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Preventive Effect of Prophylactic Oral Antibiotics Against Cholangitis After Kasai Portoenterostomy

Primary Purpose

Biliary Atresia, Cholangitis, Anti-Bacterial Agents

Status
Not yet recruiting
Phase
Not Applicable
Locations
Study Type
Interventional
Intervention
Basic treatment: sulperazone + ursodeoxycholic acid + compound glycyrrhizin + methylprednisolone + vitamin AD , D , E , K + imipenem or meropenem
Prophylactic oral antibiotics: compound sulfamethoxazole tablet (SMZ/TMP) + cefaclor
Sponsored by
Children's Hospital of Fudan University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Biliary Atresia

Eligibility Criteria

14 Days - 90 Days (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Patients whose age of operation is 14-90 d. Sex and race are not restricted; Patients who are born with gestational age older than 36 weeks; Patients whose body weight before operation > 2 kg; Patients diagnosed of type-III BA and underwent KP in Children's Hospital of Fudan University; The type-III BA diagnosis is based on cholangiography or operation; Patients whose histological features of liver biopsies are reported. HE staining and Masson staining are required, and edema, inflammation, fibrosis, and hyperplasia of intrahepatic bile duct should be reported; Patients who are not allergic to postoperative medications; Patients who haven't accepted other antibiotic or probiotic therapy. Exclusion Criteria: Patients with cholestasis of non-BA disease; Patients who have undergone KP at other institutions; Patients whose pathohistological diagnosis is in doubt; Patients who undergo liver transplantation immediately after KP; Patients with other liver diseases or severe complications (e.g., severe pulmonary hypertension, renal failure, intracranial hemorrhage, etc.) requiring surgical intervention or other medical therapy; Patients with severe cardiac, renal, or central nerve system malformations (e.g., tetralogy of Fallot, transposition of the great arteries, cerebral dysplasia, etc.) and have poor prognosis; Patients judged by the researchers that they can not comply with the study requirements.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Active Comparator

    Experimental

    Arm Label

    Antibiotics group

    Non-antibiotics group

    Arm Description

    Basic treatment + Prophylactic oral antibiotics

    Basic treatment

    Outcomes

    Primary Outcome Measures

    The occurrence of cholangitis (confirmed or suspected) within 6 months after KP
    Definition of cholangitis: A. Clinical elements Fever and/or shivering; Stool color change; New/increasing jaundice; Abdominal discomfort: vomiting, poor, feeding, irritability. B. Laboratory and imaging elements Inflammatory response (WBC and/or CRP and/or PCT); Increased/increasing transaminases; Increased/increasing GGT and/or bilirubin; Bile lakes. Suspected cholangitis: one item in A + one item in B. Confirmed cholangitis: two items in A + two items in B or "suspected cholangitis" + positive blood culture. The diagnosis of cholangitis requires the exclusion of definite infections of other systems.

    Secondary Outcome Measures

    The occurrence of cholangitis (confirmed or suspected) within 1 year after KP
    The definition of cholangitis is the same as primary outcome.
    The occurrence of jaundice clearance within 6 months after KP
    Jaundice clearance is defined as total bilirubin (TB) less than 20 μmol/L.
    The occurrence of jaundice clearance within 1 year after KP
    Jaundice clearance is defined as TB less than 20 μmol/L.
    The number of cholangitis recurrence within 6 months after KP
    The definition of cholangitis is the same as primary outcome.
    The number of cholangitis recurrence within 1 year after KP
    The definition of cholangitis is the same as primary outcome.
    The patient survive with native liver or not within 2 years after KP
    The weight gain of the patients from pre-operation to 6 months post KP
    Weight for height (length) Z-score is calculated based on the gender, age, and weight reference standards for children in China. The difference in weight for height (length) Z-score between pre-operation and 6 months post KP is regarded as weight gain.
    The weight gain of the patients from pre-operation to 1 year post KP
    Weight for height (length) Z-score is calculated based on the gender, age, and weight reference standards for children in China. The difference in weight for height (length) Z-score between pre-operation and 1 year post KP is regarded as weight gain.
    Liver parameters at post-operation month 6
    Liver parameters: pediatric end-stage liver disease (PELD) score, liver stiffness measurement. PELD score = 0.480×ln (total cholesterol) + 1.857×ln (international normalized ratio)-0.687×ln (albumin) + 0.436 × age score + 0.667 × growth arrest] × 10. Age score:1 point for age < 24 months, 0 for age ≥ 24 months. Growth arrest: 1 point for more than 2 standard deviations below the average, otherwise 0. Liver stiffness measurement is measured by liver transient elastography.
    Liver parameters at post-operation month 12
    Liver parameters: pediatric end-stage liver disease (PELD) score, liver stiffness measurement. PELD score = 0.480×ln (total cholesterol) + 1.857×ln (international normalized ratio)-0.687×ln (albumin) + 0.436 × age score + 0.667 × growth arrest] × 10. Age score:1 point for age < 24 months, 0 for age ≥ 24 months. Growth arrest: 1 point for more than 2 standard deviations below the average, otherwise 0. Liver stiffness measurement is measured by liver transient elastography.
    Changes in intestinal flora from post-operation week 2 to month 3
    Fecal samples of 40 patients in each group are collected 2 weeks and 3 months after KP, and frozen at -80℃. 16s-rDNA sequencing is used to find out the changes in intestinal flora.
    Changes in intestinal flora from post-operation week 2 to month 6
    Fecal samples of 40 patients in each group are collected 2 weeks and 6 months after KP, and frozen at -80℃. 16s-rDNA sequencing is used to find out the changes in intestinal flora.

