A Study of Efficacy and Safety of Ustekinumab in Patients With Primary Biliary Cirrhosis (PBC) Who Had an Inadequate Response to Ursodeoxycholic Acid

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 2, Multi-center, Randomized, Double-blind, Placebo-controlled, Parallel-group Study Evaluating the Efficacy and Safety of Ustekinumab in Subjects With Primary Biliary Cirrhosis Who Had an Inadequate Response to Ursodeoxycholic Acid (UDCA)

Conditions
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Primary Biliary Cirrhosis

Intervention / Treatment
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* Drug: ustekinumab 90 mg
* Drug: ustekinumab 45 mg
* Drug: ustekinumab 180 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open-label: ustekinumab 90 mg<br> | Drug: ustekinumab 90 mg<br>* 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.<br>|
| Experimental: Double-blind: ustekinumab 45 mg<br> | Drug: ustekinumab 45 mg<br>* 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.<br>|
| Experimental: Double-blind: ustekinumab 90 mg<br> | Drug: ustekinumab 90 mg<br>* 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.<br>|
| Experimental: Double-blind: ustekinumb 180 mg<br> | Drug: ustekinumab 180 mg<br>* 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.<br>|
| Placebo Comparator: Double-blind: placebo<br> | Drug: Placebo<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of Participants With ALP Response at Week 28 |  | Week 28 | 
| 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. | Week 28 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diseases [C] - Digestive System Diseases [C06], primary biliary cirrhosis, ursodeoxycholic acid (UDCA), STELARA, ustekinumab