Clinical trial NCT03371355: Study of ISIS 703802 in Participants With Hypertriglyceridemia, Type 2 Diabetes Mellitus, and Nonalcoholic Fatty Liver Disease
Official title: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Dose Finding Study of ISIS 703802 (AKCEA-ANGPTL3-LRx) Administered Subcutaneously to Subjects With Hypertriglyceridemia, Type 2 Diabetes Mellitus (T2DM), and Nonalcoholic Fatty Liver Disease (NAFLD)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: NAFLD
Diabetes Mellitus, Type 2
Hypertriglyceridemia
Fatty Liver, Nonalcoholic
Keywords: Type 2 Diabetes
Hepatic Steatosis
Triglycerides
AKCEA-ANGPTL3-Lrx
IONIS-ANGPTL3-Lrx
Fatty Liver
Fatty Liver Without Mention of Alcohol
Liver Fat
Liver Diseases
Diabetes Mellitus Type 2 in Nonobese
Diabetes Mellitus
Triglycerides High
High Triglycerides
Metabolic Disease
Endocrine System Diseases
Digestive System Disease
Glucose Metabolism Disorders
Vupanorsen
Lead sponsor: Akcea Therapeutics
Sponsor class: INDUSTRY
Collaborators: name: Ionis Pharmaceuticals, Inc.
First posted: 2017-12-13
Enrollment: 105
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the safety, including tolerability, of ISIS 703802 and to assess the efficacy of different doses and dosing regimens of ISIS 703802 on glucose and lipid metabolism, and liver fat in participants with hypertriglyceridemia, Type 2 diabetes mellitus (T2DM), and nonalcoholic fatty liver disease (NAFLD).


Eligibility criteria: Key Inclusion Criteria:

* Plasma triglycerides (TG) at Screening greater than (\>)150 milligrams per deciliter (mg/dL) and at qualification of \>150 mg/dL.
* Documented history of hepatic steatosis with baseline magnetic resonance imaging (MRI) indicating hepatic fat fraction (HFF) greater than (\>) 8%.
* Diagnosis of Type 2 diabetes mellitus with hemoglobin A1c (HbA1c) \>6.5 and less than or equal to (≤) 10% at Screening.
* Must have been on a stable dose of oral antidiabetic therapy for a minimum of 3 months prior to Screening.
* Body mass index between 27- 40 kilograms per meter square (kg/m\^2), inclusive, at Screening.

Key Exclusion Criteria:

* Type 1 diabetes mellitus.
* Active chronic liver disease, alcoholic liver disease, Wilson's disease hemochromatosis, primary biliary cirrhosis, primary sclerosing cholangitis, genetic hemochromatosis, known or suspected hepatocellular carcinoma, history of or planned liver transplant for end-stage liver disease of any etiology.
* Documented history of advanced liver fibrosis.
* History of cirrhosis and/or hepatic decompensation including ascites, hepatic encephalopathy, or variceal bleeding.
* History of clinically significant acute cardiac event within 6 months before Screening.
* History of heart failure with New York Heart Association (NYHA) greater than Class II.
* Use of Insulin or insulin analogs, glucagon-like peptide-1 (GLP-1) agonists, and peroxisome proliferator-activated receptor gamma (PPARᵞ) agonists (pioglitazone or rosiglitazone).
* Weight change \>5% within 3 months before Screening.
* Conditions contraindicated for magnetic resonance imaging (MRI) procedures including any metal implant (example, heart pacemaker, rods, screws, aneurysm clips).

