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

• ClinicalTrials.gov Identifier: NCT03371355
• Recruitment Status: Completed
• First Posted: December 13, 2017
• Results First Posted: February 1, 2021
• Last Update Posted: February 1, 2021
• Sponsor: Akcea Therapeutics
• Collaborator: Ionis Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Akcea Therapeutics

Study Description

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).

Condition or disease	Intervention/treatment	Phase
NAFLD; Diabetes Mellitus, Type 2; Hypertriglyceridemia; Fatty Liver, Nonalcoholic	Drug: Placebo; Drug: ISIS 703802 40 mg; Drug: ISIS 703802 80 mg; Drug: ISIS 703802 20 mg	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 105 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: December 21, 2017
• Actual Primary Completion Date: November 21, 2019
• Actual Study Completion Date: February 24, 2020

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Pooled Placebo; Participants from each cohort received placebo at a dose-matched volume of study drug, subcutaneously (SC).	Drug: Placebo; Placebo (Matched with ISIS 703802); Other Name: Sterile Normal Saline (0.9% NaCl)
Experimental: Cohort B: ISIS 703802, 40 mg Q4W; Participants received ISIS 703802, 40 milligrams (mg) SC once every 4 weeks for 6 doses.	Drug: ISIS 703802 40 mg; ISIS 703802 40 mg, administered via SC injection, once every 4 weeks for 6 doses.; Other Names: AKCEA-ANGPTL3-LRx; IONIS-ANGPTL3-LRx; Vupanorsen
Experimental: Cohort C: ISIS 703802, 80 mg Q4W; Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses.	Drug: ISIS 703802 80 mg; ISIS 703802 80 mg, administered via SC injection, once every 4 weeks for 6 doses.; Other Names: AKCEA-ANGPTL3-LRx; IONIS-ANGPTL3-LRx; Vupanorsen
Experimental: Cohort A: ISIS 703802, 20 mg QW; Participants received ISIS 703802, 20 mg once every week for 26 doses.	Drug: ISIS 703802 20 mg; ISIS 703802 20 mg, administered via SC injection, once every week for 26 doses.; Other Names: AKCEA-ANGPTL3-LRx; IONIS-ANGPTL3-LRx; Vupanorsen

Outcome Measures

Primary Outcome Measures :

1. 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 Outcome Measures :

1. Change From Baseline in Angiopoietin-Like 3 Protein 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 change from Baseline to Primary Analysis Time Point.
2. 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 [ Time Frame: 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.
3. Change From Baseline in Free Fatty Acid (FFA) at 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 change from Baseline to Primary Analysis Time Point.
4. Change From Baseline in Lipoprotein(a) (Lp[a]) 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 change from Baseline to Primary Analysis Time Point.
5. 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 [ 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.
6. Change From Baseline in Fasting Plasma Glucose 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 change from Baseline to Primary Analysis Time Point.
7. Change From Baseline in Hemoglobin A1c (HbA1c) 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 change from Baseline to Primary Analysis Time Point.
8. Change From Baseline in Fasting Insulin 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 change from Baseline to Primary Analysis Time Point.
9. Change From Baseline in and HOMA-IR at the Primary Analysis Time Point [ Time Frame: 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.
10. Change From Baseline in Fructosamine at 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 change from Baseline to Primary Analysis Time Point.
11. Change From Baseline in Glycated Albumin 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 change from Baseline to Primary Analysis Time Point.
12. Change From Baseline in Weight 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 change from Baseline to Primary Analysis Time Point.
13. Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) 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 change from Baseline to Primary Analysis Time Point.
14. Percent Change From Baseline in Weight, SBP and DBP at Primary Analysis Time Point [ Time Frame: 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.
15. 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 [ Time Frame: 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.
16. 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 [ Time Frame: 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.
17. Percentage of Participants With HFF ≤ 8% by MRI-PDFF at the Primary Analysis Time Point [ Time Frame: 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.
18. Change From Baseline in Fatty Liver Index (FLI) at the Primary Analysis Time Point [ Time Frame: 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.
19. Change From Baseline in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) 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 change from Baseline to Primary Analysis Time Point.
20. Change From Baseline in Leptin 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 change from Baseline to Primary Analysis Time Point.
21. Change From Baseline in Adiponectin 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 change from Baseline to Primary Analysis Time Point.
22. Change From Baseline in Subcutaneous Adipose Tissue (SAT) and Visceral Adipose Tissue (VAT) by Single Slice MRI at the Primary Analysis Timepoint [ Time Frame: 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.
23. Change From Baseline in Waist Circumference by Single Slice MRI at the Primary Analysis Timepoint [ Time Frame: 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.
24. Change From Baseline in Waist to Hip Ratio (WHR) at the Primary Analysis Timepoint [ Time Frame: 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.
25. Change From Baseline in Body Mass Index (BMI) at the Primary Analysis Timepoint [ Time Frame: 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.
26. Number of Participants With Treatment-emergent Adverse Events (TEAEs) [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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).

