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

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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:
Collaborator:
Ionis Pharmaceuticals, Inc.
Information provided by (Responsible Party):
Akcea Therapeutics

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

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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


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




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.



Information from the National Library of Medicine

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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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03371355


Locations
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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

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

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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:
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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