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CompletedNCT03371355Updated Feb 1, 2021Results posted

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

A Phase 2 interventional study of Placebo and ISIS 703802 40 mg in NAFLD, Diabetes Mellitus, Type 2 and Hypertriglyceridemia, sponsored by Akcea Therapeutics. Completed at 42 sites in 2 countries. Open to participants aged 18 Years to 70 Years. Per ClinicalTrials.gov, last updated 2021-02-01.

Sponsored by Akcea Therapeutics (part of Ionis Pharmaceuticals, Inc.) · Phase 2, Interventional, and Treatment

Phase
Phase 2
Study type
Interventional
Enrollment
105
Allocation
Randomized
Ages
18 Years to 70 Years
Sex
All
01

Study 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).

02

Conditions studied

  • NAFLD
  • Diabetes Mellitus, Type 2
  • Hypertriglyceridemia
  • Fatty Liver, Nonalcoholic

Keywords

  • 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
03

In context

Non-alcoholic Fatty Liver Disease

1,617 studies on the registry are indexed under Non-alcoholic Fatty Liver Disease; 324 are open to participants now.

This study's enrollment of 105 is above the median of 60 across 1,176 interventional studies indexed under Non-alcoholic Fatty Liver Disease.

Browse Non-alcoholic Fatty Liver Disease studies →

Lead sponsor

Akcea Therapeutics is the lead sponsor of 15 studies on the registry; 1 is open to participants now.

Of its 9 completed or terminated interventional studies of FDA-regulated products, 8 (89%) have results posted.

Browse Akcea Therapeutics studies →All Ionis Pharmaceuticals, Inc. studies →

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years to 70 Years
Sexes eligible
All
Accepts healthy volunteers
No

Eligibility criteria

Key Inclusion Criteria:

  • Plasma triglycerides (TG) at Screening greater than (>)150 milligrams per deciliter (mg/dL) and at qualification of >150 mg/dL.
  • Documented history of hepatic steatosis with baseline magnetic resonance imaging (MRI) indicating hepatic fat fraction (HFF) greater than (>) 8%.
  • Diagnosis of Type 2 diabetes mellitus with (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.
  • 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 acute cardiac event within 6 months before Screening.
  • History of heart failure with (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 for magnetic resonance imaging (MRI) procedures including any metal implant (example, heart pacemaker, rods, screws, aneurysm clips).
Terms in these criteria, in plain language(5)

Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.

HbA1c

A blood test of average blood sugar over the past two to three months, given as a percentage or in mmol/mol. 6.5% (48 mmol/mol) or more is the usual threshold for diabetes, normally confirmed by a second test.

BMI (body mass index)

Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.

What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.

Clinically significant

Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.

NYHA class (heart failure)

The New York Heart Association’s four classes of how much heart failure limits physical activity.

I
No limits: ordinary activity causes no undue tiredness or breathlessness.
II
Slight limits: comfortable at rest, ordinary activity causes symptoms.
III
Marked limits: comfortable at rest, less than ordinary activity causes symptoms.
IV
Symptoms even at rest; any activity makes them worse.

Studies set their own limit — many outside heart failure leave out class III–IV, while heart failure studies may ask for a particular class. Check the class this study names.

Contraindication

A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.

05

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Triple (Participant, Investigator, Outcomes assessor)
Enrollment
105 participants (actual)

Study arms

  • Placebo comparator
    Pooled Placebo

    Participants from each cohort received placebo at a dose-matched volume of study drug, subcutaneously (SC).

    Drug: Placebo

  • 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

  • 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

  • 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

Interventions

  • DrugPlacebo

    Placebo (Matched with ISIS 703802)

    Also known as: Sterile Normal Saline (0.9% NaCl)

  • DrugISIS 703802 40 mg

    ISIS 703802 40 mg, administered via SC injection, once every 4 weeks for 6 doses.

    Also known as: AKCEA-ANGPTL3-LRx, IONIS-ANGPTL3-LRx, Vupanorsen

  • DrugISIS 703802 80 mg

    ISIS 703802 80 mg, administered via SC injection, once every 4 weeks for 6 doses.

    Also known as: AKCEA-ANGPTL3-LRx, IONIS-ANGPTL3-LRx, Vupanorsen

  • DrugISIS 703802 20 mg

    ISIS 703802 20 mg, administered via SC injection, once every week for 26 doses.

    Also known as: AKCEA-ANGPTL3-LRx, IONIS-ANGPTL3-LRx, Vupanorsen

06

What researchers measure

Primary outcomes

  1. Percent Change From Baseline in Fasting Triglycerides Level at the Primary Analysis Time Point

    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

Secondary outcomes

  1. Change From Baseline in Angiopoietin-Like 3 Protein at the Primary Analysis Time Point

    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

  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

    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

  3. Change From Baseline in Free Fatty Acid (FFA) at Primary Analysis Time Point

    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

  4. Change From Baseline in Lipoprotein(a) (Lp[a]) at the Primary Analysis Time Point

    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

  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

    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

  6. Change From Baseline in Fasting Plasma Glucose at the Primary Analysis Time Point

    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

  7. Change From Baseline in Hemoglobin A1c (HbA1c) at the Primary Analysis Time Point

    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

  8. Change From Baseline in Fasting Insulin at the Primary Analysis Time Point

    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

  9. Change From Baseline in and HOMA-IR at the Primary Analysis Time Point

    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

  10. Change From Baseline in Fructosamine at Primary Analysis Time Point

    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

  11. Change From Baseline in Glycated Albumin at the Primary Analysis Time Point

    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

  12. Change From Baseline in Weight at the Primary Analysis Time Point

    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

  13. Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Primary Analysis Time Point

