A Double-blind, Randomized Phase 3 Trial Evaluating the Efficacy and Safety of Obecholic Acid Versus Placebo, in Combination with Ursodeoxycholic Acid in Primary Biliary Cirrhosis Patients with an Inadequate Response to Ursodeoxycholic Acid
Overview
- Phase
- Phase 3
- Intervention
- OCA
- Conditions
- PBC
- Sponsor
- Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd.
- Enrollment
- 100
- Locations
- 1
- Primary Endpoint
- Composite Endpoint Alkaline Phosphatase (ALP) And Total Bilirubin
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
This is a Phase III, randomized, double-blind, multicentre study assessing the efficacy and safety of obecholic acid and Ursodeoxycholic Acid(UDCA) compared with placebo and UDCA in treating of primary biliary cirrhosis (PBC) in adults with an inadequate response to UDCA.
Detailed Description
The main objectives of the study were to assess the effects of Obeticholic Acid (OCA) on serum alkaline phosphatase (ALP) and total bilirubin, together as a composite endpoint and on safety in participants with PBC. The study included 2 phases: a 6-month randomized, double-blind (DB), placebo-controlled, parallel-group phase, followed by a 6-month DB treatment phase. In the 6-month randomized, DB placebo-controlled phase, patients will receive OCA/placebo with a dosage of 5 mg once daily for the first 3 months. After the first 3 months, for patients who have not achieved an adequate reduction in ALP and/or total bilirubin and who are tolerating OCALIVA/placebo, increase to a maximum dosage of 10 mg once daily. Participants in the 6-month DB treatment phase were eligible to receive the treatment of OCA, especially those who received placebo, for patients who have not achieved an adequate reduction in ALP and/or total bilirubin, will receive OCA with a dosage of 5 mg once daily for the first 3 months. After the first 3 months, for patients who have not achieved an adequate reduction in ALP and/or total bilirubin and who are tolerating OCALIVA, increase to a maximum dosage of 10 mg once daily.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Definite PBC diagnosis, as demonstrated by the presence of ≥ 2 of the following 3 diagnostic factors: ① Indicators reflecting cholestasis such as elevated ALP；② Positive antimitochondrial antibody (AMA) or AMA-M2, or positive PBC-specific antibody (anti-GP210 and/or anti-SP100) if AMA negative；③ Liver biopsy consistent with PBC;
- •At least 1 of the following qualifying biochemistry values: ① ALP ≥ 1.67x ULN；② Total bilirubin \> ULN but \< 2x ULN；
- •Taking UDCA for at least 6 months (stable dose for ≥ 2 months) prior to the first dose；
- •Patients of childbearing potential must agree to take contraception during the study and for 1 month after the last day of treatment;
- •Patients capable of giving written informed consent.
Exclusion Criteria
- •History or presence of other concomitant liver diseases including:
- •Hepatitis C virus (HCV) infection; participants with active hepatitis B (HBV) infection will be excluded, however, participants who have seroconverted (hepatitis B surface antigen \[Hbs Ag\] and hepatitis B e antigen \[Hbe Ag\] negative) may be included after consultation with the medical monitor.
- •Primary sclerosing cholangitis (PSC) Alcoholic liver disease Definite autoimmune liver disease or overlap hepatitis Nonalcoholic steatohepatitis (NASH) Gilbert's Syndrome (due to interpretability of bilirubin levels)Child-pugh grade B or C
- •Presence of clinical complications of PBC or clinically significant hepatic decompensation, including:
- •History of liver transplantation, current placement on a liver transplant list or current Model for End Stage Liver Disease (MELD) score ≥ 15 Portal hypertension with complications, including: known gastric or large esophageal varices, poorly controlled or diuretic resistant ascites, history of variceal bleeds or related therapeutic or prophylactic interventions (for example, beta blockers, insertion of variceal bands or transjugular intrahepatic portosystemic shunt \[TIPS\]), or hepatic encephalopathy Cirrhosis with complications, including history or presence of: spontaneous bacterial peritonitis, hepatocellular carcinoma, bilirubin \> 2x ULN Hepatorenal syndrome (type I or II) or Screening serum creatinine \> 2 mg/deciliter dL) (178 micromoles \[µmol\])/liter \[L\])
- •Participants with severe pruritus or those requiring systemic treatment for pruritus (for example, with bile acid sequestrants \[BAS\] or rifampicin) within 2 months prior to the first dose
- •Patients who took obeticholic acid within 3 months prior to the first dose
- •Administration of the following drugs within 1 month prior to the first dose: azathioprine, colchicine, cyclosporine, methotrexate, mycophenolate mofetil, pentoxifylline, bicyclol and with S.chinensis ingredients; fenofibrate or other fibrates; budesonide and other systemic corticosteroids; hepatotoxic drugs (including α-methyldopa, sodium valproate, isoniazid, nitrofurantoin, etc.);
- •Administration of the following drugs within 2 months prior to the first dose: antibodies or immunotherapy against interleukins or other cytokines or chemokines.
- •ALT≥ 10 × ULN with/or ALT≥ 10 × ULN;
Arms & Interventions
OCA and UDCA
OCA 5 mg once daily for 3 months and then titrating up to 10 mg based on tolerability and response. Subjects receiving UDCA continued taking UDCA throughout the trial. If the subjects could not tolerate UDCA, they were not treated with UDCA.
Intervention: OCA
OCA and UDCA
OCA 5 mg once daily for 3 months and then titrating up to 10 mg based on tolerability and response. Subjects receiving UDCA continued taking UDCA throughout the trial. If the subjects could not tolerate UDCA, they were not treated with UDCA.
Intervention: UDCA
Placebo and UDCA
Placebo once daily. Subjects receiving UDCA continued taking UDCA throughout the trial.
Intervention: UDCA
Placebo and UDCA
Placebo once daily. Subjects receiving UDCA continued taking UDCA throughout the trial.
Intervention: Placebo
Outcomes
Primary Outcomes
Composite Endpoint Alkaline Phosphatase (ALP) And Total Bilirubin
Time Frame: up to 6 months
Composite Endpoint : Percentage of participants at Month 12 with ALP \< 1.67 x upper limit of normal (ULN) and total bilirubin ≤ ULN and ALP decrease of ≥ 15% from baseline.
Secondary Outcomes
- Percentage of PBC patients reaching the composite endpoint after 12 weeks, 36 weeks and 48 weeks of treatment(up to 12 months)
- Absolute change and percentage change of ALP from baseline to Month 3, 6, 9 and 12(up to 12 months)
- Absolute change and percentage change of total bilirubin from baseline to Month 3, 6, 9 and 12(up to 12 months)
- Absolute change and percentage change of direct bilirubin from baseline to Month 3, 6, 9 and 12(up to 12 months)
- Absolute change and percentage change of alanine transaminase(ALT) from baseline to Month 3, 6, 9 and 12(up to 12 months)
- Absolute change and percentage change of alkaline phosphatase(AST) from baseline to Month 3, 6, 9 and 12(up to 12 months)
- Absolute change and percentage change of gamma glutamyl transpeptidase(GGT) from baseline to Month 3, 6, 9 and 12(up to 12 months)
- Incidence of Treatment-Emergent Adverse Events(up to 12 months)