Heterozygous Familial Hypercholesterolemia
Conditions
Brief summary
The primary objective of this study is to determine the effect of once-daily oral MGL-3196 on the percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in participants with Heterozygous Familial Hypercholesterolemia (HeFH).
Interventions
DRUGMGL-3196 (resmetirom)
Oral
DRUGPlacebo
Oral
Sponsors
Madrigal Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Must be willing to participate in the study and provide written informed consent; * Male and female adults ≥18 years of age; * Female participants of child bearing potential with negative serum pregnancy (beta human chorionic gonadotropin) test who are not breastfeeding, do not plan to become pregnant during the study, and agree to use effective birth control per locally agreed requirements; male participants who have sexual intercourse with a female partner of child bearing potential from the first dose of study drug until 1 month after study completion must either be surgically sterile (confirmed by documented azoospermia \>90 days after the procedure) or agree to use a condom with spermicide. All male participants must agree not to donate sperm from the first dose of study drug until 1 month after study completion; * Must have a diagnosis of HeFH by genetic testing or by having met the diagnostic criteria for definite familial hypercholesterolemia outlined by the Simon Broome Register Group or World Health Organization/Dutch Lipid Network (score \>8); * Must have had a fasting LDL-C (low density lipoprotein cholesterol) ≥2.6 mmol/L (100 mg/dL); and * Must be on a stable or maximally tolerated dose (≥4 weeks prior to screening) of an approved statin (rosuvastatin ≤40 mg daily, atorvastatin ≤80 mg daily), with or without ezetimibe. Patients intolerant to statins were allowed.
Exclusion criteria
* Homozygous familial hypercholesterolemia * LDL or plasma apheresis within 2 months prior to randomization; * New York Heart Association class III or IV heart failure, or known left ventricular ejection fraction \<30%; * Uncontrolled cardiac arrhythmia, including confirmed QT interval corrected using Fridericia's formula \>450 msec for males and \>470 msec for females at the screening electrocardiogram assessment; * Myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass graft, or stroke within 3 months prior to randomization; * Type 1 diabetes, or newly diagnosed or uncontrolled type 2 diabetes (hemoglobin A1c \>8%); * History of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening; Note: Significant alcohol consumption is defined as average of \>20 g/day in female participants and \>30 g/day in male participants; * Hyperthyroidism; * Thyroid replacement therapy; * Hypothyroidism; * Evidence of chronic liver disease; * Hepatitis B, as defined by the presence of hepatitis B surface antigen; * Hepatitis C, as defined by the presence of hepatitis C virus (HCV) antibody (anti-HCV) and HCV ribonucleic acid (RNA). Participants with positive anti-HCV who test negative for HCV RNA at screening will be allowed to participate in the study; * Serum alanine aminotransferase \>1.5 x upper limit of normal (ULN) (one repeat allowed); * Estimated glomerular filtration rate \<60 mL/min; * Creatine kinase \>3 x ULN (one repeat allowed); * History of biliary diversion; * Positive for human immunodeficiency virus infection; * History of malignant hypertension; * Systolic blood pressure \>160 mmHg or diastolic blood pressure \>100 mmHg at screening or randomization and confirmed at an unscheduled visit; * Triglycerides \>5.7 mmol/L (500 mg/dL) at screening and confirmed by repeat assessment; * Active, serious medical disease with likely life expectancy \<2 years; * Active substance abuse, including inhaled or injection drugs within the year prior to screening; * Participation in an investigational new drug trial within the 30 days prior to randomization; or * Any other condition which, in the opinion of the Investigator, would impede compliance, hinder completion of the study, or compromise the well-being of the participants.