Primary outcomes:
measure: Percent Change From Baseline in Fasting Triglycerides Level at the Primary Analysis Time Point
timeFrame: Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
Secondary outcomes:
measure: Change From Baseline in Angiopoietin-Like 3 Protein at the Primary Analysis Time Point
timeFrame: Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
measure: Change From Baseline in TC, LDL-C, HDL-C, VLDL-C, Non-HDL-C, ApoB (ApoB-48, ApoB-100), ApoCIII, and ApoAI at the Primary Analysis Time Point
timeFrame: Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
measure: Change From Baseline in Free Fatty Acid (FFA) at Primary Analysis Time Point
timeFrame: Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
measure: Change From Baseline in Lipoprotein(a) (Lp[a]) at the Primary Analysis Time Point
timeFrame: Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
measure: Percent Change From Baseline in ANGPTL3, TC, LDL-C, HDL-C, VLDL-C, Non-HDL-C, ApoB (ApoB-48, ApoB-100), ApoCIII, ApoAI, FFA, and Lp(a) at Primary Analysis Time Point
timeFrame: Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
measure: Change From Baseline in Fasting Plasma Glucose at the Primary Analysis Time Point
timeFrame: Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
measure: Change From Baseline in Hemoglobin A1c (HbA1c) at the Primary Analysis Time Point
timeFrame: Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
measure: Change From Baseline in Fasting Insulin at the Primary Analysis Time Point
timeFrame: Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
measure: Change From Baseline in and HOMA-IR at the Primary Analysis Time Point
timeFrame: Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
measure: Change From Baseline in Fructosamine at Primary Analysis Time Point
timeFrame: Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
measure: Change From Baseline in Glycated Albumin at the Primary Analysis Time Point
timeFrame: Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
measure: Change From Baseline in Weight at the Primary Analysis Time Point
timeFrame: Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
measure: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Primary Analysis Time Point
timeFrame: Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
measure: Percent Change From Baseline in Weight, SBP and DBP at Primary Analysis Time Point
timeFrame: Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C6
measure: Change From Baseline in Hepatic Fat Fraction (HFF) by Magnetic Resonance Imaging-Derived Proton Density Fat Fraction (MRI-PDFF) at the Primary Analysis Time Point
timeFrame: Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
measure: Percent Change From Baseline in Hepatic Fat Fraction (HFF) by Magnetic Resonance Imaging-Derived Proton Density Fat Fraction (MRI-PDFF) at the Primary Analysis Time Point
timeFrame: Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
measure: Percentage of Participants With HFF ≤ 8% by MRI-PDFF at the Primary Analysis Time Point
timeFrame: Week 27 for Cohort A, and Week 25 for Cohorts B and C
measure: Change From Baseline in Fatty Liver Index (FLI) at the Primary Analysis Time Point
timeFrame: Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
measure: Change From Baseline in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) at the Primary Analysis Time Point
timeFrame: Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
measure: Change From Baseline in Leptin at the Primary Analysis Time Point
timeFrame: Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
measure: Change From Baseline in Adiponectin at the Primary Analysis Time Point
timeFrame: Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
measure: Change From Baseline in Subcutaneous Adipose Tissue (SAT) and Visceral Adipose Tissue (VAT) by Single Slice MRI at the Primary Analysis Timepoint
timeFrame: Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
measure: Change From Baseline in Waist Circumference by Single Slice MRI at the Primary Analysis Timepoint
timeFrame: Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
measure: Change From Baseline in Waist to Hip Ratio (WHR) at the Primary Analysis Timepoint
timeFrame: Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
measure: Change From Baseline in Body Mass Index (BMI) at the Primary Analysis Timepoint
timeFrame: Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
timeFrame: Up to 13 weeks post treatment period (up to 39 weeks)
Other outcomes:
Locations:
city: Chandler
country: United States
facility: Clinical Sites
state: Arizona
city: Fountain Hills
country: United States
facility: Clinical Site
state: Arizona
city: Glendale
country: United States
facility: Clinical Site
state: Arizona
city: Mesa
country: United States
facility: Clinical Site
state: Arizona
city: Mesa
country: United States
facility: Clinical Site
state: Arizona
city: Phoenix
country: United States
facility: Clinical Site
state: Arizona
city: Phoenix
country: United States
facility: Clinical Site
state: Arizona
city: Phoenix
country: United States
facility: Clinical Site
state: Arizona
city: Huntington Park
country: United States
facility: Clinical Site
state: California
city: Los Angeles
country: United States
facility: Clinical Site
state: California
city: Montclair
country: United States
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state: California
city: Panorama City
country: United States
facility: Clinical Site
state: California
city: Poway
country: United States
facility: Clinical Site
state: California
city: Boca Raton
country: United States
facility: Clinical Site
state: Florida
city: Jensen Beach
country: United States
facility: Clinical Site
state: Florida
city: Jupiter
country: United States
facility: Clinical Site
state: Florida
city: Miami
country: United States
facility: Clinical Site
state: Florida
city: Port Saint Lucie
country: United States
facility: Clinical Site
state: Florida
city: Atlanta
country: United States
facility: Clinical Site
state: Georgia
city: Chicago
country: United States
facility: Clinical Site
state: Illinois
city: Indianapolis
country: United States
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state: Indiana
city: Louisville
country: United States
facility: Clinical Site
state: Kentucky
city: Edina
country: United States
facility: Clinical Site
state: Minnesota
city: Bridgeton
country: United States
facility: Clinical Site
state: New Jersey
city: Princeton
country: United States
facility: Clinical Site
state: New Jersey
city: Greensboro
country: United States
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state: North Carolina
city: High Point
country: United States
facility: Clinical Site
state: North Carolina
city: Cincinnati
country: United States
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state: Ohio
city: Cincinnati
country: United States
facility: Clinical Site
state: Ohio
city: Charleston
country: United States
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state: South Carolina
city: Austin
country: United States
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state: Texas
city: Carrollton
country: United States
facility: Clinical Site
state: Texas
city: Dallas
country: United States
facility: Clinical Site
state: Texas
city: Houston
country: United States
facility: Clinical Site
state: Texas
city: Hurst
country: United States
facility: Clinical Site
state: Texas
city: San Antonio
country: United States
facility: Clinical Site
state: Texas
city: San Antonio
country: United States
facility: Clinical Site
state: Texas
city: Layton
country: United States
facility: Clinical Site
state: Utah
city: Hamilton
country: Canada
facility: Clinical Site
state: Ontario
city: Toronto
country: Canada
facility: Clinical Site
state: Ontario
city: Chicoutimi
country: Canada
facility: Clinical Site
state: Quebec
city: Montréal
country: Canada
facility: Clinical Site
state: Quebec
Study officials:
References: