Study of ISIS 703802 in Participants With Hypertriglyceridemia, Type 2 Diabetes Mellitus, and Nonalcoholic Fatty Liver Disease

Phase 2

Completed

Conditions: Hypertriglyceridemia
NAFLD
Fatty Liver, Nonalcoholic
Diabetes Mellitus, Type 2

Interventions: Drug: Placebo
Drug: ISIS 703802 80 mg
Drug: ISIS 703802 20 mg
Drug: ISIS 703802 40 mg

Registration Number: NCT03371355

Lead Sponsor: Akcea Therapeutics

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).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 105

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).

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Pooled Placebo	Placebo	Participants from each cohort received placebo at a dose-matched volume of study drug, subcutaneously (SC).
Cohort C: ISIS 703802, 80 mg Q4W	ISIS 703802 80 mg	Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses.
Cohort A: ISIS 703802, 20 mg QW	ISIS 703802 20 mg	Participants received ISIS 703802, 20 mg once every week for 26 doses.
Cohort B: ISIS 703802, 40 mg Q4W	ISIS 703802 40 mg	Participants received ISIS 703802, 40 milligrams (mg) SC once every 4 weeks for 6 doses.

Primary Outcome Measures

Name	Time	Method
Percent Change From Baseline in Fasting Triglycerides Level at the Primary Analysis Time Point	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 Outcome Measures

Name	Time	Method
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	An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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	An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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	An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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	An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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	An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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	An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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	HOMA-IR is a method used to quantify insulin resistance. HOMA-IR is expressed as the following: HOMA-IR = fasting serum insulin (μU/mL) \* fasting plasma glucose (mmol/L)/22.5. A negative change from Baseline indicates improvement. An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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	An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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	An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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	An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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	An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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	An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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	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.
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	An ANCOVA model was performed on the percent change from Baseline to Primary Analysis Time Point.
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	An ANCOVA model was performed on the percent change from Baseline to Primary Analysis Time Point.
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	The percentage of participants who achieved HFF ≤ 8% at the Primary Analysis Time Point was compared between each ISIS 703802 treatment group and pooled placebo group using a logistic regression model.
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	An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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	An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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	An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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	The FLI was calculated by the following formula: FLI =(e0.953×loge\[triglycerides\]+0.139× Body Mass Index \[BMI\]+0.718×loge Gamma- Glutamyl Transferase \[GGT\]+0.053×waistcircumference-15.745)/ (1 + e0.953×loge\[triglycerides\]+0.139×BMI+0.718×loge \[GGT\]+0.053×waistcircumference-15.745) × 100. An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	Up to 13 weeks post treatment period (up to 39 weeks)	An AE was defined as any unfavorable and unintended sign (including a clinically-significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE was considered related to the investigational drug product. TEAEs were defined as adverse events that occurred after the first administration of study drug.
Change From Baseline in Fructosamine at Primary Analysis Time Point	Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C	An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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	An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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	An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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	An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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	An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.