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Percent Change in LDL-C From Baseline To Week 12 | Baseline up to Week 12 | LDL-C was determined by ultracentrifugation or direct measure. Least-squares (LS) mean was provided for the comparison of MGL-3196 versus placebo and it used a linear model with percent change from baseline as the dependent variable and treatment as a factor. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline to Week 12 of Free Thyroxine (T4) | Baseline up to Week 12 | T4 was assessed at each study visit. |
| Mean Change From Baseline to Week 12 of Free Triiodothyronine (T3) | Baseline up to Week 12 | Free T3 was assessed at each study visit. |
| Mean Change From Baseline to Week 12 of Thyrotropin (TSH) | Baseline up to Week 12 | TSH was assessed at each study visit. |
| Mean Change From Baseline to Week 12 of Thyroxine Binding Globulin (TBG) | Baseline up to Week 12 | TBG was assessed at all study visits except the Screening Visit. |
| Mean Change From Baseline to Week 12 of Reverse Triiodothyronine (T3) | Baseline up to Week 12 | Reverse T3 was assessed at each study visit. |
| Mean Percent Change in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Week 12 | Baseline up to Week 12 | Non-HDL-C were determined by ultracentrifugation. LS mean was provided for the comparison of MGL-3196 versus placebo and it used a linear model with percent change from baseline as the dependent variable and treatment as a factor |
| Mean Percent Change In Triglycerides From Baseline To Week 12 | Baseline up to Week 12 | Triglycerides were determined by ultracentrifugation. LS mean was provided for the comparison of MGL-3196 versus placebo and it used a linear model with percent change from baseline as the dependent variable and treatment as a factor. |
| Mean Percent Change In Lipoprotein(a) (Lp[a]) From Baseline To Week 12 | Baseline up to Week 12 | Lp(a) was determined by ultracentrifugation. LS mean was provided for the comparison of MGL-3196 versus placebo and it used a linear model with percent change from baseline as the dependent variable and treatment as a factor. |
| Mean Percent Change in Apolipoprotein CIII From Baseline to Week 12 | Baseline up to Week 12 | Apolipoprotein CIII was determined by ultracentrifugation. LS mean was provided for the comparison of MGL-3196 versus placebo and it used a linear model with percent change from baseline as the dependent variable and treatment as a factor. |
| Mean Percent Change In Apolipoprotein B (ApoB) From Baseline To Week 12 | Baseline up to Week 12 | ApoB was determined by ultracentrifugation. LS mean was provided for the comparison of MGL-3196 versus placebo and it used a linear model with percent change from baseline as the dependent variable and treatment as a factor. |
| Mean Percent Change in Apolipoprotein B/Apolipoprotein A1 (ApoB/ApoA1) Ratio From Baseline to Week 12 | Baseline up to Week 12 | The ApoB/ApoA1 ratio was determined by ultracentrifugation. LS mean was provided for the comparison of MGL-3196 versus placebo and it used a linear model with percent change from baseline as the dependent variable and treatment as a factor. |
| Mean Percent Change In Cholesterol/HDL-C Ratio From Baseline to Week 12 | Baseline up to Week 12 | The Cholesterol/HDL-C Ratio was determined by ultracentrifugation. LS mean was provided for the comparison of MGL-3196 versus placebo and it used a linear model with percent change from baseline as the dependent variable and treatment as a factor. |
