Lipoprotein Disorder
Conditions
Keywords
Atherosclerotic cardiovascular disease, ASCVD, Dyslipidemia, Lipoprotein(a), Lp(a), Cardiovascular, Cardiovascular disease, Cholesterol, Hyperlipidemia
Brief summary
The main purpose of this study is to evaluate the efficacy and safety of LY3473329 in adult participants with elevated Lp(a) at high risk for cardiovascular events.
Interventions
DRUGLY3473329
Administered orally
DRUGPlacebo
Administered orally
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants must be at least 40 years old * Participants with Lp(a) ≥175 nmol/L at randomization, measured at the central laboratory. * High risk for cardiovascular events defined as documented coronary artery disease (CAD), stroke, or peripheral artery disease or atherosclerotic cardiovascular disease (ASCVD) risk equivalents (familial hypercholesterolemia or type 2 diabetes). * Participants on the following medications according to local practice must be on a stable regimen for at least 4 weeks prior to randomization and expected to remain on a stable regimen through the end of the post-treatment follow-up period. * lipid-lowering drugs * testosterone, estrogens, anti-estrogens, progestins, selective estrogen receptor modulators, or growth hormone * Have a body mass index within the range 18.5 to 40 kilogram/square meter (kg/m²), inclusive. * Males who agree to use highly effective or effective methods of contraception may participate in this trial. * Women of childbearing potential (WOCBP) who agree to use highly effective or effective methods of contraception and women not of childbearing potential (WNOCBP) may participate in this trial.
Exclusion criteria
* Have a history or presence of an underlying disease, or surgical, physical, medical, or psychiatric condition that, in the opinion of the investigator, would potentially affect participant safety within the study or interfere with participating in or completing the study or with the interpretation of data. * Any of the following, or other events indicating unstable medical condition in the opinion of the investigator, within 3 months of randomization: * major surgery * coronary, carotid, or peripheral arterial revascularization * stroke or transient ischemic attack * myocardial infarction or unstable angina * acute limb ischemia * Have, in the 6 months prior to day 1, uncontrolled Type 1 or Type 2 diabetes * Have uncontrolled hypertension
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Lp(a) - Assessed Via Intact Lp(a) Assay | Baseline, Week 12 | Least Squares Mean (LS Mean) was calculated using a Mixed Model for Repeated Measures (MMRM): Log (Actual Measurement/Baseline) = Log (Baseline) + Country + Treatment + Time + Treatment\*Time. |
| Percent Change From Baseline in Lp(a) - Assessed Via Apo(a) Assay | Baseline, Week 12 | LS Mean was calculated using a MMRM: Log (Actual Measurement/Baseline) = Log (Baseline) + Country + Treatment + Time + Treatment\*Time. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Apolipoprotein B (ApoB) | Baseline, Week 12 | LS Mean was calculated using a MMRM: Log (Actual Measurement/Baseline) = Log (Baseline) + Country + Baseline Lp(a) Stratum + Treatment + Time + Treatment\*Time. |
| Percentage of Participants Who Achieved Lp(a) < 125 Nmol/L - Assessed Via Intact Lp(a) Assay | Week 12 | The percentage of participants who achieved Lp(a) less than (\<) 125 nmol/L, as measured using the intact Lp(a) assay, with data analysis performed through a logistic regression model that included imputed missing values, was reported. |
| Pharmacokinetics (PK): Trough Concentrations (C-trough) of LY3473329 | Week from randomization 1, 2, 8, 12: Pre-dose | C-trough were measured at specified time points to assess the minimum concentration of LY3473329 in the blood before the next dose was administered. |
| Percent Change From Baseline in High-Sensitivity C-Reactive Protein (hsCRP) | Baseline, Week 12 | LS Mean was calculated using a MMRM: Log (Actual Measurement/Baseline) = Log (Baseline) + Country + Baseline Lp(a) Stratum + Treatment + Time + Treatment\*Time. |
| Percentage of Participants Who Achieved Lp(a) < 125 Nmol/L - Assessed Via Apo(a) Assay | Week 12 | The percentage of participants who achieved Lp(a) \< 125 nmol/L, as measured using the apo(a) assay, with data analysis performed through a logistic regression model that included imputed missing values, was reported. |
Countries
Australia, Brazil, China, Germany, Hungary, Japan, Netherlands, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 10 mg LY3473329 Participants received 10 mg of LY3473329 administered orally QD over a 12-week treatment period. | 34 |
| 60 mg LY3473329 Participants received 60 mg of LY3473329 administered orally QD over a 12-week treatment period. | 64 |
| 240 mg LY3473329 Participants received 240 mg of LY3473329 administered orally QD over a 12-week treatment period. | 68 |
| Placebo Participants received a matching dose of placebo administered orally QD over a 12-week treatment period. | 67 |
| Total | 233 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 2 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 |
| Overall Study | Physician Decision | 0 | 1 | 0 | 0 |
| Overall Study | Protocol Deviation | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | 10 mg LY3473329 | 60 mg LY3473329 | 240 mg LY3473329 | Placebo |
|---|---|---|---|---|---|
| Age, Continuous | 64.29 years STANDARD_DEVIATION 9.61 | 64.06 years STANDARD_DEVIATION 10.01 | 65.50 years STANDARD_DEVIATION 9.36 | 64.75 years STANDARD_DEVIATION 9.35 | 62.78 years STANDARD_DEVIATION 9.93 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 34 Participants | 4 Participants | 11 Participants | 10 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 195 Participants | 30 Participants | 50 Participants | 57 Participants | 58 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 0 Participants | 3 Participants | 1 Participants | 0 Participants |
| Lp(a) - Assessed via Apo(a) Assay | 265.99 nanomoles per liter (nmol/L) STANDARD_DEVIATION 88.93 | 269.67 nanomoles per liter (nmol/L) STANDARD_DEVIATION 78.1 | 256.28 nanomoles per liter (nmol/L) STANDARD_DEVIATION 96.55 | 273.84 nanomoles per liter (nmol/L) STANDARD_DEVIATION 90.68 | 265.30 nanomoles per liter (nmol/L) STANDARD_DEVIATION 85.8 |
| Lp(a) - Assessed via Intact Lp(a) Assay | 236.63 nanomoles per liter (nmol/L) STANDARD_DEVIATION 93.74 | 220.99 nanomoles per liter (nmol/L) STANDARD_DEVIATION 60.39 | 223.47 nanomoles per liter (nmol/L) STANDARD_DEVIATION 97.36 | 242.42 nanomoles per liter (nmol/L) STANDARD_DEVIATION 100.18 | 250.53 nanomoles per liter (nmol/L) STANDARD_DEVIATION 96.66 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 63 Participants | 9 Participants | 17 Participants | 19 Participants | 18 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 2 Participants | 5 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 7 Participants | 0 Participants | 1 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 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 | 153 Participants | 22 Participants | 41 Participants | 45 Participants | 45 Participants |
| Region of Enrollment Australia | 42 Participants | 6 Participants | 12 Participants | 12 Participants | 12 Participants |
| Region of Enrollment Brazil | 43 Participants | 6 Participants | 13 Participants | 12 Participants | 12 Participants |
| Region of Enrollment China | 30 Participants | 4 Participants | 8 Participants | 9 Participants | 9 Participants |
| Region of Enrollment Germany | 24 Participants | 4 Participants | 5 Participants | 8 Participants | 7 Participants |
| Region of Enrollment Hungary | 39 Participants | 6 Participants | 11 Participants | 11 Participants | 11 Participants |
| Region of Enrollment Japan | 29 Participants | 4 Participants | 8 Participants | 8 Participants | 9 Participants |
| Region of Enrollment Netherlands | 12 Participants | 2 Participants | 3 Participants | 3 Participants | 4 Participants |
| Region of Enrollment United States | 14 Participants | 2 Participants | 4 Participants | 5 Participants | 3 Participants |
| Sex: Female, Male Female | 76 Participants | 11 Participants | 22 Participants | 24 Participants | 19 Participants |
| Sex: Female, Male Male | 157 Participants | 23 Participants | 42 Participants | 44 Participants | 48 Participants |
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 / 34 | 0 / 63 | 0 / 68 | 0 / 67 |
| other Total, other adverse events | 7 / 34 | 5 / 63 | 10 / 68 | 11 / 67 |
| serious Total, serious adverse events | 2 / 34 | 2 / 63 | 2 / 68 | 4 / 67 |
Outcome results
Primary
Percent Change From Baseline in Lp(a) - Assessed Via Apo(a) Assay
LS Mean was calculated using a MMRM: Log (Actual Measurement/Baseline) = Log (Baseline) + Country + Treatment + Time + Treatment\*Time.