    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

  14. Percent Change From Baseline in Weight, SBP and DBP at Primary Analysis Time Point

    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

  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

    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

  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

    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

  17. Percentage of Participants With HFF ≤ 8% by MRI-PDFF at the Primary Analysis Time Point

    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

  18. Change From Baseline in Fatty Liver Index (FLI) at the Primary Analysis Time Point

    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

  19. Change From Baseline in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) at the Primary Analysis Time Point

    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

  20. Change From Baseline in Leptin at the Primary Analysis Time Point

    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

  21. Change From Baseline in Adiponectin at the Primary Analysis Time Point

    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

  22. Change From Baseline in Subcutaneous Adipose Tissue (SAT) and Visceral Adipose Tissue (VAT) by Single Slice MRI at the Primary Analysis Timepoint

    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

  23. Change From Baseline in Waist Circumference by Single Slice MRI at the Primary Analysis Timepoint

    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

  24. Change From Baseline in Waist to Hip Ratio (WHR) at the Primary Analysis Timepoint

    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

  25. Change From Baseline in Body Mass Index (BMI) at the Primary Analysis Timepoint

    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

  26. Number of Participants With Treatment-emergent Adverse Events (TEAEs)

    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)

07

Results

Posted Feb 1, 2021

Participant flow

The study was conducted at 42 study centers; 38 sites in the US and 4 sites in Canada.

Participant flow — Overall Study
MilestonePooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QW
Started27262626
Completed26242219
Not completed1247
Withdrew: Investigator judgment0011
Withdrew: Voluntary withdrawal1012
Withdrew: Adverse event0123
Withdrew: Reason not specified0101

Outcome measures

PrimaryPercent Change From Baseline in Fasting Triglycerides Level at the Primary Analysis Time Point

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
Reported as:
Geometric mean · percent change
Percent Change From Baseline in Fasting Triglycerides Level at the Primary Analysis Time Point
percent changePooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QW
Percent Change From Baseline in Fasting Triglycerides Level at the Primary Analysis Time Point-16 (-29 to 0)-36 (-47 to -23)-53 (-60 to -43)-47 (-57 to -35)
Statistical analysis
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.0343 · Mean difference in % cfb: -24 · 95% CI -41 to -2Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = <0.0001 · Mean difference in % cfb: -44 · 95% CI -56 to -28Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.0009 · Mean difference in % cfb: -37 · 95% CI -52 to -17Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
SecondaryChange From Baseline in Angiopoietin-Like 3 Protein at the Primary Analysis Time Point

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
Reported as:
Least squares mean · μg/L
Change From Baseline in Angiopoietin-Like 3 Protein at the Primary Analysis Time Point
μg/LPooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QW
Change From Baseline in Angiopoietin-Like 3 Protein at the Primary Analysis Time Point6.77 (-2.09 to 15.62)-43.11 (-52.27 to -33.94)-64.89 (-74.26 to -55.53)-52.98 (-63.99 to -41.96)
Statistical analysis
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = <0.0001 · Least squares mean difference: -49.87 · 95% CI -62.68 to -37.06
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = <0.0001 · Least squares mean difference: -71.66 · 95% CI -84.47 to -58.85
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = <0.0001 · Least squares mean difference: -59.74 · 95% CI -74.04 to -45.44
SecondaryChange 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

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
Reported as:
Least squares mean · mg/dL
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
mg/dLPooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QW
TC-4.8 (-15.19 to 5.51)-21.3 (-32.35 to -10.31)-41.9 (-52.88 to -30.89)-36.5 (-49.38 to -23.58)
LDL-C-2.5 (-11.21 to 6.14)5.0 (-4.78 to 14.70)-11.1 (-20.38 to -1.90)-11.3 (-21.76 to -0.84)
HDL-C2.2 (-0.38 to 4.69)-0.6 (-3.25 to 2.14)-6.4 (-9.13 to -3.77)-2.0 (-5.11 to 1.12)
VLDL-C-6.5 (-11.64 to -1.34)-15.6 (-21.47 to -9.78)-21.9 (-27.41 to -16.36)-17.3 (-23.48 to -11.13)
Non-HDL-C-7.0 (-17.45 to 3.44)-20.9 (-32.01 to -9.70)-35.4 (-46.54 to -24.33)-34.4 (-47.39 to -21.34)
ApoB-3.63 (-9.98 to 2.71)-6.08 (-12.82 to 0.66)-13.46 (-20.20 to -6.72)-8.91 (-16.91 to -0.91)
ApoB: ApoB-48-0.139 (-0.90 to 0.62)-1.140 (-1.93 to -0.35)-1.942 (-2.75 to -1.14)-1.230 (-2.16 to -0.30)
ApoB: ApoB-100-3.757 (-9.94 to 2.43)-4.643 (-11.21 to 1.92)-11.346 (-17.91 to -4.78)-7.174 (-14.97 to 0.62)
ApoCIII-0.729 (-2.58 to 1.12)-5.482 (-7.42 to -3.54)-9.228 (-11.18 to -7.28)-7.588 (-9.86 to -5.32)
ApoA15.0 (-1.11 to 11.15)-11.8 (-18.32 to -5.30)-30.1 (-36.63 to -23.65)-16.1 (-23.68 to -8.57)
Statistical analysis
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.0327 · Least squares mean difference: -16.5 · 95% CI -31.59 to -1.39
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = <0.0001 · Least squares mean difference: -37.0 · 95% CI -52.15 to -21.94
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.0003 · Least squares mean difference: -31.6 · 95% CI -48.23 to -15.05
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.2560 · Least squares mean difference: 7.5 · 95% CI -5.55 to 20.54
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.1795 · Least squares mean difference: -8.6 · 95% CI -21.26 to 4.05
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.2065 · Least squares mean difference: -8.8 · 95% CI -22.48 to 4.95
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.1515 · Least squares mean difference: -2.7 · 95% CI -6.43 to 1.01
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = <0.0001 · Least squares mean difference: -8.6 · 95% CI -12.29 to -4.91
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.0436 · Least squares mean difference: -4.1 · 95% CI -8.18 to -0.12
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.0224 · Least squares mean difference: -9.1 · 95% CI -16.94 to -1.33
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.0001 · Least squares mean difference: -15.4 · 95% CI -22.94 to -7.84
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.0091 · Least squares mean difference: -10.8 · 95% CI -18.86 to -2.78
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.0748 · Least squares mean difference: -13.9 · 95% CI -29.12 to 1.42
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.0004 · Least squares mean difference: -28.4 · 95% CI -43.68 to -13.18
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.0016 · Least squares mean difference: -27.4 · 95% CI -44.08 to -10.64
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.6005 · Least squares mean difference: -2.44 · 95% CI -11.68 to 6.80
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.0374 · Least squares mean difference: -9.83 · 95% CI -19.07 to -0.59
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.3100 · Least squares mean difference: -5.28 · 95% CI -15.55 to 5.00
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.0728 · Least squares mean difference: -1.002 · 95% CI -2.10 to 0.09
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.0018 · Least squares mean difference: -1.803 · 95% CI -2.91 to -0.69
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.0759 · Least squares mean difference: -1.091 · 95% CI -2.30 to 0.12
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.8451 · Least squares mean difference: -0.887 · 95% CI -9.89 to 8.11
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.0973 · Least squares mean difference: -7.590 · 95% CI -16.59 to 1.41
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.5000 · Least squares mean difference: -3.418 · 95% CI -13.45 to 6.61
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.0008 · Least squares mean difference: -4.753 · 95% CI -7.47 to -2.03
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = <0.0001 · Least squares mean difference: -8.499 · 95% CI -11.18 to -5.82
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = <0.0001 · Least squares mean difference: -6.860 · 95% CI -9.78 to -3.93
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.0003 · Least squares mean difference: -16.8 · 95% CI -25.80 to -7.85
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = <0.0001 · Least squares mean difference: -35.2 · 95% CI -44.07 to -26.24
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = <0.0001 · Least squares mean difference: -21.1 · 95% CI -30.89 to -11.39
SecondaryChange From Baseline in Free Fatty Acid (FFA) at Primary Analysis Time Point

