NCT04521114已完成2 期
A Phase II, Multi-center, Two-Part, Three-Arm, Dose-Ranging Study of the Safety and Efficacy of Leronlimab (PRO 140) in Adult Patients With Nonalcoholic Steatohepatitis (NASH)
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 87
- 试验地点
- 7
- 主要终点
- MRI-PDFF Change From Baseline to Week 14
研究概览
简要总结
This is a phase II study of of Leronlimab (PRO 140)-Humanized monoclonal antibody to CCR5 in patients with Nonalcoholic Steatohepatitis (NASH).
详细描述
This is an exploratory phase II, multi-center, two-part study (Part 1: randomized, placebo-controlled, two-arm with 60 patients; Part 2: non-randomized, single-arm, open-label with 30 patients) designed to evaluate the safety and efficacy of leronlimab after subcutaneous (SC) administration in patients with NASH for 13 weeks.
A Follow Up visit was conducted 28 (± 3) days after receiving the last study treatment (i.e., after last dose of Leronlimab (PRO 140) or placebo.
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
- •Subjects are required to meet ALL of the following criteria for enrollment into the study:
- •Subject is a male or female between 18 to 75 years of age inclusive.
- •Evidence of nonalcoholic steatohepatitis (NASH) based on one of the following criteria:
- •Criteria 1: Histologically-confirmed diagnosis of NASH on a liver biopsy, or
- •Criteria 2: FibroScan or Shearwave US during screening (or within 6 months before screening) shows kPa ≥7 but <14 and CAP ≥
- •Subject shows presence of hepatic fat fraction as defined by ≥ 8% on MRI-PDFF and cT1 ≥ 800 ms at Screening.
- •Has had a stable body weight (±5%) within 6 months prior to Screening.
- •Body Mass Index (BMI) ≥ 28 kg/m2 at Screening
- •Has clinically normal resting 12-lead ECG at Screening Visit or, if abnormal, considered not clinically significant by the Principal Investigator.
- •Laboratory Screening results as indicated below:
- •AST:ALT Ratio ≤ 1, if AST or ALT value is > ULN
- •Screening Liver enzymes (AST, ALT, and ALK PHOS) < 5 x ULN.
- •Total Bilirubin ≤ 1.3 mg/dL (except if Gilbert's Disease)
- •Platelet count ≥ 150,000/mm3
- •International normalized ratio (INR) < 1.3
- •Estimated Glomerular Filtration Rate (eGFR) ≥ 60/mL/min
- •Glycosylated hemoglobin (HbA1c) < 9%.
- •Thyroid-Stimulating Hormone (TSH) within normal reference range. Note: Any subject with a non-clinically significant TSH value outside of the normal range may be enrolled if their T3 and free T4 values are within the normal range.
- •Subjects with pre-diabetes or type 2 diabetes will be allowed to participate if the following criteria is met:
- •Subjects who are taking anti-diabetic medications should be on a stable dose for a period of at least 3 months prior to Screening and do not anticipate clinically significant dose adjustments during the course of study.
- •Subjects must be on a stable diet/lifestyle regimen for at least 3 months prior to screening and do not anticipate a clinically significant change during the course of study.
- •Subjects who are taking Vitamin E should be on a stable dose of Vitamin E (if ≥ 400 IU) for a period of at least 4 weeks prior to Screening and do not anticipate dose adjustments for the duration of the study.
- •Both male and female patients and their partners of childbearing potential must agree to use two medically accepted methods of contraception (e.g., barrier contraceptives [male condom, female condom, or diaphragm with a spermicidal gel], hormonal contraceptives [implants, injectables, combination oral contraceptives, transdermal patches, or contraceptive rings], or one of the following methods of birth control (intrauterine devices, tubal sterilization or vasectomy) or must practice complete abstinence from intercourse of reproductive potential from study entry to 6 months after the last day of treatment (excluding women who are not of childbearing potential and men who have been sterilized).
- •Females of child-bearing potential must have a negative serum pregnancy test at Screening Visit and negative urine pregnancy test prior to receiving the first dose of study drug; and Male participants must agree to use contraception and refrain from donating sperm for at least 90 days after the last dose of study intervention.
- •Subject is willing and able to give informed consent prior to any study specific procedures being performed.
- •Subject is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures and study restrictions
排除标准
- •Subjects meeting ANY of the following criteria will be excluded from enrollment:
- •Any concurrent clinically significant liver disease with an etiology other than NASH including autoimmune hepatitis, alcoholic hepatitis, hypoxic/ischemic hepatopathy, and biliary tract disease.
- •History of alcohol consumption greater than 21/units/week (for males) and 14/units/week (for females) within the last 2 years prior to screening.
- •Note: Use of online unit calculator for alcohol consumption is recommended (e.g., https://alcoholchange.org.uk/alcohol-facts/interactive-tools/unit-calculator)
- •Any drug-induced steatohepatitis secondary to amiodarone, corticosteroids, estrogens, methotrexate, tetracycline, or other medications known to cause hepatic steatosis.
