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

Diabetes Mellitus, Type 2 Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03371355
• Other study ID #: ISIS 703802-CS2
• Status: Completed
• Phase: Phase 2
• Start date: December 21, 2017
• Est. completion date: February 24, 2020

Study information

• Verified date: December 2020
• Source: Akcea Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 105
• Est. completion date: February 24, 2020
• Est. primary completion date: November 21, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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 (PPAR?) 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).

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Fatty Liver
• Fatty Liver, Nonalcoholic
• Hypertriglyceridemia
• Liver Diseases
• NAFLD
• Non-alcoholic Fatty Liver Disease

Intervention

Drug:
• Placebo
Placebo (Matched with ISIS 703802)
• ISIS 703802 40 mg
ISIS 703802 40 mg, administered via SC injection, once every 4 weeks for 6 doses.
• ISIS 703802 80 mg
ISIS 703802 80 mg, administered via SC injection, once every 4 weeks for 6 doses.
• ISIS 703802 20 mg
ISIS 703802 20 mg, administered via SC injection, once every week for 26 doses.

Locations

Country	Name	City	State
Canada	Clinical Site	Chicoutimi	Quebec
Canada	Clinical Site	Hamilton	Ontario
Canada	Clinical Site	Montréal	Quebec
Canada	Clinical Site	Toronto	Ontario
United States	Clinical Site	Atlanta	Georgia
United States	Clinical Site	Austin	Texas
United States	Clinical Site	Boca Raton	Florida
United States	Clinical Site	Bridgeton	New Jersey
United States	Clinical Site	Carrollton	Texas
United States	Clinical Sites	Chandler	Arizona
United States	Clinical Site	Charleston	South Carolina
United States	Clinical Site	Chicago	Illinois
United States	Clinical Site	Cincinnati	Ohio
United States	Clinical Site	Cincinnati	Ohio
United States	Clinical Site	Dallas	Texas
United States	Clinical Site	Edina	Minnesota
United States	Clinical Site	Fountain Hills	Arizona
United States	Clinical Site	Glendale	Arizona
United States	Clinical Site	Greensboro	North Carolina
United States	Clinical Site	High Point	North Carolina
United States	Clinical Site	Houston	Texas
United States	Clinical Site	Huntington Park	California
United States	Clinical Site	Hurst	Texas
United States	Clinical Site	Indianapolis	Indiana
United States	Clinical Site	Jensen Beach	Florida
United States	Clinical Site	Jupiter	Florida
United States	Clinical Site	Layton	Utah
United States	Clinical Site	Los Angeles	California
United States	Clinical Site	Louisville	Kentucky
United States	Clinical Site	Mesa	Arizona
United States	Clinical Site	Mesa	Arizona
United States	Clinical Site	Miami	Florida
United States	Clinical Site	Montclair	California
United States	Clinical Site	Panorama City	California
United States	Clinical Site	Phoenix	Arizona
United States	Clinical Site	Phoenix	Arizona
United States	Clinical Site	Phoenix	Arizona
United States	Clinical Site	Port Saint Lucie	Florida
United States	Clinical Site	Poway	California
United States	Clinical Site	Princeton	New Jersey
United States	Clinical Site	San Antonio	Texas
United States	Clinical Site	San Antonio	Texas

Sponsors (2)

Lead Sponsor	Collaborator
Akcea Therapeutics	Ionis Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)