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Clinical Trials/NCT03371355
NCT03371355
Completed
Phase 2

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)

Akcea Therapeutics2 sites in 2 countries105 target enrollmentDecember 21, 2017
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ConditionsNAFLDDiabetes Mellitus, Type 2HypertriglyceridemiaFatty Liver, Nonalcoholic
InterventionsPlaceboISIS 703802 40 mgISIS 703802 80 mgISIS 703802 20 mg
DrugsPlaceboISIS 703802 40 mgISIS 703802 80 mgISIS 703802 20 mg

Overview

Phase
Phase 2
Intervention
Placebo
Conditions
NAFLD
Sponsor
Akcea Therapeutics
Enrollment
105
Locations
2
Primary Endpoint
Percent Change From Baseline in Fasting Triglycerides Level at the Primary Analysis Time Point
Status
Completed
Last Updated
5 years ago
OverviewInvestigatorsEligibility CriteriaArms & InterventionsOutcomesSitesSimilar Trials

Overview

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).

Registry
clinicaltrials.gov
Start Date
December 21, 2017
End Date
February 24, 2020
Last Updated
5 years ago
Study Type
Interventional
Study Design
Parallel
Sex
All

Investigators

Responsible Party
Sponsor

Eligibility Criteria

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.

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).

Arms & Interventions

Pooled Placebo

Participants from each cohort received placebo at a dose-matched volume of study drug, subcutaneously (SC).

Intervention: Placebo

Cohort B: ISIS 703802, 40 mg Q4W

Participants received ISIS 703802, 40 milligrams (mg) SC once every 4 weeks for 6 doses.

Intervention: ISIS 703802 40 mg

Cohort C: ISIS 703802, 80 mg Q4W

Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses.

Intervention: ISIS 703802 80 mg

Cohort A: ISIS 703802, 20 mg QW

Participants received ISIS 703802, 20 mg once every week for 26 doses.

Intervention: ISIS 703802 20 mg

Outcomes

Primary Outcomes

Percent Change From Baseline in Fasting Triglycerides Level at the Primary Analysis Time Point

Time Frame: Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C

An ANCOVA model was performed on the log ratio of Primary Analysis Time Point to Baseline. The estimate of the log ratio was converted back to the original scale and percent change was calculated using formula: = (ratio of Primary Analysis Time Point to Baseline - 1) × 100.

Secondary Outcomes

  • Change From Baseline in Free Fatty Acid (FFA) at Primary Analysis Time Point(Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C)
  • Change From Baseline in Weight at the Primary Analysis Time Point(Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C)
  • Change From Baseline in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) at the Primary Analysis Time Point(Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C)
  • Change From Baseline in Subcutaneous Adipose Tissue (SAT) and Visceral Adipose Tissue (VAT) by Single Slice MRI at the Primary Analysis Timepoint(Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C)
  • Change From Baseline in Angiopoietin-Like 3 Protein at the Primary Analysis Time Point(Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C)
  • Change From Baseline in Hemoglobin A1c (HbA1c) at the Primary Analysis Time Point(Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C)
  • Change From Baseline in and HOMA-IR at the Primary Analysis Time Point(Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C)
  • 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(Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C)
  • Change From Baseline in Lipoprotein(a) (Lp[a]) at the Primary Analysis Time Point(Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C)
  • Change From Baseline in Fasting Plasma Glucose at the Primary Analysis Time Point(Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C)
  • Change From Baseline in Leptin at the Primary Analysis Time Point(Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C)
  • Change From Baseline in Adiponectin at the Primary Analysis Time Point(Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C)
  • 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(Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C)
  • Percent Change From Baseline in Weight, SBP and DBP at Primary Analysis Time Point(Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C6)
  • 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(Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C)
  • Percentage of Participants With HFF ≤ 8% by MRI-PDFF at the Primary Analysis Time Point(Week 27 for Cohort A, and Week 25 for Cohorts B and C)
  • Change From Baseline in Fasting Insulin at the Primary Analysis Time Point(Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C)
  • Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Primary Analysis Time Point(Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C)
  • Change From Baseline in Fatty Liver Index (FLI) at the Primary Analysis Time Point(Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C)
  • Change From Baseline in Waist to Hip Ratio (WHR) at the Primary Analysis Timepoint(Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C)
  • Number of Participants With Treatment-emergent Adverse Events (TEAEs)(Up to 13 weeks post treatment period (up to 39 weeks))
  • Change From Baseline in Fructosamine at Primary Analysis Time Point(Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C)
  • Change From Baseline in Glycated Albumin at the Primary Analysis Time Point(Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C)
  • 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(Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C)
  • Change From Baseline in Waist Circumference by Single Slice MRI at the Primary Analysis Timepoint(Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C)
  • Change From Baseline in Body Mass Index (BMI) at the Primary Analysis Timepoint(Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C)

Study Sites (2)

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