RESPONSE: A Placebo-controlled, Randomized, Phase 3 Study to Evaluate the Efficacy and Safety of Seladelpar in Patients With Primary Biliary Cholangitis (PBC) and an Inadequate Response to or an Intolerance to Ursodeoxycholic Acid (UDCA)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 193
- 试验地点
- 134
- 主要终点
- Percentage of Participants With Response Criteria for the Composite Endpoint of ALP <1.67 × Upper Limit of Normal (ULN), ≥15% Reduction in ALP, and Total Bilirubin ≤ 1.0× ULN at Month 12
研究概览
简要总结
The purposes of this study are to evaluate the treatment effect of seladelpar on composite biochemical improvement in cholestasis markers based on ALP and total bilirubin and to evaluate the safety of seladelpar over 12 months of treatment compared to placebo.
The study also checked the effect of treatment on the symptoms of PBC, including pruritus.
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
- Double (Participant, Investigator)
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 given written informed consent (signed and dated) and any authorizations required by local law.
- •Male or female with a definitive diagnosis of primary biliary cholangitis (PBC).
- •Ursodeoxycholic acid (UDCA) for the past 12 months (stable dose for >3 months prior to screening) or intolerant to UDCA (last dose of UDCA >3 months prior to screening).
- •Laboratory parameters measured by the Central Laboratory at screening:
- •Alkaline phosphatase (ALP) ≥1.67× ULN (upper limit of normal)
- •Aspartate aminotransferase (AST) ≤3× ULN
- •Alanine aminotransferase (ALT) ≤3× ULN
- •Total bilirubin ≤2× ULN
- •Estimated glomerular filtration rate (eGFR) >45 mL/min/1.73 m^2 (calculated by the Modification of Diet in Renal Disease study equation).
- •International normalized ratio (INR) below 1.1× ULN (For individuals on anticoagulation therapy, INR must be maintained in the range required for prophylaxis for their specific disease).
- •Platelet count ≥100 ×10^3/µL.
- •Females of reproductive potential must use at least 1 barrier contraceptive and a second effective birth control method during the study and for at least 90 days after the last dose. Male individuals who are sexually active with female partners of reproductive potential must use barrier contraception, and their female partners must use a second effective birth control method during the study and for at least 90 days after the last dose.
排除标准
- •Previous exposure to seladelpar (MBX-8025).
- •A medical condition other than PBC that, in the investigator's opinion, would preclude full participation in the study (e.g., cancer) or confound its results (e.g., Paget's disease, any active infection).
- •Advanced PBC as defined by the Rotterdam criteria (albumin below the lower limit of normal and total bilirubin above 1.0 × ULN).
- •Presence of clinically important hepatic decompensation, including the following:
- •History of liver transplantation, current placement on liver transplantation list, or current Model for End-Stage Liver Disease (MELD) score ≥
- •For individuals on anticoagulation medication, evaluation of the baseline INR, in concert with their current dose adjustments of their anticoagulant medication, will be taken into account when calculating the MELD score. This will be done in consultation with the medical monitor.
- •Complications of portal hypertension, including known esophageal varices, history of variceal bleeds or related interventions (e.g., transjugular intrahepatic portosystemic shunt placement), ascites, and hepatic encephalopathy.
- •Cirrhosis with complications, including history or presence of spontaneous bacterial peritonitis, hepatocellular carcinoma, or hepatorenal syndrome.
- •Other chronic liver diseases:
- •Current features of autoimmune hepatitis (AIH) as determined by the investigator based on immunoserology, liver biochemistry, or historic confirmed liver histology.
- •PSC determined by the presence of diagnostic cholangiographic findings.
- •History or clinical evidence of alcoholic liver disease.
- •History or clinical evidence of alpha-1-antitrypsin deficiency.
- •History of biopsy confirmed nonalcoholic steatohepatitis (NASH).
- •History or evidence of Gilbert's syndrome with elevated total bilirubin.
- •History or evidence of hemochromatosis.
- •Hepatitis B, defined as the presence of hepatitis B surface antigen.
- •Hepatitis C, defined as the presence of hepatitis C virus ribonucleic acid.