| Absolute Change in LDL-C From Baseline to Week 12 | Baseline up to Week 12 | LDL-C was determined by ultracentrifugation or direct measure . Least-squares (LS) mean was provided for the comparison of MGL-3196 versus placebo and it used a linear model with percent change from baseline as the dependent variable and treatment as a factor. |
| Percent Change From Baseline in LDL-C at Week 2 and Week 4 in Patients in the 100 mg and the 60 mg Groups | Baseline to Week 2 and Week 4 | LDL-C was determined by ultracentrifugation or direct measure. Least-squares (LS) mean was provided for the comparison of MGL-3196 versus placebo and it used a linear model with percent change from baseline as the dependent variable and treatment as a factor. |
| Percent Change in LDL-C From Baseline to Week 12 by Systemic Exposure Category | Baseline to Week 12 | The effect on percent change in LDL-C from baseline to Week 12 was determined by patient exposure category (higher/lower). Patients taking MGL-3196 were categorized into lower and higher exposure groups. Patients in the higher exposure group must either have had estimated Week 2 AUC ≥5,000 mg∙h/L, or if Week 2 AUC \<5,000 mg∙h/L but Week 4 pre-dose concentration \>1.5 ng/mL (if on 60 mg MGL-3196). All other patients were in the lower exposure group. |
| Mean Change in Lipid Particle Concentration From Baseline To Week 12: Total LDL Particles | Baseline up to Week 12 | The effect of once-daily oral dosing of MGL-3196 versus placebo for 12 weeks in terms of change from baseline was assessed for LDL Particles. |
| Mean Change in Lipid Particle Concentration From Baseline To Week 12: Small LDL Particles | Baseline up to Week 12 | The effect of once-daily oral dosing of MGL-3196 versus placebo for 12 weeks in terms of change from baseline was assessed for Small LDL Particles. |
| Mean Change in Lipid Particle Concentration From Baseline To Week 12: Intermediate LDL Particles | Baseline up to Week 12 | The effect of once-daily oral dosing of MGL-3196 versus placebo for 12 weeks in terms of change from baseline was assessed for Intermediate LDL Particles. |
| Mean Change in Lipid Particle Concentration From Baseline To Week 12: Large LDL Particles | Baseline up to Week 12 | The effect of once-daily oral dosing of MGL-3196 versus placebo for 12 weeks in terms of change from baseline was assessed for Large LDL Particles. |
| Mean Change in Lipid Particle Concentration From Baseline To Week 12:Total Very Low-Density Lipoprotein (VLDL) and Chylomicron Particles | Baseline up to Week 12 | The effect of once-daily oral dosing of MGL-3196 versus placebo for 12 weeks in terms of change from baseline was assessed for VLDL and Chylomicron Particles. |
| Mean Change in Lipid Particle Concentration From Baseline To Week 12: Total HDL Particles | Baseline up to Week 12 | The effect of once-daily oral dosing of MGL-3196 versus placebo for 12 weeks in terms of change from baseline was assessed for Total HDL Particles. |
| Mean Change in Lipid Particle Concentration From Baseline To Week 12: LDL Particle Size | Baseline up to Week 12 | The effect of once-daily oral dosing of MGL-3196 versus placebo for 12 weeks in terms of change from baseline was assessed for LDL Particle size. |
| Mean Change in Lipid Particle Concentration From Baseline To Week 12: VLDL Particle Size | Baseline up to Week 12 | The effect of once-daily oral dosing of MGL-3196 versus placebo for 12 weeks in terms of change from baseline was assessed for VLDL Particle Size. |
| Mean Change in Lipid Particle Concentration From Baseline To Week 12: HDL Particle Size | Baseline up to Week 12 | The effect of once-daily oral dosing of MGL-3196 versus placebo for 12 weeks in terms of change from baseline was assessed for HDL Particle Size. |
Countries
Denmark, Netherlands, Norway
Contacts
STUDY_DIRECTORRebecca Taub, MD
Madrigal Pharmaceuticals, Inc.
