Primary Sclerosing Cholangitis
Conditions
Keywords
Urso, PSC
Brief summary
This is a multicenter, randomized, controlled trial of high dose ursodiol versus placebo for patients with primary sclerosing cholangitis (PSC). The average duration of follow-up will be approximately five years with important clinical endpoints such as death, eligibility for liver transplantation, changes in histology and cholangiogram as well as liver biochemistries and quality of life data collected.
Interventions
DRUGUrsodeoxycholic Acid
Ursodeoxycholic Acid 28-30 mg/kg/day in divided doses
DRUGPlacebo
Placebo for Urso
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Chronic cholestatic disease of at least six months' duration. * Serum alkaline phosphatase at least 1 ½ times the upper limits of normal. * Retrograde, operative, percutaneous, or magnetic resonance cholangiography demonstrating intrahepatic and/or extrahepatic biliary duct obstruction, beading, or narrowing consistent with PSC within one year of the study entry. * Liver biopsy in the previous one year which is available for review and compatible with the diagnosis of PSC. Compatible biopsy features include fibrous cholangitis, ductopenia with periportal inflammation and biliary fibrosis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Failure | 5 years | Treatment failure was defined as death, transplantation, meeting minimal listing criteria, development of varices, cholangiocarcinoma, or progression to cirrhosis |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Have a Liver Transplantation | 5 years | Liver transplantation at any time up to 5 years |
| Number of Participants Meeting Minimal Listing Criteria for Liver Transplantation | 5 years | Meeting minimal listing criteria for liver transplantation at any time up to 5 years. Minimal listing criteria are defined as a MELD score of 14 or higher. The Model For End-Stage Liver Disease (MELD) is a numeric score with a range of 6 to 40, where a higher score means worse liver disease. |
| Number of Participants Who Developed Cholangiocarcinoma | 5 years | Development of cholangiocarcinoma at any time up to 5 years |
| Number of Participants Who Developed Varices | 5 years | Development of esophogeal and/or gastric varices |
| Number of Participants Who Developed Cirrhosis | 5 years | Development of cirrhosis based on liver biopsy |
| Alkaline Phosphatase at 12 Months | 12 months | Alkaline phosphatase divided by the upper limit of normal |
| Alkaline Phosphatase at 24 Months | 24 months | Alkaline phosphatase divided by the upper limit of normal |
| Number of Deaths | 5 years | Death at any time up to 5 years |
| Aspartate Aminotransferase at 12 Months | 12 months | Aspartate aminotransferase at divided by the upper limit of normal |
| Aspartate Aminotransferase at 24 Months | 24 months | Aspartate aminotransferase at divided by the upper limit of normal |
| Aspartate Aminotransferase at 36 Months | 36 months | Aspartate aminotransferase at divided by the upper limit of normal |
| Bilirubin at 12 Months | 12 months | Bilirubin divided by the upper limit of normal |
| Bilirubin at 24 Months | 24 months | Bilirubin divided by the upper limit of normal |
| Bilirubin at 36 Months | 36 months | Bilirubin divided by the upper limit of normal |
| Alkaline Phosphatase at 36 Months | 36 months | Alkaline phosphatase divided by the upper limit of normal |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ursodeoxycholic Acid Ursodeoxycholic Acid 28-30 mg/kg/day in divided doses | 76 |
| Placebo Placebo for Urso | 74 |
| Total | 150 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | drug toxicity | 0 | 3 |
| Overall Study | Protocol Violation | 1 | 3 |
| Overall Study | Withdrawal by Subject | 5 | 9 |
Baseline characteristics
| Characteristic | Ursodeoxycholic Acid | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 47.9 years | 45.3 years | 46.6 years |
| Region of Enrollment United States | 76 participants | 74 participants | 150 participants |
| Sex: Female, Male Female | 38 Participants | 26 Participants | 64 Participants |
| Sex: Female, Male Male | 38 Participants | 48 Participants | 86 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 76 | 3 / 74 |
| other Total, other adverse events | 0 / 76 | 0 / 74 |
| serious Total, serious adverse events | 0 / 76 | 0 / 74 |
Outcome results
Primary
Number of Participants With Treatment Failure
Treatment failure was defined as death, transplantation, meeting minimal listing criteria, development of varices, cholangiocarcinoma, or progression to cirrhosis
Time frame: 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ursodeoxycholic Acid | Number of Participants With Treatment Failure | 30 Participants |
| Placebo | Number of Participants With Treatment Failure | 19 Participants |
Secondary
Alkaline Phosphatase at 12 Months
Alkaline phosphatase divided by the upper limit of normal
