Diabetes Mellitus, Type 2, Fatty Liver, Nonalcoholic, Hypertriglyceridemia, NAFLD
Conditions
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
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).
Interventions
DRUGPlacebo
Placebo (Matched with ISIS 703802)
DRUGISIS 703802 40 mg
ISIS 703802 40 mg, administered via SC injection, once every 4 weeks for 6 doses.
DRUGISIS 703802 80 mg
ISIS 703802 80 mg, administered via SC injection, once every 4 weeks for 6 doses.
DRUGISIS 703802 20 mg
ISIS 703802 20 mg, administered via SC injection, once every week for 26 doses.
Sponsors
Akcea Therapeutics
Ionis Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Plasma triglycerides (TG) at Screening greater than (\>)150 milligrams per deciliter (mg/dL) and at qualification of \>150 mg/dL. * Documented history of hepatic steatosis with baseline magnetic resonance imaging (MRI) indicating hepatic fat fraction (HFF) greater than (\>) 8%. * Diagnosis of Type 2 diabetes mellitus with hemoglobin A1c (HbA1c) \>6.5 and less than or equal to (≤) 10% at Screening. * Must have been on a stable dose of oral antidiabetic therapy for a minimum of 3 months prior to Screening. * Body mass index between 27- 40 kilograms per meter square (kg/m\^2), inclusive, at Screening. Key
Exclusion criteria
* Type 1 diabetes mellitus. * Active chronic liver disease, alcoholic liver disease, Wilson's disease hemochromatosis, primary biliary cirrhosis, primary sclerosing cholangitis, genetic hemochromatosis, known or suspected hepatocellular carcinoma, history of or planned liver transplant for end-stage liver disease of any etiology. * Documented history of advanced liver fibrosis. * History of cirrhosis and/or hepatic decompensation including ascites, hepatic encephalopathy, or variceal bleeding. * History of clinically significant acute cardiac event within 6 months before Screening. * History of heart failure with New York Heart Association (NYHA) greater than Class II. * Use of Insulin or insulin analogs, glucagon-like peptide-1 (GLP-1) agonists, and peroxisome proliferator-activated receptor gamma (PPARᵞ) agonists (pioglitazone or rosiglitazone). * Weight change \>5% within 3 months before Screening. * Conditions contraindicated for magnetic resonance imaging (MRI) procedures including any metal implant (example, heart pacemaker, rods, screws, aneurysm clips).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Canada, United States
Participant flow
Recruitment details
The study was conducted at 42 study centers; 38 sites in the US and 4 sites in Canada.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Pooled Placebo Participants from each cohort received placebo at a dose-matched volume of study drug, SC. | 27 |
| Cohort B: ISIS 703802, 40 mg Q4W Participants received ISIS 703802, 40 mg SC once every 4 weeks for 6 doses. | 26 |
| Cohort C: ISIS 703802, 80 mg Q4W Participants received ISIS 703802, 80 mg SC once every 4 weeks for 6 doses. | 26 |
| Cohort A: ISIS 703802, 20 mg QW Participants received ISIS 703802, 20 mg SC once every week for 26 doses. | 26 |
| Total | 105 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 2 | 3 |
| Overall Study | Investigator judgment | 0 | 0 | 1 | 1 |
| Overall Study | Reason not Specified | 0 | 1 | 0 | 1 |
| Overall Study | Voluntary withdrawal | 1 | 0 | 1 | 2 |
Baseline characteristics
| Characteristic | Pooled Placebo | Total | Cohort A: ISIS 703802, 20 mg QW | Cohort C: ISIS 703802, 80 mg Q4W | Cohort B: ISIS 703802, 40 mg Q4W |
|---|---|---|---|---|---|
| Age, Continuous | 51.1 years STANDARD_DEVIATION 7.29 | 53.5 years STANDARD_DEVIATION 8.3 | 56.0 years STANDARD_DEVIATION 8.45 | 54.8 years STANDARD_DEVIATION 6.04 | 52.0 years STANDARD_DEVIATION 10.34 |
| Angiopoietin Like 3 (ANGPTL3) | 114.85 micrograms per liter (μg/L) STANDARD_DEVIATION 32.066 | 109.47 micrograms per liter (μg/L) STANDARD_DEVIATION 35.441 | 108.60 micrograms per liter (μg/L) STANDARD_DEVIATION 42.722 | 111.86 micrograms per liter (μg/L) STANDARD_DEVIATION 37.463 | 102.36 micrograms per liter (μg/L) STANDARD_DEVIATION 28.923 |
| Apolipoprotein A1 (ApoA1) | 141.3 mg/dL STANDARD_DEVIATION 19.3 | 137.9 mg/dL STANDARD_DEVIATION 21.13 | 133.3 mg/dL STANDARD_DEVIATION 20.18 | 139.1 mg/dL STANDARD_DEVIATION 24.12 | 137.9 mg/dL STANDARD_DEVIATION 21.12 |
| Apolipoprotein B100 (ApoB-100) | 105.89 mg/dL STANDARD_DEVIATION 25.699 | 100.62 mg/dL STANDARD_DEVIATION 28.54 | 91.79 mg/dL STANDARD_DEVIATION 25.871 | 102.14 mg/dL STANDARD_DEVIATION 35.392 | 102.48 mg/dL STANDARD_DEVIATION 25.74 |
| Apolipoprotein B48 (ApoB-48) | 2.63 mg/dL STANDARD_DEVIATION 1.455 | 3.13 mg/dL STANDARD_DEVIATION 2.511 | 3.48 mg/dL STANDARD_DEVIATION 3.228 | 3.20 mg/dL STANDARD_DEVIATION 2.863 | 3.21 mg/dL STANDARD_DEVIATION 2.239 |
| Apolipoprotein B (ApoB) | 108.68 mg/dL STANDARD_DEVIATION 25.254 | 103.90 mg/dL STANDARD_DEVIATION 28.721 | 95.48 mg/dL STANDARD_DEVIATION 26.21 | 105.34 mg/dL STANDARD_DEVIATION 36.16 | 105.90 mg/dL STANDARD_DEVIATION 25.868 |
| Apolipoprotein CIII (ApoCIII) | 14.48 mg/dL STANDARD_DEVIATION 3.981 | 16.21 mg/dL STANDARD_DEVIATION 7 | 16.19 mg/dL STANDARD_DEVIATION 5.562 | 15.54 mg/dL STANDARD_DEVIATION 4.969 | 18.71 mg/dL STANDARD_DEVIATION 11.024 |
| Body Mass Index (BMI) | 30.3 kilograms per meter square (kg/m^2) STANDARD_DEVIATION 3.03 | 31.9 kilograms per meter square (kg/m^2) STANDARD_DEVIATION 3.84 | 32.3 kilograms per meter square (kg/m^2) STANDARD_DEVIATION 4.19 | 32.1 kilograms per meter square (kg/m^2) STANDARD_DEVIATION 3.84 | 32.8 kilograms per meter square (kg/m^2) STANDARD_DEVIATION 3.97 |
| Body Weight | 79.3 kg STANDARD_DEVIATION 10.64 | 88.5 kg STANDARD_DEVIATION 17.15 | 92.0 kg STANDARD_DEVIATION 16.39 | 90.7 kg STANDARD_DEVIATION 20.83 | 92.5 kg STANDARD_DEVIATION 16.66 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 24 Participants | 65 Participants | 17 Participants | 11 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 40 Participants | 9 Participants | 15 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Fasting Triglycerides (TG) | 275.5 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 110.38 | 323.1 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 257.2 | 311.8 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 155.92 | 292.2 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 130.98 | 414.9 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 456.86 |