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
Reported as:
Least squares mean · mmol/L
Change From Baseline in Free Fatty Acid (FFA) at Primary Analysis Time Point
mmol/LPooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QW
Change From Baseline in Free Fatty Acid (FFA) at Primary Analysis Time Point-0.0734 (-0.15 to 0.01)-0.0607 (-0.15 to 0.02)-0.0878 (-0.17 to 0.00)-0.0881 (-0.19 to 0.01)
Statistical analysis
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.8299 · Least squares mean difference: 0.0128 · 95% CI -0.10 to 0.13
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.8102 · Least squares mean difference: -0.0144 · 95% CI -0.13 to 0.10
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.8223 · Least squares mean difference: -0.0146 · 95% CI -0.14 to 0.11
SecondaryChange From Baseline in Lipoprotein(a) (Lp[a]) at the Primary Analysis Time Point

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
Reported as:
Least squares mean · nmol/L
Change From Baseline in Lipoprotein(a) (Lp[a]) at the Primary Analysis Time Point
nmol/LPooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QW
Change From Baseline in Lipoprotein(a) (Lp[a]) at the Primary Analysis Time Point-1.1 (-6.67 to 4.51)6.8 (0.76 to 12.75)0.5 (-5.47 to 6.44)-2.8 (-9.74 to 4.15)
Statistical analysis
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.0604 · Least squares mean difference: 7.8 · 95% CI -0.35 to 16.02
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.7048 · Least squares mean difference: 1.6 · 95% CI -6.61 to 9.74
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.7024 · Least squares mean difference: -1.7 · 95% CI -10.65 to 7.20
SecondaryPercent 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

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
Reported as:
Geometric mean · percent change
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
percent changePooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QW
ANGPTL38 (-6 to 23)-41 (-48 to -32)-59 (-64 to -53)-54 (-61 to -46)
TC-2 (-8 to 4)-11 (-16 to -5)-21 (-26 to -16)-19 (-25 to -13)
LDL-C0 (-8 to 9)6 (-4 to 17)-7 (-15 to 2)-12 (-21 to -3)
HDL-C7 (-2 to 16)-2 (-10 to 8)-18 (-25 to -11)-4 (-13 to 6)
VLDL-C-14 (-26 to 0)-35 (-45 to -23)-47 (-55 to -37)-40 (-50 to -28)
Non-HDL-C-4 (-11 to 3)-13 (-20 to -7)-21 (-27 to -15)-22 (-29 to -15)
ApoB-3 (-9 to 3)-7 (-12 to 0)-12 (-17 to -6)-10 (-17 to -3)
ApoB: ApoB-48-21 (-40 to 5)-44 (-58 to -25)-62 (-72 to -49)-38 (-56 to -12)
ApoB: ApoB-100-3 (-9 to 3)-5 (-11 to 1)-10 (-16 to -4)-9 (-15 to -1)
ApoCIII-6 (-22 to 14)-40 (-51 to -27)-61 (-68 to -52)-50 (-61 to -37)
ApoA13 (-4 to 11)-9 (-15 to -2)-24 (-29 to -18)-12 (-19 to -4)
FFA-11 (-24 to 4)-12 (-25 to 3)-18 (-31 to -4)-11 (-27 to 8)
Lp(a)3 (-8 to 15)-4 (-15 to 8)-3 (-14 to 9)-1 (-14 to 13)
Statistical analysis
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = <0.0001 · Mean difference in % cfb: -45 · 95% CI -54 to -33Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = <0.0001 · Mean difference in % cfb: -62 · 95% CI -69 to -54Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = <0.0001 · Mean difference in % cfb: -58 · 95% CI -66 to -47Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.0309 · Mean difference in % cfb: -9 · 95% CI -16 to -1Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = <0.0001 · Mean difference in % cfb: -19 · 95% CI -26 to -12Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = <0.0001 · Mean difference in % cfb: -17 · 95% CI -25 to -9Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.4016 · Mean difference in % cfb: 6 · 95% CI -7 to 21Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.2589 · Mean difference in % cfb: -7 · 95% CI -18 to 6Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.0616 · Mean difference in % cfb: -12 · 95% CI -24 to 1Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.1918 · Mean difference in % cfb: -8 · 95% CI -18 to 4Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = <0.0001 · Mean difference in % cfb: -24 · 95% CI -32 to -14Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.1132 · Mean difference in % cfb: -10 · 95% CI -21 to 3Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.0177 · Mean difference in % cfb: -24 · 95% CI -40 to -5Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = <0.0001 · Mean difference in % cfb: -38 · 95% CI -51 to -23Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.0033 · Mean difference in % cfb: -30 · 95% CI -45 to -12Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.0523 · Mean difference in % cfb: -10 · 95% CI -18 to 0Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.0002 · Mean difference in % cfb: -18 · 95% CI -26 to -9Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.0004 · Mean difference in % cfb: -19 · 95% CI -28 to -9Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.4204 · Mean difference in % cfb: -3 · 95% CI -12 to 5Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.0441 · Mean difference in % cfb: -9 · 95% CI -16 to 0Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.1324 · Mean difference in % cfb: -7 · 95% CI -16 to 2Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.1009 · Mean difference in % cfb: -29 · 95% CI -53 to 7Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.0005 · Mean difference in % cfb: -52 · 95% CI -68 to -28Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.3004 · Mean difference in % cfb: -21 · 95% CI -50 to 24Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.6135 · Mean difference in % cfb: -2 · 95% CI -10 to 7Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.1127 · Mean difference in % cfb: -7 · 95% CI -15 to 2Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.2576 · Mean difference in % cfb: -5 · 95% CI -14 to 4Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.0017 · Mean difference in % cfb: -36 · 95% CI -52 to -16Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = <0.0001 · Mean difference in % cfb: -58 · 95% CI -68 to -45Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = <0.0001 · Mean difference in % cfb: -47 · 95% CI -61 to -29Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.0193 · Mean difference in % cfb: -11 · 95% CI -20 to -2Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = <0.0001 · Mean difference in % cfb: -26 · 95% CI -33 to -19Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.0063 · Mean difference in % cfb: -14 · 95% CI -23 to -4Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.8873 · Mean difference in % cfb: -2 · 95% CI -21 to 23Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.4404 · Mean difference in % cfb: -8 · 95% CI -27 to 15Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.9665 · Mean difference in % cfb]: -1 · 95% CI -22 to 27Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.4133 · Mean difference in % cfb]: -7 · 95% CI -21 to 10Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.4750 · Mean difference in % cfb]: -6 · 95% CI -20 to 11Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.6354 · Mean difference in % cfb]: -4 · 95% CI -20 to 15Mean difference in percent (%) change from baseline (CFB) based on difference in least square mean (LSM) of log (Primary Analysis Time Point/Baseline) was estimated.
SecondaryChange From Baseline in Fasting Plasma Glucose at the Primary Analysis Time Point

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
Reported as:
Least squares mean · mg/dL
Change From Baseline in Fasting Plasma Glucose at the Primary Analysis Time Point
mg/dLPooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QW
Change From Baseline in Fasting Plasma Glucose at the Primary Analysis Time Point-4.4 (-21.74 to 12.95)-21.6 (-40.05 to -3.17)9.4 (-9.53 to 28.40)-2.2 (-25.33 to 20.90)
Statistical analysis
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.1799 · Least squares mean difference: -17.2 · 95% CI -42.53 to 8.10
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.2867 · Least squares mean difference: 13.8 · 95% CI -11.83 to 39.49
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.8812 · Least squares mean difference: 2.2 · 95% CI -26.78 to 31.14
SecondaryChange From Baseline in Hemoglobin A1c (HbA1c) at the Primary Analysis Time Point

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
Reported as:
Least squares mean · percentage of HbA1c
Change From Baseline in Hemoglobin A1c (HbA1c) at the Primary Analysis Time Point
percentage of HbA1cPooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QW
Change From Baseline in Hemoglobin A1c (HbA1c) at the Primary Analysis Time Point0.19 (-0.27 to 0.64)-0.09 (-0.56 to 0.37)0.26 (-0.22 to 0.75)0.35 (-0.18 to 0.87)
Statistical analysis
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.3995 · Least squares mean difference: -0.28 · 95% CI -0.94 to 0.38
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.8155 · Least squares mean difference: 0.08 · 95% CI -0.59 to 0.75
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.6466 · Least squares mean difference: 0.16 · 95% CI -0.54 to 0.86
SecondaryChange From Baseline in Fasting Insulin at the Primary Analysis Time Point

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
Reported as:
Least squares mean · milli-international units per liter
Change From Baseline in Fasting Insulin at the Primary Analysis Time Point
milli-international units per literPooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QW
Change From Baseline in Fasting Insulin at the Primary Analysis Time Point-0.10 (-5.74 to 5.55)-1.48 (-7.51 to 4.54)-0.23 (-6.37 to 5.91)3.48 (-3.94 to 10.9)
Statistical analysis
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.7393 · Least squares mean difference: 1.39 · 95% CI -9.66 to 6.89
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.9744 · Least squares mean difference: -0.13 · 95% CI -8.45 to 8.18
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.4477 · Least squares mean difference: 3.58 · 95% CI -5.75 to 12.91
SecondaryChange From Baseline in and HOMA-IR at the Primary Analysis Time Point

