Primary Sclerosing Cholangitis
Conditions
Keywords
Inflammation of the bile ducts, biliary scarring, obstruction
Brief summary
Determine the benefit of oral vancomycin therapy for Primary Sclerosing Cholangitis.
Detailed description
The purpose of this study is to evaluate changes in the fecal and salivary/urinary microbiota during vancomycin treatment of children and adults with Primary Sclerosing Cholangitis (PSC), identify features of the host microbiota that are associated with disease activity and/or response to treatment and further delineate the immunological effects of oral vancomycin treatment of PSC. This study will correlate changes in microbiota with the immunological effects of oral vancomycin in children and adults with PSC. The results of this proposal will lead to new and validated targets for diagnosis and treatment of PSC that will have high impact in the short and long term for patients and their families. Interim results were published in Abarbanel et al, J Clin Immunol 2013 (see References).
Interventions
DRUGOral Vancomycin
Sponsors
Stanford University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* PSC Diagnosis: Liver biopsy and/or imaging (MRCP, ERCP, CT, or US * Colonoscopy within 1 year or starting of study * 2 groups: 1. IBD (Inflammatory bowel disease) and PSC: details of extent and type of IBD 2. No IBD and PSC, but positive p-ANCA or ASCA serologies indicating possible IBD.
Exclusion criteria
* Allergy to Vancomycin * PSC not associated with IBD or NO positive IBD antibodies (p-ANCA \[anti- neutrophil cytoplasmic antibody\] or ASCA \[anti-Saccharomyces cerevisiae antibody\]) * Cholangiocarcinoma * On oral or topical (enemas or suppositories) corticosteroids,topical mesalamine, or biologics (infliximab, adalimumab, certolizumab).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Count of Participants With Elevated Alanine Aminotransferase (ALT) at Baseline and With Clinically Significant Improvement at Month 3 | Baseline; Month 3 | Clinically significant improvement was determined by investigator assessment per participant based on their medical history and disease stage. Elevated ALT was any value greater than the upper limit of the standard reference range used by patient's laboratory. |
| Count of Participants With Elevated Gamma-glutamyltransferase (GGT) at Baseline and With Clinically Significant Improvement at Month 3 | Baseline; Month 3 | Clinically significant improvement was determined by investigator assessment per participant based on their medical history and disease stage. Elevated GGT was any value greater than the upper limit of the standard reference range used by patient's laboratory. |
| Count of Participants With Elevated ALT and/or GGT at Baseline and With Clinically Significant Improvement at Month 3 | Baseline; Month 3 | Clinically significant improvement was determined by investigator assessment per participant based on their medical history and disease stage. Elevated ALT (and GGT) was any value greater than the upper limit of the standard reference range used by patient's laboratory. |
| Count of Participants With Abnormal Magnetic Resonance Cholangiopancreatography (MRCP) Imaging at Baseline and With Clinically Significant Improvement at Year 1 | Baseline; Year 1 | Clinically significant improvement was determined by investigator assessment per participant based on their medical history and disease stage. MRCP imaging was abnormal if it included biliary beading, biliary strictures, dilated bile duct, and/or liver fibrosis. |
| Count of Participants With Abnormal Liver Biopsies at Baseline and With Clinically Significant Improvement at Year 1 | Baseline; Year 1 | Clinically significant improvement was determined by investigator assessment per participant based on their medical history and disease stage. Liver pathology was considered abnormal if the biopsy was S1 or greater on the liver fibrosis staging scale (S0 no fibrosis, S1 mild fibrosis, S2 moderate fibrosis, S3 sever fibrosis, S4 cirrhosis). |
| Count of Participants With Abnormal MRCP and/or Liver Biopsy at Baseline and With Clinically Significant Improvement at Year 1 | Baseline; Year 1 | Clinically significant improvement was determined by investigator assessment per participant based on their medical history and disease stage. MRCP imaging was abnormal if it included biliary beading, biliary strictures, dilated bile duct, and/or liver fibrosis. Liver pathology was considered abnormal if the biopsy was S1 or greater on the liver fibrosis staging scale (S0 no fibrosis, S1 mild fibrosis, S2 moderate fibrosis, S3 sever fibrosis, S4 cirrhosis). |
Countries
United States
Participant flow
Pre-assignment details
Two participants in the adult cohort completed the study but were not analyzed for outcomes (1 post-liver transplant patient; 1 completed the study but followed a diet that could influence results analysis). Two adult participants who consented but withdrew prior to treatment were not analyzed for outcomes.
