NCT02330549已完成2 期
ORION - Effect of CCR2 and CCR5 Antagonism by Cenicriviroc on Peripheral and Adipose Tissue Insulin Sensitivity in Adult Obese Subjects With Prediabetes or Type 2 Diabetes Mellitus and Suspected Non-Alcoholic Fatty Liver Disease (NAFLD)
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
- 45
- 试验地点
- 3
- 主要终点
- Change From Baseline in Adipose Tissue Insulin Resistance (Adipo-IR ) Index
研究概览
简要总结
A Phase 2a, randomized, double-blind, placebo-controlled, multi-center study of cenicriviroc (CVC) to be conducted in approximately 50 adult obese subjects [body mass index (BMI) ≥ 30 kg/m^2] with prediabetes or type 2 diabetes mellitus and suspected NALFD.
详细描述
Approximately 50 adult obese subjects (BMI ≥ 30 kg/m2) with prediabetes or type 2 diabetes mellitus and suspected NALFD will be randomized into the study.
Eligible subjects will receive either CVC (n=25) or matching placebo (n=25), once daily (QD) for 24 weeks, followed by a safety follow-up visit 4 weeks after last intake of study medication.
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, Investigator, Outcomes Assessor)
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
- •Adult male and female subjects aged between 18-75 years
- •Obesity as defined by BMI ≥ 30 kg/m2
- •Evidence of prediabetes or type 2 diabetes mellitus based on Screening laboratory values with at least one of the following criteria:
- •Fasting plasma glucose (FPG) of 100 - 270 mg/dL (5.6 - 15.0 mmol/L)
- •Hemoglobin A1c (HbA1c) of 5.7 - 10.0%
- •Participants receiving metformin alone or in combination with a sulfonylurea (glimepiride, glipizide, glyburide, or gliclazide) must be on stable therapy for at least 90 days prior to Screening.
- •Suspected diagnosis of NAFLD warranting confirmation by liver biopsy
- •Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 upper limit normal (ULN)
- •Ability to understand and sign a written informed consent form
- •Females of child-bearing potential and males participating in the study must agree to use at least 2 approved barrier methods of contraception throughout the duration of the study and for 3 months after stopping study drug. Females who are postmenopausal must have documentation of cessation of menses for ≥ 12 months and serum follicle stimulating hormone (FSH) ≥ 30 mU/mL
- •Participants receiving allowed concomitant medications need to be on stable therapy for 28 days prior to Baseline.
排除标准
- •Use of oral antihyperglycemic agents (OHAs) other than metformin or sulfonylureas, including but not limited to thiazolidinediones, DPP-4 inhibitors, SGLT2 inhibitors, GLP-1 receptor agonists, meglitinides, α-glucosidase inhibitors, colesevelam, bromocriptine, pramlintide or basal insulin within 90 days prior to Screening or anticipated use during the trial
- •Type 1 diabetes
- •Hepatitis B Surface Antigen (HBsAg) positive
- •Human Immunodeficiency Virus-1 (HIV-1) or Human Immunodeficiency Virsu-2 (HIV-2) infection
- •Hepatitis C Virus Antibody (HCVAb) positive
- •Prior or planned liver transplantation
- •Other known causes of chronic liver disease, including alcoholic liver disease
- •History of cirrhosis and/or hepatic decompensation including ascites, encephalopathy or variceal bleeding
- •Alcohol consumption greater than 14 units/week
- •Weight reduction through bariatric surgery or planned bariatric surgery during the conduct of the study (including gastric banding)
- •Any Grade ≥ 3 laboratory abnormality as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Toxicity Grading Scale, except subjects with Grade ≥ 3 dyslipidemia with triglyceride or cholesterol elevations unless clinical assessment foresees an immediate health risk to the subject
- •Serum albumin < 3.5 g/dL
- •Serum creatinine levels ≥ 1.5 mg/dL for males or ≥ 1.4 mg/dL for females if participant is receiving metformin
- •Estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73 m2 according to the Modification of Diet in Renal Disease (MDRD) equation
- •Platelet count < 100,000/mm3
- •Hemoglobin < 12 g/dL for males or < 11 g/dL for females
- •Females who are pregnant or breastfeeding
- •Receiving ongoing therapy with any disallowed medication at Screening
- •Allergy to the study drug or its components
- •Any other clinically significant disorders or prior therapy that, in the opinion of the investigator, would make the subject unsuitable for the study or unable to comply with the dosing and protocol requirements.
研究组 & 干预措施
Cenicriviroc 150 mg
Experimental
Cenicriviroc (CVC) 150 mg, administered orally once daily and taken every morning with food for up to 24 weeks.
干预措施: Cenicriviroc 150 mg (Drug)
Placebo
Placebo Comparator
Placebo-matching CVC, administered orally once daily and taken every morning with food for up to 24 weeks.
