Clinical trial NCT02330549: ORION: Effects of Cenicriviroc on Insulin Sensitivity in Subjects With Prediabetes or Type 2 Diabetes Mellitus (T2DM) and Suspected NAFLD
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Prediabetic State
Non-alcoholic Fatty Liver Disease
Type 2 Diabetes Mellitus
Lead sponsor: Tobira Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2015-01-05
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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.

Primary outcomes:
measure: Change From Baseline in Matsuda Index
timeFrame: Baseline (Day 1) to Weeks 12 and 24
measure: Change From Baseline in Adipose Tissue Insulin Resistance (Adipo-IR ) Index
timeFrame: Baseline (Day 1) to Weeks 12 and 24
Secondary outcomes:
measure: Change From Baseline in Macrophage Infiltration in Subcutaneous Adipose Tissue
timeFrame: Baseline (Day 1) to Week 24
measure: Change From Baseline in C-C Chemokine Receptor Type 2 (CCR2) and C-C Chemokine Receptor Type 5 (CCR5) in Subcutaneous Adipose Tissue
timeFrame: Baseline (Day 1) to Week 24
measure: Change From Baseline in Peripheral Monocyte Subsets (CD14/CD16)
timeFrame: Baseline (Day 1) to Week 24
measure: Change From Baseline in Fasting Plasma Glucose (FPG)
timeFrame: Baseline (Day1) to Weeks 12 and 24
measure: Change From Baseline in Fasting Plasma Insulin (FPI)
timeFrame: Baseline (Day 1) to Weeks 12 and 24
measure: Change From Baseline in Quantitative Insulin Sensitivity Check Index (QUICKI)
timeFrame: Baseline (Day1) to Weeks 12 and 24
measure: Change From Baseline in Homeostasis Model of Insulin Resistance (HOMA-IR)
timeFrame: Baseline (Day 1) to Weeks 12 and 24
measure: Change From Baseline in Homeostasis Model Assessment of β-cell Function (HOMA-%B)
timeFrame: Baseline (Day 1) to Weeks 12 and 24
measure: Change From Baseline in Fasting Glycosylated Hemoglobin A1c (HbA1c)
timeFrame: Baseline (Day 1) to Weeks 12 and 24
measure: Change From Baseline in Plasma Glucagon Concentration
timeFrame: Baseline (Day 1) to Weeks 12 and 24
measure: Plasma Glucose at 30, 60, 90 and 120 Minutes Following Glucose Load
timeFrame: Prior to Glucose Load, 30, 60, 90 and 120 minutes after glucose load on Weeks 12 and 24
measure: Plasma Insulin at 30, 60, 90 and 120 Minutes Following Glucose Load
timeFrame: Pre-glucose load, 30, 60, 90 and 120 minutes after glucose load on Weeks 12 and 24
measure: Change From Baseline in Area Under the Concentration-time Curve From Time 0 to 120 Minutes [AUC (0-120 Min)] for Serum Glucose
timeFrame: Baseline (Pre-glucose load) to 30, 60, 90 and 120 minutes after glucose load on Weeks 12 and 24
measure: Change From Baseline in Area Under the Concentration-time Curve From Time 30 to 120 Minutes [AUC (30-120 Min)] for Serum Glucose
timeFrame: Baseline (Pre-glucose load) to 30, 60, 90 and 120 minutes after glucose load on Weeks 12 and 24
measure: Change From Baseline in AUC (0-120 Min) for Plasma Insulin
timeFrame: Baseline (Pre-glucose load) to 30, 60, 90 and 120 minutes after glucose load on Weeks 12 and 24
measure: Change From Baseline in AUC (30-120 Min) for Plasma Insulin
timeFrame: Baseline (Pre-glucose load) to 30, 60, 90 and 120 minutes after glucose load on Weeks 12 and 24
measure: Change From Baseline in Fasting Free Fatty Acids
timeFrame: Baseline (Day 1) to Weeks 12 and 24
measure: Change From Baseline in Serum Adiponectin Concentration
timeFrame: Baseline (Day1) to Weeks 12 and 24
measure: Change From Baseline in Serum Resistin Concentration
timeFrame: Baseline (Day 1) to Weeks 12 and 24
measure: Serum FFA at 30, 60, 90 and 120 Minutes Following Glucose Load
timeFrame: Pre-glucose load, 30, 60, 90 and 120 minutes after glucose load on Weeks 12 and 24
measure: Change From Baseline in AUC (0-120 Min) for Serum FFA
timeFrame: Baseline (Pre-glucose load) to 30, 60, 90 and 120 minutes after glucose load on Weeks 12 and 24
measure: Change From Baseline in AUC (30-120 Min) for Serum FFA
timeFrame: Baseline (Pre-glucose load) to 30, 60, 90 and 120 minutes after glucose load on Weeks 12 and 24
measure: Change From Baseline in the Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS)
timeFrame: Baseline (Screening) to Week 24
measure: Number of Participants by NASH Clinical Research Network (CRN) Staging Categories
timeFrame: Baseline (Screening) and Week 24
measure: Change From Baseline in Serum C-C Chemokine Receptor Type 2 (CCR2) Ligand: Monocyte Chemotactic Protein 1 (MCP-1)
timeFrame: Baseline (Day 1) to Weeks 2, 12 and 24
