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

Sponsor
Akcea Therapeutics (Industry)
Overall Status
Completed
CT.gov ID
NCT03371355
Collaborator
Ionis Pharmaceuticals, Inc. (Industry)
105
Enrollment
42
Locations
4
Arms
26.1
Actual Duration (Months)
2.5
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

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
  • Drug: Placebo
  • Drug: ISIS 703802 40 mg
  • Drug: ISIS 703802 80 mg
  • Drug: ISIS 703802 20 mg
 Phase 2

Study Design

Study Type:
Interventional
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 :
Dec 21, 2017
Actual Primary Completion Date :
Nov 21, 2019
Actual Study Completion Date :
Feb 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 Names:
  • 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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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) [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

    Criteria

    Ages Eligible for Study:
    18 Years to 70 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Site City State Country Postal Code
    1 Clinical Sites Chandler Arizona United States 85224
    2 Clinical Site Fountain Hills Arizona United States 85268
    3 Clinical Site Glendale Arizona United States 85306
    4 Clinical Site Mesa Arizona United States 85206
    5 Clinical Site Mesa Arizona United States 85213
    6 Clinical Site Phoenix Arizona United States 85020
    7 Clinical Site Phoenix Arizona United States 85023
    8 Clinical Site Phoenix Arizona United States 85050
    9 Clinical Site Huntington Park California United States 90255
    10 Clinical Site Los Angeles California United States 90057
    11 Clinical Site Montclair California United States 91710
    12 Clinical Site Panorama City California United States 91402
    13 Clinical Site Poway California United States 92064
    14 Clinical Site Boca Raton Florida United States 33487
    15 Clinical Site Jensen Beach Florida United States 34957
    16 Clinical Site Jupiter Florida United States 33458
    17 Clinical Site Miami Florida United States 33165
    18 Clinical Site Port Saint Lucie Florida United States 34952
    19 Clinical Site Atlanta Georgia United States 30328
    20 Clinical Site Chicago Illinois United States 60640
    21 Clinical Site Indianapolis Indiana United States 46260
    22 Clinical Site Louisville Kentucky United States 40213
    23 Clinical Site Edina Minnesota United States 55435
    24 Clinical Site Bridgeton New Jersey United States 08302
    25 Clinical Site Princeton New Jersey United States 08540
    26 Clinical Site Greensboro North Carolina United States 27410
    27 Clinical Site High Point North Carolina United States 27265
    28 Clinical Site Cincinnati Ohio United States 45219
    29 Clinical Site Cincinnati Ohio United States 45227
    30 Clinical Site Charleston South Carolina United States 29407
    31 Clinical Site Austin Texas United States 78735
    32 Clinical Site Carrollton Texas United States 75010
    33 Clinical Site Dallas Texas United States 75234
    34 Clinical Site Houston Texas United States 77058
    35 Clinical Site Hurst Texas United States 76054
    36 Clinical Site San Antonio Texas United States 78215
    37 Clinical Site San Antonio Texas United States 78229
    38 Clinical Site Layton Utah United States 84041
    39 Clinical Site Hamilton Ontario Canada L8L 5G8
    40 Clinical Site Toronto Ontario Canada M3M 3E5
    41 Clinical Site Chicoutimi Quebec Canada G7H 7K9
    42 Clinical Site Montréal Quebec Canada H4A 2C6

    Sponsors and Collaborators

    • Akcea Therapeutics
    • Ionis Pharmaceuticals, Inc.

    Investigators

    None specified.

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Akcea Therapeutics
    ClinicalTrials.gov Identifier:
    NCT03371355
    Other Study ID Numbers:
    • ISIS 703802-CS2
    First Posted:
    Dec 13, 2017
    Last Update Posted:
    Feb 1, 2021
    Last Verified:
    Dec 1, 2020
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Akcea Therapeutics
    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
    Additional relevant MeSH terms:
    Liver Diseases
    Fatty Liver
    Non-alcoholic Fatty Liver Disease
    Diabetes Mellitus
    Diabetes Mellitus, Type 2
    Hypertriglyceridemia

    Study Results

    Participant Flow

    Recruitment Details The study was conducted at 42 study centers; 38 sites in the US and 4 sites in Canada.
    Pre-assignment Detail A total of 525 participants were screened. 105 were randomized in a 1:1:1 ratio to Cohorts A, B, or C. In each cohort, participants were randomized in a 3:1 ratio to receive ISIS 703802 or matching volume of placebo.
    Arm/Group Title Pooled Placebo Cohort B: ISIS 703802, 40 mg Q4W Cohort C: ISIS 703802, 80 mg Q4W Cohort A: ISIS 703802, 20 mg QW
    Arm/Group Description Participants from each cohort received placebo at a dose-matched volume of study drug, subcutaneously (SC). Participants received ISIS 703802, 40 milligrams (mg) SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 20 mg SC once every week for 26 doses.
    Period Title: Overall Study
    STARTED 27 26 26 26
    COMPLETED 26 24 22 19
    NOT COMPLETED 1 2 4 7

