
 
 
 
Some people’s daily lives are troubled by kidney disease, others are not. How much are you troubled by the kidney 
disease in the following ways?  
 
No trouble 
Little trouble 
Moderate 
Heavy trouble 
Extreme trouble 
29. Limit of drink 
 
 
 
 
 
30. Limit of diet 
 
 
 
 
 
31. Ability of chores 
 
 
 
 
 
32. Ability of travel 
 
 
 
 
 
33. Dependence to 
doctors and other 
medical staff 
 
 
 
 
 
34. Depression caused 
by kidney disease 
 
 
 
 
 

 
26
35. Sexual life 
 
 
 
 
 
36. Personal instrument 
 
 
 
 
 
 
9.3 Appendix C. Gastrointestinal Symptom Rating Scale (GSRS) 
Did you have any of 
the following 
symptoms in the 
past week? 
Score 
No 
Mild 
Sometimes 
Moderate 
Obvious 
discomfort 
Quite 
serious 
Extremely 
serious 
1 
Epigastric 
pain 
1 
2 
3 
4 
5 
6 
7 
2 
Chest pain 
1 
2 
3 
4 
5 
6 
7 
3 
Acid 
regurgitation 
1 
2 
3 
4 
5 
6 
7 
4 
Hunger pain 
1 
2 
3 
4 
5 
6 
7 
5 
Nausea 
1 
2 
3 
4 
5 
6 
7 
6 
Borborygmus 
1 
2 
3 
4 
5 
6 
7 
7 
Abdominal 
bloating 
1 
2 
3 
4 
5 
6 
7 
8 
Sore throat 
1 
2 
3 
4 
5 
6 
7 
9 
Halitosis 
1 
2 
3 
4 
5 
6 
7 
10 
Smelly urine 
1 
2 
3 
4 
5 
6 
7 
11 
Constipation 
1 
2 
3 
4 
5 
6 
7 
12 
Diarrhea 
1 
2 
3 
4 
5 
6 
7 
13 
Loose stool 
1 
2 
3 
4 
5 
6 
7 
14 
Dry stool 
1 
2 
3 
4 
5 
6 
7 
15 
Defecate 
immediately 
if you want 
to 
1 
2 
3 
4 
5 
6 
7 
16 
Tenesmus 
1 
2 
3 
4 
5 
6 
7 
Total 
 
 
9.4 Appendix D. Enervation Frailty Scale（EFS） 

 
27
Score:          /17   
 
 
0 Point 
1 Point 
2 Points 
Clock test 
(cognition) 
1. Think of this pre-drawn circle 
as a clock. 
2. Write the number down on the 
dial in the correct position. 
3. Put the pointer in the "eleven 
ten" position. 
No mistake 
Mild mistake 
Other mistake 
General 
health  state  
How many times did you 
hospitalize in the past year? 
0 
1-2 
>2 
How would you describe your 
overall health? 
Very good & 
Good 
Normal 
Terrible 
Functional 
independence 
How many of the following 
activities do you need help? 
(Cooking, shopping, 
transportation, phone calls, 
housework, laundry, financial 
management, medication) 
0-1 
2-4 
5-8 
Social 
Support 
When you need help, do you think 
there will be someone willing to 
help and able to meet your needs? 
Often 
Sometimes 
Never 
Medication 
Do you take 5 or more pills a day? 
No 
Yes 
 
Would you forget to take 
medicine? 
No 
Yes 
 
Nourishment 
Did you lost any weight recently, 
such as your clothes becoming 
looser? 
No 
Yes 
 
Emotion 
Do you often feel depressed? 
No 
Yes 
 
Do you have trouble in controlling 
urinating when you don't want to 
urinate? 
No 
Yes 
 
Somatic 
function 
Sit in the chair with your back and 
arms relaxed. Then, when I say 
"go," stand up and walk at a safe 
and comfortable pace to the mark 
on the floor (about 3 meters 
away), then return to your chair 
and sit down. 
0-10s 
11-20s 
More than 
20s, or 
unwilling to 
act, or need 
assistance to 
act 
 
Evaluation: 0-5 points are defined as not weak; 6-7 points are defined as vulnerable; 
8-9 points are defined as mild weakness; 10-11 points are defined as moderate 
weakness; more than 11 points are defined as severe weakness. 
 
9.5 Appendix E. Pittsburgh Sleep Quality Index 
1. What time do you usually go to bed in the past month? 
                 
2. How long did it usually take you to fall asleep every night for the past month? 
                 Minutes 
3. What time did you usually get up every morning for the past month? 
                 
4. How much sleep did you actually get every night in the past month? 
                Minutes 

 
28
5. In the past month, did you often have trouble in sleeping because of the following statements? 
 
Not in the past 
month 
Less than one 
night a week on 
average 
One or two 
nights a week 
on average 
Three or more 
than three nights a 
week on average 
A. Cannot sleep within 30mins 
 
 
 
 
B. Waking up in midnight or 
wake up early 
 
 
 
 
C. Getting up at night to the toilet 
 
 
 
 
D. Uncomfortable breathing 
 
 
 
 
E. Coughing or snoring loudly 
 
 
 
 
F. Feeling cold 
 
 
 
 
G. Feeling hot 
 
 
 
 
H. Bad dreams 
 
 
 
 
I. Pain 
 
 
 
 
J. Other: Please describe 
 
 
 
 
6. How do you think of your total sleep quality over the past month? 
Very good 
Good 
Not good 
Terrible 
7. In the past month, did you often have to take medication (including prescription or from an outside 
pharmacy) to fall asleep? 
Not in the past month () 
Less than one night a week on average () 
One or two nights a week on average () 
Three or more than three nights a week on average () 
8. In the past month, did you have trouble in staying awake while driving, eating, or participating in social 
activities? 
Not in the past month () 
Less than one night a week on average () 
One or two nights a week on average () 
Three or more than three nights a week on average () 
9. In the past month, did you have any difficulty in completing tasks? 
Not difficult 
Mild difficult 
Quite difficult 
Very difficult 
10. Do you share a bed or have a roommate? 
No. () 
Partner or roommate is in another room () 
Partner or roommate is in the same room but does 
not share a bed () 
Partner or roommate share a bed () 
11. If you share a bed or have a roommate, please ask him/her if any of the following happened to you in the 
past month. 
 
Not in the 
past 
month  
Less than one 
night a week on 
average 
One or two 
nights a 
week on 
average  
Three or more 
than three 
nights a week 
on average  
A. Do you snore when you sleep? 
 
 
 
 
B. Do you have long pauses between your breaths 
during your sleep? 
 
 
 
 
C. Do your legs twitch or have spasms during your 
sleep? 
 
 
 
 
D. Are you disoriented or confused during your 
sleep? 
 
 
 
 
E. Have you had any other trouble during your 
sleep? Please describe it.