Primary Sclerosing Cholangitis
Conditions
Brief summary
The purpose of this study is to determine whether Vancomycin or Metronidazole is safe and beneficial in the treatment of Primary Sclerosing Cholangitis.
Detailed description
In this protocol, we propose the assessment of potential beneficial effects of the antibiotics vancomycin and metronidazole on liver biochemistries, liver related symptoms and Mayo risk score in patients with PSC. The patients will be randomized into four groups of ten patients: one group will receive low dose vancomycin, one group will receive high dose vancomycin, one group will receive low dose metronidazole and one group will receive high dose metronidazole. Each group will be treated for three months.
Interventions
DRUGVancomycin
Comparison of different doses of drug
DRUGMetronidazole
Comparison of different doses of drug
Sponsors
PSC Partners Seeking a Cure
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of PSC established by alkaline phosphatase \>1.5 times and/or two fold elevation of liver transaminases (AST and/or ALT) for at least 6 months duration. * Cholangiography demonstrating intrahepatic and/or extrahepatic biliary obstruction, beading, or narrowing consistent with PSC. * Both genders. * Age ≥ 18 years old and \< than 75 years old. * Patient's informed consent for study participation.
Exclusion criteria
* Treatment with systematic antibiotics, azulfidine, ursodeoxycholic acid, corticosteroids, colchicine, methotrexate, azathioprine, cyclosporine, chlorambucil, budesonide, pentoxifylline, tacrolimus, silymarin or prednisone in the preceding three months. * Active drug or alcohol use. * Prior history of allergic reactions to the antibiotics which will be used in the study. * Any condition that, in the opinion of the investigator, would interfere with the patients' ability to complete the study safely or successfully. * Evidence of decompensated liver disease such as recurrent variceal bleeding, refractory ascites or spontaneous hepatic encephalopathy. * Anticipated need for transplantation in one year (Mayo survival model \<80% one-year survival without transplant). * Findings highly suggestive of liver disease of other etiology such as chronic alcoholic liver disease, chronic hepatitis B or C infection, hemochromatosis, Wilson's disease, 1-antitrypsin deficiency, non-alcoholic steatohepatitis, primary biliary cirrhosis or secondary sclerosing cholangitis. * Pregnancy or current lactation. Subjects becoming pregnant during the study will be withdrawn.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change From Baseline in Alkaline Phosphatase Following 12 Weeks of Treatment | baseline, 12 weeks |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Total Bilirubin Following 12 Weeks Treatment | baseline, 12 weeks | — |
| Change From Baseline in Mayo PSC Risk Score Following 12 Weeks of Treatment | baseline, 12 weeks | The Mayo PSC risk score was calculated for each patient at baseline and at 12 weeks, where Risk = 0.03 (age \[years\]) + 0.54 Ln (total bilirubin \[mg/dL\]) + 0.54 Ln (AST \[IU/L\]) + 1.24 (variceal bleeding) - 0.84 (albumin \[g/dL\]). There is no range, minimum, or maximum value but greater values indicate worse disease. |
| Change From Baseline in C-Reactive Protein Following 12 Weeks of Treatment | baseline, 12 weeks | — |
Countries
United States
Participant flow
Recruitment details
A total of 35 adult patients with primary sclerosing cholangitis (PSC) were enrolled between February 2010 and November 2011 at Mayo Clinic, Rochester MN.
