Primary Biliary Cirrhosis
Conditions
Keywords
Diseases [C] - Digestive System Diseases [C06], primary biliary cirrhosis, ursodeoxycholic acid (UDCA), STELARA, ustekinumab
Brief summary
The purpose of this study is to evaluate the efficacy and safety of ustekinumab in patients with primary biliary cirrhosis who had an inadequate response to ursodeoxycholic acid.
Detailed description
This is a multi-center, randomized (treatment will be assigned by chance), placebo-controlled (an inactive substance will be compared with the test drug to see whether the drug has a real effect), parallel-group (two or more groups of patients will receive different treatments) study that will consist of two parts. Part 1 will be an open-label (all participants will know the identity of the treatment) proof-of-concept study. Part 2 will be contingent on the results of Part 1 and will be double-blind (investigators and patients will not know what treatment is being given) and will evaluate the efficacy and safety of ustekinumab in patients with primary biliary cirrhosis (PBC) who had an inadequate response to ursodeoxycholic acid. The duration of participation in the study for an individual participant may be up to 216 weeks. Patient safety will be monitored. Part 1: ustekinumab, 90mg subcutaneous (SC) at Weeks 0 and 4 and every 8 weeks through Week 20; Part 2: Depending on Part 1 results, either (ustekinumab 90mg or 45mg or placebo) or (ustekinumab 90mg or 180mg or placebo) SC at Weeks 0 and 4 and every 8 weeks through Week 20; Long-term Extension (including Part 1 and Part 2): beginning at Week 28, every 8 weeks with initially assigned dose until the extension dose has been selected; then every 8 weeks through Week 196 with the selected dose.
Interventions
Subcutaneous injections of ustekinumb 90 mg at Weeks 0 and 4 and every 8 weeks until the dose for the Long-Term Extension has been selected then every 8 weeks through Week 196 with the selected dose.
Subcutaneous injections of ustekinumb 45 mg at Weeks 0 and 4 and every 8 weeks until the dose for the Long-Term Extension has been selected then every 8 weeks through Week 196 with the selected dose.
DRUGustekinumab 180 mg
Subcutaneous injections of ustekinumb 180 mg at Weeks 0 and 4 and every 8 weeks until the dose for the Long-Term Extension has been selected then every 8 weeks through Week 196 with the selected dose.
DRUGPlacebo
Subcutaneous injections of placebo at Weeks 0 and 4 and every 8 weeks until the dose for the Long-Term Extension has been selected then every 8 weeks through Week 196 with the selected dose.
Sponsors
Janssen Research & Development, LLC
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 99 Years
Healthy volunteers
No
Inclusion criteria
* Have proven or are likely to have Primary Biliary Cirrhosis (PBC) * Be on a stable dose of ursodeoxycholic acid for at least 6 months prior to Week 0 * Have screening alkaline phosphatase (ALP) level \> 1.67 ULN (the upper limit of normal) * Have screening laboratory test results within protocol-specified limits * Have no history of latent or active tuberculosis (TB) prior to screening and no signs or symptoms suggestive of active TB upon medical history and/or physical examination.
Exclusion criteria
* Has history of gastrointestinal bleeding, secondary to portal hypertension, hepatic encephalopathy, or ascites requiring treatment with diuretics * Has a screening direct bilirubin \> 1.0 mg/dL * Has a previous liver histology with a diagnosis of steatohepatitis or has a high risk of nonalcoholic steatohepatitis * Has a previous liver histology with a diagnosis of chronic autoimmune hepatitis or has a high risk of autoimmune hepatitis overlap syndrome * Testing positive for surface antigen (HBsAg+), regardless of the results of other hepatitis B tests * Have used colchicine, methotrexate (MTX), azathioprine (AZA), or systemic corticosteroids within 3 months prior to the first administration of study drug.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Number of Participants With Alkaline Phosphatase (ALP) Response at Week 12 | Week 12 | The ALP response was defined as a greater than 40 percent (%) decrease from Baseline in ALP concentration at Week 12. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Number of Participants With ALP Response at Week 28 | Week 28 | — |
| Part 1: Number of Participants With ALP Remission at Week 28 | Week 28 | ALP remission is defined as either normalization of ALP (for participants with baseline ALP between 1.67\*and 2.8\* upper limit of normal \[ULN\] or an ALP less than \[˂\]1.67\*ULN \[for participants with baseline ALP greater than {˃} 2.8\* ULN\]). ALP levels above 1.67\* ULN level were associated with an increased rate of disease progression. |
| Part 1: Percent Change From Baseline in ALP Concentration at Week 28 | Baseline and Week 28 | — |
| Part 1: Percent Change From Baseline in Alanine Aminotransferase, Aspartate Aminotransferase, and Bilirubin Concentration at Week 28 | Baseline and Week 28 | — |
Countries
Canada, United States
Participant flow
Recruitment details
The study had 2 parts, Part 1 (proof of concept) and Part 2. As per the study design, the study was considered completed after part 1 and part 2 was not initiated. Results shown below are for Part 1 of the study.