| Fatty Liver Index (FLI) | 77.20 index STANDARD_DEVIATION 22.618 | 82.51 index STANDARD_DEVIATION 17.907 | 84.45 index STANDARD_DEVIATION 13.926 | 83.16 index STANDARD_DEVIATION 19.846 | 85.55 index STANDARD_DEVIATION 12.802 |
| Free Fatty Acid (FFA) | 0.62 millimole per liter (mmol/L) STANDARD_DEVIATION 0.261 | 0.62 millimole per liter (mmol/L) STANDARD_DEVIATION 0.243 | 0.58 millimole per liter (mmol/L) STANDARD_DEVIATION 0.213 | 0.61 millimole per liter (mmol/L) STANDARD_DEVIATION 0.237 | 0.66 millimole per liter (mmol/L) STANDARD_DEVIATION 0.266 |
| Fructosamine | 325.2 micromoles per liter (μmol/L) STANDARD_DEVIATION 49.62 | 314.7 micromoles per liter (μmol/L) STANDARD_DEVIATION 55.85 | 312.9 micromoles per liter (μmol/L) STANDARD_DEVIATION 48.19 | 317.6 micromoles per liter (μmol/L) STANDARD_DEVIATION 59.33 | 302.7 micromoles per liter (μmol/L) STANDARD_DEVIATION 65.51 |
| Glycated Albumin | 0.84 grams per deciliter (g/dL) STANDARD_DEVIATION 0.183 | 0.79 grams per deciliter (g/dL) STANDARD_DEVIATION 0.211 | 0.79 grams per deciliter (g/dL) STANDARD_DEVIATION 0.187 | 0.80 grams per deciliter (g/dL) STANDARD_DEVIATION 0.216 | 0.74 grams per deciliter (g/dL) STANDARD_DEVIATION 0.254 |
| Hemoglobin A1C (HbA1C) | 8.30 percentage of HbA1c STANDARD_DEVIATION 1.26 | 8.22 percentage of HbA1c STANDARD_DEVIATION 1.091 | 8.19 percentage of HbA1c STANDARD_DEVIATION 0.901 | 8.36 percentage of HbA1c STANDARD_DEVIATION 1.091 | 8.04 percentage of HbA1c STANDARD_DEVIATION 1.113 |
| Hepatic Fat Fraction (HFF) | 16.84 percentage (Hepatic Fat Fraction) STANDARD_DEVIATION 6.144 | 17.63 percentage (Hepatic Fat Fraction) STANDARD_DEVIATION 7.642 | 19.32 percentage (Hepatic Fat Fraction) STANDARD_DEVIATION 10.445 | 17.23 percentage (Hepatic Fat Fraction) STANDARD_DEVIATION 7.262 | 17.17 percentage (Hepatic Fat Fraction) STANDARD_DEVIATION 6.15 |
| High density lipoprotein cholesterol (HDL-C) | 39.4 mg/dL STANDARD_DEVIATION 10.43 | 37.1 mg/dL STANDARD_DEVIATION 10.26 | 35.6 mg/dL STANDARD_DEVIATION 9.89 | 37.1 mg/dL STANDARD_DEVIATION 10.37 | 36.3 mg/dL STANDARD_DEVIATION 10.54 |
| Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) | 12.40 index STANDARD_DEVIATION 8.548 | 11.10 index STANDARD_DEVIATION 7.5 | 9.54 index STANDARD_DEVIATION 6.278 | 13.02 index STANDARD_DEVIATION 8.331 | 9.42 index STANDARD_DEVIATION 6.178 |
| Insulin | 26.35 milli international units per liter STANDARD_DEVIATION 16.965 | 24.31 milli international units per liter STANDARD_DEVIATION 14.542 | 23.19 milli international units per liter STANDARD_DEVIATION 12.887 | 26.32 milli international units per liter STANDARD_DEVIATION 15.353 | 21.35 milli international units per liter STANDARD_DEVIATION 12.602 |
| Lipoprotein-a (Lp[a]) | 51.7 nanomoles per liter (nmol/L) STANDARD_DEVIATION 66.79 | 48.8 nanomoles per liter (nmol/L) STANDARD_DEVIATION 67.69 | 38.3 nanomoles per liter (nmol/L) STANDARD_DEVIATION 54.81 | 46.7 nanomoles per liter (nmol/L) STANDARD_DEVIATION 74.88 | 58.2 nanomoles per liter (nmol/L) STANDARD_DEVIATION 74.74 |
| Low Density Lipoprotein Cholesterol (LDL-C) | 111.5 mg/dL STANDARD_DEVIATION 43.06 | 99.8 mg/dL STANDARD_DEVIATION 43.05 | 88.6 mg/dL STANDARD_DEVIATION 37.69 | 101.0 mg/dL STANDARD_DEVIATION 53.13 | 98.2 mg/dL STANDARD_DEVIATION 36.13 |
| Non- High density lipoprotein cholesterol (Non-HDL-C) | 162.7 mg/dL STANDARD_DEVIATION 39.9 | 157.0 mg/dL STANDARD_DEVIATION 48.3 | 146.8 mg/dL STANDARD_DEVIATION 46.79 | 154.1 mg/dL STANDARD_DEVIATION 58.28 | 164.3 mg/dL STANDARD_DEVIATION 47.5 |
| Plasma Glucose | 188.6 mg/dL STANDARD_DEVIATION 59.06 | 184.4 mg/dL STANDARD_DEVIATION 55.55 | 164.6 mg/dL STANDARD_DEVIATION 47.69 | 201.4 mg/dL STANDARD_DEVIATION 52.16 | 182.6 mg/dL STANDARD_DEVIATION 58.87 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 3 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 5 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 25 Participants | 97 Participants | 25 Participants | 24 Participants | 23 Participants |
| Sex: Female, Male Female | 16 Participants | 49 Participants | 11 Participants | 13 Participants | 9 Participants |
| Sex: Female, Male Male | 11 Participants | 56 Participants | 15 Participants | 13 Participants | 17 Participants |
| Subcutaneous Adipose Tissue (SAT) | 2634.49 millimeters square (mm^2) STANDARD_DEVIATION 1235.433 | 2856.41 millimeters square (mm^2) STANDARD_DEVIATION 1113.22 | 2701.94 millimeters square (mm^2) STANDARD_DEVIATION 1000.756 | 3021.37 millimeters square (mm^2) STANDARD_DEVIATION 1080.432 | 3076.36 millimeters square (mm^2) STANDARD_DEVIATION 1114.681 |
| Total Cholesterol (TC) | 202.1 mg/dL STANDARD_DEVIATION 43.64 | 194.2 mg/dL STANDARD_DEVIATION 49.78 | 182.4 mg/dL STANDARD_DEVIATION 47.06 | 191.2 mg/dL STANDARD_DEVIATION 61.63 | 200.7 mg/dL STANDARD_DEVIATION 45.27 |
| Very Low Density Lipoprotein Cholesterol (VLDL-C) | 47.8 mg/dL STANDARD_DEVIATION 12.9 | 49.4 mg/dL STANDARD_DEVIATION 12.71 | 49.6 mg/dL STANDARD_DEVIATION 13.11 | 47.6 mg/dL STANDARD_DEVIATION 9.92 | 52.6 mg/dL STANDARD_DEVIATION 14.59 |
| Visceral Adipose Tissue (VAT), | 2275.05 mm^2 STANDARD_DEVIATION 605.492 | 2637.85 mm^2 STANDARD_DEVIATION 903.168 | 2773.11 mm^2 STANDARD_DEVIATION 894.63 | 2826.84 mm^2 STANDARD_DEVIATION 1105.086 | 2690.34 mm^2 STANDARD_DEVIATION 888.431 |
| Waist to Hip Ratio | 0.98 ratio STANDARD_DEVIATION 0.07 | 1.00 ratio STANDARD_DEVIATION 0.163 | 0.97 ratio STANDARD_DEVIATION 0.068 | 1.01 ratio STANDARD_DEVIATION 0.216 | 1.05 ratio STANDARD_DEVIATION 0.225 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 27 | 0 / 26 | 0 / 26 | 0 / 26 |
| other Total, other adverse events | 13 / 27 | 15 / 26 | 20 / 26 | 14 / 26 |
| serious Total, serious adverse events | 1 / 27 | 1 / 26 | 2 / 26 | 1 / 26 |
Outcome results
Primary
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
Population: FAS population included all participants who were randomized and received at least 1 dose of study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Pooled Placebo | Percent Change From Baseline in Fasting Triglycerides Level at the Primary Analysis Time Point | -16 percent change |
| Cohort B: ISIS 703802, 40 mg Q4W | Percent Change From Baseline in Fasting Triglycerides Level at the Primary Analysis Time Point | -36 percent change |