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| MGL-3196 Participants randomized to MGL-3196 received 100 mg daily during the first 2 weeks, 60 mg daily during Weeks 2 to 4, and then either 60 or 100 mg daily to Week 12 based on Week 2 measured PK assessments of MGL-3196 exposure. | 78 |
| Placebo Participants administered matching oral placebo once daily for 12 weeks. | 38 |
| Total | 116 |
Baseline characteristics
| Characteristic | MGL-3196 | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 22 Participants | 13 Participants | 35 Participants |
| Age, Categorical Between 18 and 65 years | 56 Participants | 25 Participants | 81 Participants |
| Age, Continuous | 56.4 years STANDARD_DEVIATION 12.38 | 59.1 years STANDARD_DEVIATION 11.33 | 57.3 years STANDARD_DEVIATION 12.06 |
| Baseline Low-density Lipoprotein Cholesterol (LDL-C) (Direct measure or ultracentrifugation) | 131.4 mg/dL STANDARD_DEVIATION 47.24 | 137.0 mg/dL STANDARD_DEVIATION 57.53 | 133.3 mg/dL STANDARD_DEVIATION 50.65 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 78 Participants | 38 Participants | 116 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 78 Participants | 37 Participants | 115 Participants |
| Sex: Female, Male Female | 39 Participants | 16 Participants | 55 Participants |
| Sex: Female, Male Male | 39 Participants | 22 Participants | 61 Participants |
| Statin Use Atorvastatin | 40 Participants | 16 Participants | 56 Participants |
| Statin Use None | 3 Participants | 4 Participants | 7 Participants |
| Statin Use Pravastatin | 1 Participants | 1 Participants | 2 Participants |
| Statin Use Rosuvastatin | 34 Participants | 17 Participants | 51 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 78 | 0 / 38 |
| other Total, other adverse events | 65 / 78 | 28 / 38 |
| serious Total, serious adverse events | 0 / 78 | 1 / 38 |
Outcome results
Primary
Mean Percent Change in LDL-C From Baseline To Week 12
LDL-C was determined by ultracentrifugation or direct measure. Least-squares (LS) mean was provided for the comparison of MGL-3196 versus placebo and it used a linear model with percent change from baseline as the dependent variable and treatment as a factor.
Time frame: Baseline up to Week 12
Population: Modified Intent-to-Treat (mITT) population: all participants who were randomized in the study, received at least 2 weeks of study drug, and had a valid lipid measurement at Week 2 or later.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MGL-3196 | Mean Percent Change in LDL-C From Baseline To Week 12 | -10.6 percent change | Standard Error 2.59 |
| Placebo | Mean Percent Change in LDL-C From Baseline To Week 12 | 8.2 percent change | Standard Error 3.71 |
Comparison: LS mean difference in LDL-C between MGL-3196 and placebo.p-value: <0.000195% CI: [-27.8, -9.8]ANOVA
Secondary
Absolute Change in LDL-C From Baseline to Week 12
LDL-C was determined by ultracentrifugation or direct measure . Least-squares (LS) mean was provided for the comparison of MGL-3196 versus placebo and it used a linear model with percent change from baseline as the dependent variable and treatment as a factor.
Time frame: Baseline up to Week 12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MGL-3196 | Absolute Change in LDL-C From Baseline to Week 12 | -17.0 mg/dL | Standard Error 3.31 |
| Placebo | Absolute Change in LDL-C From Baseline to Week 12 | 9.9 mg/dL | Standard Error 4.74 |
p-value: <0.000195% CI: [-38.4, -15.5]ANOVA
Secondary
Mean Change From Baseline to Week 12 of Free Thyroxine (T4)
T4 was assessed at each study visit.
Time frame: Baseline up to Week 12
Population: Safety population: all participants who were randomized in the study and received at least 1 dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MGL-3196 | Mean Change From Baseline to Week 12 of Free Thyroxine (T4) | -0.268 ng/dL | Standard Error 0.013 |
| Placebo | Mean Change From Baseline to Week 12 of Free Thyroxine (T4) | 0.009 ng/dL | Standard Error 0.0185 |
Secondary
Mean Change From Baseline to Week 12 of Free Triiodothyronine (T3)
Free T3 was assessed at each study visit.
Time frame: Baseline up to Week 12
Population: Safety population: all participants who were randomized in the study and received at least 1 dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MGL-3196 | Mean Change From Baseline to Week 12 of Free Triiodothyronine (T3) | -0.04 ng/L | Standard Error 0.038 |
| Placebo | Mean Change From Baseline to Week 12 of Free Triiodothyronine (T3) | 0.10 ng/L | Standard Error 0.054 |
Secondary
Mean Change From Baseline to Week 12 of Reverse Triiodothyronine (T3)
Reverse T3 was assessed at each study visit.