Participants by arm
| Arm | Count |
|---|---|
| Open-label: Ustekinumab 90 mg In proof of concept phase of Part 1, participants received ustekinumab 90 milligram (mg) subcutaneously at Week 0, 4 and thereafter every 8 weeks through Week 20. Eligible participants entered long-term extension which began at Week 28 and continued through Week 216. | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Other | 10 |
| Overall Study | Trial Stopped by Sponsor | 9 |
Baseline characteristics
| Characteristic | Open-label: Ustekinumab 90 mg |
|---|---|
| Age, Continuous | 48.8 years STANDARD_DEVIATION 10.13 |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 18 / 20 |
| serious Total, serious adverse events | 1 / 20 |
Outcome results
Primary
Part 1: Number of Participants With Alkaline Phosphatase (ALP) Response at Week 12
The ALP response was defined as a greater than 40 percent (%) decrease from Baseline in ALP concentration at Week 12.
Time frame: Week 12
Population: Efficacy analysis set included all participants who received at least 1 administration of ustekinumab (full or partial).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Open-label: Ustekinumab 90 mg | Part 1: Number of Participants With Alkaline Phosphatase (ALP) Response at Week 12 | 0 participants |
Secondary
Part 1: Number of Participants With ALP Remission at Week 28
ALP remission is defined as either normalization of ALP (for participants with baseline ALP between 1.67\*and 2.8\* upper limit of normal \[ULN\] or an ALP less than \[˂\]1.67\*ULN \[for participants with baseline ALP greater than {˃} 2.8\* ULN\]). ALP levels above 1.67\* ULN level were associated with an increased rate of disease progression.
Time frame: Week 28
Population: Efficacy analysis set included all participants who received at least 1 administration of ustekinumab (full or partial).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Open-label: Ustekinumab 90 mg | Part 1: Number of Participants With ALP Remission at Week 28 | 0 participants |
Secondary
Part 1: Number of Participants With ALP Response at Week 28
Time frame: Week 28
Population: Efficacy analysis set included all participants who received at least 1 administration of ustekinumab (full or partial).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Open-label: Ustekinumab 90 mg | Part 1: Number of Participants With ALP Response at Week 28 | 0 participants |
Secondary
Part 1: Percent Change From Baseline in Alanine Aminotransferase, Aspartate Aminotransferase, and Bilirubin Concentration at Week 28
Time frame: Baseline and Week 28
Population: Efficacy analysis set included all participants who received at least 1 administration of ustekinumab (full or partial). N (number of participants analyzed) signifies participants who were evalubale for this outcome measure. n signifies participants who were evalubale for each specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open-label: Ustekinumab 90 mg | Part 1: Percent Change From Baseline in Alanine Aminotransferase, Aspartate Aminotransferase, and Bilirubin Concentration at Week 28 | Alanine Aminotransferase (n=18) | -9.21 percent change | Standard Deviation 32.362 |
| Open-label: Ustekinumab 90 mg | Part 1: Percent Change From Baseline in Alanine Aminotransferase, Aspartate Aminotransferase, and Bilirubin Concentration at Week 28 | Aspartate Aminotransferase (n=18) | -7.22 percent change | Standard Deviation 27.188 |
| Open-label: Ustekinumab 90 mg | Part 1: Percent Change From Baseline in Alanine Aminotransferase, Aspartate Aminotransferase, and Bilirubin Concentration at Week 28 | Bilirubin (n=3) | -4.61 percent change | Standard Deviation 14.183 |
Secondary
Part 1: Percent Change From Baseline in ALP Concentration at Week 28
Time frame: Baseline and Week 28
Population: Efficacy analysis set included all participants who received at least 1 administration of ustekinumab (full or partial).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open-label: Ustekinumab 90 mg | Part 1: Percent Change From Baseline in ALP Concentration at Week 28 | -11.25 percent change | Standard Deviation 17.462 |