Effects of Synbiotics Supplementation on the Uremic Toxin Indoxyl Sulfate Level and Constipation in End-stage Renal Disease Patients Undergoing Hemodialysis

Study Overview
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Brief Summary
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This is a double-blind, placebo-controlled, randomized clinical trial conducted to evaluate the effects of synbiotics supplementation on the level of the uremic toxin indoxyl sulfate, symptoms of constipation, and constipation-related quality of life in end-stage renal disease patients undergoing hemodialysis.

Detailed Description
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One of the most common gastrointestinal symptoms in end-stage renal disease patients undergoing hemodialysis is constipation, which is one of the risk factors of microbiota dysbiosis. One effect of dysbiosis is the increased level of a uremic toxin known as indoxyl sulfate. The accumulated concentration of indoxyl sulfate in end-stage renal disease patients undergoing hemodialysis is associated with inflammation and oxidative stress, which in turn increases the risk of cardiovascular event. Constipation and an increased risk of cardiovascular event is associated with low quality of life in chronic kidney disease patients undergoing hemodialysis. Synbiotics administrations had become one of the many ways to improve gut dysbiosis as it is expected to lower the level of indoxyl sulfate and improve the symptoms of constipation and constipation-related quality of life. Although studies had investigated the role of probiotics/prebiotics/synbiotics, the role of synbiotics in lowering the concentration of the uremic toxin indoxyl sulfate remains inconclusive. Therefore, this study is conducted to demonstrate the benefits of synbiotics administration in lowering the concentration of indoxyl sulfate in end-stage renal disease patients undergoing hemodialysis, This is the first study in Indonesia investigating the effects of synbiotics supplementation in end-stage renal disease patients undergoing hemodialysis. This study is a double-blind, placebo-controlled, randomized clinical trial conducted on end-stage renal disease patients undergoing hemodialysis. Patients will be divided into two arms: synbiotics and placebo. The study will take place in the hemodialysis unit of Dr. Cipto Mangunkusumo General Hospital in September 2020 to February 2021. A total of 60 participants will be recruited for the study (30 in each arm), who will be randomized into the synbiotic arm or the placebo arm. Both investigators and patients will be blinded to the treatment, and blinding will be conducted by the pharmacy unit of Dr. Cipto Mangunkusumo General Hospital. Patients who had consented to participate will be assessed for medical history and physical examination. Food recall evaluation will also be performed by a nutritionist. Blood samples will be collected from the patient for laboratory examinations, including haemoglobin, white blood cells (WBC), platelet, urea, creatinine, albumin, and indoxyl sulfate. Patients will also be asked to complete two questionnaires: the Patient Assessment of Constipation Symptoms (PAC-SYM) questionnaire to assess the symptoms of constipation and the Patient Assessment of Constipation Quality of Life (PAC-QOL) questionnaire to assess constipation-related quality of life. After this, patients will be randomized into one of the two study arms. The data will serve as baseline data. Patients will receive 2 capsules containing either synbiotics or placebo per day for the next 30 days. Afterwards, the patients will undergo examination to evaluate food recall and side effects. After evaluation, the patients will once again receive 2 capsules containing either synbiotics or placebo per day for the next 30 days, and after a total 2 months of interventions, will undergo examinations similar to that done in baseline examination. The primary outcome of this study is the concentration of indoxyl sulfate in end-stage renal disease patients undergoing hemodialysis. Secondary outcomes include the symptoms of constipation and constipation-related quality of life in end-stage renal disease patients undergoing hemodialysis. This study will be done according to the principles detailed in Helsinki declaration, Guideline for Good Clinical Practice from ICH Tripartite Guideline (ICH-GCP), and had been approved by the Ethical Committee of the Faculty of Medicine of Indonesia University.