Contacts and Locations

Locations

United States, Arizona

Clinical Sites

Chandler, Arizona, United States, 85224

Clinical Site

Fountain Hills, Arizona, United States, 85268

Clinical Site

Glendale, Arizona, United States, 85306

Clinical Site

Mesa, Arizona, United States, 85206

Clinical Site

Mesa, Arizona, United States, 85213

Clinical Site

Phoenix, Arizona, United States, 85020

Clinical Site

Phoenix, Arizona, United States, 85023

Clinical Site

Phoenix, Arizona, United States, 85050

United States, California

Clinical Site

Huntington Park, California, United States, 90255

Clinical Site

Los Angeles, California, United States, 90057

Clinical Site

Montclair, California, United States, 91710

Clinical Site

Panorama City, California, United States, 91402

Clinical Site

Poway, California, United States, 92064

United States, Florida

Clinical Site

Boca Raton, Florida, United States, 33487

Clinical Site

Jensen Beach, Florida, United States, 34957

Clinical Site

Jupiter, Florida, United States, 33458

Clinical Site

Miami, Florida, United States, 33165

Clinical Site

Port Saint Lucie, Florida, United States, 34952

United States, Georgia

Clinical Site

Atlanta, Georgia, United States, 30328

United States, Illinois

Clinical Site

Chicago, Illinois, United States, 60640

United States, Indiana

Clinical Site

Indianapolis, Indiana, United States, 46260

United States, Kentucky

Clinical Site

Louisville, Kentucky, United States, 40213

United States, Minnesota

Clinical Site

Edina, Minnesota, United States, 55435

United States, New Jersey

Clinical Site

Bridgeton, New Jersey, United States, 08302

Clinical Site

Princeton, New Jersey, United States, 08540

United States, North Carolina

Clinical Site

Greensboro, North Carolina, United States, 27410

Clinical Site

High Point, North Carolina, United States, 27265

United States, Ohio

Clinical Site

Cincinnati, Ohio, United States, 45219

Clinical Site

Cincinnati, Ohio, United States, 45227

United States, South Carolina

Clinical Site

Charleston, South Carolina, United States, 29407

United States, Texas

Clinical Site

Austin, Texas, United States, 78735

Clinical Site

Carrollton, Texas, United States, 75010

Clinical Site

Dallas, Texas, United States, 75234

Clinical Site

Houston, Texas, United States, 77058

Clinical Site

Hurst, Texas, United States, 76054

Clinical Site

San Antonio, Texas, United States, 78215

Clinical Site

San Antonio, Texas, United States, 78229

United States, Utah

Clinical Site

Layton, Utah, United States, 84041

Canada, Ontario

Clinical Site

Hamilton, Ontario, Canada, L8L 5G8

Clinical Site

Toronto, Ontario, Canada, M3M 3E5

Canada, Quebec

Clinical Site

Chicoutimi, Quebec, Canada, G7H 7K9

Clinical Site

Montréal, Quebec, Canada, H4A 2C6

Sponsors and Collaborators

Akcea Therapeutics

Ionis Pharmaceuticals, Inc.

  Study Documents (Full-Text)

Documents provided by Akcea Therapeutics:

Study Protocol  [PDF] March 21, 2019

Statistical Analysis Plan  [PDF] December 12, 2019

More Information

• Responsible Party: Akcea Therapeutics
• ClinicalTrials.gov Identifier: NCT03371355
• Other Study ID Numbers: ISIS 703802-CS2
• First Posted: December 13, 2017
• Results First Posted: February 1, 2021
• Last Update Posted: February 1, 2021
• Last Verified: December 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Akcea Therapeutics:

AKCEA-ANGPTL3-Lrx; Type 2 Diabetes; Hepatic Steatosis; Triglycerides; 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

Additional relevant MeSH terms:

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