A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-Finding, Clinical Trial Evaluating the Efficacy and Safety of Obeticholic Acid in Subjects With Primary Sclerosing Cholangitis
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 77
- 试验地点
- 35
- 主要终点
- DB Phase: Change From Baseline In Serum Alkaline Phosphatase (ALP)
研究概览
简要总结
This was a phase 2, double-blind (DB), placebo-controlled trial in participants with primary sclerosing cholangitis to evaluate the effect of obeticholic acid on liver biochemistry, in particular, serum alkaline phosphatase; and, safety. The long-term safety extension (LTSE) phase was conducted to evaluate the safety, tolerability, and efficacy of long-term, open-label use of OCA in participants with PSC who had completed the DB phase of the study.
详细描述
This was a phase 2, randomized, double-blind, placebo-controlled, dose-finding evaluation of the efficacy and safety of OCA in participants with PSC. Approximately 75 participants who provided written informed consent and met all of the inclusion and none of the exclusion criteria were randomized to 1 of 3 treatment groups as follows: 1.5 milligrams (mg) titrating to 3 mg OCA, 5 mg titrating to 10 mg OCA, or placebo, in a 1:1:1 ratio. Participants self-administered investigational product (IP) orally, once daily for 2 consecutive 12-week periods.
For the first 12 weeks, the participant's dose was 1.5 mg OCA, 5 mg OCA, or placebo. After 12 weeks, the participant's dose was titrated as follows, providing there were no limiting safety or tolerability concerns in the opinion of the Investigator, while maintaining the trial blind: the 1.5 mg OCA treatment group titrated to 3 mg, the 5 mg OCA treatment group titrated to 10 mg OCA, and the placebo group remained on placebo. Double-blind treatment continued for a further 12 weeks at that dose.
Any participant whose dose was not titrated, due to safety or tolerability concerns, remained on their starting treatment (1.5 mg OCA, 5 mg OCA, or placebo) for the remainder of the DB phase to Week 24.
Randomization was stratified by the presence or absence of concomitant ursodeoxycholic acid (UDCA) use and total bilirubin level (≤1.5x upper limit of normal [ULN] or >1.5x ULN but <2.5x ULN).
Following completion of the DB phase, participants were asked to reconfirm their consent for participation in the open-label LTSE phase (planned as a further 24 months).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
盲法说明
Following completion of the DB phase, participants were asked to reconfirm their consent for participation in the open-label LTSE phase.
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Must have had a diagnosis of PSC (based on cholangiography at any point in time).
- •Alkaline phosphatase at Screening ≥2x ULN.
- •Total bilirubin at Screening <2.5x ULN.
- •For participants with concomitant inflammatory bowel disease (IBD):
- •Colonoscopy (if participant has a colon) or other appropriate endoscopic procedure within 12 months of Day 0 confirming no dysplasia or colorectal cancer
- •Participants with Crohn's Disease (CD) must have been in remission as defined by a Crohn's Disease Activity Index (CDAI) <150
- •Participants with ulcerative colitis (UC) must either have been in remission or have had mild disease. Remission was defined as a partial Mayo score of ≤2 with no individual sub-score exceeding
- •Mild disease was defined as a partial Mayo score ≤3 with no individual sub-score exceeding 1 point.
- •For participants being administered UDCA as part of their standard of care, the dose must have been stable for ≥3 months prior to, and including, Day 0 and must not have exceeded 20 mg/kilograms/day during this time.
- •Participants being administered biologic treatments (for example, anti-tumor necrosis factor or anti-integrin monoclonal antibodies), immunosuppressants, systemic corticosteroids, or statins, must have been on a stable dose for ≥3 months prior to, and including, Day 0 and should plan to remain on a stable dose throughout the trial.
- •Contraception: female participants of childbearing potential must have used ≥1 effective method (≤1% failure rate) of contraception during the trial and until 4 weeks following the last dose of IP (including LTSE doses).
排除标准
- •Evidence of a secondary cause of sclerosing cholangitis at Screening.
- •Immunoglobulin G4 (IgG4) >4x ULN at Screening or evidence of IgG4 sclerosing cholangitis.
- •Small duct cholangitis in the absence of large duct disease.
- •Presence of clinical complications of chronic liver disease or clinically significant hepatic decompensation, including:
- •Current Child Pugh classification B or C
- •History of, or current diagnosis or suspicion of, cholangiocarcinoma or other hepatobiliary malignancy, or biliary tract dysplasia.
