ORION: Effects of Cenicriviroc on Insulin Sensitivity in Subjects With Prediabetes or Type 2 Diabetes Mellitus (T2DM) and Suspected NAFLD

Phase 2

Completed

Conditions: Type 2 Diabetes Mellitus
Prediabetic State
Non-alcoholic Fatty Liver Disease

Interventions: Drug: Cenicriviroc 150 mg
Drug: Placebo

Registration Number: NCT02330549

Lead Sponsor: Tobira Therapeutics, Inc.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 45

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cenicriviroc 150 mg	Cenicriviroc 150 mg	Cenicriviroc (CVC) 150 mg, administered orally once daily and taken every morning with food for up to 24 weeks.
Placebo	Placebo	Placebo-matching CVC, administered orally once daily and taken every morning with food for up to 24 weeks.

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Adipose Tissue Insulin Resistance (Adipo-IR ) Index	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	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.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Fasting Glycosylated Hemoglobin A1c (HbA1c)	Baseline (Day 1) to Weeks 12 and 24	A fasting blood sample was collected and was sent to a central laboratory for analysis of glucose. A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
Change From Baseline in Macrophage Infiltration in Subcutaneous Adipose Tissue	Baseline (Day 1) to Week 24	Macrophage infiltration in adipose tissue was assessed in paraffin-embedded adipose punch biopsies by immunohistochemistry stained for cluster of differentiation 68 (CD68), cluster of differentiation 163 (CD163), C-C chemokine receptor type 2 (CCR2), C-C chemokine receptor type 5 (CCR5) and cluster of differentiation 206 (CD206). A reduction in infiltration indicates less inflammation. A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
Change From Baseline in Quantitative Insulin Sensitivity Check Index (QUICKI)	Baseline (Day1) to Weeks 12 and 24	QUICKI is used to measure insulin sensitivity. QUICKI = 1/(log FPI μIU/mL + log FPG mg/dL). A positive change from Baseline indicates improvement and a negative change from Baseline indicates a worsening.
Change From Baseline in Homeostasis Model Assessment of β-cell Function (HOMA-%B)	Baseline (Day 1) to Weeks 12 and 24	HOMA-%B= (20 × FPI)/(FPG - 3.5). A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
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	AUC(0-120 min) was derived from the serum glucose values obtained during the oral glucose tolerance test. A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
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	CCR2 and CCR5 corresponding ligands' messenger ribonucleic acid (mRNA) gene expression were assessed in frozen adipose tissue by quantitative polymerase chain reaction (PCR). A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
Change From Baseline in Peripheral Monocyte Subsets (CD14/CD16)	Baseline (Day 1) to Week 24	Peripheral monocyte subsets (cluster of differentiation 14 (CD14/cluster of differentiation 16 (CD16)\] were measured in fresh peripheral blood mononuclear cells (PBMCs) samples by flow cytometry. Monocyte results are reported for Total, Classical (CD14+CD16-), Intermediate (CD14+CD16+) and Non-classical (CD14lowCD16+). A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
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	Blood was collected during the oral glucose tolerance test and was sent to a central laboratory for analysis of insulin.
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	Blood was collected during the oral glucose tolerance test and was sent to a central laboratory for analysis of glucose.
Change From Baseline in Fasting Plasma Glucose (FPG)	Baseline (Day1) to Weeks 12 and 24	A fasting blood sample was collected and was sent to a central laboratory for analysis of glucose. A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
Change From Baseline in Fasting Plasma Insulin (FPI)	Baseline (Day 1) to Weeks 12 and 24	A fasting blood sample was collected and was sent to a central laboratory for analysis of insulin. A positive change from Baseline indicates improvement and a negative change from Baseline indicates a worsening.
Change From Baseline in Homeostasis Model of Insulin Resistance (HOMA-IR)	Baseline (Day 1) to Weeks 12 and 24	HOMA-IR = (FPG mg/dL x FPI μIU/mL)/405. A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
Change From Baseline in Plasma Glucagon Concentration	Baseline (Day 1) to Weeks 12 and 24	A fasting blood sample was collected and was sent to a central laboratory for analysis of glucagon. A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
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	AUC(30-120 min) was derived from the serum glucose values obtained during the oral glucose tolerance test. A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
Change From Baseline in Serum Resistin Concentration	Baseline (Day 1) to Weeks 12 and 24	A fasting blood sample was collected and was sent to a central laboratory for analysis of resistin. A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