measure: Change From Baseline in Serum C-C Chemokine Receptor Type 5 (CCR5) Ligand: RANTES
timeFrame: Baseline (Day 1) to Weeks 2, 12 and 24
measure: Change From Baseline in Serum CCR5 Ligand: Macrophage Inflammatory Protein 1 Alpha (MIP-1α)
timeFrame: Baseline (Day 1) to Weeks 2, 12 and 24
measure: Change From Baseline in Serum CCR5 Ligand: Macrophage Inflammatory Protein 1 Beta (MIP-1β)
timeFrame: Baseline (Day 1) to Weeks 2, 12 and 24
measure: Change From Baseline in Biomarker of Inflammation: Interleukin 1 Beta (IL-1β)
timeFrame: Baseline (Day 1) to Weeks 2, 12 and 24
measure: Change From Baseline in Biomarker of Inflammation: Interleukin 6 (IL-6)
timeFrame: Baseline (Day 1) to Weeks 2, 12 and 24
measure: Change From Baseline in Biomarker of Inflammation: Interleukin 8 (IL-8)
timeFrame: Baseline (Day 1) to Weeks 2, 12 and 24
measure: Change From Baseline in Biomarker of Inflammation: Interleukin 10 (IL-10)
timeFrame: Baseline (Day 1) to Weeks 2, 12 and 24
measure: Change From Baseline in Biomarker of Inflammation: High Sensitivity C Reactive Protein (Hs-CRP)
timeFrame: Baseline (Day 1) to Weeks 2, 12, 24
measure: Change From Baseline in Biomarker of Inflammation: Tumor Necrosis Factor Alpha (TNF-α)
timeFrame: Baseline (Day 1) to Weeks 2, 12, 24
measure: Change From Baseline in Noninvasive Metabolic Biomarker: Hyaluronic Acid
timeFrame: Baseline (Day 1) to Week 24
measure: Change From Baseline in Noninvasive Metabolic Biomarker: Cytokeratin-18 (CK-18) [M30 and M65]
timeFrame: Baseline (Day 1) to Week 24
measure: Change From Baseline in Noninvasive Metabolic Biomarker: Fibroblast Growth Factor-21 (FGF-21)
timeFrame: Baseline (Day 1) to Week 24
measure: Change From Baseline in Noninvasive Metabolic Biomarker: Mac-2 Binding Protein (Mac-2BP)
timeFrame: Baseline (Day 1) to Week 24
measure: Change From Baseline in Noninvasive Metabolic Serum Biomarker: Cluster of Differentiation (CD95)
timeFrame: Baseline (Day 1) to Week 24
measure: Change From Baseline in Noninvasive Metabolic Marker: Alpha-fetoprotein (AFP)
timeFrame: Baseline (Day 1) to Week 24
measure: Change From Baseline in Non-invasive Imaging by Multiparametric Magnetic Resonance Imaging (MRI) for Liver Disease (LiverMultiScan™) Test: Fat Fraction
timeFrame: Baseline to Weeks 12 and 24
measure: Change From Baseline in Non-invasive Imaging by Multiparametric Magnetic Resonance Imaging (MRI) for Liver Disease (LiverMultiScan™) Test: Corrected T1 (cT1)
timeFrame: Baseline to Weeks 12 and 24
measure: Change From Baseline in Non-invasive Imaging by Multiparametric Magnetic Resonance Imaging (MRI) for Liver Disease (LiverMultiScan™) Test: cT1 Mode Values Within the Liver
timeFrame: Baseline to Weeks 12 and 24
measure: Change From Baseline in Non-invasive Imaging by Multiparametric Magnetic Resonance Imaging (MRI) for Liver Disease (LiverMultiScan™) Test: Liver Inflammation and Fibrosis (LIF) Score
timeFrame: Baseline to Weeks 12 and 24
measure: Change From Baseline in Non-invasive Imaging by Multiparametric Magnetic Resonance Imaging (MRI) for Liver Disease (LiverMultiScan™) Test: Iron Content
timeFrame: Baseline to Weeks 12 and 24
measure: Change From Baseline in Body Weight
timeFrame: Baseline to Weeks 2, 4, 8, 12, 16, 20 and 24
measure: Change From Baseline in Liver Transaminase: Alanine Aminotransferase (ALT)
timeFrame: Baseline to Weeks 12 and 24
measure: Change From Baseline in Liver Transaminase: Aspartate Aminotransferase (AST)
timeFrame: Baseline to Weeks 12 and 24
measure: Number of Participants With at Least One Treatment-emergent Adverse Event (TEAE)
timeFrame: 24 weeks
measure: Number of Participants With Clinically Relevant Changes From Baseline in Vital Signs
timeFrame: 24 weeks
measure: Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG) Results
timeFrame: Baseline 24 weeks
measure: Plasma Cenicriviroc Concentrations
timeFrame: Baseline (Day 1) one sample predose; Weeks 2, 12 and 24 one sample predose and one sample postdose
measure: Number of Participants With Abnormal Physical Examination Findings
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Fort Sam Houston
country: United States
facility: San Antonio Military Medical Center
state: Texas
city: San Antonio
country: United States
facility: Gastroenterology Consultants of San Antonio Digestive Research Center
state: Texas
city: San Juan
country: Puerto Rico
facility: Fundacion de Investigacion
Study officials:
affiliation: Allergan
name: Eric Lefebvre, MD
role: STUDY_DIRECTOR
References: