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

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ClinicalTrials.gov Identifier: NCT03371355
Recruitment Status : Recruiting
First Posted : December 13, 2017
Last Update Posted : June 20, 2018
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 subjects 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: ISIS 703802 Drug: Placebo Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 144 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 18, 2017
Estimated Primary Completion Date : February 28, 2019
Estimated Study Completion Date : May 31, 2019


Arm Intervention/treatment
Experimental: ISIS 703802 Dose 1
Cohort A
Drug: ISIS 703802
Randomly assigned to one of the dosing cohorts.
Other Name: AKCEA-ANGPTL3-LRx, IONIS-ANGPTL3-LRx

Experimental: ISIS 703802 Dose 2
Cohort B
Drug: ISIS 703802
Randomly assigned to one of the dosing cohorts.
Other Name: AKCEA-ANGPTL3-LRx, IONIS-ANGPTL3-LRx

Experimental: ISIS 703802 Dose 3
Cohort C
Drug: ISIS 703802
Randomly assigned to one of the dosing cohorts.
Other Name: AKCEA-ANGPTL3-LRx, IONIS-ANGPTL3-LRx

Placebo Comparator: Placebo: Sterile Normal Saline
Sterile Normal Saline (0.9% NaCl) by volume to match dose and regimen of active comparator depending on Cohort assignment
Drug: Placebo
Randomly assigned to one of the dosing cohorts. Dose of placebo in each cohort will match volume of active in that cohort.
Other Name: Sterile Normal Saline (0.9% NaCl)




Primary Outcome Measures :
  1. Percent change in fasting TG level from Baseline at the primary analysis time point. [ Time Frame: 6 months ]
    Analysis will be the pairwise comparison of percent change from Baseline to primary analysis time point in TG between ISIS 703802 treatment groups and pooled placebo group.


Secondary Outcome Measures :
  1. The safety of ISIS 703802 by the incidence of treatment-emergent adverse events [ Time Frame: 6 months ]
    The safety of ISIS 703802 will be assessed by determining adverse effects by dose. Safety results in subjects dosed with ISIS 703802 will be compared with those from subjects dosed with placebo.

  2. The effect of ISIS 703802 on changes from Baseline at End-of-Treatment on glucose metabolism [ Time Frame: 6 months ]
    Analysis will be the change at the primary analysis time point in blood glucose metabolism.

  3. The effect of ISIS 703802 on changes from Baseline at End-of-Treatment lipid metabolism [ Time Frame: 6 months ]
    Analysis will be the change at the primary analysis time point in markers of lipid metabolism.

  4. The effect of ISIS 703802 on changes from Baseline at End-of-Treatment on liver fat [ Time Frame: 6 months ]
    Analysis will be the change of hepatic fat fraction (HFF) by MRI-PDFF compared between each ISIS 703802 treatment groups and pooled. placebo group.

  5. Plasma Cmax of ISIS 703802 across different doses and dose regimens [ Time Frame: 6 months ]
    Cmax of ISIS 703802 in plasma will be calculated for the treatment groups.

  6. Plasma Tmax of ISIS 703802 across different doses and dose regimens [ Time Frame: 6 months ]
    Tmax of ISIS 703802 in plasma will be calculated for the treatment groups.

  7. Plasma AUC values of ISIS 703802 across different doses and dose regimens [ Time Frame: 6 months ]
    Plasma AUC values of ISIS 703802 will be calculated for the treatment groups.

  8. The effect of ISIS 703802 on changes from Baseline on biomarkers related to liver inflammation [ Time Frame: 6 months ]
    Absolute change in ALT and AST and various markers of liver inflammation and fibrosis will be compared between each ISIS 703802 treatment group and pooled placebo group.

  9. The effect of ISIS 703802 on changes from Baseline on adipose tissue as related to body composition [ Time Frame: 6 months ]
    Absolute change in body composition as measured by single slice MRI of adipose tissue will be compared between each ISIS 703802 treatment group and pooled placebo group.

  10. The effect of ISIS 703802 on changes from Baseline on WHR (waist-to-hip ratio) as related to body composition. [ Time Frame: 6 months ]
    Absolute change in Body composition as measured WHR (waist-to-hip ratio) will be compared between each ISIS 703802 treatment group and pooled placebo group.

  11. The effect of ISIS 703802 on changes from Baseline on BMI (Body Mass Index) as related to body composition [ Time Frame: 6 months ]
    Absolute change in Body composition as measured by BMI will be compared between each ISIS 703802 treatment group and pooled placebo group.



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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

Inclusion Criteria:

  • Plasma TG at Screening > 200 mg/dL and at qualification of ≥ 150 mg/dL
  • Documented history of hepatic steatosis with baseline MRI indicating hepatic fat fraction (HFF) ≥ 10%
  • Diagnosis of Type 2 Diabetes Mellitus with Hemoglobin A1c ≥ 7 and ≤ 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 kg/m2, inclusive, at Screening

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 NYHA greater than Class II
  • Use of Insulin or insulin analogs, GLP-1 agonists, and PPARᵞ agonists (pioglitazone or rosiglitazone)
  • Weight change > 5% within 3 months before Screening
  • Conditions contraindicated for MRI procedures including any metal implant (e.g., 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


Contacts
Contact: Akcea Therapeutics 617-207-0289 clinicalstudies@akceatx.com

Locations
United States, Arizona
Clinical Site Recruiting
Phoenix, Arizona, United States, 85023
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United States, California
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Huntington Park, California, United States, 90255
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Los Angeles, California, United States, 90057
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Montclair, California, United States, 91710
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Panorama City, California, United States, 91402
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United States, Florida
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Boca Raton, Florida, United States, 33487
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Jupiter, Florida, United States, 33458
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Port Saint Lucie, Florida, United States, 34952
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United States, Georgia
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Atlanta, Georgia, United States, 30328
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United States, Illinois
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Chicago, Illinois, United States, 60640
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United States, Kentucky
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Louisville, Kentucky, United States, 40213
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United States, North Carolina
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Greensboro, North Carolina, United States, 27410
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High Point, North Carolina, United States, 27265
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United States, Ohio
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Cincinnati, Ohio, United States, 45219
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Cincinnati, Ohio, United States, 45227
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United States, South Carolina
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Charleston, South Carolina, United States, 29407
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United States, Texas
Clinical Site Recruiting
Austin, Texas, United States, 78735
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Carrollton, Texas, United States, 75010
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Hurst, Texas, United States, 76054
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San Antonio, Texas, United States, 78215
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Canada, Ontario
Clinical Site Recruiting
Hamilton, Ontario, Canada, L8L 5G8
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Toronto, Ontario, Canada, M3M 3E5
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Canada, Quebec
Clinical Site Recruiting
Chicoutimi, Quebec, Canada, G7H 7K9
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Sponsors and Collaborators
Akcea Therapeutics
Ionis Pharmaceuticals, Inc.

Responsible Party: Akcea Therapeutics
ClinicalTrials.gov Identifier: NCT03371355     History of Changes
Other Study ID Numbers: ISIS 703802-CS2
First Posted: December 13, 2017    Key Record Dates
Last Update Posted: June 20, 2018
Last Verified: June 2018

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

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Liver Diseases
Fatty Liver
Hypertriglyceridemia
Non-alcoholic Fatty Liver Disease
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Digestive System Diseases
Hyperlipidemias
Dyslipidemias
Lipid Metabolism Disorders