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
Reported as:
Least squares mean · index
Change From Baseline in and HOMA-IR at the Primary Analysis Time Point
indexPooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QW
Change From Baseline in and HOMA-IR at the Primary Analysis Time Point-0.119 (-3.47 to 3.24)-1.914 (-5.50 to 1.67)0.141 (-3.52 to 3.80)2.013 (-2.41 to 6.44)
Statistical analysis
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.4710 · Least squares mean difference: -1.794 · 95% CI -6.72 to 3.14
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.9169 · Least squares mean difference: 0.260 · 95% CI -4.68 to 5.20
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.4484 · Least squares mean difference: 2.133 · 95% CI -3.44 to 7.70
SecondaryChange From Baseline in Fructosamine at Primary Analysis Time Point

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
Reported as:
Least squares mean · μmol/L
Change From Baseline in Fructosamine at Primary Analysis Time Point
μmol/LPooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QW
Change From Baseline in Fructosamine at Primary Analysis Time Point13.2 (-5.40 to 31.80)-10.0 (-29.34 to 9.40)1.8 (-17.92 to 21.44)15.1 (-7.74 to 38.04)
Statistical analysis
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.0916 · Least squares mean difference: -23.2 · 95% CI -50.17 to 3.83
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.4032 · Least squares mean difference: -11.4 · 95% CI -38.51 to 15.63
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.8959 · Least squares mean difference: 1.9 · 95% CI -27.56 to 31.45
SecondaryChange From Baseline in Glycated Albumin at the Primary Analysis Time Point

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
Reported as:
Least squares mean · grams per deciliter (g/dL)
Change From Baseline in Glycated Albumin at the Primary Analysis Time Point
grams per deciliter (g/dL)Pooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QW
Change From Baseline in Glycated Albumin at the Primary Analysis Time Point-0.0033 (-0.07 to 0.07)-0.0553 (-0.13 to 0.02)-0.0133 (-0.09 to 0.06)0.0280 (-0.06 to 0.12)
Statistical analysis
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.3202 · Least squares mean difference: -0.0520 · 95% CI -0.16 to 0.05
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.8485 · Least squares mean difference: -0.0100 · 95% CI -0.11 to 0.09
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.5812 · Least squares mean difference: 0.0314 · 95% CI -0.08 to 0.14
SecondaryChange From Baseline in Weight at the Primary Analysis Time Point

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
Reported as:
Least squares mean · kg
Change From Baseline in Weight at the Primary Analysis Time Point
kgPooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QW
Change From Baseline in Weight at the Primary Analysis Time Point-1.00 (-2.19 to 0.18)-0.57 (-1.76 to 0.62)-0.99 (-2.15 to 0.17)-1.33 (-2.57 to -0.09)
Statistical analysis
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.6157 · Least squares mean difference: 0.43 · 95% CI -1.28 to 2.15
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.9869 · Least squares mean difference: 0.01 · 95% CI -1.66 to 1.69
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.7084 · Least squares mean difference: -0.33 · 95% CI -2.07 to 1.42
SecondaryChange From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Primary Analysis Time Point

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
Reported as:
Least squares mean · millimeters of mercury (mmHg)
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Primary Analysis Time Point
millimeters of mercury (mmHg)Pooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QW
SBP-1.66 (-6.66 to 3.33)1.13 (-4.07 to 6.34)0.42 (-4.67 to 5.51)-3.29 (-8.76 to 2.17)
DBP-2.35 (-5.71 to 1.00)1.75 (-1.70 to 5.20)1.13 (-2.26 to 4.52)-0.73 (-4.35 to 2.88)
Statistical analysis
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.4431 · Least squares mean difference: 2.79 · 95% CI -4.41 to 10.00
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.5630 · Least squares mean difference: 2.08 · 95% CI -5.05 to 9.22
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.6634 · Least squares mean difference: -1.63 · 95% CI -9.06 to 5.79
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.0937 · Least squares mean difference: 4.11 · 95% CI -0.71 to 8.92
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.1522 · Least squares mean difference: 3.49 · 95% CI -1.31 to 8.28
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.5188 · Least squares mean difference: 1.62 · 95% CI -3.35 to 6.59
SecondaryPercent Change From Baseline in Weight, SBP and DBP at Primary Analysis Time Point

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
Reported as:
Least squares mean · percent change
Percent Change From Baseline in Weight, SBP and DBP at Primary Analysis Time Point
percent changePooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QW
Weight-0.98 (-2.23 to 0.27)-0.40 (-1.66 to 0.85)-1.10 (-2.32 to 0.12)-1.38 (-2.69 to -0.07)
SBP-0.55 (-4.57 to 3.46)1.80 (-2.38 to 5.98)0.68 (-3.41 to 4.77)-1.79 (-6.17 to 2.60)
DBP-1.83 (-6.22 to 2.56)3.18 (-1.33 to 7.69)2.11 (-2.32 to 6.54)-0.13 (-4.85 to 4.60)
Statistical analysis
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.5299 · Least squares mean difference: 0.57 · 95% CI -1.24 to 2.39
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.8919 · Least squares mean difference: -0.12 · 95% CI -1.89 to 1.65
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.6653 · Least squares mean difference: -0.40 · 95% CI -2.25 to 1.44
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.4213 · Least squares mean difference: 2.35 · 95% CI -3.43 to 8.14
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.6696 · Least squares mean difference: 1.23 · 95% CI -4.49 to 6.96
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.6819 · Least squares mean difference: -1.23 · 95% CI -7.20 to 4.73
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.1171 · Least squares mean difference: 5.01 · 95% CI -1.28 to 11.31
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.2155 · Least squares mean difference: 3.94 · 95% CI -2.33 to 10.21
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.6034 · Least squares mean difference: 1.70 · 95% CI -4.79 to 8.20
SecondaryChange From Baseline in Hepatic Fat Fraction (HFF) by Magnetic Resonance Imaging-Derived Proton Density Fat Fraction (MRI-PDFF) at the Primary Analysis Time Point

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
Reported as:
Least squares mean · percentage (Hepatic Fat Fraction)
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
percentage (Hepatic Fat Fraction)Pooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QW
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-1.69 (-4.09 to 0.71)-0.71 (-3.21 to 1.78)2.39 (-0.16 to 4.94)-0.12 (-2.87 to 2.64)
Statistical analysis
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.5752 · Least squares mean difference: 0.98 · 95% CI -2.48 to 4.44
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.0230 · Least squares mean difference: 4.09 · 95% CI 0.58 to 7.59
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.3965 · Least squares mean difference: 1.57 · 95% CI -2.10 to 5.25
SecondaryPercent 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

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
Reported as:
Least squares mean · percent change
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
percent changePooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QW
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-7.09 (-23.63 to 9.45)5.34 (-11.83 to 22.52)18.94 (1.38 to 36.51)5.18 (-13.80 to 24.15)
Statistical analysis
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.3023 · Least squares mean difference: 12.44 · 95% CI -11.39 to 36.26
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.0350 · Least squares mean difference: 26.03 · 95% CI 1.87 to 50.19
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.3374 · Least squares mean difference: 12.27 · 95% CI -13.02 to 37.55
SecondaryPercentage of Participants With HFF ≤ 8% by MRI-PDFF at the Primary Analysis Time Point

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
Reported as:
Number · percentage of participants
Percentage of Participants With HFF ≤ 8% by MRI-PDFF at the Primary Analysis Time Point
percentage of participantsPooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QW
Percentage of Participants With HFF ≤ 8% by MRI-PDFF at the Primary Analysis Time Point16.08.74.515.8
SecondaryChange From Baseline in Fatty Liver Index (FLI) at the Primary Analysis Time Point

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
Reported as:
Least squares mean · index
Change From Baseline in Fatty Liver Index (FLI) at the Primary Analysis Time Point
indexPooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QW
Change From Baseline in Fatty Liver Index (FLI) at the Primary Analysis Time Point-3.50 (-8.21 to 1.22)-6.08 (-11.08 to -1.09)-9.21 (-13.99 to -4.44)-8.07 (-13.06 to -3.07)
Statistical analysis
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.4583 · Least squares mean difference: -2.59 · 95% CI -9.49 to 4.31
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.0943 · Least squares mean difference: -5.71 · 95% CI -12.43 to 1.00
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.1909 · Least squares mean difference: -4.57 · 95% CI -11.45 to 2.32
SecondaryChange From Baseline in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) at the Primary Analysis Time Point

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
Reported as:
Least squares mean · units per liter (U/L)
Change From Baseline in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) at the Primary Analysis Time Point
units per liter (U/L)Pooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QW
ALT-2.2 (-8.48 to 3.99)4.8 (-1.75 to 11.38)12.5 (6.30 to 18.79)6.6 (-0.06 to 13.32)
AST-1.8 (-5.50 to 1.93)3.2 (-0.71 to 7.12)6.7 (2.93 to 10.37)4.7 (0.77 to 8.71)
Statistical analysis
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.1294 · Least squares mean difference: 7.1 · 95% CI -2.10 to 16.22
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.0012 · Least squares mean difference: 14.8 · 95% CI 5.98 to 23.59
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.0594 · Least squares mean difference: 8.9 · 95% CI -0.36 to 18.11
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.0730 · [least squares mean difference: 5.0 · 95% CI -0.47 to 10.45
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.0020 · Least squares mean difference: 8.4 · 95% CI 3.17 to 13.70
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.0200 · Least squares mean difference: 6.5 · 95% CI 1.05 to 12.00
SecondaryChange From Baseline in Leptin at the Primary Analysis Time Point

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
Reported as:
Least squares mean · μg/L
Change From Baseline in Leptin at the Primary Analysis Time Point
μg/LPooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QW
Change From Baseline in Leptin at the Primary Analysis Time Point0.95 (-1.37 to 3.27)-0.24 (-2.66 to 2.18)-0.57 (-2.99 to 1.85)-3.23 (-5.90 to -0.56)
Statistical analysis
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.4812 · Least squares mean difference: -1.19 · 95% CI -4.55 to 2.16
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.3679 · Least squares mean difference: -1.53 · 95% CI -4.88 to 1.83
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.0210 · Least squares mean difference: -4.18 · 95% CI -7.72 to -0.65
SecondaryChange From Baseline in Adiponectin at the Primary Analysis Time Point

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
Reported as:
Least squares mean · milligrams per liter (mg/L)
Change From Baseline in Adiponectin at the Primary Analysis Time Point
milligrams per liter (mg/L)Pooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QW
Change From Baseline in Adiponectin at the Primary Analysis Time Point0.20 (-0.20 to 0.60)0.05 (-0.37 to 0.48)-0.18 (-0.61 to 0.24)-0.18 (-0.65 to 0.29)
Statistical analysis
  • Pooled Placebo · ANCOVA · p = 0.6227 · Least squares mean difference: -0.15 · 95% CI -0.73 to 0.44
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.1950 · Least squares mean difference: -0.38 · 95% CI -0.97 to 0.20
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.2271 · Least squares mean difference: -0.38 · 95% CI -1.00 to 0.24
SecondaryChange From Baseline in Subcutaneous Adipose Tissue (SAT) and Visceral Adipose Tissue (VAT) by Single Slice MRI at the Primary Analysis Timepoint