Official Title
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Effects of Synbiotics Supplementation on the Concentration of the Uremic Toxin Indoxyl Sulfate, Symptoms of Constipation, and Constipation-related Quality of Life in End-stage Renal Disease Patients Undergoing Hemodialysis

Conditions
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Constipation, End Stage Renal Disease on Dialysis

Intervention / Treatment
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* Dietary Supplement: Synbiotics containing Lactobacillus acidophilus & Bifidobacterium longum 5x10^9 CFU and FOS 60 mg
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged more than 18 years old Had undergone hemodialysis twice a week for a minimum of 3 months, with each visit lasting 5 hours Had only undergone hemodialysis therapy (not peritoneal dialysis/kidney transplantation) No history of malignancy or undergoing chemotherapy/radiation therapy No history of autoimmune disease or consuming immunosuppressants No history of bowel resection Had never been diagnosed with Crohn's disease or ulcerative colitis Exclusion Criteria: Patients whose hemodialysis schedule was changed from twice a week to three times a week Patients consuming prebiotics/probiotics/synbiotics within the past 3 weeks Patients experiencing infection or is consuming antibiotics Patients who are not willing to participate

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This study is a double-blind, placebo-controlled, randomized clinical trial conducted on end-stage renal disease patients undergoing hemodialysis. Patients will be randomized into two arms: symbiotic and placebo. The study will take place in the hemodialysis unit of Dr. Cipto Mangunkusumo General Hospital in September 2020 to February 2021. A total of 60 participants will be recruited for the study (30 in each arm). Both investigators and patients will be blinded to the treatment, and blinding will be conducted by the pharmacy unit of Dr. Cipto Mangunkusumo General Hospital.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Synbiotic Arm<br>Patients receiving synbiotics: Lactobacillus acidophilus & Bifidobacterium longum 5x10^9 Colony Forming Unit (CFU) and Fructooligosaccharides (FOS) 60 mg, 2 capsules/day for 60 days | Dietary Supplement: Synbiotics containing Lactobacillus acidophilus & Bifidobacterium longum 5x10^9 CFU and FOS 60 mg<br>* Patients will undergo baseline examination including medical history and physical examination, blood samples will be collected for hemoglobin, WBC, platelet, urea, creatinine, albumin and indoxyl sulfate level. Patients will be asked to complete 2 questionnaires the PAC-SYM and PAC-QOL questionnaires, and will undergo food recall evaluations by a nutritionist. They will then be given 2 capsules of synbiotics per day for 30 days. After 1 month of intervention, the patients will be evaluated for food recall and side effects. Afterwards, the patients will receive 2 capsules of the same synbiotics per day for the next 30 days. After 2 months of intervention, the patients' history will be taken, they will be asked to complete the PAC-SYM and PAC-QOL questionnaires, undergo food recall examination, and side effects evaluation. Blood samples will be taken for indoxyl sulfate examination.<br>|
| Placebo Comparator: Placebo Arm<br>Patients receiving placebo capsules containing saccharum lactis (2 capsules/day for 60 days) | Other: Placebo<br>* Patients will undergo baseline examination including medical history and physical examination, blood samples will be collected for hemoglobin, WBC, platelet, urea, creatinine, albumin and indoxyl sulfate level. Patients will be asked to complete 2 questionnaires the PAC-SYM and PAC-QOL questionnaires, and will undergo food recall evaluations by a nutritionist. They will then be given 2 capsules of placebo per day for 30 days. After 1 month of intervention, the patients will be evaluated for food recall and side effects. Afterwards, the patients will receive 2 capsules of the same placebo per day for the next 30 days. After 2 months of intervention, the patients' history will be taken, they will be asked to complete the PAC-SYM and PAC-QOL questionnaires, undergo food recall examination, and side effects evaluation. Blood samples will be taken for indoxyl sulfate examination.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Indoxyl Sulfate concentration | Concentration of indoxyl sulfates in the subjects' blood samples | Through study completion, an average of 60 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Symptoms of constipation | Constipation-related symptoms as assessed using Patient Assessment of Constipation Symptoms (PAC-SYM) questionnaire. Score will be assessed at the start and at the end of the study. Symptoms will be considered improved if there is a reduction of total score by 1 or more point(s). | Through study completion, an average of 60 days | 
| Constipation-related quality of life | Constipation-related quality of life as assessed using Patient Assessment of Constipation Quality of Life (PAC-QOL) questionnaire. Score will be assessed at the start and at the end of the study. Quality of life will be considered improved if there is a reduction of total score by 1 or more point(s). | Through study completion, an average of 60 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Synbiotics, Indoxyl Sulfate, Constipation, Quality of life, Dysbiosis, End-Stage Renal Disease, Hemodialysis