Time frame: Baseline up to Week 12
Population: Safety population: all participants who were randomized in the study and received at least 1 dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MGL-3196 | Mean Change From Baseline to Week 12 of Reverse Triiodothyronine (T3) | -4.36 ng/dL | Standard Error 0.392 |
| Placebo | Mean Change From Baseline to Week 12 of Reverse Triiodothyronine (T3) | -0.58 ng/dL | Standard Error 0.554 |
Secondary
Mean Change From Baseline to Week 12 of Thyrotropin (TSH)
TSH was assessed at each study visit.
Time frame: Baseline up to Week 12
Population: Safety population: all participants who were randomized in the study and received at least 1 dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MGL-3196 | Mean Change From Baseline to Week 12 of Thyrotropin (TSH) | -0.027 mIU/L | Standard Error 0.069 |
| Placebo | Mean Change From Baseline to Week 12 of Thyrotropin (TSH) | 0.114 mIU/L | Standard Error 0.0987 |
Secondary
Mean Change From Baseline to Week 12 of Thyroxine Binding Globulin (TBG)
TBG was assessed at all study visits except the Screening Visit.
Time frame: Baseline up to Week 12
Population: Safety population: all participants who were randomized in the study and received at least 1 dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MGL-3196 | Mean Change From Baseline to Week 12 of Thyroxine Binding Globulin (TBG) | -2.31 mg/L | Standard Error 0.256 |
| Placebo | Mean Change From Baseline to Week 12 of Thyroxine Binding Globulin (TBG) | -0.44 mg/L | Standard Error 0.367 |
Secondary
Mean Change in Lipid Particle Concentration From Baseline To Week 12: HDL Particle Size
The effect of once-daily oral dosing of MGL-3196 versus placebo for 12 weeks in terms of change from baseline was assessed for HDL Particle Size.
Time frame: Baseline up to Week 12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MGL-3196 | Mean Change in Lipid Particle Concentration From Baseline To Week 12: HDL Particle Size | 9.30 nm | Standard Deviation 0.589 |
| Placebo | Mean Change in Lipid Particle Concentration From Baseline To Week 12: HDL Particle Size | 9.19 nm | Standard Deviation 0.586 |
p-value: 0.106695% CI: [-0.03, 0.26]ANOVA
Secondary
Mean Change in Lipid Particle Concentration From Baseline To Week 12: Intermediate LDL Particles
The effect of once-daily oral dosing of MGL-3196 versus placebo for 12 weeks in terms of change from baseline was assessed for Intermediate LDL Particles.
Time frame: Baseline up to Week 12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MGL-3196 | Mean Change in Lipid Particle Concentration From Baseline To Week 12: Intermediate LDL Particles | 157 nmol/L | Standard Deviation 96 |
| Placebo | Mean Change in Lipid Particle Concentration From Baseline To Week 12: Intermediate LDL Particles | 168 nmol/L | Standard Deviation 184 |
p-value: 0.524595% CI: [-60.5, 31]ANOVA
Secondary
Mean Change in Lipid Particle Concentration From Baseline To Week 12: Large LDL Particles
The effect of once-daily oral dosing of MGL-3196 versus placebo for 12 weeks in terms of change from baseline was assessed for Large LDL Particles.
Time frame: Baseline up to Week 12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MGL-3196 | Mean Change in Lipid Particle Concentration From Baseline To Week 12: Large LDL Particles | 411 nmol/L | Standard Deviation 247 |
| Placebo | Mean Change in Lipid Particle Concentration From Baseline To Week 12: Large LDL Particles | 501 nmol/L | Standard Deviation 302 |
p-value: 0.003495% CI: [-224.7, -45.8]ANOVA
Secondary
Mean Change in Lipid Particle Concentration From Baseline To Week 12: LDL Particle Size
The effect of once-daily oral dosing of MGL-3196 versus placebo for 12 weeks in terms of change from baseline was assessed for LDL Particle size.