    Baseline Characteristics

    Arm/Group Title Pooled Placebo Cohort B: ISIS 703802, 40 mg Q4W Cohort C: ISIS 703802, 80 mg Q4W Cohort A: ISIS 703802, 20 mg QW Total
    Arm/Group Description Participants from each cohort received placebo at a dose-matched volume of study drug, SC. Participants received ISIS 703802, 40 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 20 mg SC once every week for 26 doses. Total of all reporting groups
    Overall Participants 27 26 26 26 105
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    51.1
    (7.29)
    52.0
    (10.34)
    54.8
    (6.04)
    56.0
    (8.45)
    53.5
    (8.30)
    Sex: Female, Male (Count of Participants)
    Female
    16
    59.3%
    9
    34.6%
    13
    50%
    11
    42.3%
    49
    46.7%
    Male
    11
    40.7%
    17
    65.4%
    13
    50%
    15
    57.7%
    56
    53.3%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    24
    88.9%
    13
    50%
    11
    42.3%
    17
    65.4%
    65
    61.9%
    Not Hispanic or Latino
    3
    11.1%
    13
    50%
    15
    57.7%
    9
    34.6%
    40
    38.1%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    1
    3.7%
    1
    3.8%
    1
    3.8%
    0
    0%
    3
    2.9%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    1
    3.7%
    2
    7.7%
    1
    3.8%
    1
    3.8%
    5
    4.8%
    White
    25
    92.6%
    23
    88.5%
    24
    92.3%
    25
    96.2%
    97
    92.4%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Fasting Triglycerides (TG) (milligrams per deciliter (mg/dL)) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [milligrams per deciliter (mg/dL)]
    275.5
    (110.38)
    414.9
    (456.86)
    292.2
    (130.98)
    311.8
    (155.92)
    323.1
    (257.20)
    Angiopoietin Like 3 (ANGPTL3) (micrograms per liter (μg/L)) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [micrograms per liter (μg/L)]
    114.85
    (32.066)
    102.36
    (28.923)
    111.86
    (37.463)
    108.60
    (42.722)
    109.47
    (35.441)
    Total Cholesterol (TC) (mg/dL) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [mg/dL]
    202.1
    (43.64)
    200.7
    (45.27)
    191.2
    (61.63)
    182.4
    (47.06)
    194.2
    (49.78)
    Non- High density lipoprotein cholesterol (Non-HDL-C) (mg/dL) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [mg/dL]
    162.7
    (39.90)
    164.3
    (47.50)
    154.1
    (58.28)
    146.8
    (46.79)
    157.0
    (48.30)
    High density lipoprotein cholesterol (HDL-C) (mg/dL) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [mg/dL]
    39.4
    (10.43)
    36.3
    (10.54)
    37.1
    (10.37)
    35.6
    (9.89)
    37.1
    (10.26)
    Low Density Lipoprotein Cholesterol (LDL-C) (mg/dL) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [mg/dL]
    111.5
    (43.06)
    98.2
    (36.13)
    101.0
    (53.13)
    88.6
    (37.69)
    99.8
    (43.05)
    Very Low Density Lipoprotein Cholesterol (VLDL-C) (mg/dL) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [mg/dL]
    47.8
    (12.90)
    52.6
    (14.59)
    47.6
    (9.92)
    49.6
    (13.11)
    49.4
    (12.71)
    Apolipoprotein CIII (ApoCIII) (mg/dL) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [mg/dL]
    14.48
    (3.981)
    18.71
    (11.024)
    15.54
    (4.969)
    16.19
    (5.562)
    16.21
    (7.000)
    Apolipoprotein A1 (ApoA1) (mg/dL) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [mg/dL]
    141.3
    (19.30)
    137.9
    (21.12)
    139.1
    (24.12)
    133.3
    (20.18)
    137.9
    (21.13)
    Apolipoprotein B (ApoB) (mg/dL) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [mg/dL]
    108.68
    (25.254)
    105.90
    (25.868)
    105.34
    (36.160)
    95.48
    (26.210)
    103.90
    (28.721)
    Apolipoprotein B48 (ApoB-48) (mg/dL) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [mg/dL]
    2.63
    (1.455)
    3.21
    (2.239)
    3.20
    (2.863)
    3.48
    (3.228)
    3.13
    (2.511)
    Apolipoprotein B100 (ApoB-100) (mg/dL) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [mg/dL]
    105.89
    (25.699)
    102.48
    (25.740)
    102.14
    (35.392)
    91.79
    (25.871)
    100.62
    (28.540)
    Lipoprotein-a (Lp[a]) (nanomoles per liter (nmol/L)) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [nanomoles per liter (nmol/L)]
    51.7
    (66.79)
    58.2
    (74.74)
    46.7
    (74.88)
    38.3
    (54.81)
    48.8
    (67.69)
    Free Fatty Acid (FFA) (millimole per liter (mmol/L)) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [millimole per liter (mmol/L)]
    0.62
    (0.261)
    0.66
    (0.266)
    0.61
    (0.237)
    0.58
    (0.213)
    0.62
    (0.243)
    Insulin (milli international units per liter) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [milli international units per liter]
    26.35
    (16.965)
    21.35
    (12.602)
    26.32
    (15.353)
    23.19
    (12.887)
    24.31
    (14.542)
    Plasma Glucose (mg/dL) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [mg/dL]
    188.6
    (59.06)
    182.6
    (58.87)
    201.4
    (52.16)
    164.6
    (47.69)
    184.4
    (55.55)
    Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) (index) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [index]
    12.40
    (8.548)
    9.42
    (6.178)
    13.02
    (8.331)
    9.54
    (6.278)
    11.10
    (7.500)
    Fructosamine (micromoles per liter (μmol/L)) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [micromoles per liter (μmol/L)]
    325.2
    (49.62)
    302.7
    (65.51)
    317.6
    (59.33)
    312.9
    (48.19)
    314.7
    (55.85)
    Glycated Albumin (grams per deciliter (g/dL)) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [grams per deciliter (g/dL)]
    0.84
    (0.183)
    0.74
    (0.254)
    0.80
    (0.216)
    0.79
    (0.187)
    0.79
    (0.211)
    Hemoglobin A1C (HbA1C) (percentage of HbA1c) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [percentage of HbA1c]
    8.30
    (1.260)
    8.04
    (1.113)
    8.36
    (1.091)
    8.19
    (0.901)
    8.22
    (1.091)
    Hepatic Fat Fraction (HFF) (percentage (Hepatic Fat Fraction)) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [percentage (Hepatic Fat Fraction)]
    16.84
    (6.144)
    17.17
    (6.150)
    17.23
    (7.262)
    19.32
    (10.445)
    17.63
    (7.642)
    Subcutaneous Adipose Tissue (SAT) (millimeters square (mm^2)) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [millimeters square (mm^2)]
    2634.49
    (1235.433)
    3076.36
    (1114.681)
    3021.37
    (1080.432)
    2701.94
    (1000.756)
    2856.41
    (1113.220)
    Visceral Adipose Tissue (VAT), (mm^2) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [mm^2]
    2275.05
    (605.492)
    2690.34
    (888.431)
    2826.84
    (1105.086)
    2773.11
    (894.630)
    2637.85
    (903.168)
    Fatty Liver Index (FLI) (index) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [index]
    77.20
    (22.618)
    85.55
    (12.802)
    83.16
    (19.846)
    84.45
    (13.926)
    82.51
    (17.907)
    Body Weight (kg) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [kg]
    79.3
    (10.64)
    92.5
    (16.66)
    90.7
    (20.83)
    92.0
    (16.39)
    88.5
    (17.15)
    Body Mass Index (BMI) (kilograms per meter square (kg/m^2)) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [kilograms per meter square (kg/m^2)]
    30.3
    (3.03)
    32.8
    (3.97)
    32.1
    (3.84)
    32.3
    (4.19)
    31.9
    (3.84)
    Waist to Hip Ratio (ratio) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [ratio]
    0.98
    (0.070)
    1.05
    (0.225)
    1.01
    (0.216)
    0.97
    (0.068)
    1.00
    (0.163)

    Outcome Measures

    1. Primary Outcome
    Title Percent Change From Baseline in Fasting Triglycerides Level at the Primary Analysis Time Point
    Description 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.
    Time Frame Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C

    Outcome Measure Data

    Analysis Population Description
    FAS population included all participants who were randomized and received at least 1 dose of study drug.
    Arm/Group Title Pooled Placebo Cohort B: ISIS 703802, 40 mg Q4W Cohort C: ISIS 703802, 80 mg Q4W Cohort A: ISIS 703802, 20 mg QW
    Arm/Group Description Participants from each cohort received placebo at a dose-matched volume of study drug, SC. Participants received ISIS 703802, 40 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 20 mg SC once every week for 26 doses.
    Measure Participants 27 26 26 26
    Geometric Mean (95% Confidence Interval) [percent change]
    -16
    -36
    -53
    -47
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0343
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -24
    Confidence Interval (2-Sided) 95%
    -41 to -2
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -44
    Confidence Interval (2-Sided) 95%
    -56 to -28
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0009
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -37
    Confidence Interval (2-Sided) 95%
    -52 to -17
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    2. Secondary Outcome
    Title Change From Baseline in Angiopoietin-Like 3 Protein at the Primary Analysis Time Point
    Description An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
    Time Frame Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C

    Outcome Measure Data

    Analysis Population Description
    FAS population included all participants who were randomized and received at least 1 dose of study drug. Here, overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Pooled Placebo Cohort B: ISIS 703802, 40 mg Q4W Cohort C: ISIS 703802, 80 mg Q4W Cohort A: ISIS 703802, 20 mg QW
    Arm/Group Description Participants from each cohort received placebo at a dose-matched volume of study drug, SC. Participants received ISIS 703802, 40 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 20 mg SC once every week for 26 doses.
    Measure Participants 26 24 23 17
    Least Squares Mean (95% Confidence Interval) [μg/L]
    6.77
    -43.11
    -64.89
    -52.98
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -49.87
    Confidence Interval (2-Sided) 95%
    -62.68 to -37.06
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -71.66
    Confidence Interval (2-Sided) 95%
    -84.47 to -58.85
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -59.74
    Confidence Interval (2-Sided) 95%
    -74.04 to -45.44
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    Title 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
    Description An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
    Time Frame Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C

    Outcome Measure Data

    Analysis Population Description
    FAS population included all participants who were randomized and received at least 1 dose of study drug. Here, 'number analyzed' (n) signifies participants evaluable for this outcome measure for each specified category.
    Arm/Group Title Pooled Placebo Cohort B: ISIS 703802, 40 mg Q4W Cohort C: ISIS 703802, 80 mg Q4W Cohort A: ISIS 703802, 20 mg QW
    Arm/Group Description Participants from each cohort received placebo at a dose-matched volume of study drug, SC. Participants received ISIS 703802, 40 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 20 mg SC once every week for 26 doses.
    Measure Participants 27 26 26 26
    TC
    -4.8
    -21.3
    -41.9
    -36.5
    LDL-C
    -2.5
    5.0
    -11.1
    -11.3
    HDL-C
    2.2
    -0.6
    -6.4
    -2.0
    VLDL-C
    -6.5
    -15.6
    -21.9
    -17.3
    Non-HDL-C
    -7.0
    -20.9
    -35.4
    -34.4
    ApoB
    -3.63
    -6.08
    -13.46
    -8.91
    ApoB: ApoB-48
    -0.139
    -1.140
    -1.942
    -1.230
    ApoB: ApoB-100
    -3.757
    -4.643
    -11.346
    -7.174
    ApoCIII
    -0.729
    -5.482
    -9.228
    -7.588
    ApoA1
    5.0
    -11.8
    -30.1
    -16.1
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments TC
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0327
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -16.5
    Confidence Interval (2-Sided) 95%
    -31.59 to -1.39
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments TC
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -37.0
    Confidence Interval (2-Sided) 95%
    -52.15 to -21.94
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments TC
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0003
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -31.6
    Confidence Interval (2-Sided) 95%
    -48.23 to -15.05
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments LDL-C
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2560
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 7.5
    Confidence Interval (2-Sided) 95%
    -5.55 to 20.54
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments LDL-C
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1795
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -8.6
    Confidence Interval (2-Sided) 95%
    -21.26 to 4.05
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments LDL-C
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2065
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -8.8
    Confidence Interval (2-Sided) 95%
    -22.48 to 4.95
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments HDL-C
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1515
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -2.7
    Confidence Interval (2-Sided) 95%
    -6.43 to 1.01
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments HDL-C
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -8.6
    Confidence Interval (2-Sided) 95%
    -12.29 to -4.91
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments HDL-C
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0436
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -4.1
    Confidence Interval (2-Sided) 95%
    -8.18 to -0.12
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 10
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments VLDL-C
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0224
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -9.1
    Confidence Interval (2-Sided) 95%
    -16.94 to -1.33
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 11
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments VLDL-C
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -15.4
    Confidence Interval (2-Sided) 95%
    -22.94 to -7.84
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 12
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments VLDL-C
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0091
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -10.8
    Confidence Interval (2-Sided) 95%
    -18.86 to -2.78
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 13
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments Non-HDL-C
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0748
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -13.9
    Confidence Interval (2-Sided) 95%
    -29.12 to 1.42
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 14
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments Non-HDL-C
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0004
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -28.4
    Confidence Interval (2-Sided) 95%
    -43.68 to -13.18
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 15
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments Non-HDL-C
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0016
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -27.4
    Confidence Interval (2-Sided) 95%
    -44.08 to -10.64
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 16
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments ApoB
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6005
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -2.44
    Confidence Interval (2-Sided) 95%
    -11.68 to 6.80
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 17
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments ApoB
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0374
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -9.83
    Confidence Interval (2-Sided) 95%
    -19.07 to -0.59
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 18
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments ApoB
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3100
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -5.28
    Confidence Interval (2-Sided) 95%
    -15.55 to 5.00
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 19
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments ApoB-48
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0728
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -1.002
    Confidence Interval (2-Sided) 95%
    -2.10 to 0.09
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 20
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments ApoB-48
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0018
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -1.803
    Confidence Interval (2-Sided) 95%
    -2.91 to -0.69
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 21
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments ApoB-48
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0759
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -1.091
    Confidence Interval (2-Sided) 95%
    -2.30 to 0.12
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 22
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments ApoB-100
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8451
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.887
    Confidence Interval (2-Sided) 95%
    -9.89 to 8.11
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 23
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments ApoB-100
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0973
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -7.590
    Confidence Interval (2-Sided) 95%
    -16.59 to 1.41
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 24
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments ApoB-100
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5000
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -3.418
    Confidence Interval (2-Sided) 95%
    -13.45 to 6.61
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 25
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments ApoCIII
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0008
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -4.753
    Confidence Interval (2-Sided) 95%
    -7.47 to -2.03
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 26
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments ApoCIII
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -8.499
    Confidence Interval (2-Sided) 95%
    -11.18 to -5.82
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 27
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments ApoCIII
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -6.860
    Confidence Interval (2-Sided) 95%
    -9.78 to -3.93
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 28
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments ApoA1
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0003
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -16.8
    Confidence Interval (2-Sided) 95%
    -25.80 to -7.85
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 29
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments ApoA1
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -35.2
    Confidence Interval (2-Sided) 95%
    -44.07 to -26.24
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 30
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments ApoA1
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -21.1
    Confidence Interval (2-Sided) 95%
    -30.89 to -11.39
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    4. Secondary Outcome
    Title Change From Baseline in Free Fatty Acid (FFA) at Primary Analysis Time Point
    Description An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
    Time Frame Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C

    Outcome Measure Data

    Analysis Population Description
    FAS population included all participants who were randomized and received at least 1 dose of study drug. Here, overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Pooled Placebo Cohort B: ISIS 703802, 40 mg Q4W Cohort C: ISIS 703802, 80 mg Q4W Cohort A: ISIS 703802, 20 mg QW
    Arm/Group Description Participants from each cohort received placebo at a dose-matched volume of study drug, SC. Participants received ISIS 703802, 40 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 20 mg SC once every week for 26 doses.
    Measure Participants 26 24 23 17
    Least Squares Mean (95% Confidence Interval) [mmol/L]
    -0.0734
    -0.0607
    -0.0878
    -0.0881
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8299
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 0.0128
    Confidence Interval (2-Sided) 95%
    -0.10 to 0.13
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8102
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.0144
    Confidence Interval (2-Sided) 95%
    -0.13 to 0.10
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8223
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.0146
    Confidence Interval (2-Sided) 95%
    -0.14 to 0.11
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    5. Secondary Outcome
    Title Change From Baseline in Lipoprotein(a) (Lp[a]) at the Primary Analysis Time Point
    Description An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
    Time Frame Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C

    Outcome Measure Data

    Analysis Population Description
    FAS population included all participants who were randomized and received at least 1 dose of study drug. Here, overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Pooled Placebo Cohort B: ISIS 703802, 40 mg Q4W Cohort C: ISIS 703802, 80 mg Q4W Cohort A: ISIS 703802, 20 mg QW
    Arm/Group Description Participants from each cohort received placebo at a dose-matched volume of study drug, SC. Participants received ISIS 703802, 40 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 20 mg SC once every week for 26 doses.
    Measure Participants 26 23 23 17
    Least Squares Mean (95% Confidence Interval) [nmol/L]
    -1.1
    6.8
    0.5
    -2.8
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments Lp(a)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0604
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 7.8
    Confidence Interval (2-Sided) 95%
    -0.35 to 16.02
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments Lp(a)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7048
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 1.6
    Confidence Interval (2-Sided) 95%
    -6.61 to 9.74
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments Lp(a)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7024
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -1.7
    Confidence Interval (2-Sided) 95%
    -10.65 to 7.20
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    6. Secondary Outcome
    Title 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
    Description 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.
    Time Frame Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C

    Outcome Measure Data

    Analysis Population Description
    FAS population included all participants who were randomized and received at least 1 dose of study drug. Here, 'n' signifies participants evaluable for this outcome measure for each specified category.
    Arm/Group Title Pooled Placebo Cohort B: ISIS 703802, 40 mg Q4W Cohort C: ISIS 703802, 80 mg Q4W Cohort A: ISIS 703802, 20 mg QW
    Arm/Group Description Participants from each cohort received placebo at a dose-matched volume of study drug, SC. Participants received ISIS 703802, 40 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 20 mg SC once every week for 26 doses.
    Measure Participants 27 26 26 26
    ANGPTL3
    8
    -41
    -59
    -54
    TC
    -2
    -11
    -21
    -19
    LDL-C
    0
    6
    -7
    -12
    HDL-C
    7
    -2
    -18
    -4
    VLDL-C
    -14
    -35
    -47
    -40
    Non-HDL-C
    -4
    -13
    -21
    -22
    ApoB
    -3
    -7
    -12
    -10
    ApoB: ApoB-48
    -21
    -44
    -62
    -38
    ApoB: ApoB-100
    -3
    -5
    -10
    -9
    ApoCIII
    -6
    -40
    -61
    -50
    ApoA1
    3
    -9
    -24
    -12
    FFA
    -11
    -12
    -18
    -11
    Lp(a)
    3
    -4
    -3
    -1
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments ANGPTL3
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -45
    Confidence Interval (2-Sided) 95%
    -54 to -33
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments ANGPTL3
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -62
    Confidence Interval (2-Sided) 95%
    -69 to -54
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments ANGPTL3
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -58
    Confidence Interval (2-Sided) 95%
    -66 to -47
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments TC
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0309
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -9
    Confidence Interval (2-Sided) 95%
    -16 to -1
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments TC
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -19
    Confidence Interval (2-Sided) 95%
    -26 to -12
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments TC
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -17
    Confidence Interval (2-Sided) 95%
    -25 to -9
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments LDL-C
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4016
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value 6
    Confidence Interval (2-Sided) 95%
    -7 to 21
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments LDL-C
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2589
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -7
    Confidence Interval (2-Sided) 95%
    -18 to 6
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments LDL-C
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0616
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -12
    Confidence Interval (2-Sided) 95%
    -24 to 1
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 10
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments HDL-C
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1918
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -8
    Confidence Interval (2-Sided) 95%
    -18 to 4
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 11
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments HDL-C
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -24
    Confidence Interval (2-Sided) 95%
    -32 to -14
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 12
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments HDL-C
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1132
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -10
    Confidence Interval (2-Sided) 95%
    -21 to 3
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 13
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments VLDL-C
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0177
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -24
    Confidence Interval (2-Sided) 95%
    -40 to -5
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 14
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments VLDL-C
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -38
    Confidence Interval (2-Sided) 95%
    -51 to -23
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 15
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments VLDL-C
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0033
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -30
    Confidence Interval (2-Sided) 95%
    -45 to -12
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 16
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments Non-HDL-C
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0523
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -10
    Confidence Interval (2-Sided) 95%
    -18 to 0
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 17
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments Non-HDL-C
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0002
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -18
    Confidence Interval (2-Sided) 95%
    -26 to -9
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 18
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments Non-HDL-C
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0004
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -19
    Confidence Interval (2-Sided) 95%
    -28 to -9
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 19
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments ApoB
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4204
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -3
    Confidence Interval (2-Sided) 95%
    -12 to 5
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 20
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments ApoB
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0441
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -9
    Confidence Interval (2-Sided) 95%
    -16 to 0
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 21
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments ApoB
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1324
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -7
    Confidence Interval (2-Sided) 95%
    -16 to 2
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 22
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments ApoB-48
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1009
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -29
    Confidence Interval (2-Sided) 95%
    -53 to 7
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 23
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments ApoB-48
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0005
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -52
    Confidence Interval (2-Sided) 95%
    -68 to -28
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 24
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments ApoB-48
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3004
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -21
    Confidence Interval (2-Sided) 95%
    -50 to 24
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 25
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments ApoB-100
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6135
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -2
    Confidence Interval (2-Sided) 95%
    -10 to 7
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 26
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments ApoB-100
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1127
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -7
    Confidence Interval (2-Sided) 95%
    -15 to 2
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 27
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments ApoB-100
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2576
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -5
    Confidence Interval (2-Sided) 95%
    -14 to 4
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 28
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments ApoCIII
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0017
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -36
    Confidence Interval (2-Sided) 95%
    -52 to -16
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 29
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments ApoCIII
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -58
    Confidence Interval (2-Sided) 95%
    -68 to -45
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 30
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments ApoCIII
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -47
    Confidence Interval (2-Sided) 95%
    -61 to -29
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 31
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments ApoAI
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0193
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -11
    Confidence Interval (2-Sided) 95%
    -20 to -2
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 32
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments ApoAI
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -26
    Confidence Interval (2-Sided) 95%
    -33 to -19
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 33
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments ApoAI
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0063
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -14
    Confidence Interval (2-Sided) 95%
    -23 to -4
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 34
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments FFA
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8873
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -2
    Confidence Interval (2-Sided) 95%
    -21 to 23
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 35
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments FFA
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4404
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB
    Estimated Value -8
    Confidence Interval (2-Sided) 95%
    -27 to 15
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 36
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments FFA
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9665
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB]
    Estimated Value -1
    Confidence Interval (2-Sided) 95%
    -22 to 27
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 37
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments Lp[a]
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4133
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB]
    Estimated Value -7
    Confidence Interval (2-Sided) 95%
    -21 to 10
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 38
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments Lp[a]
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4750
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB]
    Estimated Value -6
    Confidence Interval (2-Sided) 95%
    -20 to 11
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    Statistical Analysis 39
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments Lp[a]
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6354
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference in % CFB]
    Estimated Value -4
    Confidence Interval (2-Sided) 95%
    -20 to 15
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
    7. Secondary Outcome
    Title Change From Baseline in Fasting Plasma Glucose at the Primary Analysis Time Point
    Description An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
    Time Frame Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C

    Outcome Measure Data

    Analysis Population Description
    FAS population included all participants who were randomized and received at least 1 dose of study drug. Here, overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Pooled Placebo Cohort B: ISIS 703802, 40 mg Q4W Cohort C: ISIS 703802, 80 mg Q4W Cohort A: ISIS 703802, 20 mg QW
    Arm/Group Description Participants from each cohort received placebo at a dose-matched volume of study drug, SC. Participants received ISIS 703802, 40 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 20 mg SC once every week for 26 doses.
    Measure Participants 26 23 23 16
    Least Squares Mean (95% Confidence Interval) [mg/dL]
    -4.4
    -21.6
    9.4
    -2.2
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1799
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -17.2
    Confidence Interval (2-Sided) 95%
    -42.53 to 8.10
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2867
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 13.8
    Confidence Interval (2-Sided) 95%
    -11.83 to 39.49
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8812
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 2.2
    Confidence Interval (2-Sided) 95%
    -26.78 to 31.14
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    8. Secondary Outcome
    Title Change From Baseline in Hemoglobin A1c (HbA1c) at the Primary Analysis Time Point
    Description An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
    Time Frame Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C

    Outcome Measure Data

    Analysis Population Description
    FAS population included all participants who were randomized and received at least 1 dose of study drug. Here, overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Pooled Placebo Cohort B: ISIS 703802, 40 mg Q4W Cohort C: ISIS 703802, 80 mg Q4W Cohort A: ISIS 703802, 20 mg QW
    Arm/Group Description Participants from each cohort received placebo at a dose-matched volume of study drug, SC. Participants received ISIS 703802, 40 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 20 mg SC once every week for 26 doses.
    Measure Participants 25 24 22 19
    Least Squares Mean (95% Confidence Interval) [percentage of HbA1c]
    0.19
    -0.09
    0.26
    0.35
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3995
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.28
    Confidence Interval (2-Sided) 95%
    -0.94 to 0.38
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8155
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 0.08
    Confidence Interval (2-Sided) 95%
    -0.59 to 0.75
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6466
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 0.16
    Confidence Interval (2-Sided) 95%
    -0.54 to 0.86
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    9. Secondary Outcome
    Title Change From Baseline in Fasting Insulin at the Primary Analysis Time Point
    Description An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
    Time Frame Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C

    Outcome Measure Data

    Analysis Population Description
    FAS population included all participants who were randomized and received at least 1 dose of study drug. Here, overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Pooled Placebo Cohort B: ISIS 703802, 40 mg Q4W Cohort C: ISIS 703802, 80 mg Q4W Cohort A: ISIS 703802, 20 mg QW
    Arm/Group Description Participants from each cohort received placebo at a dose-matched volume of study drug, SC. Participants received ISIS 703802, 40 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 20 mg SC once every week for 26 doses.
    Measure Participants 26 23 23 16
    Least Squares Mean (95% Confidence Interval) [milli-international units per liter]
    -0.10
    -1.48
    -0.23
    3.48
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7393
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 1.39
    Confidence Interval (2-Sided) 95%
    -9.66 to 6.89
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9744
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.13
    Confidence Interval (2-Sided) 95%
    -8.45 to 8.18
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4477
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 3.58
    Confidence Interval (2-Sided) 95%
    -5.75 to 12.91
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    10. Secondary Outcome
    Title Change From Baseline in and HOMA-IR at the Primary Analysis Time Point
    Description 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.
    Time Frame Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C

    Outcome Measure Data

    Analysis Population Description
    FAS population included all participants who were randomized and received at least 1 dose of study drug. Here, overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Pooled Placebo Cohort B: ISIS 703802, 40 mg Q4W Cohort C: ISIS 703802, 80 mg Q4W Cohort A: ISIS 703802, 20 mg QW
    Arm/Group Description Participants from each cohort received placebo at a dose-matched volume of study drug, SC. Participants received ISIS 703802, 40 milligrams (mg) SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 20 mg once every week for 26 doses.
    Measure Participants 26 23 23 16
    Least Squares Mean (95% Confidence Interval) [index]
    -0.119
    -1.914
    0.141
    2.013
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4710
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -1.794
    Confidence Interval (2-Sided) 95%
    -6.72 to 3.14
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9169
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 0.260
    Confidence Interval (2-Sided) 95%
    -4.68 to 5.20
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4484
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 2.133
    Confidence Interval (2-Sided) 95%
    -3.44 to 7.70
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    11. Secondary Outcome
    Title Change From Baseline in Fructosamine at Primary Analysis Time Point
    Description An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
    Time Frame Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C

    Outcome Measure Data

    Analysis Population Description
    FAS population included all participants who were randomized and received at least 1 dose of study drug. Here, overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Pooled Placebo Cohort B: ISIS 703802, 40 mg Q4W Cohort C: ISIS 703802, 80 mg Q4W Cohort A: ISIS 703802, 20 mg QW
    Arm/Group Description Participants from each cohort received placebo at a dose-matched volume of study drug, SC. Participants received ISIS 703802, 40 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 20 mg SC once every week for 26 doses.
    Measure Participants 26 24 23 17
    Least Squares Mean (95% Confidence Interval) [μmol/L]
    13.2
    -10.0
    1.8
    15.1
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0916
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -23.2
    Confidence Interval (2-Sided) 95%
    -50.17 to 3.83
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4032
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -11.4
    Confidence Interval (2-Sided) 95%
    -38.51 to 15.63
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8959
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 1.9
    Confidence Interval (2-Sided) 95%
    -27.56 to 31.45
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    12. Secondary Outcome
    Title Change From Baseline in Glycated Albumin at the Primary Analysis Time Point
    Description An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
    Time Frame Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C

    Outcome Measure Data

    Analysis Population Description
    FAS population included all participants who were randomized and received at least 1 dose of study drug. Here, overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Pooled Placebo Cohort B: ISIS 703802, 40 mg Q4W Cohort C: ISIS 703802, 80 mg Q4W Cohort A: ISIS 703802, 20 mg QW
    Arm/Group Description Participants from each cohort received placebo at a dose-matched volume of study drug, SC. Participants received ISIS 703802, 40 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 20 mg SC once every week for 26 doses.
    Measure Participants 26 24 23 17
    Least Squares Mean (95% Confidence Interval) [grams per deciliter (g/dL)]
    -0.0033
    -0.0553
    -0.0133
    0.0280
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3202
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.0520
    Confidence Interval (2-Sided) 95%
    -0.16 to 0.05
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8485
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.0100
    Confidence Interval (2-Sided) 95%
    -0.11 to 0.09
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5812
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 0.0314
    Confidence Interval (2-Sided) 95%
    -0.08 to 0.14
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    13. Secondary Outcome
    Title Change From Baseline in Weight at the Primary Analysis Time Point
    Description An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
    Time Frame Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C

    Outcome Measure Data

    Analysis Population Description
    FAS population included all participants who were randomized and received at least 1 dose of study drug. Here, overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Pooled Placebo Cohort B: ISIS 703802, 40 mg Q4W Cohort C: ISIS 703802, 80 mg Q4W Cohort A: ISIS 703802, 20 mg QW
    Arm/Group Description Participants from each cohort received placebo at a dose-matched volume of study drug, SC. Participants received ISIS 703802, 40 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 20 mg SC once every week for 26 doses.
    Measure Participants 26 24 25 22
    Least Squares Mean (95% Confidence Interval) [kg]
    -1.00
    -0.57
    -0.99
    -1.33
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6157
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 0.43
    Confidence Interval (2-Sided) 95%
    -1.28 to 2.15
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9869
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 0.01
    Confidence Interval (2-Sided) 95%
    -1.66 to 1.69
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7084
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.33
    Confidence Interval (2-Sided) 95%
    -2.07 to 1.42
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    14. Secondary Outcome
    Title Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Primary Analysis Time Point
    Description An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
    Time Frame Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C

    Outcome Measure Data

    Analysis Population Description
    FAS population included all participants who were randomized and received at least 1 dose of study drug. Here, overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Pooled Placebo Cohort B: ISIS 703802, 40 mg Q4W Cohort C: ISIS 703802, 80 mg Q4W Cohort A: ISIS 703802, 20 mg QW
    Arm/Group Description Participants from each cohort received placebo at a dose-matched volume of study drug, SC. Participants received ISIS 703802, 40 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 20 mg SC once every week for 26 doses.
    Measure Participants 26 24 25 22
    SBP
    -1.66
    1.13
    0.42
    -3.29
    DBP
    -2.35
    1.75
    1.13
    -0.73
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments SBP
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4431
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 2.79
    Confidence Interval (2-Sided) 95%
    -4.41 to 10.00
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments SBP
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5630
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 2.08
    Confidence Interval (2-Sided) 95%
    -5.05 to 9.22
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments SBP
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6634
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -1.63
    Confidence Interval (2-Sided) 95%
    -9.06 to 5.79
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments DBP
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0937
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 4.11
    Confidence Interval (2-Sided) 95%
    -0.71 to 8.92
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments DBP
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1522
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 3.49
    Confidence Interval (2-Sided) 95%
    -1.31 to 8.28
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments DBP
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5188
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 1.62
    Confidence Interval (2-Sided) 95%
    -3.35 to 6.59
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    15. Secondary Outcome
    Title Percent Change From Baseline in Weight, SBP and DBP at Primary Analysis Time Point
    Description An ANCOVA model was performed on the percent change from Baseline to Primary Analysis Time Point.
    Time Frame Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C6

    Outcome Measure Data

    Analysis Population Description
    FAS population included all participants who were randomized and received at least 1 dose of study drug. Here, overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Pooled Placebo Cohort B: ISIS 703802, 40 mg Q4W Cohort C: ISIS 703802, 80 mg Q4W Cohort A: ISIS 703802, 20 mg QW
    Arm/Group Description Participants from each cohort received placebo at a dose-matched volume of study drug, SC. Participants received ISIS 703802, 40 milligrams (mg) SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 20 mg once every week for 26 doses.
    Measure Participants 26 24 25 22
    Weight
    -0.98
    -0.40
    -1.10
    -1.38
    SBP
    -0.55
    1.80
    0.68
    -1.79
    DBP
    -1.83
    3.18
    2.11
    -0.13
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments Weight
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5299
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 0.57
    Confidence Interval (2-Sided) 95%
    -1.24 to 2.39
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments Weight
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8919
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.12
    Confidence Interval (2-Sided) 95%
    -1.89 to 1.65
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments Weight
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6653
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.40
    Confidence Interval (2-Sided) 95%
    -2.25 to 1.44
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments SBP
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4213
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 2.35
    Confidence Interval (2-Sided) 95%
    -3.43 to 8.14
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments SBP
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6696
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 1.23
    Confidence Interval (2-Sided) 95%
    -4.49 to 6.96
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments SBP
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6819
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -1.23
    Confidence Interval (2-Sided) 95%
    -7.20 to 4.73
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments DBP
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1171
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 5.01
    Confidence Interval (2-Sided) 95%
    -1.28 to 11.31
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments DBP
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2155
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 3.94
    Confidence Interval (2-Sided) 95%
    -2.33 to 10.21
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments DBP
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6034
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 1.70
    Confidence Interval (2-Sided) 95%
    -4.79 to 8.20
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    16. Secondary Outcome
    Title 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
    Description An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
    Time Frame Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C

    Outcome Measure Data

    Analysis Population Description
    FAS population included all participants who were randomized and received at least 1 dose of study drug. Here, overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Pooled Placebo Cohort B: ISIS 703802, 40 mg Q4W Cohort C: ISIS 703802, 80 mg Q4W Cohort A: ISIS 703802, 20 mg QW
    Arm/Group Description Participants from each cohort received placebo at a dose-matched volume of study drug, SC. Participants received ISIS 703802, 40 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 20 mg SC once every week for 26 doses.
    Measure Participants 25 23 22 19
    Least Squares Mean (95% Confidence Interval) [percentage (Hepatic Fat Fraction)]
    -1.69
    -0.71
    2.39
    -0.12
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5752
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 0.98
    Confidence Interval (2-Sided) 95%
    -2.48 to 4.44
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0230
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 4.09
    Confidence Interval (2-Sided) 95%
    0.58 to 7.59
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3965
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 1.57
    Confidence Interval (2-Sided) 95%
    -2.10 to 5.25
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    17. Secondary Outcome
    Title 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
    Description An ANCOVA model was performed on the percent change from Baseline to Primary Analysis Time Point.
    Time Frame Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C

    Outcome Measure Data

    Analysis Population Description
    FAS population included all participants who were randomized and received at least 1 dose of study drug. Here, overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Pooled Placebo Cohort B: ISIS 703802, 40 mg Q4W Cohort C: ISIS 703802, 80 mg Q4W Cohort A: ISIS 703802, 20 mg QW
    Arm/Group Description Participants from each cohort received placebo at a dose-matched volume of study drug, SC. Participants received ISIS 703802, 40 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 20 mg SC once every week for 26 doses.
    Measure Participants 25 23 22 19
    Least Squares Mean (95% Confidence Interval) [percent change]
    -7.09
    5.34
    18.94
    5.18
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3023
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 12.44
    Confidence Interval (2-Sided) 95%
    -11.39 to 36.26
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0350
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 26.03
    Confidence Interval (2-Sided) 95%
    1.87 to 50.19
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3374
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 12.27
    Confidence Interval (2-Sided) 95%
    -13.02 to 37.55
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    18. Secondary Outcome
    Title Percentage of Participants With HFF ≤ 8% by MRI-PDFF at the Primary Analysis Time Point
    Description 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.
    Time Frame Week 27 for Cohort A, and Week 25 for Cohorts B and C

    Outcome Measure Data

    Analysis Population Description
    FAS population included all participants who were randomized and received at least 1 dose of study drug. Here, overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Pooled Placebo Cohort B: ISIS 703802, 40 mg Q4W Cohort C: ISIS 703802, 80 mg Q4W Cohort A: ISIS 703802, 20 mg QW
    Arm/Group Description Participants from each cohort received placebo at a dose-matched volume of study drug, SC. Participants received ISIS 703802, 40 milligrams (mg) SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 20 mg SC once every week for 26 doses.
    Measure Participants 25 23 22 19
    Number [percentage of participants]
    16.0
    59.3%
    8.7
    33.5%
    4.5
    17.3%
    15.8
    60.8%
    19. Secondary Outcome
    Title Change From Baseline in Fatty Liver Index (FLI) at the Primary Analysis Time Point
    Description 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.
    Time Frame Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C

    Outcome Measure Data

    Analysis Population Description
    FAS population included all participants who were randomized and received at least 1 dose of study drug. Here, overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Pooled Placebo Cohort B: ISIS 703802, 40 mg Q4W Cohort C: ISIS 703802, 80 mg Q4W Cohort A: ISIS 703802, 20 mg QW
    Arm/Group Description Participants from each cohort received placebo at a dose-matched volume of study drug, SC. Participants received ISIS 703802, 40 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 20 mg SC once every week for 26 doses.
    Measure Participants 25 23 24 22
    Least Squares Mean (95% Confidence Interval) [index]
    -3.50
    -6.08
    -9.21
    -8.07
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4583
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -2.59
    Confidence Interval (2-Sided) 95%
    -9.49 to 4.31
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0943
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -5.71
    Confidence Interval (2-Sided) 95%
    -12.43 to 1.00
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1909
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -4.57
    Confidence Interval (2-Sided) 95%
    -11.45 to 2.32
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    20. Secondary Outcome
    Title Change From Baseline in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) at the Primary Analysis Time Point
    Description An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
    Time Frame Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C

    Outcome Measure Data

    Analysis Population Description
    FAS population included all participants who were randomized and received at least 1 dose of study drug. Here, overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Pooled Placebo Cohort B: ISIS 703802, 40 mg Q4W Cohort C: ISIS 703802, 80 mg Q4W Cohort A: ISIS 703802, 20 mg QW
    Arm/Group Description Participants from each cohort received placebo at a dose-matched volume of study drug, SC. Participants received ISIS 703802, 40 milligrams (mg) SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 20 mg once every week for 26 doses.
    Measure Participants 26 23 25 22
    ALT
    -2.2
    4.8
    12.5
    6.6
    AST
    -1.8
    3.2
    6.7
    4.7
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments ALT
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1294
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 7.1
    Confidence Interval (2-Sided) 95%
    -2.10 to 16.22
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments ALT
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0012
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 14.8
    Confidence Interval (2-Sided) 95%
    5.98 to 23.59
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments ALT
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0594
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 8.9
    Confidence Interval (2-Sided) 95%
    -0.36 to 18.11
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments AST
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0730
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter [Least Squares Mean Difference
    Estimated Value 5.0
    Confidence Interval (2-Sided) 95%
    -0.47 to 10.45
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments AST
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0020
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 8.4
    Confidence Interval (2-Sided) 95%
    3.17 to 13.70
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments AST
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0200
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 6.5
    Confidence Interval (2-Sided) 95%
    1.05 to 12.00
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    21. Secondary Outcome
    Title Change From Baseline in Leptin at the Primary Analysis Time Point
    Description An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
    Time Frame Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C

