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

NCT03371355 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: ISIS 703802-CS2
• Study Type: interventional
• Target: 105
• Locations: 2 countries
• Sites: 42

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).

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (26)

• 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 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 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 Lipoprotein(a) (Lp[a]) 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

Study Arms (4)

Pooled Placebo

PLACEBO COMPARATOR

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

Drug: Placebo

Cohort B: ISIS 703802, 40 mg Q4W

EXPERIMENTAL

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

Drug: ISIS 703802 40 mg

Cohort C: ISIS 703802, 80 mg Q4W

EXPERIMENTAL

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

Drug: ISIS 703802 80 mg

Cohort A: ISIS 703802, 20 mg QW

EXPERIMENTAL

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

Drug: ISIS 703802 20 mg

Interventions

Placebo DRUG

Placebo (Matched with ISIS 703802)

Also known as: Sterile Normal Saline (0.9% NaCl)

Pooled Placebo

ISIS 703802 40 mg DRUG

ISIS 703802 40 mg, administered via SC injection, once every 4 weeks for 6 doses.

Also known as: AKCEA-ANGPTL3-LRx, IONIS-ANGPTL3-LRx, Vupanorsen

Cohort B: ISIS 703802, 40 mg Q4W

ISIS 703802 80 mg DRUG

ISIS 703802 80 mg, administered via SC injection, once every 4 weeks for 6 doses.

Also known as: AKCEA-ANGPTL3-LRx, IONIS-ANGPTL3-LRx, Vupanorsen

Cohort C: ISIS 703802, 80 mg Q4W

ISIS 703802 20 mg DRUG

ISIS 703802 20 mg, administered via SC injection, once every week for 26 doses.

Also known as: AKCEA-ANGPTL3-LRx, IONIS-ANGPTL3-LRx, Vupanorsen

Cohort A: ISIS 703802, 20 mg QW

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• Akcea Therapeutics: lead
• Ionis Pharmaceuticals, Inc.: collaborator

Study Sites (42)

Clinical Sites

Chandler, Arizona, 85224, United States

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Fountain Hills, Arizona, 85268, United States

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Glendale, Arizona, 85306, United States

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Mesa, Arizona, 85206, United States

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Mesa, Arizona, 85213, United States

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Phoenix, Arizona, 85020, United States

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Phoenix, Arizona, 85023, United States

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Phoenix, Arizona, 85050, United States

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Huntington Park, California, 90255, United States

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Los Angeles, California, 90057, United States

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Montclair, California, 91710, United States

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Panorama City, California, 91402, United States

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Poway, California, 92064, United States

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Boca Raton, Florida, 33487, United States

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Jensen Beach, Florida, 34957, United States

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Jupiter, Florida, 33458, United States

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Miami, Florida, 33165, United States

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Port Saint Lucie, Florida, 34952, United States

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Atlanta, Georgia, 30328, United States

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Chicago, Illinois, 60640, United States

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Indianapolis, Indiana, 46260, United States

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Louisville, Kentucky, 40213, United States

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Edina, Minnesota, 55435, United States

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Bridgeton, New Jersey, 08302, United States

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Princeton, New Jersey, 08540, United States

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Greensboro, North Carolina, 27410, United States

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High Point, North Carolina, 27265, United States

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Cincinnati, Ohio, 45219, United States

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Cincinnati, Ohio, 45227, United States

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Charleston, South Carolina, 29407, United States

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Austin, Texas, 78735, United States

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Carrollton, Texas, 75010, United States

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Dallas, Texas, 75234, United States

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Houston, Texas, 77058, United States

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Hurst, Texas, 76054, United States

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San Antonio, Texas, 78215, United States

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San Antonio, Texas, 78229, United States

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Layton, Utah, 84041, United States

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Hamilton, Ontario, L8L 5G8, Canada

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Toronto, Ontario, M3M 3E5, Canada

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Chicoutimi, Quebec, G7H 7K9, Canada

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Montreal, Quebec, H4A 2C6, Canada

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MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease; Diabetes Mellitus, Type 2; Hypertriglyceridemia; Fatty Liver; Liver Diseases; Diabetes Mellitus; Metabolic Diseases; Endocrine System Diseases; Digestive System Diseases; Glucose Metabolism Disorders

Interventions

IONIS-ANGPTL3-LRx; vupanorsen

Condition Hierarchy (Ancestors)

Nutritional and Metabolic Diseases; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders

Results Point of Contact

• Title: Study Director
• Organization: Akcea Therapeutics

clinicalstudies@akceatx.com

617-207-0289

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 27, 2017
• First Posted: December 13, 2017
• Study Start: December 21, 2017
• Primary Completion: November 21, 2019
• Study Completion: February 24, 2020
• Last Updated: February 1, 2021
• Results First Posted: February 1, 2021

Record last verified: 2020-12

Locations

US (38); CA (4)