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

Study Overview
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Brief Summary
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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).

Official Title
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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)

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

Intervention / Treatment
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* Drug: Placebo
* Drug: ISIS 703802 40 mg
* Drug: ISIS 703802 80 mg
* Drug: ISIS 703802 20 mg


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Pooled Placebo<br>Participants from each cohort received placebo at a dose-matched volume of study drug, subcutaneously (SC). | Drug: Placebo<br>* Placebo (Matched with ISIS 703802)<br>* Other names: Sterile Normal Saline (0.9% NaCl);|
| Experimental: Cohort B: ISIS 703802, 40 mg Q4W<br>Participants received ISIS 703802, 40 milligrams (mg) SC once every 4 weeks for 6 doses. | Drug: ISIS 703802 40 mg<br>* ISIS 703802 40 mg, administered via SC injection, once every 4 weeks for 6 doses.<br>* Other names: Vupanorsen;|
| Experimental: Cohort C: ISIS 703802, 80 mg Q4W<br>Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses. | Drug: ISIS 703802 80 mg<br>* ISIS 703802 80 mg, administered via SC injection, once every 4 weeks for 6 doses.<br>* Other names: Vupanorsen;|
| Experimental: Cohort A: ISIS 703802, 20 mg QW<br>Participants received ISIS 703802, 20 mg once every week for 26 doses. | Drug: ISIS 703802 20 mg<br>* ISIS 703802 20 mg, administered via SC injection, once every week for 26 doses.<br>* Other names: Vupanorsen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Fasting Triglycerides Level at the Primary Analysis Time Point | 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. | Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Angiopoietin-Like 3 Protein at the Primary Analysis Time Point | An ANCOVA model was performed on the change from Baseline to 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 | An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point. | Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C | 
| Change From Baseline in Free Fatty Acid (FFA) at Primary Analysis Time Point | An ANCOVA model was performed on the change from Baseline to 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 | An ANCOVA model was performed on the change from Baseline to 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 | 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. | 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 | An ANCOVA model was performed on the change from Baseline to 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 | An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point. | Baseline, 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 | An ANCOVA model was performed on the change from Baseline to 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 | 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. | Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C | 
| Change From Baseline in Fructosamine at Primary Analysis Time Point | An ANCOVA model was performed on the change from Baseline to 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 | An ANCOVA model was performed on the change from Baseline to 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 | An ANCOVA model was performed on the change from Baseline to 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 | An ANCOVA model was performed on the change from Baseline to 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 | An ANCOVA model was performed on the percent change from Baseline to Primary Analysis Time Point. | Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C6 | 
| 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 | An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point. | Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C | 
| 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 | An ANCOVA model was performed on the percent change from Baseline to 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 | 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. | 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 | 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. | 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 | An ANCOVA model was performed on the change from Baseline to 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 | An ANCOVA model was performed on the change from Baseline to 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 | An ANCOVA model was performed on the change from Baseline to 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 | An ANCOVA model was performed on the change from Baseline to 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 | An ANCOVA model was performed on the change from Baseline to 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 | An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point. | 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 | An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point. | Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 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. | Up to 13 weeks post treatment period (up to 39 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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