    Outcome Measure Data

    Analysis Population Description
    FAS population included all participants who were randomized and received at least 1 dose of study drug. Here, overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Pooled Placebo Cohort B: ISIS 703802, 40 mg Q4W Cohort C: ISIS 703802, 80 mg Q4W Cohort A: ISIS 703802, 20 mg QW
    Arm/Group Description Participants from each cohort received placebo at a dose-matched volume of study drug, SC. Participants received ISIS 703802, 40 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 20 mg SC once every week for 26 doses.
    Measure Participants 25 24 23 19
    Least Squares Mean (95% Confidence Interval) [μg/L]
    0.95
    -0.24
    -0.57
    -3.23
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4812
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -1.19
    Confidence Interval (2-Sided) 95%
    -4.55 to 2.16
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3679
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -1.53
    Confidence Interval (2-Sided) 95%
    -4.88 to 1.83
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0210
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -4.18
    Confidence Interval (2-Sided) 95%
    -7.72 to -0.65
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    22. Secondary Outcome
    Title Change From Baseline in Adiponectin at the Primary Analysis Time Point
    Description An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
    Time Frame Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C

    Outcome Measure Data

    Analysis Population Description
    FAS population included all participants who were randomized and received at least 1 dose of study drug. Here, overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Pooled Placebo Cohort B: ISIS 703802, 40 mg Q4W Cohort C: ISIS 703802, 80 mg Q4W Cohort A: ISIS 703802, 20 mg QW
    Arm/Group Description Participants from each cohort received placebo at a dose-matched volume of study drug, SC. Participants received ISIS 703802, 40 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 20 mg SC once every week for 26 doses.
    Measure Participants 25 24 23 19
    Least Squares Mean (95% Confidence Interval) [milligrams per liter (mg/L)]
    0.20
    0.05
    -0.18
    -0.18
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6227
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.15
    Confidence Interval (2-Sided) 95%
    -0.73 to 0.44
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1950
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.38
    Confidence Interval (2-Sided) 95%
    -0.97 to 0.20
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2271
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.38
    Confidence Interval (2-Sided) 95%
    -1.00 to 0.24
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    23. Secondary Outcome
    Title Change From Baseline in Subcutaneous Adipose Tissue (SAT) and Visceral Adipose Tissue (VAT) by Single Slice MRI at the Primary Analysis Timepoint
    Description An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
    Time Frame Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C

    Outcome Measure Data

    Analysis Population Description
    FAS population included all participants who were randomized and received at least 1 dose of study drug. Here, overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Pooled Placebo Cohort B: ISIS 703802, 40 mg Q4W Cohort C: ISIS 703802, 80 mg Q4W Cohort A: ISIS 703802, 20 mg QW
    Arm/Group Description Participants from each cohort received placebo at a dose-matched volume of study drug, SC. Participants received ISIS 703802, 40 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 20 mg SC once every week for 26 doses.
    Measure Participants 25 23 20 19
    SAT
    -25.61
    -8.55
    7.31
    -41.91
    VAT
    14.83
    19.78
    -9.42
    36.85
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments SAT
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8591
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 17.06
    Confidence Interval (2-Sided) 95%
    -173.57 to 207.69
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments SAT
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7404
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 32.92
    Confidence Interval (2-Sided) 95%
    -164.11 to 229.95
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments SAT
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8711
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -16.30
    Confidence Interval (2-Sided) 95%
    -215.50 to 182.90
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments VAT
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9569
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 4.95
    Confidence Interval (2-Sided) 95%
    -176.64 to 186.53
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments VAT
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8025
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -24.26
    Confidence Interval (2-Sided) 95%
    -216.53 to 168.02
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments VAT
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8202
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 22.02
    Confidence Interval (2-Sided) 95%
    -170.09 to 214.12
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    24. Secondary Outcome
    Title Change From Baseline in Waist Circumference by Single Slice MRI at the Primary Analysis Timepoint
    Description An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
    Time Frame Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C

    Outcome Measure Data

    Analysis Population Description
    FAS population included all participants who were randomized and received at least 1 dose of study drug. Here, overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Pooled Placebo Cohort B: ISIS 703802, 40 mg Q4W Cohort C: ISIS 703802, 80 mg Q4W Cohort A: ISIS 703802, 20 mg Q4W
    Arm/Group Description Participants from each cohort received placebo at a dose-matched volume of study drug, SC. Participants received ISIS 703802, 40 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 20 mg SC once every week for 26 doses.
    Measure Participants 25 24 25 22
    Least Squares Mean (95% Confidence Interval) [cm]
    -2.25
    -2.14
    -2.95
    -0.59
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9734
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 0.11
    Confidence Interval (2-Sided) 95%
    -6.47 to 6.69
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8333
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.70
    Confidence Interval (2-Sided) 95%
    -7.25 to 5.86
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6207
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 1.66
    Confidence Interval (2-Sided) 95%
    -4.99 to 8.31
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    25. Secondary Outcome
    Title Change From Baseline in Waist to Hip Ratio (WHR) at the Primary Analysis Timepoint
    Description An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
    Time Frame Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C

    Outcome Measure Data

    Analysis Population Description
    FAS population included all participants who were randomized and received at least 1 dose of study drug. Here, overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Pooled Placebo Cohort B: ISIS 703802, 40 mg Q4W Cohort C: ISIS 703802, 80 mg Q4W Cohort A: ISIS 703802, 20 mg QW
    Arm/Group Description Participants from each cohort received placebo at a dose-matched volume of study drug, SC. Participants received ISIS 703802, 40 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 20 mg SC once every week for 26 doses.
    Measure Participants 24 24 25 22
    Least Squares Mean (95% Confidence Interval) [ratio]
    0.01
    0.01
    -0.01
    0.01
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8026
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 0.01
    Confidence Interval (2-Sided) 95%
    -0.04 to 0.06
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4917
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.02
    Confidence Interval (2-Sided) 95%
    -0.07 to 0.03
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8916
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 0.00
    Confidence Interval (2-Sided) 95%
    -0.05 to 0.05
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    26. Secondary Outcome
    Title Change From Baseline in Body Mass Index (BMI) at the Primary Analysis Timepoint
    Description An ANCOVA model was performed on the change from Baseline to Primary Analysis Time Point.
    Time Frame Baseline, Week 27 for Cohort A, and Week 25 for Cohorts B and C