- •Undergone major surgery, including liver surgery, within 6 months prior to screening deemed clinically significant by the investigator.
- •Prior or pending liver transplantation.
- •History or presence of cirrhosis or stage 4 fibrosis in historical liver biopsy and/or hepatic decompensation including ascites, hepatic encephalopathy or variceal bleeding.
- •Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test), hepatitis C (defined as having a positive Anti-HCV test with detectable reflex HCV RNA; Note: Subject with positive Anti-HCV test and with undetectable HCV RNA would not be excluded), acute hepatitis A (defined as subjects with serum positive for hepatitis A IgM (HAV) antibody) or acute hepatitis E (defined as having anti-HEV IgM antibody).
- •Any active infection requiring systemic therapy at the time of screening, which is considered clinically significant per the Investigator.
- •Positive test for human immunodeficiency virus (HIV) or HIV infection.
- •History of bleeding diathesis within 6 months of screening.
- •Any malignancy within the past 5 years, excluding successfully treated basal cell carcinoma or squamous cell carcinoma without evidence of metastases.
- •Seizure disorder requiring ongoing antiseizure therapy or with any condition that, in the judgment of the investigator, is likely to increase the risk of seizure (e.g. CNS malignancy)
- •Clinically significant active cardiac disease which would interfere with study conduct or study results interpretation per the PI.
- •Any known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- •Prior therapy with Leronlimab or any other CCR5 antagonist (e.g. maraviroc) within 6 months prior to screening.
- •History of severe allergic, anaphylactic, or other hypersensitivity reactions to humanized monoclonal antibodies.
- •Any condition requiring continuous systemic treatment with immunosuppressive (such as corticosteroids) or immunomodulatory medications.
- •Note: Inhaled or topical steroids of up to 5 mg daily prednisone equivalent dose are permitted in the bsence of active autoimmune disease.
- •History of administration of a live, attenuated vaccine within four weeks prior to start of PRO 140 treatment or anticipation that such a live attenuated vaccine will be required during the remainder of the study.
- •Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed. However intranasal influenza vaccines (e.g., Flu-Mist ®) are live attenuated vaccines, and are not allowed.
- •Currently participating in an investigational study or received an investigational drug within 28 days or 5 half-lives (whichever is longer) prior to study drug administration
研究组 & 干预措施
Leronlimab 700 mg
Experimental
Leronlimab 700 mg SC weekly injection
干预措施: leronlimab 700 mg (Drug)
Leronlimab 350 mg
Experimental
Leronlimab 350 mg SC weekly injection
干预措施: leronlimab 350 mg (Drug)
Placebo
Placebo Comparator
Placebo SC weekly injection
干预措施: Placebo (Drug)
结局指标
主要结局
MRI-PDFF Change From Baseline to Week 14
时间窗: Change from baseline (day one, first day of treatment) to EOT (day 92, 13 weeks of treatment)
Change in hepatic fat fraction from baseline assessed by magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) at week 14
次要结局
- Alkaline Phosphatase(Measured at baseline (day 1) and at EOT (day 92))
- Alanine Aminotraferase (ALT)(Measured at baseline (day 1) and at day 92)
- CCL5 (Rantes)(Measured at baseline (day 1) and at EOT (day 92))
- CCL18(Measured at baseline (day 1) and at EOT (day 92))
- Interleukin-1 Beta(Measured at baseline (day 1) and at EOT (day 92))
- IL-1RA(Measured at baseline (day 1) and at EOT (day 92))
- CCL3(Measured at baseline (day 1, start of treatment) and at EOT (day 92))
- Fibro Test Score(Measured at baseline (day 1, start of treatment) and at EOT (day 92))
- CCL11( Eotaxin-1)(Measured at baseline (day 1, start of treatment) and at EOT (day 92))
- IL-6(Measured at baseline (day 1) and at EOT (day 92))
- IL-8(Measured at baseline (day 1) and at EOT (day 92))
- TIMP-1(Measured at baseline (day 1) and at EOT (day 92))
- En Rage(Measured at baseline (day 1) and at EOT (day 92))
- MRI-cT1 Change From Baseline to Week 14(Measured at baseline (day 1) and at EOT (day 92))
- GGT S(Measured at baseline (day 1) and at EOT (day 92))
- CCL2(Measured at baseline (day 1) and at EOT (day 92))
- TNF Receptor 2(Measured at baseline (day 1, start of treatment) and at EOT (day 92))
- Aspartate Aminotransferase (AST)(Measured at baseline (day 1) and at EOT (day 92))
- Neutrophils/Leukocytes(Measured at baseline (day 1, start of treatment) and at EOT (day 92))
- VCAM(Measured at baseline (day 1) and at EOT (day 92))
研究者
研究点 (7)
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