    Full Information

    First Posted
    June 14, 2023
    Last Updated
    June 28, 2023
    Sponsor
    Children's Hospital of Fudan University
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    1. Study Identification

    Unique Protocol Identification Number
    NCT05925309
    Brief Title
    Preventive Effect of Prophylactic Oral Antibiotics Against Cholangitis After Kasai Portoenterostomy
    Official Title
    Preventive Effect of Prophylactic Oral Antibiotics Against Cholangitis After Kasai Portoenterostomy in Biliary Atresia: a Randomized Controlled Trial
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    June 2023
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    June 28, 2023 (Anticipated)
    Primary Completion Date
    December 31, 2025 (Anticipated)
    Study Completion Date
    June 30, 2027 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Children's Hospital of Fudan University

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    This study is non-inferiority trial design. This study aimed to investigate the effect of prophylactic oral antibiotics on preventing cholangitis in biliary atresia (BA) patients after Kasai portoenterostomy (KP) by comparing the cholangitis rate in BA patients who received prophylactic oral antibiotics and those who did not. The patients were followed up for 2 years after KP.
    Detailed Description
    Biliary atresia (BA) is a devastating inflammatory obstructive neonatal disease affecting intrahepatic and extrahepatic bile ducts. Kasai portoenterostomy (KP) is the mainstay of treatment for BA. Cholangitis is a common complication after KP, with an overall incidence of 22-93%, and an incidence of 30-70% within 6 months after KP. The mechanism of cholangitis may be intestinal bacteria ascending into the intrahepatic biliary system or bacterial colonization, etc. Common causative organisms include Klebsiella, Escherichia coli, Pseudomonas aeruginosa, Enterobacter cloacae, Acinetobacter baumannii, Streptococcus, and Salmonella typhi. There is some controversy about prophylactic antibiotics after KP, and the type, dosage and course of antibiotics in medical institutions around the world vary greatly. After years of improvement, although the postoperative management and short-term prognosis of BA have improved, the overall incidence of cholangitis has not changed much. High-quality evidence for antibiotic prophylaxis after KP remains lacking. It still remains unknown that whether long-term prophylactic oral antibiotics could benefit the patients. Long-term use of antibiotics may not only increase the burden of liver dysfunction in patients, but also lead to antibiotic resistance, intestinal flora disturbance, and increase the risk of allergies and autoimmune diseases. It is of great significance to use evidence-based medicine to find a relatively reasonable cholangitis prevention program. This study is non-inferiority trial design. This study aimed to investigate the effect of prophylactic oral antibiotics on preventing cholangitis by comparing the cholangitis rate in BA patients who received prophylactic oral antibiotics after KP and those who did not. Patients diagnosed with type III BA and receiving KP at Children's Hospital of Fudan University will be assigned to 2 groups. Both groups received the same basic treatment, then the patients in the antibiotics group received prophylactic oral antibiotics until the 6th month after KP, while the non-antibiotics group no longer used prophylactic antibiotics until cholangitis occurred. The cholangitis rate within 6 months after KP were measured to evaluate the preventive effect of prophylactic oral antibiotics on cholangitis. The patients were followed up for 2 years after KP.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Biliary Atresia, Cholangitis, Anti-Bacterial Agents

    7. Study Design

    Primary Purpose
    Prevention
    Study Phase
    Not Applicable
    Interventional Study Model
    Parallel Assignment
    Masking
    Outcomes Assessor
    Allocation
    Randomized
    Enrollment
    356 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Antibiotics group
    Arm Type
    Active Comparator
    Arm Description
    Basic treatment + Prophylactic oral antibiotics
    Arm Title
    Non-antibiotics group
    Arm Type
    Experimental
    Arm Description
    Basic treatment
    Intervention Type
    Drug
    Intervention Name(s)
    Basic treatment: sulperazone + ursodeoxycholic acid + compound glycyrrhizin + methylprednisolone + vitamin AD , D , E , K + imipenem or meropenem
    Intervention Description
    Sulperazone 50mg/kg q8h is used intravenously from the first day to the 14th day after KP surgery. Ursodeoxycholic acid 20mg/kg/d p.o, starting from the 5th day after surgery for at least 2 years. Compound glycyrrhizin 20mg/d i.v, 1-4 days after operation, then switch to compound glycyrrhizin tablets 12.5mg b.i.d p.o until 6 months after KP. Methylprednisolone start at 4mg/kg/d i.v on the 8th day after operation, and decrease by 1mg/kg/d every three days. Starting at about the 15th day after operation, methylprednisolone 4mg/kg is given orally every other day, and the dose is gradually reduced at 10-12 weeks. Vitamin AD , D , E , K, are given orally from the 5th day after the KP for at least 2 months. Treatment of cholangitis: sulperazone 50mg/kg q8h i.v., and methylprednisolone could be used. If cholangitis is not controlled, imipenem or meropenem may be used.
    Intervention Type
    Drug
    Intervention Name(s)
    Prophylactic oral antibiotics: compound sulfamethoxazole tablet (SMZ/TMP) + cefaclor
    Intervention Description
    Compound sulfamethoxazole tablet (SMZ/TMP) 25 mg/kg/d p.o. and cefaclor 12.5 mg/kg/d p.o. alternately every 2 weeks, from post-operation day 15 to month 6.
    Primary Outcome Measure Information:
    Title
    The occurrence of cholangitis (confirmed or suspected) within 6 months after KP
    Description
    Definition of cholangitis: A. Clinical elements Fever and/or shivering; Stool color change; New/increasing jaundice; Abdominal discomfort: vomiting, poor, feeding, irritability. B. Laboratory and imaging elements Inflammatory response (WBC and/or CRP and/or PCT); Increased/increasing transaminases; Increased/increasing GGT and/or bilirubin; Bile lakes. Suspected cholangitis: one item in A + one item in B. Confirmed cholangitis: two items in A + two items in B or "suspected cholangitis" + positive blood culture. The diagnosis of cholangitis requires the exclusion of definite infections of other systems.
    Time Frame
    6 months after KP
    Secondary Outcome Measure Information:
    Title
    The occurrence of cholangitis (confirmed or suspected) within 1 year after KP
    Description
    The definition of cholangitis is the same as primary outcome.
    Time Frame
    1 year after KP
    Title
    The occurrence of jaundice clearance within 6 months after KP
    Description
    Jaundice clearance is defined as total bilirubin (TB) less than 20 μmol/L.
    Time Frame
    6 months after KP
    Title
    The occurrence of jaundice clearance within 1 year after KP
    Description
    Jaundice clearance is defined as TB less than 20 μmol/L.
    Time Frame
    1 year after KP
    Title
    The number of cholangitis recurrence within 6 months after KP
    Description
    The definition of cholangitis is the same as primary outcome.
    Time Frame
    6 months after KP
    Title
    The number of cholangitis recurrence within 1 year after KP
    Description
    The definition of cholangitis is the same as primary outcome.
    Time Frame
    1 year after KP
    Title
    The patient survive with native liver or not within 2 years after KP
    Time Frame
    2 years after KP
    Title
    The weight gain of the patients from pre-operation to 6 months post KP
    Description
    Weight for height (length) Z-score is calculated based on the gender, age, and weight reference standards for children in China. The difference in weight for height (length) Z-score between pre-operation and 6 months post KP is regarded as weight gain.
    Time Frame
    From pre-operation to 6 months post KP
    Title
    The weight gain of the patients from pre-operation to 1 year post KP
    Description
    Weight for height (length) Z-score is calculated based on the gender, age, and weight reference standards for children in China. The difference in weight for height (length) Z-score between pre-operation and 1 year post KP is regarded as weight gain.
    Time Frame
    From pre-operation to 1 year post KP
    Title
    Liver parameters at post-operation month 6
    Description
    Liver parameters: pediatric end-stage liver disease (PELD) score, liver stiffness measurement. PELD score = 0.480×ln (total cholesterol) + 1.857×ln (international normalized ratio)-0.687×ln (albumin) + 0.436 × age score + 0.667 × growth arrest] × 10. Age score:1 point for age < 24 months, 0 for age ≥ 24 months. Growth arrest: 1 point for more than 2 standard deviations below the average, otherwise 0. Liver stiffness measurement is measured by liver transient elastography.
    Time Frame
    6 months after KP
    Title
    Liver parameters at post-operation month 12
    Description
    Liver parameters: pediatric end-stage liver disease (PELD) score, liver stiffness measurement. PELD score = 0.480×ln (total cholesterol) + 1.857×ln (international normalized ratio)-0.687×ln (albumin) + 0.436 × age score + 0.667 × growth arrest] × 10. Age score:1 point for age < 24 months, 0 for age ≥ 24 months. Growth arrest: 1 point for more than 2 standard deviations below the average, otherwise 0. Liver stiffness measurement is measured by liver transient elastography.
    Time Frame
    1 year after KP
    Title
    Changes in intestinal flora from post-operation week 2 to month 3
    Description
    Fecal samples of 40 patients in each group are collected 2 weeks and 3 months after KP, and frozen at -80℃. 16s-rDNA sequencing is used to find out the changes in intestinal flora.
    Time Frame
    From pre-operation week 2 to month 3
    Title
    Changes in intestinal flora from post-operation week 2 to month 6
    Description
    Fecal samples of 40 patients in each group are collected 2 weeks and 6 months after KP, and frozen at -80℃. 16s-rDNA sequencing is used to find out the changes in intestinal flora.
    Time Frame
    From pre-operation week 2 to month 6

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    14 Days
    Maximum Age & Unit of Time
    90 Days
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Patients whose age of operation is 14-90 d. Sex and race are not restricted; Patients who are born with gestational age older than 36 weeks; Patients whose body weight before operation > 2 kg; Patients diagnosed of type-III BA and underwent KP in Children's Hospital of Fudan University; The type-III BA diagnosis is based on cholangiography or operation; Patients whose histological features of liver biopsies are reported. HE staining and Masson staining are required, and edema, inflammation, fibrosis, and hyperplasia of intrahepatic bile duct should be reported; Patients who are not allergic to postoperative medications; Patients who haven't accepted other antibiotic or probiotic therapy. Exclusion Criteria: Patients with cholestasis of non-BA disease; Patients who have undergone KP at other institutions; Patients whose pathohistological diagnosis is in doubt; Patients who undergo liver transplantation immediately after KP; Patients with other liver diseases or severe complications (e.g., severe pulmonary hypertension, renal failure, intracranial hemorrhage, etc.) requiring surgical intervention or other medical therapy; Patients with severe cardiac, renal, or central nerve system malformations (e.g., tetralogy of Fallot, transposition of the great arteries, cerebral dysplasia, etc.) and have poor prognosis; Patients judged by the researchers that they can not comply with the study requirements.
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Gong Chen, Phd
    Phone
    (+86)13918330650
    Email
    chengongzlp@hotmail.com
    First Name & Middle Initial & Last Name or Official Title & Degree
    Di Chen
    Phone
    (+86)18930942535
    Email
    george19981206@126.com

    12. IPD Sharing Statement

    Plan to Share IPD
    No
    Citations:
    PubMed Identifier
    35159946
    Citation
    Calinescu AM, Madadi-Sanjani O, Mack C, Schreiber RA, Superina R, Kelly D, Petersen C, Wildhaber BE. Cholangitis Definition and Treatment after Kasai Hepatoportoenterostomy for Biliary Atresia: A Delphi Process and International Expert Panel. J Clin Med. 2022 Jan 19;11(3):494. doi: 10.3390/jcm11030494.
    Results Reference
    background
    PubMed Identifier
    34013444
    Citation
    Chen G, Liu J, Huang Y, Wu Y, Lu X, Dong R, Shen Z, Sun S, Jiang J, Zheng S. Preventive effect of prophylactic intravenous antibiotics against cholangitis in biliary atresia: a randomized controlled trial. Pediatr Surg Int. 2021 Aug;37(8):1089-1097. doi: 10.1007/s00383-021-04916-z. Epub 2021 May 19.
    Results Reference
    background
    PubMed Identifier
    26183324
    Citation
    Decharun K, Leys CM, West KW, Finnell SM. Prophylactic Antibiotics for Prevention of Cholangitis in Patients With Biliary Atresia Status Post-Kasai Portoenterostomy: A Systematic Review. Clin Pediatr (Phila). 2016 Jan;55(1):66-72. doi: 10.1177/0009922815594760. Epub 2015 Jul 15.
    Results Reference
    background
    PubMed Identifier
    25974298
    Citation
    Vangay P, Ward T, Gerber JS, Knights D. Antibiotics, pediatric dysbiosis, and disease. Cell Host Microbe. 2015 May 13;17(5):553-64. doi: 10.1016/j.chom.2015.04.006.
    Results Reference
    background

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    Preventive Effect of Prophylactic Oral Antibiotics Against Cholangitis After Kasai Portoenterostomy

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