    Outcome Measure Data

    Analysis Population Description
    FAS population included all participants who were randomized and received at least 1 dose of study drug. Here, overall number of participants analyzed signifies participants who were evaluable for this outcome measure
    Arm/Group Title Pooled Placebo Cohort B: ISIS 703802, 40 mg Q4W Cohort C: ISIS 703802, 80 mg Q4W Cohort A: ISIS 703802, 20 mg QW
    Arm/Group Description Participants from each cohort received placebo at a dose-matched volume of study drug, SC. Participants received ISIS 703802, 40 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 20 mg SC once every week for 26 doses.
    Measure Participants 26 24 25 22
    Least Squares Mean (95% Confidence Interval) [kg/m^2]
    -0.27
    -0.17
    -0.37
    -0.50
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort B: ISIS 703802, 40 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7280
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 0.11
    Confidence Interval (2-Sided) 95%
    -0.50 to 0.71
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort C: ISIS 703802, 80 mg Q4W
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7354
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.10
    Confidence Interval (2-Sided) 95%
    -0.69 to 0.49
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Pooled Placebo, Cohort A: ISIS 703802, 20 mg QW
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4682
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -0.23
    Confidence Interval (2-Sided) 95%
    -0.84 to 0.39
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    27. Secondary Outcome
    Title Number of Participants With Treatment-emergent Adverse Events (TEAEs)
    Description 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.
    Time Frame Up to 13 weeks post treatment period (up to 39 weeks)

    Outcome Measure Data

    Analysis Population Description
    Safety set included all participants who were randomized and received at least 1 dose of study drug.
    Arm/Group Title Pooled Placebo Cohort B: ISIS 703802, 40 mg Q4W Cohort C: ISIS 703802, 80 mg Q4W Cohort A: ISIS 703802, 20 mg Q4W
    Arm/Group Description Participants from each cohort received placebo at a dose-matched volume of study drug, SC. Participants received ISIS 703802, 40 milligrams (mg) SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 20 mg once every week for 26 doses.
    Measure Participants 27 26 26 26
    Count of Participants [Participants]
    18
    66.7%
    21
    80.8%
    24
    92.3%
    23
    88.5%

    Adverse Events

    Time Frame Up to 13 weeks post-treatment period (up to 39 weeks)
    Adverse Event Reporting Description Safety population included all participants who were randomized and received at least 1 dose of study drug.
    Arm/Group Title Pooled Placebo Cohort B: ISIS 703802, 40 mg Q4W Cohort C: ISIS 703802, 80 mg Q4W Cohort A: ISIS 703802, 20 mg QW
    Arm/Group Description Participants from each cohort received placebo at a dose-matched volume of study drug, SC. Participants received ISIS 703802, 40 milligrams (mg) SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses. Participants received ISIS 703802, 20 mg once every week for 26 doses.
    All Cause Mortality
    Pooled Placebo Cohort B: ISIS 703802, 40 mg Q4W Cohort C: ISIS 703802, 80 mg Q4W Cohort A: ISIS 703802, 20 mg QW
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/27 (0%) 0/26 (0%) 0/26 (0%) 0/26 (0%)
    Serious Adverse Events
    Pooled Placebo Cohort B: ISIS 703802, 40 mg Q4W Cohort C: ISIS 703802, 80 mg Q4W Cohort A: ISIS 703802, 20 mg QW
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/27 (3.7%) 1/26 (3.8%) 2/26 (7.7%) 1/26 (3.8%)
    General disorders
    Non-cardiac chest pain 0/27 (0%) 1/26 (3.8%) 0/26 (0%) 0/26 (0%)
    Infections and infestations
    Actinomycosis 0/27 (0%) 0/26 (0%) 1/26 (3.8%) 0/26 (0%)
    Diverticulitis 0/27 (0%) 0/26 (0%) 0/26 (0%) 1/26 (3.8%)
    Injury, poisoning and procedural complications
    Procedural complication 0/27 (0%) 0/26 (0%) 1/26 (3.8%) 0/26 (0%)
    Renal and urinary disorders
    Nephrolithiasis 1/27 (3.7%) 0/26 (0%) 0/26 (0%) 0/26 (0%)
    Other (Not Including Serious) Adverse Events
    Pooled Placebo Cohort B: ISIS 703802, 40 mg Q4W Cohort C: ISIS 703802, 80 mg Q4W Cohort A: ISIS 703802, 20 mg QW
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 13/27 (48.1%) 15/26 (57.7%) 20/26 (76.9%) 14/26 (53.8%)
    Gastrointestinal disorders
    Diarrhoea 3/27 (11.1%) 0/26 (0%) 3/26 (11.5%) 2/26 (7.7%)
    Nausea 2/27 (7.4%) 2/26 (7.7%) 3/26 (11.5%) 0/26 (0%)
    Dyspepsia 2/27 (7.4%) 0/26 (0%) 2/26 (7.7%) 0/26 (0%)
    General disorders
    Injection site pruritus 0/27 (0%) 1/26 (3.8%) 8/26 (30.8%) 2/26 (7.7%)
    Injection site erythema 0/27 (0%) 1/26 (3.8%) 6/26 (23.1%) 2/26 (7.7%)
    Pyrexia 0/27 (0%) 0/26 (0%) 2/26 (7.7%) 0/26 (0%)
    Infections and infestations
    Pharyngitis 0/27 (0%) 2/26 (7.7%) 3/26 (11.5%) 1/26 (3.8%)
    Nasopharyngitis 0/27 (0%) 1/26 (3.8%) 3/26 (11.5%) 1/26 (3.8%)
    Urinary tract infection 4/27 (14.8%) 1/26 (3.8%) 1/26 (3.8%) 1/26 (3.8%)
    Bronchitis 0/27 (0%) 0/26 (0%) 2/26 (7.7%) 2/26 (7.7%)
    Sinusitis 1/27 (3.7%) 2/26 (7.7%) 2/26 (7.7%) 0/26 (0%)
    Upper respiratory tract infection 2/27 (7.4%) 2/26 (7.7%) 0/26 (0%) 3/26 (11.5%)
    Vulvovaginal mycotic infection 2/27 (7.4%) 0/26 (0%) 0/26 (0%) 2/26 (7.7%)
    Vaginal infection 3/27 (11.1%) 0/26 (0%) 0/26 (0%) 0/26 (0%)
    Injury, poisoning and procedural complications
    Muscle strain 0/27 (0%) 3/26 (11.5%) 0/26 (0%) 0/26 (0%)
    Investigations
    Blood creatine phosphokinase increased 0/27 (0%) 0/26 (0%) 0/26 (0%) 2/26 (7.7%)
    Blood glucose increased 0/27 (0%) 0/26 (0%) 2/26 (7.7%) 0/26 (0%)
    Transaminases increased 0/27 (0%) 0/26 (0%) 0/26 (0%) 2/26 (7.7%)
    Metabolism and nutrition disorders
    Hyperglycaemia 0/27 (0%) 3/26 (11.5%) 1/26 (3.8%) 2/26 (7.7%)
    Musculoskeletal and connective tissue disorders
    Osteoarthritis 0/27 (0%) 1/26 (3.8%) 2/26 (7.7%) 0/26 (0%)
    Pain in extremity 1/27 (3.7%) 0/26 (0%) 2/26 (7.7%) 0/26 (0%)
    Nervous system disorders
    Headache 2/27 (7.4%) 1/26 (3.8%) 1/26 (3.8%) 2/26 (7.7%)
    Skin and subcutaneous tissue disorders
    Rash 0/27 (0%) 1/26 (3.8%) 2/26 (7.7%) 1/26 (3.8%)
    Vascular disorders
    Hypertension 2/27 (7.4%) 0/26 (0%) 0/26 (0%) 0/26 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days from the time submitted to the sponsor for review. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/Title Study Director
    Organization Akcea Therapeutics
    Phone 617-207-0289
    Email clinicalstudies@akceatx.com
    Responsible Party:
    Akcea Therapeutics
    ClinicalTrials.gov Identifier:
    NCT03371355
    Other Study ID Numbers:
    • ISIS 703802-CS2
    First Posted:
    Dec 13, 2017
    Last Update Posted:
    Feb 1, 2021
    Last Verified:
    Dec 1, 2020