干预措施: Placebo (Drug)
结局指标
主要结局
Change From Baseline in Adipose Tissue Insulin Resistance (Adipo-IR ) Index
时间窗: Baseline (Day 1) to Weeks 12 and 24
Change in adipose insulin sensitivity was measured by Adipo-IR. Adipo-IR= (Fasting Serum free fatty acid (FFA) mmol/L x FPI μIU/mL). A higher Adipo-IR index indicates the worst disease state. A lower Adipo-IR Index is best. A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
Change From Baseline in Matsuda Index
时间窗: Baseline (Day 1) to Weeks 12 and 24
Change in peripheral insulin sensitivity was measured by the Matsuda Index. Fasting plasma glucose (FPG) and fasting plasma insulin (FPI) concentrations measured during the oral glucose tolerance test (OGTT) were used to calculate the Matsuda Index. Matsuda Index=10,000/square root \[FPG mg/dL x FPI μIU/mL) x (mean glucose mg/dL x mean insulin μIU/mL during OGTT)\]. A Matsuda index of \<2.5 indicates whole body insulin resistance. A lower Matsuda Index indicates the worst disease state. An increase in the Matsuda Index indicates an improvement in insulin sensitivity (best). A positive change from Baseline indicates improvement and a negative change from Baseline indicates a worsening.
次要结局
- Change From Baseline in Fasting Glycosylated Hemoglobin A1c (HbA1c)(Baseline (Day 1) to Weeks 12 and 24)
- Change From Baseline in Macrophage Infiltration in Subcutaneous Adipose Tissue(Baseline (Day 1) to Week 24)
- Change From Baseline in Quantitative Insulin Sensitivity Check Index (QUICKI)(Baseline (Day1) to Weeks 12 and 24)
- Change From Baseline in Homeostasis Model Assessment of β-cell Function (HOMA-%B)(Baseline (Day 1) to Weeks 12 and 24)
- Change From Baseline in Area Under the Concentration-time Curve From Time 0 to 120 Minutes [AUC (0-120 Min)] for Serum Glucose(Baseline (Pre-glucose load) to 30, 60, 90 and 120 minutes after glucose load on Weeks 12 and 24)
- Change From Baseline in C-C Chemokine Receptor Type 2 (CCR2) and C-C Chemokine Receptor Type 5 (CCR5) in Subcutaneous Adipose Tissue(Baseline (Day 1) to Week 24)
- Change From Baseline in Peripheral Monocyte Subsets (CD14/CD16)(Baseline (Day 1) to Week 24)
- Plasma Insulin at 30, 60, 90 and 120 Minutes Following Glucose Load(Pre-glucose load, 30, 60, 90 and 120 minutes after glucose load on Weeks 12 and 24)
- Plasma Glucose at 30, 60, 90 and 120 Minutes Following Glucose Load(Prior to Glucose Load, 30, 60, 90 and 120 minutes after glucose load on Weeks 12 and 24)
- Change From Baseline in Fasting Plasma Glucose (FPG)(Baseline (Day1) to Weeks 12 and 24)
- Change From Baseline in Fasting Plasma Insulin (FPI)(Baseline (Day 1) to Weeks 12 and 24)
- Change From Baseline in Homeostasis Model of Insulin Resistance (HOMA-IR)(Baseline (Day 1) to Weeks 12 and 24)
- Change From Baseline in Plasma Glucagon Concentration(Baseline (Day 1) to Weeks 12 and 24)
- Change From Baseline in Area Under the Concentration-time Curve From Time 30 to 120 Minutes [AUC (30-120 Min)] for Serum Glucose(Baseline (Pre-glucose load) to 30, 60, 90 and 120 minutes after glucose load on Weeks 12 and 24)
- Change From Baseline in Serum Resistin Concentration(Baseline (Day 1) to Weeks 12 and 24)
- Change From Baseline in Serum C-C Chemokine Receptor Type 2 (CCR2) Ligand: Monocyte Chemotactic Protein 1 (MCP-1)(Baseline (Day 1) to Weeks 2, 12 and 24)
- Change From Baseline in Serum C-C Chemokine Receptor Type 5 (CCR5) Ligand: RANTES(Baseline (Day 1) to Weeks 2, 12 and 24)
- Change From Baseline in AUC (0-120 Min) for Plasma Insulin(Baseline (Pre-glucose load) to 30, 60, 90 and 120 minutes after glucose load on Weeks 12 and 24)
- Change From Baseline in Fasting Free Fatty Acids(Baseline (Day 1) to Weeks 12 and 24)
- Change From Baseline in Serum Adiponectin Concentration(Baseline (Day1) to Weeks 12 and 24)
- Serum FFA at 30, 60, 90 and 120 Minutes Following Glucose Load(Pre-glucose load, 30, 60, 90 and 120 minutes after glucose load on Weeks 12 and 24)
- Change From Baseline in AUC (30-120 Min) for Serum FFA(Baseline (Pre-glucose load) to 30, 60, 90 and 120 minutes after glucose load on Weeks 12 and 24)