Participants by arm
| Arm | Count |
|---|---|
| Low Dose Vancomycin Vancomycin 125 mg 4 times a day | 8 |
| High Dose Vancomycin Vancomycin 250 mg 4 times a day | 9 |
| Low Dose Metronidazole Metronidazole 250 mg 3 times a day | 9 |
| High Dose Metronidazole metronidazole 500 mg 3 times a day | 9 |
| Total | 35 |
Baseline characteristics
| Characteristic | Total | Low Dose Vancomycin | High Dose Vancomycin | Low Dose Metronidazole | High Dose Metronidazole |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 32 Participants | 8 Participants | 6 Participants | 9 Participants | 9 Participants |
| Age Continuous | 40 years | 40 years | 42 years | 35 years | 40 years |
| Region of Enrollment United States | 35 participants | 8 participants | 9 participants | 9 participants | 9 participants |
| Sex: Female, Male Female | 21 Participants | 4 Participants | 9 Participants | 4 Participants | 4 Participants |
| Sex: Female, Male Male | 14 Participants | 4 Participants | 0 Participants | 5 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 8 | 3 / 9 | 6 / 9 | 8 / 9 |
| serious Total, serious adverse events | 0 / 8 | 0 / 9 | 0 / 9 | 0 / 9 |
Outcome results
Primary
Change From Baseline in Alkaline Phosphatase Following 12 Weeks of Treatment
Time frame: baseline, 12 weeks
Population: The number of participants was based on a per protocol analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Dose Vancomycin | Change From Baseline in Alkaline Phosphatase Following 12 Weeks of Treatment | -117 U/L |
| High Dose Vancomycin | Change From Baseline in Alkaline Phosphatase Following 12 Weeks of Treatment | -49 U/L |
| Low Dose Metronidazole | Change From Baseline in Alkaline Phosphatase Following 12 Weeks of Treatment | -62 U/L |
| High Dose Metronidazole | Change From Baseline in Alkaline Phosphatase Following 12 Weeks of Treatment | -36 U/L |
Secondary
Change From Baseline in C-Reactive Protein Following 12 Weeks of Treatment
Time frame: baseline, 12 weeks
Population: Per protocol analysis done
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Dose Vancomycin | Change From Baseline in C-Reactive Protein Following 12 Weeks of Treatment | -2.2 mg/L |
| High Dose Vancomycin | Change From Baseline in C-Reactive Protein Following 12 Weeks of Treatment | 1 mg/L |
| Low Dose Metronidazole | Change From Baseline in C-Reactive Protein Following 12 Weeks of Treatment | -3.6 mg/L |
| High Dose Metronidazole | Change From Baseline in C-Reactive Protein Following 12 Weeks of Treatment | 0 mg/L |
Secondary
Change From Baseline in Mayo PSC Risk Score Following 12 Weeks of Treatment
The Mayo PSC risk score was calculated for each patient at baseline and at 12 weeks, where Risk = 0.03 (age \[years\]) + 0.54 Ln (total bilirubin \[mg/dL\]) + 0.54 Ln (AST \[IU/L\]) + 1.24 (variceal bleeding) - 0.84 (albumin \[g/dL\]). There is no range, minimum, or maximum value but greater values indicate worse disease.
Time frame: baseline, 12 weeks
Population: Per protocol analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Dose Vancomycin | Change From Baseline in Mayo PSC Risk Score Following 12 Weeks of Treatment | -0.65 units on a scale |
| High Dose Vancomycin | Change From Baseline in Mayo PSC Risk Score Following 12 Weeks of Treatment | -0.01 units on a scale |
| Low Dose Metronidazole | Change From Baseline in Mayo PSC Risk Score Following 12 Weeks of Treatment | -0.26 units on a scale |
| High Dose Metronidazole | Change From Baseline in Mayo PSC Risk Score Following 12 Weeks of Treatment | -0.20 units on a scale |
Secondary
Change From Baseline in Total Bilirubin Following 12 Weeks Treatment
Time frame: baseline, 12 weeks
Population: Per protocol analysis done
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Dose Vancomycin | Change From Baseline in Total Bilirubin Following 12 Weeks Treatment | -0.4 mg/dl |
| High Dose Vancomycin | Change From Baseline in Total Bilirubin Following 12 Weeks Treatment | 0.05 mg/dl |
| Low Dose Metronidazole | Change From Baseline in Total Bilirubin Following 12 Weeks Treatment | -0.3 mg/dl |
| High Dose Metronidazole | Change From Baseline in Total Bilirubin Following 12 Weeks Treatment | 0.05 mg/dl |