- •History of liver transplantation, or current model of end stage liver disease score ≥12
- •History of, or current, cirrhosis with complications, including history or presence of spontaneous bacterial peritonitis hepatocellular carcinoma or hepatic encephalopathy (as assessed by the Investigator)
- •Current known 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).
- •History of, or current, hepatorenal syndrome (type I or II) or Screening serum creatinine >2 mg/deciliter (178 micromoles/liter [L]).
- •Platelet count <50 x 10^9/L.
- •Current clinical evidence of dominant strictures that were considered clinically relevant in the opinion of the Investigator or current biliary stent at Screening.
- •Current cholecystitis or evidence of current biliary obstruction due to gallstones. Asymptomatic gallstones that were not considered a safety risk in the opinion of the Investigator might have been acceptable, subject to discussion and agreement with the Medical Monitor.
- •Colonic dysplasia within ≤5 years prior to Day
- •History of small bowel resection.
- •History of other chronic liver diseases, including, but not limited to, primary biliary cholangitis (PBC), alcoholic liver disease, non-alcoholic fatty liver disease, autoimmune hepatitis, hepatitis B virus (unless seroconverted and no positive Hepatitis B Virus deoxyribonucleic acid), hepatitis C virus and overlap syndrome.
- •Known Gilbert's syndrome or history of elevations in unconjugated (indirect) bilirubin >ULN or unconjugated (indirect) bilirubin >ULN at Screening.
- •Known history of human immunodeficiency virus infection.
- •Currently experiencing, or experienced within ≤3 months of Screening, pruritus requiring systemic or enteral treatment.
- •Known or suspected acute cholangitis in the 3 months prior to, and including, Day 0 including cholangitis treated with antibiotics.
- •Administration of antibiotics is prohibited ≤1 month of Day 0 (unless participant was on a stable prophylaxis dose for at least 3 months prior to Day 0).
- •Administration of the following medications was prohibited ≤6 months of Day 0 and throughout the trial: fenofibrate or other fibrates and potentially hepatotoxic medications (including alpha-methyl-dopa, sodium valproic acid, isoniazide, or nitrofurantoin).
- •IBD flare during Screening (up to and including Day 0), where "flare" was defined as follows:
- •UC flare: partial Mayo Score ≥5, and
- •CD flare: CDAI ≥250
- •Evidence of deleterious effects of alcohol abuse (as assessed by the Investigator) or excessive alcohol consumption (>4 units/day for males, >2 units/day for females).
- •Known or suspected use of illicit drugs or drugs of abuse (allowed if medically prescribed or indicated) within 3 months of Day
- •If female: known pregnancy, or had a positive urine pregnancy test (confirmed by a positive serum pregnancy test), or lactating.
- •Other concomitant disease, malignancy, or condition likely to significantly decrease life expectancy to less than the duration of the trial (for example, moderate to severe congestive heart failure).
- •Participation in another investigational drug, biologic, or medical device trial within 30 days prior to Screening.
- •History of noncompliance with medical regimens, or participants who were considered to be potentially unreliable.
- •Blood or plasma donation within 30 days prior to Day
- •Mental instability or incompetence such that the validity of informed consent or compliance with the trial was uncertain.
研究组 & 干预措施
1.5 mg OCA titrating to 3 mg OCA
Participants randomized to 1.5 mg OCA took 1.5 mg OCA daily for 12 weeks during the DB phase. If tolerated, the dose was increased to 3 mg OCA daily for an additional 12 weeks.
干预措施: Obeticholic Acid (OCA) (Drug)
5 mg OCA titrating to 10 mg OCA
Participants randomized to 5 mg OCA took 5 mg OCA daily for 12 weeks during the DB phase. If tolerated, the dose was increased to 10 mg OCA daily for an additional 12 weeks.
干预措施: Obeticholic Acid (OCA) (Drug)
Placebo
Participants randomized to placebo took placebo for 24 weeks during the DB phase.
干预措施: Placebo (Drug)
LTSE OCA Total
Following completion of the DB phase, participants were asked to reconfirm their consent for participation in the LTSE phase (planned as a further 24 months) beginning at 5 or 10 mg OCA, based on the last treatment received during the DB phase. Doses up to 10 mg daily were evaluated. All participants received open-label OCA during the LTSE phase of the study.