Time frame: Baseline, Week 12
Population: All randomized participants who received at least one dose of the study drug, had a non-missing baseline value, and at least one post-baseline value, as assessed by the apo(a) assay, excluding data after discontinuation of the study drug or initiation of new Lp(a) modifying medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg LY3473329 | Percent Change From Baseline in Lp(a) - Assessed Via Apo(a) Assay | -42.26 Percent change | Standard Error 4.477 |
| 60 mg LY3473329 | Percent Change From Baseline in Lp(a) - Assessed Via Apo(a) Assay | -70.90 Percent change | Standard Error 1.669 |
| 240 mg LY3473329 | Percent Change From Baseline in Lp(a) - Assessed Via Apo(a) Assay | -69.88 Percent change | Standard Error 1.676 |
| Placebo | Percent Change From Baseline in Lp(a) - Assessed Via Apo(a) Assay | -3.15 Percent change | Standard Error 5.342 |
p-value: <0.00195% CI: [-50.45, -28.27]Mixed Models Analysis
p-value: <0.00195% CI: [-74.23, -64.96]Mixed Models Analysis
p-value: <0.00195% CI: [-73.27, -63.81]Mixed Models Analysis
Primary
Percent Change From Baseline in Lp(a) - Assessed Via Intact Lp(a) Assay
Least Squares Mean (LS Mean) was calculated using a Mixed Model for Repeated Measures (MMRM): Log (Actual Measurement/Baseline) = Log (Baseline) + Country + Treatment + Time + Treatment\*Time.
Time frame: Baseline, Week 12
Population: All randomized participants who received at least one dose of the study drug had a non-missing baseline value and at least one post-baseline value, as assessed by the intact Lp(a) assay, excluding data after discontinuation of the study drug or initiation of new Lp(a) modifying medication. As pre-specified in the statistical analysis plan, intact Lp(a) assay measurements were not collected from participants at Chinese sites due to country-specific restrictions on sample storage.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg LY3473329 | Percent Change From Baseline in Lp(a) - Assessed Via Intact Lp(a) Assay | -47.35 Percent change | Standard Error 4.811 |
| 60 mg LY3473329 | Percent Change From Baseline in Lp(a) - Assessed Via Intact Lp(a) Assay | -81.57 Percent change | Standard Error 1.23 |
| 240 mg LY3473329 | Percent Change From Baseline in Lp(a) - Assessed Via Intact Lp(a) Assay | -85.71 Percent change | Standard Error 0.927 |
| Placebo | Percent Change From Baseline in Lp(a) - Assessed Via Intact Lp(a) Assay | 0.48 Percent change | Standard Error 6.382 |
p-value: <0.00195% CI: [-57.68, -35.14]Mixed Models Analysis
p-value: <0.00195% CI: [-84.62, -78.13]Mixed Models Analysis
p-value: <0.00195% CI: [-88.03, -83.09]Mixed Models Analysis
Secondary
Percentage of Participants Who Achieved Lp(a) < 125 Nmol/L - Assessed Via Apo(a) Assay
The percentage of participants who achieved Lp(a) \< 125 nmol/L, as measured using the apo(a) assay, with data analysis performed through a logistic regression model that included imputed missing values, was reported.
Time frame: Week 12
Population: All randomized participants who received at least one dose of the study drug and had a non-missing baseline value, as assessed by the apo(a) assay, excluding data after discontinuation of the study drug or initiation of new Lp(a) modifying medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 10 mg LY3473329 | Percentage of Participants Who Achieved Lp(a) < 125 Nmol/L - Assessed Via Apo(a) Assay | 37.9 Percentage of participants |
| 60 mg LY3473329 | Percentage of Participants Who Achieved Lp(a) < 125 Nmol/L - Assessed Via Apo(a) Assay | 82.1 Percentage of participants |
| 240 mg LY3473329 | Percentage of Participants Who Achieved Lp(a) < 125 Nmol/L - Assessed Via Apo(a) Assay | 77.2 Percentage of participants |
| Placebo | Percentage of Participants Who Achieved Lp(a) < 125 Nmol/L - Assessed Via Apo(a) Assay | 3.3 Percentage of participants |
p-value: <0.00195% CI: [18.9, 51.46]Regression, Logistic
p-value: <0.00195% CI: [67.7, 88.65]Regression, Logistic
p-value: <0.00195% CI: [63.65, 83.58]Regression, Logistic
Secondary
Percentage of Participants Who Achieved Lp(a) < 125 Nmol/L - Assessed Via Intact Lp(a) Assay
The percentage of participants who achieved Lp(a) less than (\<) 125 nmol/L, as measured using the intact Lp(a) assay, with data analysis performed through a logistic regression model that included imputed missing values, was reported.
Time frame: Week 12
Population: All randomized participants who received at least one dose of the study drug and had a non-missing baseline value, as assessed by the intact Lp(a) assay, excluding data after discontinuation of the study drug or initiation of new Lp(a) modifying medication. As pre-specified in the statistical analysis plan, intact Lp(a) assay measurements were not collected from participants at Chinese sites due to country-specific restrictions on sample storage.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 10 mg LY3473329 | Percentage of Participants Who Achieved Lp(a) < 125 Nmol/L - Assessed Via Intact Lp(a) Assay | 69.6 Percentage of participants |
| 60 mg LY3473329 | Percentage of Participants Who Achieved Lp(a) < 125 Nmol/L - Assessed Via Intact Lp(a) Assay | 95.6 Percentage of participants |
| 240 mg LY3473329 | Percentage of Participants Who Achieved Lp(a) < 125 Nmol/L - Assessed Via Intact Lp(a) Assay | 95.7 Percentage of participants |
| Placebo | Percentage of Participants Who Achieved Lp(a) < 125 Nmol/L - Assessed Via Intact Lp(a) Assay | 6.1 Percentage of participants |
p-value: <0.00195% CI: [40.3, 75.99]Regression, Logistic
p-value: <0.00195% CI: [81.54, 98.2]Regression, Logistic
p-value: <0.00195% CI: [82.8, 98.62]Regression, Logistic
Secondary
Percent Change From Baseline in Apolipoprotein B (ApoB)
LS Mean was calculated using a MMRM: Log (Actual Measurement/Baseline) = Log (Baseline) + Country + Baseline Lp(a) Stratum + Treatment + Time + Treatment\*Time.
Time frame: Baseline, Week 12
Population: All randomized participants who received at least one dose of the study drug and had a non-missing baseline value and at least one post-baseline value for this outcome, excluding data after discontinuation of the study drug or initiation of new Lp(a) modifying medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg LY3473329 | Percent Change From Baseline in Apolipoprotein B (ApoB) | -10.49 Percent change | Standard Error 4.349 |
| 60 mg LY3473329 | Percent Change From Baseline in Apolipoprotein B (ApoB) | -14.53 Percent change | Standard Error 3.055 |
| 240 mg LY3473329 | Percent Change From Baseline in Apolipoprotein B (ApoB) | -17.56 Percent change | Standard Error 2.877 |
| Placebo | Percent Change From Baseline in Apolipoprotein B (ApoB) | -1.70 Percent change | Standard Error 3.362 |
p-value: 0.1195% CI: [-18.84, 2.17]Mixed Models Analysis
p-value: 0.00495% CI: [-20.92, -4.4]Mixed Models Analysis
p-value: <0.00195% CI: [-23.69, -7.84]Mixed Models Analysis
Secondary
Percent Change From Baseline in High-Sensitivity C-Reactive Protein (hsCRP)
LS Mean was calculated using a MMRM: Log (Actual Measurement/Baseline) = Log (Baseline) + Country + Baseline Lp(a) Stratum + Treatment + Time + Treatment\*Time.