Time frame: Baseline up to Week 12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MGL-3196 | Mean Change in Lipid Particle Concentration From Baseline To Week 12: LDL Particle Size | 20.94 nm | Standard Deviation 0.546 |
| Placebo | Mean Change in Lipid Particle Concentration From Baseline To Week 12: LDL Particle Size | 20.89 nm | Standard Deviation 0.549 |
p-value: 0.690595% CI: [-0.15, 0.23]ANOVA
Secondary
Mean Change in Lipid Particle Concentration From Baseline To Week 12: Small LDL Particles
The effect of once-daily oral dosing of MGL-3196 versus placebo for 12 weeks in terms of change from baseline was assessed for Small LDL Particles.
Time frame: Baseline up to Week 12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MGL-3196 | Mean Change in Lipid Particle Concentration From Baseline To Week 12: Small LDL Particles | 655 nmol/L | Standard Deviation 214 |
| Placebo | Mean Change in Lipid Particle Concentration From Baseline To Week 12: Small LDL Particles | 760 nmol/L | Standard Deviation 265 |
p-value: 0.006795% CI: [-170.6, -28.2]ANOVA
Secondary
Mean Change in Lipid Particle Concentration From Baseline To Week 12: Total HDL Particles
The effect of once-daily oral dosing of MGL-3196 versus placebo for 12 weeks in terms of change from baseline was assessed for Total HDL Particles.
Time frame: Baseline up to Week 12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MGL-3196 | Mean Change in Lipid Particle Concentration From Baseline To Week 12: Total HDL Particles | 29.79 micromol/L | Standard Deviation 4.699 |
| Placebo | Mean Change in Lipid Particle Concentration From Baseline To Week 12: Total HDL Particles | 30.92 micromol/L | Standard Deviation 5.94 |
p-value: 0.308895% CI: [-2.26, 0.72]ANOVA
Secondary
Mean Change in Lipid Particle Concentration From Baseline To Week 12: Total LDL Particles
The effect of once-daily oral dosing of MGL-3196 versus placebo for 12 weeks in terms of change from baseline was assessed for LDL Particles.
Time frame: Baseline up to Week 12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MGL-3196 | Mean Change in Lipid Particle Concentration From Baseline To Week 12: Total LDL Particles | 1223 nmol/L | Standard Deviation 334 |
| Placebo | Mean Change in Lipid Particle Concentration From Baseline To Week 12: Total LDL Particles | 1428 nmol/L | Standard Deviation 475 |
p-value: <0.000195% CI: [-363.7, -126.7]ANOVA
Secondary
Mean Change in Lipid Particle Concentration From Baseline To Week 12:Total Very Low-Density Lipoprotein (VLDL) and Chylomicron Particles
The effect of once-daily oral dosing of MGL-3196 versus placebo for 12 weeks in terms of change from baseline was assessed for VLDL and Chylomicron Particles.
Time frame: Baseline up to Week 12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MGL-3196 | Mean Change in Lipid Particle Concentration From Baseline To Week 12:Total Very Low-Density Lipoprotein (VLDL) and Chylomicron Particles | 24.8 nmol/L | Standard Deviation 18.5 |
| Placebo | Mean Change in Lipid Particle Concentration From Baseline To Week 12:Total Very Low-Density Lipoprotein (VLDL) and Chylomicron Particles | 37.3 nmol/L | Standard Deviation 24.7 |
p-value: 0.012995% CI: [-17.9, -2.2]ANOVA
Secondary
Mean Change in Lipid Particle Concentration From Baseline To Week 12: VLDL Particle Size
The effect of once-daily oral dosing of MGL-3196 versus placebo for 12 weeks in terms of change from baseline was assessed for VLDL Particle Size.
Time frame: Baseline up to Week 12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MGL-3196 | Mean Change in Lipid Particle Concentration From Baseline To Week 12: VLDL Particle Size | 52.27 nm | Standard Deviation 7.063 |
| Placebo | Mean Change in Lipid Particle Concentration From Baseline To Week 12: VLDL Particle Size | 51.33 nm | Standard Deviation 8.801 |
p-value: 0.500895% CI: [-1.86, 3.78]ANOVA
Secondary
Mean Percent Change In Apolipoprotein B (ApoB) From Baseline To Week 12
ApoB was determined by ultracentrifugation. LS mean was provided for the comparison of MGL-3196 versus placebo and it used a linear model with percent change from baseline as the dependent variable and treatment as a factor.