Time frame: 12 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ursodeoxycholic Acid | Alkaline Phosphatase at 12 Months | 1.9 Ratio |
| Placebo | Alkaline Phosphatase at 12 Months | 2.9 Ratio |
Secondary
Alkaline Phosphatase at 24 Months
Alkaline phosphatase divided by the upper limit of normal
Time frame: 24 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ursodeoxycholic Acid | Alkaline Phosphatase at 24 Months | 1.8 Ratio |
| Placebo | Alkaline Phosphatase at 24 Months | 2.6 Ratio |
Secondary
Alkaline Phosphatase at 36 Months
Alkaline phosphatase divided by the upper limit of normal
Time frame: 36 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ursodeoxycholic Acid | Alkaline Phosphatase at 36 Months | 1.7 Ratio |
| Placebo | Alkaline Phosphatase at 36 Months | 2.4 Ratio |
Secondary
Aspartate Aminotransferase at 12 Months
Aspartate aminotransferase at divided by the upper limit of normal
Time frame: 12 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ursodeoxycholic Acid | Aspartate Aminotransferase at 12 Months | 1.0 Ratio |
| Placebo | Aspartate Aminotransferase at 12 Months | 1.9 Ratio |
Secondary
Aspartate Aminotransferase at 24 Months
Aspartate aminotransferase at divided by the upper limit of normal
Time frame: 24 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ursodeoxycholic Acid | Aspartate Aminotransferase at 24 Months | 1.1 Ratio |
| Placebo | Aspartate Aminotransferase at 24 Months | 1.9 Ratio |
Secondary
Aspartate Aminotransferase at 36 Months
Aspartate aminotransferase at divided by the upper limit of normal
Time frame: 36 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ursodeoxycholic Acid | Aspartate Aminotransferase at 36 Months | 1.1 Ratio |
| Placebo | Aspartate Aminotransferase at 36 Months | 1.7 Ratio |
Secondary
Bilirubin at 12 Months
Bilirubin divided by the upper limit of normal
Time frame: 12 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ursodeoxycholic Acid | Bilirubin at 12 Months | 0.8 Ratio |
| Placebo | Bilirubin at 12 Months | 0.9 Ratio |
Secondary
Bilirubin at 24 Months
Bilirubin divided by the upper limit of normal
Time frame: 24 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ursodeoxycholic Acid | Bilirubin at 24 Months | 0.8 Ratio |
| Placebo | Bilirubin at 24 Months | 1.0 Ratio |
Secondary
Bilirubin at 36 Months
Bilirubin divided by the upper limit of normal
Time frame: 36 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ursodeoxycholic Acid | Bilirubin at 36 Months | 0.8 Ratio |
| Placebo | Bilirubin at 36 Months | 0.9 Ratio |
Secondary
Number of Deaths
Death at any time up to 5 years
Time frame: 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ursodeoxycholic Acid | Number of Deaths | 5 participants |
| Placebo | Number of Deaths | 3 participants |
Secondary
Number of Participants Meeting Minimal Listing Criteria for Liver Transplantation
Meeting minimal listing criteria for liver transplantation at any time up to 5 years. Minimal listing criteria are defined as a MELD score of 14 or higher. The Model For End-Stage Liver Disease (MELD) is a numeric score with a range of 6 to 40, where a higher score means worse liver disease.
Time frame: 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ursodeoxycholic Acid | Number of Participants Meeting Minimal Listing Criteria for Liver Transplantation | 13 participants |
| Placebo | Number of Participants Meeting Minimal Listing Criteria for Liver Transplantation | 10 participants |
Secondary
Number of Participants Who Developed Cholangiocarcinoma
Development of cholangiocarcinoma at any time up to 5 years
Time frame: 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ursodeoxycholic Acid | Number of Participants Who Developed Cholangiocarcinoma | 2 participants |
| Placebo | Number of Participants Who Developed Cholangiocarcinoma | 2 participants |
Secondary
Number of Participants Who Developed Cirrhosis
Development of cirrhosis based on liver biopsy
Time frame: 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ursodeoxycholic Acid | Number of Participants Who Developed Cirrhosis | 6 participants |
| Placebo | Number of Participants Who Developed Cirrhosis | 4 participants |
Secondary
Number of Participants Who Developed Varices
Development of esophogeal and/or gastric varices
Time frame: 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ursodeoxycholic Acid | Number of Participants Who Developed Varices | 15 participants |
| Placebo | Number of Participants Who Developed Varices | 5 participants |
Secondary
Number of Participants Who Have a Liver Transplantation
Liver transplantation at any time up to 5 years
Time frame: 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ursodeoxycholic Acid | Number of Participants Who Have a Liver Transplantation | 11 participants |
| Placebo | Number of Participants Who Have a Liver Transplantation | 5 participants |