- Change From Baseline in Noninvasive Metabolic Biomarker: Hyaluronic Acid(Baseline (Day 1) to Week 24)
- Change From Baseline in AUC (30-120 Min) for Plasma Insulin(Baseline (Pre-glucose load) to 30, 60, 90 and 120 minutes after glucose load on Weeks 12 and 24)
- Change From Baseline in AUC (0-120 Min) for Serum FFA(Baseline (Pre-glucose load) to 30, 60, 90 and 120 minutes after glucose load on Weeks 12 and 24)
- Number of Participants by NASH Clinical Research Network (CRN) Staging Categories(Baseline (Screening) and Week 24)
- Change From Baseline in Serum CCR5 Ligand: Macrophage Inflammatory Protein 1 Alpha (MIP-1α)(Baseline (Day 1) to Weeks 2, 12 and 24)
- Change From Baseline in Serum CCR5 Ligand: Macrophage Inflammatory Protein 1 Beta (MIP-1β)(Baseline (Day 1) to Weeks 2, 12 and 24)
- Change From Baseline in Biomarker of Inflammation: Interleukin 8 (IL-8)(Baseline (Day 1) to Weeks 2, 12 and 24)
- Change From Baseline in Biomarker of Inflammation: Tumor Necrosis Factor Alpha (TNF-α)(Baseline (Day 1) to Weeks 2, 12, 24)
- Change From Baseline in Noninvasive Metabolic Biomarker: Mac-2 Binding Protein (Mac-2BP)(Baseline (Day 1) to Week 24)
- Change From Baseline in Noninvasive Metabolic Serum Biomarker: Cluster of Differentiation (CD95)(Baseline (Day 1) to Week 24)
- Change From Baseline in Noninvasive Metabolic Marker: Alpha-fetoprotein (AFP)(Baseline (Day 1) to Week 24)
- Change From Baseline in Non-invasive Imaging by Multiparametric Magnetic Resonance Imaging (MRI) for Liver Disease (LiverMultiScan™) Test: cT1 Mode Values Within the Liver(Baseline to Weeks 12 and 24)
- Change From Baseline in Biomarker of Inflammation: Interleukin 1 Beta (IL-1β)(Baseline (Day 1) to Weeks 2, 12 and 24)
- Change From Baseline in the Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS)(Baseline (Screening) to Week 24)
- Change From Baseline in Biomarker of Inflammation: Interleukin 6 (IL-6)(Baseline (Day 1) to Weeks 2, 12 and 24)
- Change From Baseline in Noninvasive Metabolic Biomarker: Cytokeratin-18 (CK-18) [M30 and M65](Baseline (Day 1) to Week 24)
- Change From Baseline in Biomarker of Inflammation: Interleukin 10 (IL-10)(Baseline (Day 1) to Weeks 2, 12 and 24)
- Change From Baseline in Biomarker of Inflammation: High Sensitivity C Reactive Protein (Hs-CRP)(Baseline (Day 1) to Weeks 2, 12, 24)
- Change From Baseline in Noninvasive Metabolic Biomarker: Fibroblast Growth Factor-21 (FGF-21)(Baseline (Day 1) to Week 24)
- Change From Baseline in Non-invasive Imaging by Multiparametric Magnetic Resonance Imaging (MRI) for Liver Disease (LiverMultiScan™) Test: Fat Fraction(Baseline to Weeks 12 and 24)
- Change From Baseline in Non-invasive Imaging by Multiparametric Magnetic Resonance Imaging (MRI) for Liver Disease (LiverMultiScan™) Test: Corrected T1 (cT1)(Baseline to Weeks 12 and 24)
- Change From Baseline in Non-invasive Imaging by Multiparametric Magnetic Resonance Imaging (MRI) for Liver Disease (LiverMultiScan™) Test: Liver Inflammation and Fibrosis (LIF) Score(Baseline to Weeks 12 and 24)
- Change From Baseline in Non-invasive Imaging by Multiparametric Magnetic Resonance Imaging (MRI) for Liver Disease (LiverMultiScan™) Test: Iron Content(Baseline to Weeks 12 and 24)
- Change From Baseline in Body Weight(Baseline to Weeks 2, 4, 8, 12, 16, 20 and 24)
- Change From Baseline in Liver Transaminase: Alanine Aminotransferase (ALT)(Baseline to Weeks 12 and 24)
- Change From Baseline in Liver Transaminase: Aspartate Aminotransferase (AST)(Baseline to Weeks 12 and 24)
- Number of Participants With at Least One Treatment-emergent Adverse Event (TEAE)(24 weeks)
- Number of Participants With Clinically Relevant Changes From Baseline in Vital Signs(24 weeks)
- Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG) Results(Baseline 24 weeks)
- Plasma Cenicriviroc Concentrations(Baseline (Day 1) one sample predose; Weeks 2, 12 and 24 one sample predose and one sample postdose)
- Number of Participants With Abnormal Physical Examination Findings(24 weeks)
研究者
研究点 (3)
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