- •History, evidence, or high suspicion of hepatobiliary malignancy based on imaging, screening laboratory values, and/or clinical symptoms.
- •Known history of human immunodeficiency virus (HIV) or positive antibody test at screening
- •Clinically important alcohol consumption, defined as more than 2 drink units per day (equivalent to 20 g) in women and 3 drink units per day (equivalent to 30 g) in men, or inability to quantify alcohol intake reliably.
- •History of malignancy diagnosed or treated, actively or within 2 years, or ongoing evaluation for malignancy; localized treatment of squamous or noninvasive basal cell skin cancers and cervical carcinoma in situ is allowed if appropriately treated prior to screening.
- •Treatment with obeticholic acid (OCA) or fibrates (e.g., bezafibrate, fenofibrate, elafibranor, lanifibranor, pemafibrate, saroglitizar) 6 weeks prior to screening.
- •Treatment with colchicine, methotrexate, azathioprine, or long-term systemic corticosteroids (>2 weeks) during 2 months prior to screening
- •Treatment with anti-pruritic drugs (e.g., cholestyramine, naltrexone, rifampicin, sertraline, or any experimental approach) must be on a stable dose within 1 month prior to screening
- •Treatment with any other investigational therapy or device within 30 days or within 5 half-lives, whichever is longer, prior to screening
- •For females, pregnancy or breastfeeding.
- •Any other condition(s) that would compromise the safety of the individual or compromise the quality of the clinical study, as judged by the investigator.
- •Immunosuppressant therapies.
- •Other medications that effect liver or gastrointestinal (GI) functions, such as absorption of medications or the roux-en-y gastric bypass procedure, may be prohibited and should be discussed with the medical monitor on a case-by-case basis.
- •Active Coronavirus Disease-2019 (COVID-19) infection during Screening.
- •Note: Other protocol defined Inclusion/Exclusion criteria may apply.
研究组 & 干预措施
Placebo
Participants will receive placebo to match seladelpar, orally, once daily, for a duration of up to 12 months.
干预措施: Placebo (Drug)
Seladelpar
Participants will receive seladelpar 10 mg (or 5 mg down-titrated, for those participants who met specific safety monitoring criteria or had tolerability issues), orally, once daily, for a duration of up to 12 months.
干预措施: Seladelpar 10 mg (Drug)
Seladelpar
Participants will receive seladelpar 10 mg (or 5 mg down-titrated, for those participants who met specific safety monitoring criteria or had tolerability issues), orally, once daily, for a duration of up to 12 months.
干预措施: Seladelpar 5 mg (Drug)
结局指标
主要结局
Percentage of Participants With Response Criteria for the Composite Endpoint of ALP <1.67 × Upper Limit of Normal (ULN), ≥15% Reduction in ALP, and Total Bilirubin ≤ 1.0× ULN at Month 12
时间窗: Month 12
Percentages were rounded-off.
Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs
时间窗: First dose date up to last dose plus 30 days (up to 13.4 months)
Percentages were rounded-off.
Percentage of Participants With Shift of ≥ 2 CTCAE Grades From Baseline in Treatment-emergent Laboratory Abnormalities Related to Hematology and Select Liver Biochemistry
时间窗: First dose date up to last dose (up to 13.4 months)
Treatment-emergent graded laboratory abnormalities were defined as values that increase at least 2 toxicity grade from baseline at any time post baseline. The laboratory abnormalities were graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), where Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 4: potentially life-threatening laboratory abnormality. The data is reported for shift of ≥ 2 grades from baseline in values for hematology and select liver biochemistry. Hematology includes parameters like RBCs, (erythrocytes), hemoglobin, hematocrit, platelets, WBC, WBC differentials (absolute and percentage) including basophils, neutrophils, lymphocytes, eosinophils, and monocytes, etc. Biochemistry included select liver function tests like blood bilirubin, gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase. Percentages were rounded-off.
次要结局
- Percentage of Participants With ALP ≤1.0× ULN at Month 12(Month 12)
- Change From Baseline in Weekly Averaged Pruritus Numerical Rating Scale (NRS) in Participants With NRS ≥ 4 at Month 6(Baseline, Month 6)