Time frame: Baseline up to Week 12
Population: mITT population: all participants who were randomized in the study, received at least 2 weeks of study drug, and had a valid lipid measurement at Week 2 or later.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MGL-3196 | Mean Percent Change In Apolipoprotein B (ApoB) From Baseline To Week 12 | -14.2 percent change | Standard Error 1.66 |
| Placebo | Mean Percent Change In Apolipoprotein B (ApoB) From Baseline To Week 12 | 3.8 percent change | Standard Error 2.37 |
Comparison: LS mean difference in ApoB between MGL-3196 and placebo.p-value: <0.000195% CI: [-23.7, -12.2]ANOVA
Secondary
Mean Percent Change in Apolipoprotein B/Apolipoprotein A1 (ApoB/ApoA1) Ratio From Baseline to Week 12
The ApoB/ApoA1 ratio was determined by ultracentrifugation. LS mean was provided for the comparison of MGL-3196 versus placebo and it used a linear model with percent change from baseline as the dependent variable and treatment as a factor.
Time frame: Baseline up to Week 12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MGL-3196 | Mean Percent Change in Apolipoprotein B/Apolipoprotein A1 (ApoB/ApoA1) Ratio From Baseline to Week 12 | -5.0 percent change | Standard Error 1.8 |
| Placebo | Mean Percent Change in Apolipoprotein B/Apolipoprotein A1 (ApoB/ApoA1) Ratio From Baseline to Week 12 | 4.2 percent change | Standard Error 2.5 |
p-value: 0.003795% CI: [-15.3, -3]ANOVA
Secondary
Mean Percent Change in Apolipoprotein CIII From Baseline to Week 12
Apolipoprotein CIII was determined by ultracentrifugation. LS mean was provided for the comparison of MGL-3196 versus placebo and it used a linear model with percent change from baseline as the dependent variable and treatment as a factor.
Time frame: Baseline up to Week 12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MGL-3196 | Mean Percent Change in Apolipoprotein CIII From Baseline to Week 12 | -19.3 percent change | Standard Error 2.9 |
| Placebo | Mean Percent Change in Apolipoprotein CIII From Baseline to Week 12 | 3.4 percent change | Standard Error 4.1 |
p-value: <0.000195% CI: [-32.6, -12.8]ANOVA
Secondary
Mean Percent Change In Cholesterol/HDL-C Ratio From Baseline to Week 12
The Cholesterol/HDL-C Ratio was determined by ultracentrifugation. LS mean was provided for the comparison of MGL-3196 versus placebo and it used a linear model with percent change from baseline as the dependent variable and treatment as a factor.
Time frame: Baseline up to Week 12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MGL-3196 | Mean Percent Change In Cholesterol/HDL-C Ratio From Baseline to Week 12 | -3.5 percent change | Standard Error 2.3 |
| Placebo | Mean Percent Change In Cholesterol/HDL-C Ratio From Baseline to Week 12 | 6.3 percent change | Standard Error 3.3 |
p-value: 0.01795% CI: [-17.8, -1.8]ANOVA
Secondary
Mean Percent Change In Lipoprotein(a) (Lp[a]) From Baseline To Week 12
Lp(a) was determined by ultracentrifugation. LS mean was provided for the comparison of MGL-3196 versus placebo and it used a linear model with percent change from baseline as the dependent variable and treatment as a factor.
Time frame: Baseline up to Week 12
Population: mITT population: all participants who were randomized in the study, received at least 2 weeks of study drug, and had a valid lipid measurement at Week 2 or later.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MGL-3196 | Mean Percent Change In Lipoprotein(a) (Lp[a]) From Baseline To Week 12 | -21.8 percent change | Standard Error 2.87 |
| Placebo | Mean Percent Change In Lipoprotein(a) (Lp[a]) From Baseline To Week 12 | 4.4 percent change | Standard Error 4.11 |
Comparison: LS mean difference in Lp(a) between MGL-3196 and placebo.p-value: <0.000195% CI: [-36.2, -16.4]ANOVA
Secondary
Mean Percent Change in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Week 12
Non-HDL-C were determined by ultracentrifugation. LS mean was provided for the comparison of MGL-3196 versus placebo and it used a linear model with percent change from baseline as the dependent variable and treatment as a factor
Time frame: Baseline up to Week 12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MGL-3196 | Mean Percent Change in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Week 12 | -12.0 percent change | Standard Error 2.41 |
| Placebo | Mean Percent Change in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Week 12 | 7.5 percent change | Standard Error 3.46 |
p-value: <0.000195% CI: [-27.9, -11.1]ANOVA
Secondary
Mean Percent Change In Triglycerides From Baseline To Week 12
Triglycerides were determined by ultracentrifugation. LS mean was provided for the comparison of MGL-3196 versus placebo and it used a linear model with percent change from baseline as the dependent variable and treatment as a factor.
Time frame: Baseline up to Week 12
Population: mITT population: all participants who were randomized in the study, received at least 2 weeks of study drug, and had a valid lipid measurement at Week 2 or later.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MGL-3196 | Mean Percent Change In Triglycerides From Baseline To Week 12 | -18.3 percent change | Standard Error 3.24 |
| Placebo | Mean Percent Change In Triglycerides From Baseline To Week 12 | 7.2 percent change | Standard Error 4.64 |
Comparison: LS mean difference in triglycerides between MGL-3196 and placebo.p-value: <0.000195% CI: [-36.7, -14.2]ANOVA
Secondary
Percent Change From Baseline in LDL-C at Week 2 and Week 4 in Patients in the 100 mg and the 60 mg Groups
LDL-C was determined by ultracentrifugation or direct measure. Least-squares (LS) mean was provided for the comparison of MGL-3196 versus placebo and it used a linear model with percent change from baseline as the dependent variable and treatment as a factor.
Time frame: Baseline to Week 2 and Week 4
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| MGL-3196 | Percent Change From Baseline in LDL-C at Week 2 and Week 4 in Patients in the 100 mg and the 60 mg Groups | Week 2 | -16.6 percent change |
| MGL-3196 | Percent Change From Baseline in LDL-C at Week 2 and Week 4 in Patients in the 100 mg and the 60 mg Groups | Week 4 | -9.8 percent change |
| Placebo | Percent Change From Baseline in LDL-C at Week 2 and Week 4 in Patients in the 100 mg and the 60 mg Groups | Week 2 | 1.6 percent change |
| Placebo | Percent Change From Baseline in LDL-C at Week 2 and Week 4 in Patients in the 100 mg and the 60 mg Groups | Week 4 | 0.1 percent change |
Secondary
Percent Change in LDL-C From Baseline to Week 12 by Systemic Exposure Category
The effect on percent change in LDL-C from baseline to Week 12 was determined by patient exposure category (higher/lower). Patients taking MGL-3196 were categorized into lower and higher exposure groups. Patients in the higher exposure group must either have had estimated Week 2 AUC ≥5,000 mg∙h/L, or if Week 2 AUC \<5,000 mg∙h/L but Week 4 pre-dose concentration \>1.5 ng/mL (if on 60 mg MGL-3196). All other patients were in the lower exposure group.
Time frame: Baseline to Week 12
Population: mITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MGL-3196 | Percent Change in LDL-C From Baseline to Week 12 by Systemic Exposure Category | -8.1 percent change | Standard Error 3.71 |
| Placebo | Percent Change in LDL-C From Baseline to Week 12 by Systemic Exposure Category | -13.0 percent change | Standard Error 3.62 |
| Placebo | Percent Change in LDL-C From Baseline to Week 12 by Systemic Exposure Category | 8.2 percent change | Standard Error 3.71 |
p-value: 0.002595% CI: [-26.7, -5.9]ANOVA
p-value: <0.000195% CI: [-31.4, -10.9]ANOVA