干预措施: Obeticholic Acid (OCA) (Drug)
结局指标
主要结局
DB Phase: Change From Baseline In Serum Alkaline Phosphatase (ALP)
时间窗: Baseline, Week 24
The primary efficacy analysis compared the Week 24 change from Baseline in ALP between OCA treatment group and placebo using an analysis of covariance (ANCOVA) model with fixed effects for treatment group and randomization strata, and Baseline as a covariate. Results are reported in U/L.
LTSE Phase: Incidence Of Adverse Events Of Special Interest (AESIs)
时间窗: LTSE Baseline (DB Week 24) to Month 26
The primary safety analysis evaluated the effects of OCA treatment on AESIs of pruritus, hepatic disorders, and dyslipidemia. All adverse event (AE) summaries were restricted to treatment emergent AEs (TEAEs), which were defined as any AEs that newly appeared, increased in frequency, or worsened in severity following initiation of investigational product. Treatment-emergent pruritus was defined as any preferred term (PT) including "Prur-". Hepatic disorder AESIs were defined using specific Hepatic Disorders Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ) terms. AE lipid profile changes, defined in the Dyslipidemia SMQ, were reported. Verbatim terms were mapped to PTs and system organ classes (SOCs) using MedDRA version 17.1 for all AE summaries except those for hepatic disorder AESIs, which used MedDRA version 18.1. A summary of serious and all other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module.
次要结局
- DB Phase: Change From Baseline In Serum Aspartate Aminotransferase (AST)(Baseline, Week 24)
- LTSE Phase: Change From Baseline In Serum Direct Bilirubin At Month 12(LTSE Baseline (DB Week 24), Month 12)
- LTSE Phase: Change From Baseline In Serum GGT At Month 12(LTSE Baseline (DB Week 24), Month 12)
- LTSE Phase: Change From Baseline In Enhanced Liver Fibrosis (ELF) At Month 12(LTSE Baseline (DB Week 24), Month 12)
- LTSE Phase: Participants Experiencing Crohn's Disease Remission At Month 12(Month 12)
- LTSE Phase: Change From Baseline In INR At Month 12(LTSE Baseline (DB Week 24), Month 12)
- DB Phase: Change From Baseline In Serum Alanine Transaminase (ALT)(Baseline, Week 24)
- LTSE Phase: Change From Baseline In Albumin At Month 12(LTSE Baseline (DB Week 24), Month 12)
- LTSE Phase: Change From Baseline In Transient Elastography (TE) At Month 12(LTSE Baseline (DB Week 24), Month 12)
- DB Phase: Change From Baseline In Serum Total Bilirubin(Baseline, Week 24)
- DB Phase: Change From Baseline In Serum Direct Bilirubin(Baseline, Week 24)
- DB Phase: Change From Baseline In Serum Gamma-glutamyl Transferase (GGT)(Baseline, Week 24)
- DB Phase: Change From Baseline In Plasma Fibroblast Growth Factor-19 (FGF-19)(Baseline, Week 24)
- DB Phase: Change From Baseline In Plasma 7α-Hydroxy-4-cholesten-3-one (C4)(Baseline, Week 24)
- LTSE Phase: Change From Baseline In Serum ALP At Month 12(LTSE Baseline (DB Week 24), Month 12)
- LTSE Phase: Change From Baseline In Serum ALT At Month 12(LTSE Baseline (DB Week 24), Month 12)
- LTSE Phase: Change From Baseline In Serum AST At Month 12(LTSE Baseline (DB Week 24), Month 12)
- LTSE Phase: Change From Baseline In Serum Total Bilirubin At Month 12(LTSE Baseline (DB Week 24), Month 12)
- LTSE Phase: Change From Baseline In Plasma FGF-19 At Month 12(LTSE Baseline (DB Week 24), Month 12)
- LTSE Phase: Change From Baseline In Pruritus Visual Analogue Scale (VAS) At Month 12(LTSE Baseline (DB Week 24), Month 12)
- LTSE Phase: Participants Experiencing Ulcerative Colitis Remission At Month 12(Month 12)
- LTSE Phase: Change From Baseline In Plasma C4 At Month 12(LTSE Baseline (DB Week 24), Month 12)
- LTSE Phase: Change From Baseline In Total Bile Acids At Month 12(Month 12)