| Cohort C: ISIS 703802, 80 mg Q4W | Percent Change From Baseline in Fasting Triglycerides Level at the Primary Analysis Time Point | -53 percent change |
| Cohort A: ISIS 703802, 20 mg QW | Percent Change From Baseline in Fasting Triglycerides Level at the Primary Analysis Time Point | -47 percent change |
p-value: 0.034395% CI: [-41, -2]ANCOVA
p-value: <0.000195% CI: [-56, -28]ANCOVA
p-value: 0.000995% CI: [-52, -17]ANCOVA
Secondary
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pooled Placebo | Change From Baseline in Adiponectin at the Primary Analysis Time Point | 0.20 milligrams per liter (mg/L) |
| Cohort B: ISIS 703802, 40 mg Q4W | Change From Baseline in Adiponectin at the Primary Analysis Time Point | 0.05 milligrams per liter (mg/L) |
| Cohort C: ISIS 703802, 80 mg Q4W | Change From Baseline in Adiponectin at the Primary Analysis Time Point | -0.18 milligrams per liter (mg/L) |
| Cohort A: ISIS 703802, 20 mg QW | Change From Baseline in Adiponectin at the Primary Analysis Time Point | -0.18 milligrams per liter (mg/L) |
p-value: 0.622795% CI: [-0.73, 0.44]ANCOVA
p-value: 0.19595% CI: [-0.97, 0.2]ANCOVA
p-value: 0.227195% CI: [-1, 0.24]ANCOVA
Secondary
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
Population: 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 | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Pooled Placebo | Change From Baseline in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) at the Primary Analysis Time Point | ALT | -2.2 units per liter (U/L) |
| Pooled Placebo | Change From Baseline in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) at the Primary Analysis Time Point | AST | -1.8 units per liter (U/L) |
| Cohort B: ISIS 703802, 40 mg Q4W | Change From Baseline in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) at the Primary Analysis Time Point | AST | 3.2 units per liter (U/L) |
| Cohort B: ISIS 703802, 40 mg Q4W | Change From Baseline in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) at the Primary Analysis Time Point | ALT | 4.8 units per liter (U/L) |
| Cohort C: ISIS 703802, 80 mg Q4W | Change From Baseline in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) at the Primary Analysis Time Point | ALT | 12.5 units per liter (U/L) |
| Cohort C: ISIS 703802, 80 mg Q4W | Change From Baseline in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) at the Primary Analysis Time Point | AST | 6.7 units per liter (U/L) |
| Cohort A: ISIS 703802, 20 mg QW | Change From Baseline in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) at the Primary Analysis Time Point | ALT | 6.6 units per liter (U/L) |
| Cohort A: ISIS 703802, 20 mg QW | Change From Baseline in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) at the Primary Analysis Time Point | AST | 4.7 units per liter (U/L) |
Comparison: ALTp-value: 0.129495% CI: [-2.1, 16.22]ANCOVA
Comparison: ALTp-value: 0.001295% CI: [5.98, 23.59]ANCOVA
Comparison: ALTp-value: 0.059495% CI: [-0.36, 18.11]ANCOVA
Comparison: ASTp-value: 0.07395% CI: [-0.47, 10.45]ANCOVA
Comparison: ASTp-value: 0.00295% CI: [3.17, 13.7]ANCOVA
Comparison: ASTp-value: 0.0295% CI: [1.05, 12]ANCOVA
Secondary
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pooled Placebo | Change From Baseline in and HOMA-IR at the Primary Analysis Time Point | -0.119 index |
| Cohort B: ISIS 703802, 40 mg Q4W | Change From Baseline in and HOMA-IR at the Primary Analysis Time Point | -1.914 index |
| Cohort C: ISIS 703802, 80 mg Q4W | Change From Baseline in and HOMA-IR at the Primary Analysis Time Point | 0.141 index |
| Cohort A: ISIS 703802, 20 mg QW | Change From Baseline in and HOMA-IR at the Primary Analysis Time Point | 2.013 index |
p-value: 0.47195% CI: [-6.72, 3.14]ANCOVA
p-value: 0.916995% CI: [-4.68, 5.2]ANCOVA
p-value: 0.448495% CI: [-3.44, 7.7]ANCOVA
Secondary
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pooled Placebo | Change From Baseline in Angiopoietin-Like 3 Protein at the Primary Analysis Time Point | 6.77 μg/L |
| Cohort B: ISIS 703802, 40 mg Q4W | Change From Baseline in Angiopoietin-Like 3 Protein at the Primary Analysis Time Point | -43.11 μg/L |
| Cohort C: ISIS 703802, 80 mg Q4W | Change From Baseline in Angiopoietin-Like 3 Protein at the Primary Analysis Time Point | -64.89 μg/L |
| Cohort A: ISIS 703802, 20 mg QW | Change From Baseline in Angiopoietin-Like 3 Protein at the Primary Analysis Time Point | -52.98 μg/L |
p-value: <0.000195% CI: [-62.68, -37.06]ANCOVA
p-value: <0.000195% CI: [-84.47, -58.85]ANCOVA
p-value: <0.000195% CI: [-74.04, -45.44]ANCOVA
Secondary
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pooled Placebo | Change From Baseline in Body Mass Index (BMI) at the Primary Analysis Timepoint | -0.27 kg/m^2 |
| Cohort B: ISIS 703802, 40 mg Q4W | Change From Baseline in Body Mass Index (BMI) at the Primary Analysis Timepoint | -0.17 kg/m^2 |
| Cohort C: ISIS 703802, 80 mg Q4W | Change From Baseline in Body Mass Index (BMI) at the Primary Analysis Timepoint | -0.37 kg/m^2 |
| Cohort A: ISIS 703802, 20 mg QW | Change From Baseline in Body Mass Index (BMI) at the Primary Analysis Timepoint | -0.50 kg/m^2 |
p-value: 0.72895% CI: [-0.5, 0.71]ANCOVA
p-value: 0.735495% CI: [-0.69, 0.49]ANCOVA
p-value: 0.468295% CI: [-0.84, 0.39]ANCOVA
Secondary
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pooled Placebo | Change From Baseline in Fasting Insulin at the Primary Analysis Time Point | -0.10 milli-international units per liter |
| Cohort B: ISIS 703802, 40 mg Q4W | Change From Baseline in Fasting Insulin at the Primary Analysis Time Point | -1.48 milli-international units per liter |
| Cohort C: ISIS 703802, 80 mg Q4W | Change From Baseline in Fasting Insulin at the Primary Analysis Time Point | -0.23 milli-international units per liter |
| Cohort A: ISIS 703802, 20 mg QW | Change From Baseline in Fasting Insulin at the Primary Analysis Time Point | 3.48 milli-international units per liter |
p-value: 0.739395% CI: [-9.66, 6.89]ANCOVA
p-value: 0.974495% CI: [-8.45, 8.18]ANCOVA
p-value: 0.447795% CI: [-5.75, 12.91]ANCOVA
Secondary
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pooled Placebo | Change From Baseline in Fasting Plasma Glucose at the Primary Analysis Time Point | -4.4 mg/dL |