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
Reported as:
Least squares mean · mm^2
Change From Baseline in Subcutaneous Adipose Tissue (SAT) and Visceral Adipose Tissue (VAT) by Single Slice MRI at the Primary Analysis Timepoint
mm^2Pooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QW
SAT-25.61 (-156.99 to 105.76)-8.55 (-145.57 to 128.47)7.31 (-139.08 to 153.70)-41.91 (-192.12 to 108.29)
VAT14.83 (-112.13 to 141.79)19.78 (-109.07 to 148.63)-9.42 (-149.27 to 130.42)36.85 (-105.21 to 178.91)
Statistical analysis
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.8591 · Least squares mean difference: 17.06 · 95% CI -173.57 to 207.69
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.7404 · Least squares mean difference: 32.92 · 95% CI -164.11 to 229.95
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.8711 · Least squares mean difference: -16.30 · 95% CI -215.50 to 182.90
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.9569 · Least squares mean difference: 4.95 · 95% CI -176.64 to 186.53
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.8025 · Least squares mean difference: -24.26 · 95% CI -216.53 to 168.02
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.8202 · Least squares mean difference: 22.02 · 95% CI -170.09 to 214.12
SecondaryChange From Baseline in Waist Circumference by Single Slice MRI at the Primary Analysis Timepoint

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
Reported as:
Least squares mean · cm
Change From Baseline in Waist Circumference by Single Slice MRI at the Primary Analysis Timepoint
cmPooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg Q4W
Change From Baseline in Waist Circumference by Single Slice MRI at the Primary Analysis Timepoint-2.25 (-6.85 to 2.35)-2.14 (-6.77 to 2.49)-2.95 (-7.51 to 1.61)-0.59 (-5.41 to 4.23)
Statistical analysis
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.9734 · Least squares mean difference: 0.11 · 95% CI -6.47 to 6.69
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.8333 · Least squares mean difference: -0.70 · 95% CI -7.25 to 5.86
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg Q4W · ANCOVA · p = 0.6207 · Least squares mean difference: 1.66 · 95% CI -4.99 to 8.31
SecondaryChange From Baseline in Waist to Hip Ratio (WHR) at the Primary Analysis Timepoint

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
Reported as:
Least squares mean · ratio
Change From Baseline in Waist to Hip Ratio (WHR) at the Primary Analysis Timepoint
ratioPooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QW
Change From Baseline in Waist to Hip Ratio (WHR) at the Primary Analysis Timepoint0.01 (-0.03 to 0.04)0.01 (-0.02 to 0.05)-0.01 (-0.04 to 0.02)0.01 (-0.03 to 0.05)
Statistical analysis
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.8026 · Least squares mean difference: 0.01 · 95% CI -0.04 to 0.06
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.4917 · Least squares mean difference: -0.02 · 95% CI -0.07 to 0.03
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.8916 · Least squares mean difference: 0.00 · 95% CI -0.05 to 0.05
SecondaryChange From Baseline in Body Mass Index (BMI) at the Primary Analysis Timepoint

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
Reported as:
Least squares mean · kg/m^2
Change From Baseline in Body Mass Index (BMI) at the Primary Analysis Timepoint
kg/m^2Pooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QW
Change From Baseline in Body Mass Index (BMI) at the Primary Analysis Timepoint-0.27 (-0.69 to 0.15)-0.17 (-0.59 to 0.26)-0.37 (-0.79 to 0.04)-0.50 (-0.94 to -0.05)
Statistical analysis
  • Pooled Placebo vs Cohort B: ISIS 703802, 40 mg Q4W · ANCOVA · p = 0.7280 · Least squares mean difference: 0.11 · 95% CI -0.50 to 0.71
  • Pooled Placebo vs Cohort C: ISIS 703802, 80 mg Q4W · ANCOVA · p = 0.7354 · Least squares mean difference: -0.10 · 95% CI -0.69 to 0.49
  • Pooled Placebo vs Cohort A: ISIS 703802, 20 mg QW · ANCOVA · p = 0.4682 · Least squares mean difference: -0.23 · 95% CI -0.84 to 0.39
SecondaryNumber of Participants With Treatment-emergent Adverse Events (TEAEs)

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)
Reported as:
Count of participants · Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
ParticipantsPooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg Q4W
Number of Participants With Treatment-emergent Adverse Events (TEAEs)18212423

Adverse events

Collected over Up to 13 weeks post-treatment period (up to 39 weeks). Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Pooled Placebo0/27 (0%)1/27 (3.7%)13/27 (48.1%)
Cohort B: ISIS 703802, 40 mg Q4W0/26 (0%)1/26 (3.8%)15/26 (57.7%)
Cohort C: ISIS 703802, 80 mg Q4W0/26 (0%)2/26 (7.7%)20/26 (76.9%)
Cohort A: ISIS 703802, 20 mg QW0/26 (0%)1/26 (3.8%)14/26 (53.8%)
Most frequent serious events
Most frequent serious events
EventPooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QW
ActinomycosisInfections and infestations0/270/261/260/26
DiverticulitisInfections and infestations0/270/260/261/26
Non-cardiac chest painGeneral disorders0/271/260/260/26
Procedural complicationInjury, poisoning and procedural complications0/270/261/260/26
NephrolithiasisRenal and urinary disorders1/270/260/260/26
Most frequent other events
Showing 10 of 24
Most frequent other events
EventPooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QW
Injection site pruritusGeneral disorders0/271/268/262/26
Injection site erythemaGeneral disorders0/271/266/262/26
Urinary tract infectionInfections and infestations4/271/261/261/26
PharyngitisInfections and infestations0/272/263/261/26
NasopharyngitisInfections and infestations0/271/263/261/26
Upper respiratory tract infectionInfections and infestations2/272/260/263/26
DiarrhoeaGastrointestinal disorders3/270/263/262/26
NauseaGastrointestinal disorders2/272/263/260/26
HyperglycaemiaMetabolism and nutrition disorders0/273/261/262/26
Muscle strainInjury, poisoning and procedural complications0/273/260/260/26

Baseline characteristics

Full Analysis Set (FAS) population included all participants who were randomized and received at least 1 dose of study drug.