Time frame: Baseline, Week 12
Population: All randomized participants who received at least one dose of the study drug and had a non-missing baseline value and at least one post-baseline value for this outcome, excluding data after discontinuation of the study drug or initiation of new Lp(a) modifying medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg LY3473329 | Percent Change From Baseline in High-Sensitivity C-Reactive Protein (hsCRP) | 21.87 Percent change | Standard Error 20.029 |
| 60 mg LY3473329 | Percent Change From Baseline in High-Sensitivity C-Reactive Protein (hsCRP) | -2.41 Percent change | Standard Error 11.713 |
| 240 mg LY3473329 | Percent Change From Baseline in High-Sensitivity C-Reactive Protein (hsCRP) | -15.39 Percent change | Standard Error 9.921 |
| Placebo | Percent Change From Baseline in High-Sensitivity C-Reactive Protein (hsCRP) | -9.91 Percent change | Standard Error 10.526 |
p-value: 0.13195% CI: [-8.63, 100.27]Mixed Models Analysis
p-value: 0.62795% CI: [-21.62, 49.7]Mixed Models Analysis
p-value: 0.70195% CI: [-31.89, 29.51]Mixed Models Analysis
Secondary
Pharmacokinetics (PK): Trough Concentrations (C-trough) of LY3473329
C-trough were measured at specified time points to assess the minimum concentration of LY3473329 in the blood before the next dose was administered.
Time frame: Week from randomization 1, 2, 8, 12: Pre-dose
Population: All randomized participants who received at least one dose of the study drug and had evaluable PK samples for the relevant weeks were included in this outcome analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 10 mg LY3473329 | Pharmacokinetics (PK): Trough Concentrations (C-trough) of LY3473329 | Week 1 | 13.0 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 81 |
| 10 mg LY3473329 | Pharmacokinetics (PK): Trough Concentrations (C-trough) of LY3473329 | Week 2 | 14.8 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 73 |
| 10 mg LY3473329 | Pharmacokinetics (PK): Trough Concentrations (C-trough) of LY3473329 | Week 12 | 15.4 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 64 |
| 10 mg LY3473329 | Pharmacokinetics (PK): Trough Concentrations (C-trough) of LY3473329 | Week 8 | 14.5 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 67 |
| 60 mg LY3473329 | Pharmacokinetics (PK): Trough Concentrations (C-trough) of LY3473329 | Week 2 | 39.3 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 76 |
| 60 mg LY3473329 | Pharmacokinetics (PK): Trough Concentrations (C-trough) of LY3473329 | Week 8 | 38.8 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 89 |
| 60 mg LY3473329 | Pharmacokinetics (PK): Trough Concentrations (C-trough) of LY3473329 | Week 12 | 37.7 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 95 |
| 60 mg LY3473329 | Pharmacokinetics (PK): Trough Concentrations (C-trough) of LY3473329 | Week 1 | 42.4 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 79 |
| 240 mg LY3473329 | Pharmacokinetics (PK): Trough Concentrations (C-trough) of LY3473329 | Week 1 | 83.3 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 70 |
| 240 mg LY3473329 | Pharmacokinetics (PK): Trough Concentrations (C-trough) of LY3473329 | Week 12 | 74.0 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 111 |
| 240 mg LY3473329 | Pharmacokinetics (PK): Trough Concentrations (C-trough) of LY3473329 | Week 8 | 73.9 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 110 |
| 240 mg LY3473329 | Pharmacokinetics (PK): Trough Concentrations (C-trough) of LY3473329 | Week 2 | 77.9 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 62 |