| Cohort B: ISIS 703802, 40 mg Q4W | Change From Baseline in Fasting Plasma Glucose at the Primary Analysis Time Point | -21.6 mg/dL |
| Cohort C: ISIS 703802, 80 mg Q4W | Change From Baseline in Fasting Plasma Glucose at the Primary Analysis Time Point | 9.4 mg/dL |
| Cohort A: ISIS 703802, 20 mg QW | Change From Baseline in Fasting Plasma Glucose at the Primary Analysis Time Point | -2.2 mg/dL |
p-value: 0.179995% CI: [-42.53, 8.1]ANCOVA
p-value: 0.286795% CI: [-11.83, 39.49]ANCOVA
p-value: 0.881295% CI: [-26.78, 31.14]ANCOVA
Secondary
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pooled Placebo | Change From Baseline in Fatty Liver Index (FLI) at the Primary Analysis Time Point | -3.50 index |
| Cohort B: ISIS 703802, 40 mg Q4W | Change From Baseline in Fatty Liver Index (FLI) at the Primary Analysis Time Point | -6.08 index |
| Cohort C: ISIS 703802, 80 mg Q4W | Change From Baseline in Fatty Liver Index (FLI) at the Primary Analysis Time Point | -9.21 index |
| Cohort A: ISIS 703802, 20 mg QW | Change From Baseline in Fatty Liver Index (FLI) at the Primary Analysis Time Point | -8.07 index |
p-value: 0.458395% CI: [-9.49, 4.31]ANCOVA
p-value: 0.094395% CI: [-12.43, 1]ANCOVA
p-value: 0.190995% CI: [-11.45, 2.32]ANCOVA
Secondary
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pooled Placebo | Change From Baseline in Free Fatty Acid (FFA) at Primary Analysis Time Point | -0.0734 mmol/L |
| Cohort B: ISIS 703802, 40 mg Q4W | Change From Baseline in Free Fatty Acid (FFA) at Primary Analysis Time Point | -0.0607 mmol/L |
| Cohort C: ISIS 703802, 80 mg Q4W | Change From Baseline in Free Fatty Acid (FFA) at Primary Analysis Time Point | -0.0878 mmol/L |
| Cohort A: ISIS 703802, 20 mg QW | Change From Baseline in Free Fatty Acid (FFA) at Primary Analysis Time Point | -0.0881 mmol/L |
p-value: 0.829995% CI: [-0.1, 0.13]ANCOVA
p-value: 0.810295% CI: [-0.13, 0.1]ANCOVA
p-value: 0.822395% CI: [-0.14, 0.11]ANCOVA
Secondary
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pooled Placebo | Change From Baseline in Fructosamine at Primary Analysis Time Point | 13.2 μmol/L |
| Cohort B: ISIS 703802, 40 mg Q4W | Change From Baseline in Fructosamine at Primary Analysis Time Point | -10.0 μmol/L |
| Cohort C: ISIS 703802, 80 mg Q4W | Change From Baseline in Fructosamine at Primary Analysis Time Point | 1.8 μmol/L |
| Cohort A: ISIS 703802, 20 mg QW | Change From Baseline in Fructosamine at Primary Analysis Time Point | 15.1 μmol/L |
p-value: 0.091695% CI: [-50.17, 3.83]ANCOVA
p-value: 0.403295% CI: [-38.51, 15.63]ANCOVA
p-value: 0.895995% CI: [-27.56, 31.45]ANCOVA
Secondary
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pooled Placebo | Change From Baseline in Glycated Albumin at the Primary Analysis Time Point | -0.0033 grams per deciliter (g/dL) |
| Cohort B: ISIS 703802, 40 mg Q4W | Change From Baseline in Glycated Albumin at the Primary Analysis Time Point | -0.0553 grams per deciliter (g/dL) |
| Cohort C: ISIS 703802, 80 mg Q4W | Change From Baseline in Glycated Albumin at the Primary Analysis Time Point | -0.0133 grams per deciliter (g/dL) |
| Cohort A: ISIS 703802, 20 mg QW | Change From Baseline in Glycated Albumin at the Primary Analysis Time Point | 0.0280 grams per deciliter (g/dL) |
p-value: 0.320295% CI: [-0.16, 0.05]ANCOVA
p-value: 0.848595% CI: [-0.11, 0.09]ANCOVA
p-value: 0.581295% CI: [-0.08, 0.14]ANCOVA
Secondary
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pooled Placebo | Change From Baseline in Hemoglobin A1c (HbA1c) at the Primary Analysis Time Point | 0.19 percentage of HbA1c |
| Cohort B: ISIS 703802, 40 mg Q4W | Change From Baseline in Hemoglobin A1c (HbA1c) at the Primary Analysis Time Point | -0.09 percentage of HbA1c |
| Cohort C: ISIS 703802, 80 mg Q4W | Change From Baseline in Hemoglobin A1c (HbA1c) at the Primary Analysis Time Point | 0.26 percentage of HbA1c |
| Cohort A: ISIS 703802, 20 mg QW | Change From Baseline in Hemoglobin A1c (HbA1c) at the Primary Analysis Time Point | 0.35 percentage of HbA1c |
p-value: 0.399595% CI: [-0.94, 0.38]ANCOVA
p-value: 0.815595% CI: [-0.59, 0.75]ANCOVA
p-value: 0.646695% CI: [-0.54, 0.86]ANCOVA
Secondary
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pooled Placebo | 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 percentage (Hepatic Fat Fraction) |
| Cohort B: ISIS 703802, 40 mg Q4W | 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 | -0.71 percentage (Hepatic Fat Fraction) |
| Cohort C: ISIS 703802, 80 mg Q4W | 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 | 2.39 percentage (Hepatic Fat Fraction) |
| Cohort 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 | -0.12 percentage (Hepatic Fat Fraction) |
p-value: 0.575295% CI: [-2.48, 4.44]ANCOVA
p-value: 0.02395% CI: [0.58, 7.59]ANCOVA
p-value: 0.396595% CI: [-2.1, 5.25]ANCOVA
Secondary
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pooled Placebo | Change From Baseline in Leptin at the Primary Analysis Time Point | 0.95 μg/L |
| Cohort B: ISIS 703802, 40 mg Q4W | Change From Baseline in Leptin at the Primary Analysis Time Point | -0.24 μg/L |
| Cohort C: ISIS 703802, 80 mg Q4W | Change From Baseline in Leptin at the Primary Analysis Time Point | -0.57 μg/L |
| Cohort A: ISIS 703802, 20 mg QW | Change From Baseline in Leptin at the Primary Analysis Time Point | -3.23 μg/L |
p-value: 0.481295% CI: [-4.55, 2.16]ANCOVA
p-value: 0.367995% CI: [-4.88, 1.83]ANCOVA
p-value: 0.02195% CI: [-7.72, -0.65]ANCOVA
Secondary
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pooled Placebo | Change From Baseline in Lipoprotein(a) (Lp[a]) at the Primary Analysis Time Point | -1.1 nmol/L |
| Cohort B: ISIS 703802, 40 mg Q4W | Change From Baseline in Lipoprotein(a) (Lp[a]) at the Primary Analysis Time Point | 6.8 nmol/L |
| Cohort C: ISIS 703802, 80 mg Q4W | Change From Baseline in Lipoprotein(a) (Lp[a]) at the Primary Analysis Time Point | 0.5 nmol/L |
| Cohort A: ISIS 703802, 20 mg QW | Change From Baseline in Lipoprotein(a) (Lp[a]) at the Primary Analysis Time Point | -2.8 nmol/L |
Comparison: Lp(a)p-value: 0.060495% CI: [-0.35, 16.02]ANCOVA
Comparison: Lp(a)p-value: 0.704895% CI: [-6.61, 9.74]ANCOVA
Comparison: Lp(a)p-value: 0.702495% CI: [-10.65, 7.2]ANCOVA
Secondary
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
