- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03371355
Study of ISIS 703802 in Participants With Hypertriglyceridemia, Type 2 Diabetes Mellitus, and Nonalcoholic Fatty Liver Disease
January 28, 2021 updated by: Akcea Therapeutics
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)
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).
Study Overview
Status
Completed
Intervention / Treatment
Study Type
Interventional
Enrollment (Actual)
105
Phase
- Phase 2
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
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Ontario
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Hamilton, Ontario, Canada, L8L 5G8
- Clinical Site
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Toronto, Ontario, Canada, M3M 3E5
- Clinical Site
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Quebec
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Chicoutimi, Quebec, Canada, G7H 7K9
- Clinical Site
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Montréal, Quebec, Canada, H4A 2C6
- Clinical Site
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Arizona
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Chandler, Arizona, United States, 85224
- Clinical Sites
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Fountain Hills, Arizona, United States, 85268
- Clinical Site
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Glendale, Arizona, United States, 85306
- Clinical Site
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Mesa, Arizona, United States, 85206
- Clinical Site
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Mesa, Arizona, United States, 85213
- Clinical Site
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Phoenix, Arizona, United States, 85020
- Clinical Site
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Phoenix, Arizona, United States, 85023
- Clinical Site
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Phoenix, Arizona, United States, 85050
- Clinical Site
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California
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Huntington Park, California, United States, 90255
- Clinical Site
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Los Angeles, California, United States, 90057
- Clinical Site
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Montclair, California, United States, 91710
- Clinical Site
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Panorama City, California, United States, 91402
- Clinical Site
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Poway, California, United States, 92064
- Clinical Site
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Florida
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Boca Raton, Florida, United States, 33487
- Clinical Site
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Jensen Beach, Florida, United States, 34957
- Clinical Site
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Jupiter, Florida, United States, 33458
- Clinical Site
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Miami, Florida, United States, 33165
- Clinical Site
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Port Saint Lucie, Florida, United States, 34952
- Clinical Site
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Georgia
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Atlanta, Georgia, United States, 30328
- Clinical Site
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Illinois
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Chicago, Illinois, United States, 60640
- Clinical Site
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Indiana
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Indianapolis, Indiana, United States, 46260
- Clinical Site
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Kentucky
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Louisville, Kentucky, United States, 40213
- Clinical Site
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Minnesota
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Edina, Minnesota, United States, 55435
- Clinical Site
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New Jersey
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Bridgeton, New Jersey, United States, 08302
- Clinical Site
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Princeton, New Jersey, United States, 08540
- Clinical Site
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North Carolina
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Greensboro, North Carolina, United States, 27410
- Clinical Site
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High Point, North Carolina, United States, 27265
- Clinical Site
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Ohio
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Cincinnati, Ohio, United States, 45219
- Clinical Site
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Cincinnati, Ohio, United States, 45227
- Clinical Site
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South Carolina
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Charleston, South Carolina, United States, 29407
- Clinical Site
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Texas
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Austin, Texas, United States, 78735
- Clinical Site
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Carrollton, Texas, United States, 75010
- Clinical Site
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Dallas, Texas, United States, 75234
- Clinical Site
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Houston, Texas, United States, 77058
- Clinical Site
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Hurst, Texas, United States, 76054
- Clinical Site
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San Antonio, Texas, United States, 78215
- Clinical Site
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San Antonio, Texas, United States, 78229
- Clinical Site
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Utah
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Layton, Utah, United States, 84041
- Clinical Site
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Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years to 70 years (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
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).
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Triple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Placebo Comparator: Pooled Placebo
Participants from each cohort received placebo at a dose-matched volume of study drug, subcutaneously (SC).
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Placebo (Matched with ISIS 703802)
Other Names:
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Experimental: Cohort B: ISIS 703802, 40 mg Q4W
Participants received ISIS 703802, 40 milligrams (mg) SC once every 4 weeks for 6 doses.
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ISIS 703802 40 mg, administered via SC injection, once every 4 weeks for 6 doses.
Other Names:
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Experimental: Cohort C: ISIS 703802, 80 mg Q4W
Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses.
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ISIS 703802 80 mg, administered via SC injection, once every 4 weeks for 6 doses.
Other Names:
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Experimental: Cohort A: ISIS 703802, 20 mg QW
Participants received ISIS 703802, 20 mg once every week for 26 doses.
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ISIS 703802 20 mg, administered via SC injection, once every week for 26 doses.
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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
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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.
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Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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
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An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
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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
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An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
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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
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An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
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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
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An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
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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
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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.
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Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
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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
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An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
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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
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An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
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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
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An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
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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
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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.
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Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
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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
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An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
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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
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An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
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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
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An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
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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
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An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
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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
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An ANCOVA model was performed on the percent change from Baseline to Primary Analysis Time Point.
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Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C6
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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
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An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
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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
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An ANCOVA model was performed on the percent change from Baseline to Primary Analysis Time Point.
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Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
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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
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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.
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Week 27 for Cohort A, and Week 25 for Cohorts B and C
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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
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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.
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Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
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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
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An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
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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
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An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
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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
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An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
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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
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An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
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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
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An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
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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
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An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
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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
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An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
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Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C
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Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Time Frame: Up to 13 weeks post treatment period (up to 39 weeks)
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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.
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Up to 13 weeks post treatment period (up to 39 weeks)
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Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Collaborators
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
December 21, 2017
Primary Completion (Actual)
November 21, 2019
Study Completion (Actual)
February 24, 2020
Study Registration Dates
First Submitted
November 27, 2017
First Submitted That Met QC Criteria
December 11, 2017
First Posted (Actual)
December 13, 2017
Study Record Updates
Last Update Posted (Actual)
February 1, 2021
Last Update Submitted That Met QC Criteria
January 28, 2021
Last Verified
December 1, 2020
More Information
Terms related to this study
Keywords
- Diabetes Mellitus
- Type 2 Diabetes
- Hepatic Steatosis
- Liver Diseases
- Metabolic Disease
- Triglycerides High
- Glucose Metabolism Disorders
- Endocrine System Diseases
- Fatty Liver
- Triglycerides
- Digestive System Disease
- Liver Fat
- AKCEA-ANGPTL3-Lrx
- IONIS-ANGPTL3-Lrx
- Fatty Liver Without Mention of Alcohol
- Diabetes Mellitus Type 2 in Nonobese
- High Triglycerides
- Vupanorsen
Additional Relevant MeSH Terms
Other Study ID Numbers
- ISIS 703802-CS2
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Yes
Studies a U.S. FDA-regulated device product
No
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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