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	Blood was collected and was sent to a central laboratory for analysis of MCP-1. A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
Change From Baseline in Serum C-C Chemokine Receptor Type 5 (CCR5) Ligand: RANTES	Baseline (Day 1) to Weeks 2, 12 and 24	Blood was collected and was sent to a central laboratory for analysis of RANTES (regulated on activation normal T-cell expressed and secreted). A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
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	AUC(0-120 min) was derived from the plasma insulin values obtained during the oral glucose tolerance test. A positive change from Baseline indicates improvement and a negative change from Baseline indicates a worsening.
Change From Baseline in Fasting Free Fatty Acids	Baseline (Day 1) to Weeks 12 and 24	A fasting blood sample was collected and was sent to a central laboratory for analysis of free fatty acids. A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
Change From Baseline in Serum Adiponectin Concentration	Baseline (Day1) to Weeks 12 and 24	A fasting blood sample was collected and was sent to a central laboratory for analysis of adiponectin. A positive change from Baseline indicates improvement and a negative change from Baseline indicates a worsening.
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	Blood was collected during the oral glucose tolerance test and was sent to a central laboratory for analysis of FFA.
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	AUC(30-120 min) was derived from the serum FFA values obtained during the oral glucose tolerance test. A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
Change From Baseline in Noninvasive Metabolic Biomarker: Hyaluronic Acid	Baseline (Day 1) to Week 24	Blood was collected and was sent to a central laboratory for analysis of Hyaluronic Acid. A positive change from Baseline indicates improvement and a negative change from Baseline indicates improvement.
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	AUC(30-120 min) was derived from the plasma insulin values obtained during the oral glucose tolerance test. A positive change from Baseline indicates improvement and a negative change from Baseline indicates a worsening.
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	AUC(0-120 min) was derived from the serum FFA values obtained during the oral glucose tolerance test. A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
Number of Participants by NASH Clinical Research Network (CRN) Staging Categories	Baseline (Screening) and Week 24	Liver biopsy were performed during Screening and at Week 24 for participants diagnosed with NASH. The NASH CRN Brunt/Kleiner Fibrosis Staging System Fibrosis Stages are: 0 (None), 1 (Perisinusoidal or periportal), 1A (Mild, zone 3, perisinusoidal), 1B (Moderate, zone 3, perisinusoidal), 1C (Portal/periportal), 2 (Perisinusoidal and portal/periportal), 3 (Bridging fibrosis) and 4 (Cirrhosis).
Change From Baseline in Serum CCR5 Ligand: Macrophage Inflammatory Protein 1 Alpha (MIP-1α)	Baseline (Day 1) to Weeks 2, 12 and 24	Blood was collected and was sent to a central laboratory for analysis of MIP-1α. A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
Change From Baseline in Serum CCR5 Ligand: Macrophage Inflammatory Protein 1 Beta (MIP-1β)	Baseline (Day 1) to Weeks 2, 12 and 24	Blood was collected and was sent to a central laboratory for analysis of MIP-1β. A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
Change From Baseline in Biomarker of Inflammation: Interleukin 8 (IL-8)	Baseline (Day 1) to Weeks 2, 12 and 24	Blood was collected and was sent to a central laboratory for analysis of IL-8. A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
Change From Baseline in Biomarker of Inflammation: Tumor Necrosis Factor Alpha (TNF-α)	Baseline (Day 1) to Weeks 2, 12, 24	Blood was collected and was sent to a central laboratory for analysis of TNF-α. A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
Change From Baseline in Noninvasive Metabolic Biomarker: Mac-2 Binding Protein (Mac-2BP)	Baseline (Day 1) to Week 24	Blood was collected and was sent to a central laboratory for analysis of Mac-2BP. A negative change from Baseline indicates improvement and a positive change from Baseline indicates improvement.
Change From Baseline in Noninvasive Metabolic Serum Biomarker: Cluster of Differentiation (CD95)	Baseline (Day 1) to Week 24	Blood was collected and was sent to a central laboratory for analysis of CD95. A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
Change From Baseline in Noninvasive Metabolic Marker: Alpha-fetoprotein (AFP)	Baseline (Day 1) to Week 24	Blood was collected and was sent to a central laboratory for analysis of AFP. A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
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	LiverMultiscan™ via MRI were obtained at Baseline and at Weeks 12 and 24. A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