Population: 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 | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Pooled Placebo | Change From Baseline in Subcutaneous Adipose Tissue (SAT) and Visceral Adipose Tissue (VAT) by Single Slice MRI at the Primary Analysis Timepoint | VAT | 14.83 mm^2 |
| Pooled Placebo | Change From Baseline in Subcutaneous Adipose Tissue (SAT) and Visceral Adipose Tissue (VAT) by Single Slice MRI at the Primary Analysis Timepoint | SAT | -25.61 mm^2 |
| Cohort B: ISIS 703802, 40 mg Q4W | Change From Baseline in Subcutaneous Adipose Tissue (SAT) and Visceral Adipose Tissue (VAT) by Single Slice MRI at the Primary Analysis Timepoint | SAT | -8.55 mm^2 |
| Cohort B: ISIS 703802, 40 mg Q4W | Change From Baseline in Subcutaneous Adipose Tissue (SAT) and Visceral Adipose Tissue (VAT) by Single Slice MRI at the Primary Analysis Timepoint | VAT | 19.78 mm^2 |
| Cohort C: ISIS 703802, 80 mg Q4W | Change From Baseline in Subcutaneous Adipose Tissue (SAT) and Visceral Adipose Tissue (VAT) by Single Slice MRI at the Primary Analysis Timepoint | VAT | -9.42 mm^2 |
| Cohort C: ISIS 703802, 80 mg Q4W | Change From Baseline in Subcutaneous Adipose Tissue (SAT) and Visceral Adipose Tissue (VAT) by Single Slice MRI at the Primary Analysis Timepoint | SAT | 7.31 mm^2 |
| Cohort A: ISIS 703802, 20 mg QW | Change From Baseline in Subcutaneous Adipose Tissue (SAT) and Visceral Adipose Tissue (VAT) by Single Slice MRI at the Primary Analysis Timepoint | VAT | 36.85 mm^2 |
| Cohort A: ISIS 703802, 20 mg QW | Change From Baseline in Subcutaneous Adipose Tissue (SAT) and Visceral Adipose Tissue (VAT) by Single Slice MRI at the Primary Analysis Timepoint | SAT | -41.91 mm^2 |
Comparison: SATp-value: 0.859195% CI: [-173.57, 207.69]ANCOVA
Comparison: SATp-value: 0.740495% CI: [-164.11, 229.95]ANCOVA
Comparison: SATp-value: 0.871195% CI: [-215.5, 182.9]ANCOVA
Comparison: VATp-value: 0.956995% CI: [-176.64, 186.53]ANCOVA
Comparison: VATp-value: 0.802595% CI: [-216.53, 168.02]ANCOVA
Comparison: VATp-value: 0.820295% CI: [-170.09, 214.12]ANCOVA
Secondary
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
Population: 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 | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Pooled Placebo | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Primary Analysis Time Point | SBP | -1.66 millimeters of mercury (mmHg) |
| Pooled Placebo | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Primary Analysis Time Point | DBP | -2.35 millimeters of mercury (mmHg) |
| Cohort B: ISIS 703802, 40 mg Q4W | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Primary Analysis Time Point | DBP | 1.75 millimeters of mercury (mmHg) |
| Cohort B: ISIS 703802, 40 mg Q4W | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Primary Analysis Time Point | SBP | 1.13 millimeters of mercury (mmHg) |
| Cohort C: ISIS 703802, 80 mg Q4W | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Primary Analysis Time Point | SBP | 0.42 millimeters of mercury (mmHg) |
| Cohort C: ISIS 703802, 80 mg Q4W | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Primary Analysis Time Point | DBP | 1.13 millimeters of mercury (mmHg) |
| Cohort A: ISIS 703802, 20 mg QW | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Primary Analysis Time Point | SBP | -3.29 millimeters of mercury (mmHg) |
| Cohort A: ISIS 703802, 20 mg QW | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Primary Analysis Time Point | DBP | -0.73 millimeters of mercury (mmHg) |
Comparison: SBPp-value: 0.443195% CI: [-4.41, 10]ANCOVA
Comparison: SBPp-value: 0.56395% CI: [-5.05, 9.22]ANCOVA
Comparison: SBPp-value: 0.663495% CI: [-9.06, 5.79]ANCOVA
Comparison: DBPp-value: 0.093795% CI: [-0.71, 8.92]ANCOVA
Comparison: DBPp-value: 0.152295% CI: [-1.31, 8.28]ANCOVA
Comparison: DBPp-value: 0.518895% CI: [-3.35, 6.59]ANCOVA
Secondary
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
Population: 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 | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Pooled Placebo | 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 | TC | -4.8 mg/dL |
| Pooled Placebo | 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 | LDL-C | -2.5 mg/dL |
| Pooled Placebo | 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 | HDL-C | 2.2 mg/dL |
| Pooled Placebo | 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 | VLDL-C | -6.5 mg/dL |
| Pooled Placebo | 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 | Non-HDL-C | -7.0 mg/dL |
| Pooled Placebo | 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 | ApoB | -3.63 mg/dL |
| Pooled Placebo | 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 | ApoB: ApoB-48 | -0.139 mg/dL |
| Pooled Placebo | 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 | ApoB: ApoB-100 | -3.757 mg/dL |
| Pooled Placebo | 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 | ApoCIII | -0.729 mg/dL |
| Pooled Placebo | 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 | ApoA1 | 5.0 mg/dL |
| Cohort B: ISIS 703802, 40 mg Q4W | 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 | HDL-C | -0.6 mg/dL |
| Cohort B: ISIS 703802, 40 mg Q4W | 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 | ApoCIII | -5.482 mg/dL |
| Cohort B: ISIS 703802, 40 mg Q4W | 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 | VLDL-C | -15.6 mg/dL |
| Cohort B: ISIS 703802, 40 mg Q4W | 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 | Non-HDL-C | -20.9 mg/dL |
| Cohort B: ISIS 703802, 40 mg Q4W | 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 | ApoB | -6.08 mg/dL |
| Cohort B: ISIS 703802, 40 mg Q4W | 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 | ApoB: ApoB-48 | -1.140 mg/dL |
| Cohort B: ISIS 703802, 40 mg Q4W | 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 | ApoA1 | -11.8 mg/dL |
| Cohort B: ISIS 703802, 40 mg Q4W | 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 | ApoB: ApoB-100 | -4.643 mg/dL |
| Cohort B: ISIS 703802, 40 mg Q4W | 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 | TC | -21.3 mg/dL |
| Cohort B: ISIS 703802, 40 mg Q4W | 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 | LDL-C | 5.0 mg/dL |
| Cohort C: ISIS 703802, 80 mg Q4W | 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 | ApoB: ApoB-100 | -11.346 mg/dL |
| Cohort C: ISIS 703802, 80 mg Q4W | 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 | ApoB: ApoB-48 | -1.942 mg/dL |
| Cohort C: ISIS 703802, 80 mg Q4W | 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 | ApoA1 | -30.1 mg/dL |
| Cohort C: ISIS 703802, 80 mg Q4W | 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 | TC | -41.9 mg/dL |
| Cohort C: ISIS 703802, 80 mg Q4W | 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 | VLDL-C | -21.9 mg/dL |
| Cohort C: ISIS 703802, 80 mg Q4W | 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 | ApoB | -13.46 mg/dL |
| Cohort C: ISIS 703802, 80 mg Q4W | 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 | ApoCIII | -9.228 mg/dL |
| Cohort C: ISIS 703802, 80 mg Q4W | 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 | LDL-C | -11.1 mg/dL |
| Cohort C: ISIS 703802, 80 mg Q4W | 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 | Non-HDL-C | -35.4 mg/dL |
| Cohort C: ISIS 703802, 80 mg Q4W | 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 | HDL-C | -6.4 mg/dL |
| Cohort A: ISIS 703802, 20 mg QW | 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 | Non-HDL-C | -34.4 mg/dL |
| Cohort A: ISIS 703802, 20 mg QW | 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 | ApoB: ApoB-100 | -7.174 mg/dL |
| Cohort A: ISIS 703802, 20 mg QW | 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 | ApoB | -8.91 mg/dL |
| Cohort A: ISIS 703802, 20 mg QW | 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 | ApoA1 | -16.1 mg/dL |
| Cohort A: ISIS 703802, 20 mg QW | 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 | ApoB: ApoB-48 | -1.230 mg/dL |
| Cohort A: ISIS 703802, 20 mg QW | 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 | LDL-C | -11.3 mg/dL |
| Cohort A: ISIS 703802, 20 mg QW | 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 | HDL-C | -2.0 mg/dL |
| Cohort A: ISIS 703802, 20 mg QW | 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 | VLDL-C | -17.3 mg/dL |
| Cohort A: ISIS 703802, 20 mg QW | 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 | TC | -36.5 mg/dL |
| Cohort A: ISIS 703802, 20 mg QW | 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 | ApoCIII | -7.588 mg/dL |
Comparison: ApoCIIIp-value: 0.000895% CI: [-7.47, -2.03]ANCOVA
Comparison: ApoCIIIp-value: <0.000195% CI: [-11.18, -5.82]ANCOVA
Comparison: ApoCIIIp-value: <0.000195% CI: [-9.78, -3.93]ANCOVA
Comparison: TCp-value: 0.032795% CI: [-31.59, -1.39]ANCOVA
Comparison: TCp-value: <0.000195% CI: [-52.15, -21.94]ANCOVA
Comparison: TCp-value: 0.000395% CI: [-48.23, -15.05]ANCOVA
Comparison: LDL-Cp-value: 0.25695% CI: [-5.55, 20.54]ANCOVA
Comparison: LDL-Cp-value: 0.179595% CI: [-21.26, 4.05]ANCOVA
Comparison: LDL-Cp-value: 0.206595% CI: [-22.48, 4.95]ANCOVA
Comparison: HDL-Cp-value: 0.151595% CI: [-6.43, 1.01]ANCOVA
Comparison: HDL-Cp-value: <0.000195% CI: [-12.29, -4.91]ANCOVA
Comparison: HDL-Cp-value: 0.043695% CI: [-8.18, -0.12]ANCOVA
Comparison: VLDL-Cp-value: 0.022495% CI: [-16.94, -1.33]ANCOVA
Comparison: VLDL-Cp-value: 0.000195% CI: [-22.94, -7.84]ANCOVA
Comparison: VLDL-Cp-value: 0.009195% CI: [-18.86, -2.78]ANCOVA
Comparison: Non-HDL-Cp-value: 0.074895% CI: [-29.12, 1.42]ANCOVA
Comparison: Non-HDL-Cp-value: 0.000495% CI: [-43.68, -13.18]ANCOVA
Comparison: Non-HDL-Cp-value: 0.001695% CI: [-44.08, -10.64]ANCOVA
Comparison: ApoBp-value: 0.600595% CI: [-11.68, 6.8]ANCOVA
Comparison: ApoBp-value: 0.037495% CI: [-19.07, -0.59]ANCOVA
Comparison: ApoBp-value: 0.3195% CI: [-15.55, 5]ANCOVA
Comparison: ApoB-48p-value: 0.072895% CI: [-2.1, 0.09]ANCOVA
Comparison: ApoB-48p-value: 0.001895% CI: [-2.91, -0.69]ANCOVA
Comparison: ApoB-48p-value: 0.075995% CI: [-2.3, 0.12]ANCOVA
Comparison: ApoB-100p-value: 0.845195% CI: [-9.89, 8.11]ANCOVA
Comparison: ApoB-100p-value: 0.097395% CI: [-16.59, 1.41]ANCOVA
Comparison: ApoB-100p-value: 0.595% CI: [-13.45, 6.61]ANCOVA
Comparison: ApoA1p-value: 0.000395% CI: [-25.8, -7.85]ANCOVA
Comparison: ApoA1p-value: <0.000195% CI: [-44.07, -26.24]ANCOVA
Comparison: ApoA1p-value: <0.000195% CI: [-30.89, -11.39]ANCOVA
Secondary
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pooled Placebo | Change From Baseline in Waist Circumference by Single Slice MRI at the Primary Analysis Timepoint | -2.25 cm |
| Cohort B: ISIS 703802, 40 mg Q4W | Change From Baseline in Waist Circumference by Single Slice MRI at the Primary Analysis Timepoint | -2.14 cm |
| Cohort C: ISIS 703802, 80 mg Q4W | Change From Baseline in Waist Circumference by Single Slice MRI at the Primary Analysis Timepoint | -2.95 cm |
| Cohort A: ISIS 703802, 20 mg QW | Change From Baseline in Waist Circumference by Single Slice MRI at the Primary Analysis Timepoint | -0.59 cm |
p-value: 0.973495% CI: [-6.47, 6.69]ANCOVA
p-value: 0.833395% CI: [-7.25, 5.86]ANCOVA
p-value: 0.620795% CI: [-4.99, 8.31]ANCOVA
Secondary
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pooled Placebo | Change From Baseline in Waist to Hip Ratio (WHR) at the Primary Analysis Timepoint | 0.01 ratio |
| Cohort B: ISIS 703802, 40 mg Q4W | Change From Baseline in Waist to Hip Ratio (WHR) at the Primary Analysis Timepoint | 0.01 ratio |
| Cohort C: ISIS 703802, 80 mg Q4W | Change From Baseline in Waist to Hip Ratio (WHR) at the Primary Analysis Timepoint | -0.01 ratio |
| Cohort A: ISIS 703802, 20 mg QW | Change From Baseline in Waist to Hip Ratio (WHR) at the Primary Analysis Timepoint | 0.01 ratio |
p-value: 0.802695% CI: [-0.04, 0.06]ANCOVA
p-value: 0.491795% CI: [-0.07, 0.03]ANCOVA
p-value: 0.891695% CI: [-0.05, 0.05]ANCOVA
Secondary
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pooled Placebo | Change From Baseline in Weight at the Primary Analysis Time Point | -1.00 kg |
| Cohort B: ISIS 703802, 40 mg Q4W | Change From Baseline in Weight at the Primary Analysis Time Point | -0.57 kg |
| Cohort C: ISIS 703802, 80 mg Q4W | Change From Baseline in Weight at the Primary Analysis Time Point | -0.99 kg |
| Cohort A: ISIS 703802, 20 mg QW | Change From Baseline in Weight at the Primary Analysis Time Point | -1.33 kg |
p-value: 0.615795% CI: [-1.28, 2.15]ANCOVA
p-value: 0.986995% CI: [-1.66, 1.69]ANCOVA
p-value: 0.708495% CI: [-2.07, 1.42]ANCOVA
Secondary
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)
Population: Safety set included all participants who were randomized and received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pooled Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 18 Participants |
