Preventive Effect of Prophylactic Oral Antibiotics Against Cholangitis After Kasai Portoenterostomy

Sponsor

Children's Hospital of Fudan University (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05925309

Collaborator

(none)

356

Enrollment

Arms

48.1

Anticipated Duration (Months)

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Biliary Atresia Cholangitis Anti-Bacterial Agents	Drug: Basic treatment: sulperazone + ursodeoxycholic acid + compound glycyrrhizin + methylprednisolone + vitamin AD , D , E , K + imipenem or meropenem Drug: Prophylactic oral antibiotics: compound sulfamethoxazole tablet (SMZ/TMP) + cefaclor	N/A

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

356 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (Outcomes Assessor)

Primary Purpose:

Prevention

Official Title:

Preventive Effect of Prophylactic Oral Antibiotics Against Cholangitis After Kasai Portoenterostomy in Biliary Atresia: a Randomized Controlled Trial

Anticipated Study Start Date :

Jun 28, 2023

Anticipated Primary Completion Date :

Dec 31, 2025

Anticipated Study Completion Date :

Jun 30, 2027

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Antibiotics group Basic treatment + Prophylactic oral antibiotics	Drug: Basic treatment: sulperazone + ursodeoxycholic acid + compound glycyrrhizin + methylprednisolone + vitamin AD , D , E , K + imipenem or meropenem 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. Drug: Prophylactic oral antibiotics: compound sulfamethoxazole tablet (SMZ/TMP) + cefaclor 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.
Experimental: Non-antibiotics group Basic treatment	Drug: Basic treatment: sulperazone + ursodeoxycholic acid + compound glycyrrhizin + methylprednisolone + vitamin AD , D , E , K + imipenem or meropenem 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.

Arm

Intervention/Treatment

Active Comparator: Antibiotics group

Basic treatment + Prophylactic oral antibiotics

Drug: Basic treatment: sulperazone + ursodeoxycholic acid + compound glycyrrhizin + methylprednisolone + vitamin AD , D , E , K + imipenem or meropenem

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.

Drug: Prophylactic oral antibiotics: compound sulfamethoxazole tablet (SMZ/TMP) + cefaclor

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.

Experimental: Non-antibiotics group

Basic treatment

Drug: Basic treatment: sulperazone + ursodeoxycholic acid + compound glycyrrhizin + methylprednisolone + vitamin AD , D , E , K + imipenem or meropenem

Outcome Measures

Primary Outcome Measures

The occurrence of cholangitis (confirmed or suspected) within 6 months after KP [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 [1 year after KP]
The definition of cholangitis is the same as primary outcome.
The occurrence of jaundice clearance within 6 months after KP [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 [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 [6 months after KP]
The definition of cholangitis is the same as primary outcome.
The number of cholangitis recurrence within 1 year after KP [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 [2 years after KP]
The weight gain of the patients from pre-operation to 6 months post KP [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 [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 [6 months after KP]
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 [1 year after KP]
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 [From pre-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 [From pre-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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

14 Days to 90 Days

Sexes Eligible for Study:

All

Accepts 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.