Change From Baseline in Biomarker of Inflammation: Interleukin 1 Beta (IL-1β)	Baseline (Day 1) to Weeks 2, 12 and 24	Blood was collected and was sent to a central laboratory for analysis of IL-1β. A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
Change From Baseline in the Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS)	Baseline (Screening) to Week 24	Liver biopsy were performed during Screening and at Week 24 only for participants diagnosed with NASH. NAFLD activity score was determined based on 3 components: steatosis (0=\<5% to 3=\>66%), lobular inflammation (0=no foci to 3=\>4 foci/200x) and hepatocellular ballooning (0=none to 2= many cells/prominent ballooning) for a total possible score of 0 to 8. A negative change from Baseline indicates improvement.
Change From Baseline in Biomarker of Inflammation: Interleukin 6 (IL-6)	Baseline (Day 1) to Weeks 2, 12 and 24	Blood was collected and was sent to a central laboratory for analysis of IL-6. A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
Change From Baseline in Noninvasive Metabolic Biomarker: Cytokeratin-18 (CK-18) [M30 and M65]	Baseline (Day 1) to Week 24	Blood was collected and was sent to a central laboratory for analysis of CK-18. A positive change from Baseline indicates improvement and a negative change from Baseline indicates improvement.
Change From Baseline in Noninvasive Metabolic Biomarker: Fibroblast Growth Factor-21 (FGF-21)	Baseline (Day 1) to Week 24	Blood was collected and was sent to a central laboratory for analysis of FGF-21. A negative change from Baseline indicates improvement and a positive change from Baseline indicates improvement.
Change From Baseline in Biomarker of Inflammation: Interleukin 10 (IL-10)	Baseline (Day 1) to Weeks 2, 12 and 24	Blood was collected and was sent to a central laboratory for analysis of IL-1β. A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
Change From Baseline in Biomarker of Inflammation: High Sensitivity C Reactive Protein (Hs-CRP)	Baseline (Day 1) to Weeks 2, 12, 24	Blood was collected and was sent to a central laboratory for analysis of hs-CRP. A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
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	LiverMultiscan™ tests via MRI were obtained at Baseline and at Weeks 12 and 24. A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
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	LiverMultiscan™ via MRI were obtained at Baseline and at Weeks 12 and 24. The mean of 4 regions of interest as selected by the technician is reported. A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
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	LiverMultiscan™ tests via MRI were obtained at Baseline and at Weeks 12 and 24. The mean of 4 regions of interest as selected by the technician is reported. The LIF Score ranges from 0=no liver disease to 4=severe liver disease. A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
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	LiverMultiscan™ tests via MRI were obtained at Baseline and at Weeks 12 and 24. A positive change from Baseline indicates improvement and a negative change from Baseline indicates a worsening.
Change From Baseline in Body Weight	Baseline to Weeks 2, 4, 8, 12, 16, 20 and 24	A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
Change From Baseline in Liver Transaminase: Alanine Aminotransferase (ALT)	Baseline to Weeks 12 and 24	Blood was collected and was sent to a central laboratory for analysis of ALT. A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
Change From Baseline in Liver Transaminase: Aspartate Aminotransferase (AST)	Baseline to Weeks 12 and 24	Blood was collected and was sent to a central laboratory for analysis of AST. A negative change from Baseline indicates improvement and a positive change from Baseline indicates a worsening.
Number of Participants With at Least One Treatment-emergent Adverse Event (TEAE)	24 weeks	An AE is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A TEAE is an AE that occurs or worsens after receiving study drug.
Number of Participants With Clinically Relevant Changes From Baseline in Vital Signs	24 weeks	Vital signs included Systolic Blood Pressure, Diastolic Blood Pressure, Heart Rate, Respiratory Rate and Temperature. The investigator determined if the vital sign measurements were clinically relevant.
Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG) Results	Baseline 24 weeks	A standard 12 lead ECG was performed. The investigator determined if the abnormal results were clinically significant.
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	Physical examination included assessment of the following body systems: Abdomen, Cardiovascular, Extremities, Head, Eyes, Ears, Nose, Throat, Lungs, Lymph Nodes, Neurological, Skin and Thyroid. The number of participants with any abnormal findings at Baseline and participants with any abnormal findings Post-Baseline are reported.

Trial Locations

Locations (3): Fundacion de Investigacion
🇵🇷
San Juan, Puerto Rico
Gastroenterology Consultants of San Antonio Digestive Research Center
🇺🇸
San Antonio, Texas, United States
San Antonio Military Medical Center
🇺🇸
Fort Sam Houston, Texas, United States