| Cohort B: ISIS 703802, 40 mg Q4W | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 21 Participants |
| Cohort C: ISIS 703802, 80 mg Q4W | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 24 Participants |
| Cohort A: ISIS 703802, 20 mg QW | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 23 Participants |
Secondary
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Pooled Placebo | Percentage of Participants With HFF ≤ 8% by MRI-PDFF at the Primary Analysis Time Point | 16.0 percentage of participants |
| Cohort B: ISIS 703802, 40 mg Q4W | Percentage of Participants With HFF ≤ 8% by MRI-PDFF at the Primary Analysis Time Point | 8.7 percentage of participants |
| Cohort C: ISIS 703802, 80 mg Q4W | Percentage of Participants With HFF ≤ 8% by MRI-PDFF at the Primary Analysis Time Point | 4.5 percentage of participants |
| Cohort A: ISIS 703802, 20 mg QW | Percentage of Participants With HFF ≤ 8% by MRI-PDFF at the Primary Analysis Time Point | 15.8 percentage of participants |
Secondary
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
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Pooled Placebo | 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 | ANGPTL3 | 8 percent change |
| Pooled Placebo | 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 | TC | -2 percent change |
| Pooled Placebo | 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 | LDL-C | 0 percent change |
| Pooled Placebo | 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 | HDL-C | 7 percent change |
| Pooled Placebo | 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 | VLDL-C | -14 percent change |
| Pooled Placebo | 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 | Non-HDL-C | -4 percent change |
| Pooled Placebo | 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 | ApoB | -3 percent change |
| Pooled Placebo | 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 | ApoB: ApoB-48 | -21 percent change |
| Pooled Placebo | 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 | ApoB: ApoB-100 | -3 percent change |
| Pooled Placebo | 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 | ApoCIII | -6 percent change |
| Pooled Placebo | 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 | ApoA1 | 3 percent change |
| Pooled Placebo | 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 | FFA | -11 percent change |
| Pooled Placebo | 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 | Lp(a) | 3 percent change |
| Cohort B: ISIS 703802, 40 mg Q4W | 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 | HDL-C | -2 percent change |
| Cohort B: ISIS 703802, 40 mg Q4W | 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 | Lp(a) | -4 percent change |
| Cohort B: ISIS 703802, 40 mg Q4W | 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 | ApoA1 | -9 percent change |
| Cohort B: ISIS 703802, 40 mg Q4W | 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 | ApoB: ApoB-48 | -44 percent change |
| Cohort B: ISIS 703802, 40 mg Q4W | 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 | LDL-C | 6 percent change |
| Cohort B: ISIS 703802, 40 mg Q4W | 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 | ANGPTL3 | -41 percent change |
| Cohort B: ISIS 703802, 40 mg Q4W | 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 | ApoCIII | -40 percent change |
| Cohort B: ISIS 703802, 40 mg Q4W | 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 | ApoB: ApoB-100 | -5 percent change |
| Cohort B: ISIS 703802, 40 mg Q4W | 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 | Non-HDL-C | -13 percent change |
| Cohort B: ISIS 703802, 40 mg Q4W | 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 | VLDL-C | -35 percent change |
| Cohort B: ISIS 703802, 40 mg Q4W | 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 | TC | -11 percent change |
| Cohort B: ISIS 703802, 40 mg Q4W | 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 | FFA | -12 percent change |
| Cohort B: ISIS 703802, 40 mg Q4W | 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 | ApoB | -7 percent change |
| Cohort C: ISIS 703802, 80 mg Q4W | 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 | ApoA1 | -24 percent change |
| Cohort C: ISIS 703802, 80 mg Q4W | 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 | HDL-C | -18 percent change |
| Cohort C: ISIS 703802, 80 mg Q4W | 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 | VLDL-C | -47 percent change |
| Cohort C: ISIS 703802, 80 mg Q4W | 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 | Lp(a) | -3 percent change |
| Cohort C: ISIS 703802, 80 mg Q4W | 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 | Non-HDL-C | -21 percent change |
| Cohort C: ISIS 703802, 80 mg Q4W | 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 | ApoB | -12 percent change |
| Cohort C: ISIS 703802, 80 mg Q4W | 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 | FFA | -18 percent change |
| Cohort C: ISIS 703802, 80 mg Q4W | 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 | ApoB: ApoB-48 | -62 percent change |
| Cohort C: ISIS 703802, 80 mg Q4W | 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 | ApoB: ApoB-100 | -10 percent change |
| Cohort C: ISIS 703802, 80 mg Q4W | 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 | ApoCIII | -61 percent change |
| Cohort C: ISIS 703802, 80 mg Q4W | 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 | ANGPTL3 | -59 percent change |
| Cohort C: ISIS 703802, 80 mg Q4W | 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 | TC | -21 percent change |
| Cohort C: ISIS 703802, 80 mg Q4W | 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 | LDL-C | -7 percent change |
| Cohort A: ISIS 703802, 20 mg QW | 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 | ApoCIII | -50 percent change |
| Cohort A: ISIS 703802, 20 mg QW | 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 | ApoB: ApoB-48 | -38 percent change |
| Cohort A: ISIS 703802, 20 mg QW | 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 | HDL-C | -4 percent change |
| Cohort A: ISIS 703802, 20 mg QW | 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 | ANGPTL3 | -54 percent change |
| Cohort A: ISIS 703802, 20 mg QW | 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 | ApoB | -10 percent change |