Participants by arm
| Arm | Count |
|---|---|
| Oral Vancomycin-Children For children who weight \< or = 30 kg, the vancomycin dose will be 50 mg/kg/day given orally 3 times per day for the 1st month and continue with the same dose for subsequent months if the clinical laboratory studies improved and are normal. If the laboratory studies are not normal the dose will be increased to 75 mg/kg/day given orally 3 times per day for the 2nd month and 100mg/kg/day given orally 3 times per day the 3rd month. If the laboratory studies do not improve by the end of the 3rd month since starting the vancomycin, the vancomycin will be stopped and the child will not continue the study.
Oral Vancomycin | 14 |
| Oral Vancomycin-Adults For adults and children who weigh \>30 kg, the vancomycin dose will be 500 mg given orally 3 times per day for the 1st month and continue with this dose if the clinical laboratory studies improve and are normal. If the laboratory studies are not normal the dose will be increased to 750 mg 3 times per day for the 2nd month and 1000 mg 3 times per day the 3rd month.
Oral Vancomycin | 20 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Non-compliant | 4 | 2 |
| Overall Study | Physician Decision | 0 | 7 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Oral Vancomycin-Adults | Total | Oral Vancomycin-Children |
|---|---|---|---|
| Age, Customized 0-6 years | 0 Participants | 2 Participants | 2 Participants |
| Age, Customized 13-17 years | 0 Participants | 6 Participants | 6 Participants |
| Age, Customized 18-64 years | 20 Participants | 21 Participants | 1 Participants |
| Age, Customized 7-12 years | 0 Participants | 5 Participants | 5 Participants |
| Sex: Female, Male Female | 2 Participants | 8 Participants | 6 Participants |
| Sex: Female, Male Male | 18 Participants | 26 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 20 |
| other Total, other adverse events | 0 / 14 | 0 / 20 |
| serious Total, serious adverse events | 1 / 14 | 0 / 20 |
Outcome results
Primary
Count of Participants With Abnormal Liver Biopsies at Baseline and With Clinically Significant Improvement at Year 1
Clinically significant improvement was determined by investigator assessment per participant based on their medical history and disease stage. Liver pathology was considered abnormal if the biopsy was S1 or greater on the liver fibrosis staging scale (S0 no fibrosis, S1 mild fibrosis, S2 moderate fibrosis, S3 sever fibrosis, S4 cirrhosis).
Time frame: Baseline; Year 1
Population: Participants with abnormal liver biopsy at baseline and who had a post-treatment liver biopsy are included in the analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Vancomycin-Children | Count of Participants With Abnormal Liver Biopsies at Baseline and With Clinically Significant Improvement at Year 1 | 3 Participants |
| Oral Vancomycin-Adults | Count of Participants With Abnormal Liver Biopsies at Baseline and With Clinically Significant Improvement at Year 1 | 0 Participants |
Primary
Count of Participants With Abnormal Magnetic Resonance Cholangiopancreatography (MRCP) Imaging at Baseline and With Clinically Significant Improvement at Year 1
Clinically significant improvement was determined by investigator assessment per participant based on their medical history and disease stage. MRCP imaging was abnormal if it included biliary beading, biliary strictures, dilated bile duct, and/or liver fibrosis.