Age, Continuous
Age, Continuous(years)Pooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QWTotal
Mean51.1 ± 7.2952.0 ± 10.3454.8 ± 6.0456.0 ± 8.4553.5 ± 8.30
Sex: Female, Male
Sex: Female, Male(Participants)Pooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QWTotal
Female169131149
Male1117131556
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Pooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QWTotal
Hispanic or Latino2413111765
Not Hispanic or Latino31315940
Unknown or Not Reported00000
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Pooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QWTotal
American Indian or Alaska Native00000
Asian11103
Native Hawaiian or Other Pacific Islander00000
Black or African American12115
White2523242597
More than one race00000
Unknown or Not Reported00000
Fasting Triglycerides (TG)
Fasting Triglycerides (TG)(milligrams per deciliter (mg/dL))Pooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QWTotal
Mean275.5 ± 110.38414.9 ± 456.86292.2 ± 130.98311.8 ± 155.92323.1 ± 257.20
Angiopoietin Like 3 (ANGPTL3)
Angiopoietin Like 3 (ANGPTL3)(micrograms per liter (μg/L))Pooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QWTotal
Mean114.85 ± 32.066102.36 ± 28.923111.86 ± 37.463108.60 ± 42.722109.47 ± 35.441
Total Cholesterol (TC)
Total Cholesterol (TC)(mg/dL)Pooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QWTotal
Mean202.1 ± 43.64200.7 ± 45.27191.2 ± 61.63182.4 ± 47.06194.2 ± 49.78
Non- High density lipoprotein cholesterol (Non-HDL-C)
Non- High density lipoprotein cholesterol (Non-HDL-C)(mg/dL)Pooled PlaceboCohort B: ISIS 703802, 40 mg Q4WCohort C: ISIS 703802, 80 mg Q4WCohort A: ISIS 703802, 20 mg QWTotal
Mean162.7 ± 39.90164.3 ± 47.50154.1 ± 58.28146.8 ± 46.79157.0 ± 48.30

23 further baseline measures are reported on the registry.

08

Study locations

42 sites
  • Clinical Sites
    Chandler, Arizona 85224, United States
  • Clinical Site
    Fountain Hills, Arizona 85268, United States
  • Clinical Site
    Glendale, Arizona 85306, United States
  • Clinical Site
    Mesa, Arizona 85206, United States
  • Clinical Site
    Mesa, Arizona 85213, United States
  • Clinical Site
    Phoenix, Arizona 85020, United States
  • Clinical Site
    Phoenix, Arizona 85023, United States
  • Clinical Site
    Phoenix, Arizona 85050, United States
  • Clinical Site
    Huntington Park, California 90255, United States
  • Clinical Site
    Los Angeles, California 90057, United States
  • Clinical Site
    Montclair, California 91710, United States
  • Clinical Site
    Panorama City, California 91402, United States
  • Clinical Site
    Poway, California 92064, United States
  • Clinical Site
    Boca Raton, Florida 33487, United States
  • Clinical Site
    Jensen Beach, Florida 34957, United States
  • Clinical Site
    Jupiter, Florida 33458, United States
  • Clinical Site
    Miami, Florida 33165, United States
  • Clinical Site
    Port Saint Lucie, Florida 34952, United States
  • Clinical Site
    Atlanta, Georgia 30328, United States
  • Clinical Site
    Chicago, Illinois 60640, United States
  • Clinical Site
    Indianapolis, Indiana 46260, United States
  • Clinical Site
    Louisville, Kentucky 40213, United States
  • Clinical Site
    Edina, Minnesota 55435, United States
  • Clinical Site
    Bridgeton, New Jersey 08302, United States
  • Clinical Site
    Princeton, New Jersey 08540, United States
  • Clinical Site
    Greensboro, North Carolina 27410, United States
  • Clinical Site
    High Point, North Carolina 27265, United States
  • Clinical Site
    Cincinnati, Ohio 45219, United States
  • Clinical Site
    Cincinnati, Ohio 45227, United States
  • Clinical Site
    Charleston, South Carolina 29407, United States
  • Clinical Site
    Austin, Texas 78735, United States
  • Clinical Site
    Carrollton, Texas 75010, United States
  • Clinical Site
    Dallas, Texas 75234, United States
  • Clinical Site
    Houston, Texas 77058, United States
  • Clinical Site
    Hurst, Texas 76054, United States
  • Clinical Site
    San Antonio, Texas 78215, United States
  • Clinical Site
    San Antonio, Texas 78229, United States
  • Clinical Site
    Layton, Utah 84041, United States
  • Clinical Site
    Hamilton, Ontario L8L 5G8, Canada
  • Clinical Site
    Toronto, Ontario M3M 3E5, Canada
  • Clinical Site
    Chicoutimi, Quebec G7H 7K9, Canada
  • Clinical Site
    Montréal, Quebec H4A 2C6, Canada
09

References and documents

Study documents

PDFs hosted by the registry, ClinicalTrials.gov.

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Feb 1, 2021, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
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Registry details

Key details

Study ID
NCT03371355
Lead sponsor
Akcea Therapeutics
Collaborators
Ionis Pharmaceuticals, Inc.
Responsible party
Sponsor
First posted
Dec 13, 2017
Start date
Dec 21, 2017
Primary completion
Nov 21, 2019
Completion
Feb 24, 2020
Results posted
Feb 1, 2021
Last update
Feb 1, 2021

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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This study is completed, as verified in Dec 2020. You cannot join it, but the record below documents what was studied.

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Discussion

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Studies of the drug tested here: Vupanorsen

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