| Cohort A: ISIS 703802, 20 mg QW | 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 | Non-HDL-C | -22 percent change |
| Cohort A: ISIS 703802, 20 mg QW | 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 | LDL-C | -12 percent change |
| Cohort A: ISIS 703802, 20 mg QW | 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 | TC | -19 percent change |
| Cohort A: ISIS 703802, 20 mg QW | 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 | VLDL-C | -40 percent change |
| Cohort A: ISIS 703802, 20 mg QW | 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 | ApoB: ApoB-100 | -9 percent change |
| Cohort A: ISIS 703802, 20 mg QW | 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 | Lp(a) | -1 percent change |
| Cohort A: ISIS 703802, 20 mg QW | 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 | FFA | -11 percent change |
| Cohort A: ISIS 703802, 20 mg QW | 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 | ApoA1 | -12 percent change |
Comparison: ANGPTL3p-value: <0.000195% CI: [-54, -33]ANCOVA
Comparison: ANGPTL3p-value: <0.000195% CI: [-69, -54]ANCOVA
Comparison: ANGPTL3p-value: <0.000195% CI: [-66, -47]ANCOVA
Comparison: TCp-value: 0.030995% CI: [-16, -1]ANCOVA
Comparison: TCp-value: <0.000195% CI: [-26, -12]ANCOVA
Comparison: TCp-value: <0.000195% CI: [-25, -9]ANCOVA
Comparison: LDL-Cp-value: 0.401695% CI: [-7, 21]ANCOVA
Comparison: LDL-Cp-value: 0.258995% CI: [-18, 6]ANCOVA
Comparison: LDL-Cp-value: 0.061695% CI: [-24, 1]ANCOVA
Comparison: HDL-Cp-value: 0.191895% CI: [-18, 4]ANCOVA
Comparison: HDL-Cp-value: <0.000195% CI: [-32, -14]ANCOVA
Comparison: HDL-Cp-value: 0.113295% CI: [-21, 3]ANCOVA
Comparison: VLDL-Cp-value: 0.017795% CI: [-40, -5]ANCOVA
Comparison: VLDL-Cp-value: <0.000195% CI: [-51, -23]ANCOVA
Comparison: VLDL-Cp-value: 0.003395% CI: [-45, -12]ANCOVA
Comparison: Non-HDL-Cp-value: 0.052395% CI: [-18, 0]ANCOVA
Comparison: Non-HDL-Cp-value: 0.000295% CI: [-26, -9]ANCOVA
Comparison: Non-HDL-Cp-value: 0.000495% CI: [-28, -9]ANCOVA
Comparison: ApoBp-value: 0.420495% CI: [-12, 5]ANCOVA
Comparison: ApoBp-value: 0.044195% CI: [-16, 0]ANCOVA
Comparison: ApoBp-value: 0.132495% CI: [-16, 2]ANCOVA
Comparison: ApoB-48p-value: 0.100995% CI: [-53, 7]ANCOVA
Comparison: ApoB-48p-value: 0.000595% CI: [-68, -28]ANCOVA
Comparison: ApoB-48p-value: 0.300495% CI: [-50, 24]ANCOVA
Comparison: ApoB-100p-value: 0.613595% CI: [-10, 7]ANCOVA
Comparison: ApoB-100p-value: 0.112795% CI: [-15, 2]ANCOVA
Comparison: ApoB-100p-value: 0.257695% CI: [-14, 4]ANCOVA
Comparison: ApoCIIIp-value: 0.001795% CI: [-52, -16]ANCOVA
Comparison: ApoCIIIp-value: <0.000195% CI: [-68, -45]ANCOVA
Comparison: ApoCIIIp-value: <0.000195% CI: [-61, -29]ANCOVA
Comparison: ApoAIp-value: 0.019395% CI: [-20, -2]ANCOVA
Comparison: ApoAIp-value: <0.000195% CI: [-33, -19]ANCOVA
Comparison: ApoAIp-value: 0.006395% CI: [-23, -4]ANCOVA
Comparison: FFAp-value: 0.887395% CI: [-21, 23]ANCOVA
Comparison: FFAp-value: 0.440495% CI: [-27, 15]ANCOVA
Comparison: FFAp-value: 0.966595% CI: [-22, 27]ANCOVA
Comparison: Lp\[a\]p-value: 0.413395% CI: [-21, 10]ANCOVA
Comparison: Lp\[a\]p-value: 0.47595% CI: [-20, 11]ANCOVA
Comparison: Lp\[a\]p-value: 0.635495% CI: [-20, 15]ANCOVA
Secondary
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pooled Placebo | 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 percent change |
| Cohort B: ISIS 703802, 40 mg Q4W | 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 | 5.34 percent change |
| Cohort C: ISIS 703802, 80 mg Q4W | 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 | 18.94 percent change |
| Cohort 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 | 5.18 percent change |
p-value: 0.302395% CI: [-11.39, 36.26]ANCOVA
p-value: 0.03595% CI: [1.87, 50.19]ANCOVA
p-value: 0.337495% CI: [-13.02, 37.55]ANCOVA
Secondary
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
Population: 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 | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Pooled Placebo | Percent Change From Baseline in Weight, SBP and DBP at Primary Analysis Time Point | Weight | -0.98 percent change |
| Pooled Placebo | Percent Change From Baseline in Weight, SBP and DBP at Primary Analysis Time Point | DBP | -1.83 percent change |
| Pooled Placebo | Percent Change From Baseline in Weight, SBP and DBP at Primary Analysis Time Point | SBP | -0.55 percent change |
| Cohort B: ISIS 703802, 40 mg Q4W | Percent Change From Baseline in Weight, SBP and DBP at Primary Analysis Time Point | Weight | -0.40 percent change |
| Cohort B: ISIS 703802, 40 mg Q4W | Percent Change From Baseline in Weight, SBP and DBP at Primary Analysis Time Point | DBP | 3.18 percent change |
| Cohort B: ISIS 703802, 40 mg Q4W | Percent Change From Baseline in Weight, SBP and DBP at Primary Analysis Time Point | SBP | 1.80 percent change |
| Cohort C: ISIS 703802, 80 mg Q4W | Percent Change From Baseline in Weight, SBP and DBP at Primary Analysis Time Point | SBP | 0.68 percent change |
| Cohort C: ISIS 703802, 80 mg Q4W | Percent Change From Baseline in Weight, SBP and DBP at Primary Analysis Time Point | Weight | -1.10 percent change |
| Cohort C: ISIS 703802, 80 mg Q4W | Percent Change From Baseline in Weight, SBP and DBP at Primary Analysis Time Point | DBP | 2.11 percent change |
| Cohort A: ISIS 703802, 20 mg QW | Percent Change From Baseline in Weight, SBP and DBP at Primary Analysis Time Point | Weight | -1.38 percent change |
| Cohort A: ISIS 703802, 20 mg QW | Percent Change From Baseline in Weight, SBP and DBP at Primary Analysis Time Point | DBP | -0.13 percent change |
| Cohort A: ISIS 703802, 20 mg QW | Percent Change From Baseline in Weight, SBP and DBP at Primary Analysis Time Point | SBP | -1.79 percent change |
Comparison: Weightp-value: 0.529995% CI: [-1.24, 2.39]ANCOVA
Comparison: Weightp-value: 0.891995% CI: [-1.89, 1.65]ANCOVA
Comparison: Weightp-value: 0.665395% CI: [-2.25, 1.44]ANCOVA
Comparison: SBPp-value: 0.421395% CI: [-3.43, 8.14]ANCOVA
Comparison: SBPp-value: 0.669695% CI: [-4.49, 6.96]ANCOVA
Comparison: SBPp-value: 0.681995% CI: [-7.2, 4.73]ANCOVA
Comparison: DBPp-value: 0.117195% CI: [-1.28, 11.31]ANCOVA
Comparison: DBPp-value: 0.215595% CI: [-2.33, 10.21]ANCOVA
Comparison: DBPp-value: 0.603495% CI: [-4.79, 8.2]ANCOVA