Time frame: Baseline; Year 1
Population: Participants with abnormal MRCP at baseline are included in the analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Vancomycin-Children | Count of Participants With Abnormal Magnetic Resonance Cholangiopancreatography (MRCP) Imaging at Baseline and With Clinically Significant Improvement at Year 1 | 6 Participants |
| Oral Vancomycin-Adults | Count of Participants With Abnormal Magnetic Resonance Cholangiopancreatography (MRCP) Imaging at Baseline and With Clinically Significant Improvement at Year 1 | 4 Participants |
Primary
Count of Participants With Abnormal MRCP and/or Liver Biopsy at Baseline and With Clinically Significant Improvement at Year 1
Clinically significant improvement was determined by investigator assessment per participant based on their medical history and disease stage. MRCP imaging was abnormal if it included biliary beading, biliary strictures, dilated bile duct, and/or liver fibrosis. Liver pathology was considered abnormal if the biopsy was S1 or greater on the liver fibrosis staging scale (S0 no fibrosis, S1 mild fibrosis, S2 moderate fibrosis, S3 sever fibrosis, S4 cirrhosis).
Time frame: Baseline; Year 1
Population: Participants with abnormal MRCP and/or liver biopsy at baseline are included in the analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Vancomycin-Children | Count of Participants With Abnormal MRCP and/or Liver Biopsy at Baseline and With Clinically Significant Improvement at Year 1 | 10 Participants |
| Oral Vancomycin-Adults | Count of Participants With Abnormal MRCP and/or Liver Biopsy at Baseline and With Clinically Significant Improvement at Year 1 | 4 Participants |
Primary
Count of Participants With Elevated Alanine Aminotransferase (ALT) at Baseline and With Clinically Significant Improvement at Month 3
Clinically significant improvement was determined by investigator assessment per participant based on their medical history and disease stage. Elevated ALT was any value greater than the upper limit of the standard reference range used by patient's laboratory.
Time frame: Baseline; Month 3
Population: Participants with ALT elevated at baseline are included in the analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Vancomycin-Children | Count of Participants With Elevated Alanine Aminotransferase (ALT) at Baseline and With Clinically Significant Improvement at Month 3 | 10 Participants |
| Oral Vancomycin-Adults | Count of Participants With Elevated Alanine Aminotransferase (ALT) at Baseline and With Clinically Significant Improvement at Month 3 | 6 Participants |
Primary
Count of Participants With Elevated ALT and/or GGT at Baseline and With Clinically Significant Improvement at Month 3
Clinically significant improvement was determined by investigator assessment per participant based on their medical history and disease stage. Elevated ALT (and GGT) was any value greater than the upper limit of the standard reference range used by patient's laboratory.
Time frame: Baseline; Month 3
Population: Participants with ALT and/or GGT elevated at baseline are included in the analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Vancomycin-Children | Count of Participants With Elevated ALT and/or GGT at Baseline and With Clinically Significant Improvement at Month 3 | 10 Participants |
| Oral Vancomycin-Adults | Count of Participants With Elevated ALT and/or GGT at Baseline and With Clinically Significant Improvement at Month 3 | 8 Participants |
Primary
Count of Participants With Elevated Gamma-glutamyltransferase (GGT) at Baseline and With Clinically Significant Improvement at Month 3
Clinically significant improvement was determined by investigator assessment per participant based on their medical history and disease stage. Elevated GGT was any value greater than the upper limit of the standard reference range used by patient's laboratory.
Time frame: Baseline; Month 3
Population: Participants with GGT elevated at baseline are included in the analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Vancomycin-Children | Count of Participants With Elevated Gamma-glutamyltransferase (GGT) at Baseline and With Clinically Significant Improvement at Month 3 | 8 Participants |
| Oral Vancomycin-Adults | Count of Participants With Elevated Gamma-glutamyltransferase (GGT) at Baseline and With Clinically Significant Improvement at Month 3 | 6 Participants |