Subjects With Hyperlipidemia, Dyslipidemia
Conditions
Keywords
Hyperlipidemia, Dyslipidemia, Proprotein convertase subtilisin/kexin type 9 (PCSK9) Inhibition, Arterial Wall Inflamation, Elevated lipoprotein a
Brief summary
A study to assess the effects of proprotein convertase subtilisin/ kexin type 9 (PCSK9) inhibition on the arterial wall inflammation in patients with elevated lipoprotein(a).
Interventions
DRUGEvolocumab
Administered subcutaneously once a month using an autoinjector/pen.
DRUGPlacebo
Administered subcutaneously once a month using an autoinjector/pen.
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Fasting lipoprotein(a) (Lp(a)) 50 mg/dL or more at screening 1 * Fasting Low-density lipoprotein-cholesterol (LDL-C) 100 mg/dL or more at screening 1 * Lipid lowering therapy including statin dose unchanged for at least 8 weeks prior to screening * Target-to-background ratio (TBR) maximum higher than 1.6 (either right, left carotid or thoracic aorta) on fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT).
Exclusion criteria
* Currently receiving, or less than 4 weeks since receiving, treatment in another investigational device or drug study(ies), or participating in other investigational procedures * Known diagnosis of diabetes mellitus or screening fasting serum glucose ≥ 126 mg/dL or hemoglobin A1C (HbA1C) ≥ 6.5% * Subject with a history of homozygous familial hypercholesterolemia * History of a Cardiovascular event * Subject currently undergoing lipid apheresis * Known contraindications or limitations to FDG-PET/ CT (scanner weight limit, devices that can cause image artifacts, or carotid/aortic stents/grafts * Subject has had exposure to investigational drugs targeting Lp(a) within the last 12 months, prior to Screening * Other
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Maximum Target-to-background Ratio in the Most Diseased Segment of the Index Vessel at Week 16 | Baseline and week 16 | Arterial inflammation was assessed using 18F-fluoro-deoxyglucose positron-emission tomography/computed tomography (18F-FDG PET/CT). Arterial 18F-FDG uptake is correlated with arterial macrophage content and predicts cardiovascular events. Images were analyzed by an experienced radiologist blinded to all patient characteristics. The maximum standardized uptake value was calculated as a time- and dose- corrected tissue radioactivity divided by body weight in the index and the target-to-background ratio (TBR) was calculated from the ratio of the standardized uptake value of the artery compared to mean background venous activity. The average maximum TBR for the most diseased segment (MDS) was calculated from a group of 3 contiguous slices (approximately 1.5 cm), centered on the slice with the highest maximum TBR in the index vessel. The index vessel was defined as the vessel (either the right or left carotid or aorta) with the highest mean TBR at baseline. |
Secondary
| Measure | Time frame |
|---|---|
| Percent Change From Baseline in Lipoprotein(a) Concentration at Week 16 | Baseline and week 16 |
| Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) Concentration at Week 16 | Baseline and week 16 |
| Percent Change From Baseline in Apolipoprotein B Concentration at Week 16 | Baseline and week 16 |
Countries
Canada, Netherlands, United States
Participant flow
Recruitment details
This study was conducted at 14 centers in Canada, the Netherlands, and the United States. Participants were enrolled from 14 April 2016 to 07 December 2017.
Pre-assignment details
Eligible participants were randomized in a 1:1 ratio to receive either evolocumab or placebo. Randomization was stratified by baseline background statin therapy (on statin versus not on statin) and by screening lipoprotein(a) (Lp\[a\]) (\< 175 mg/dL or ≥ 175 mg/dL).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo to evolocumab by subcutaneous injection once a month (QM) for 12 weeks. | 64 |
| Evolocumab 420 mg QM Participants received 420 mg evolocumab by subcutaneous injection once a month (QM) for 12 weeks. | 65 |
| Total | 129 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Sponsor Decision | 0 | 1 |
Baseline characteristics
| Characteristic | Evolocumab 420 mg QM | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 60.0 years STANDARD_DEVIATION 6.8 | 60.7 years STANDARD_DEVIATION 7.6 | 60.3 years STANDARD_DEVIATION 7.2 |
| Age, Customized 18 - 64 years | 48 Participants | 41 Participants | 89 Participants |
| Age, Customized ≥ 65 years | 17 Participants | 23 Participants | 40 Participants |
| Apolipoprotein B Concentration | 109.9 mg/dL STANDARD_DEVIATION 23.7 | 108.0 mg/dL STANDARD_DEVIATION 22.9 | 108.9 mg/dL STANDARD_DEVIATION 23.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 64 Participants | 64 Participants | 128 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Lipoprotein(a) Concentration | 203.0 nmol/L | 198.0 nmol/L | 200.0 nmol/L |
| Location of the Index Vessel Used for Calculation of Maximum Target-to-background Ratio Ascending thoracic aorta | 49 Participants | 54 Participants | 103 Participants |
| Location of the Index Vessel Used for Calculation of Maximum Target-to-background Ratio Left common carotid | 3 Participants | 1 Participants | 4 Participants |
| Location of the Index Vessel Used for Calculation of Maximum Target-to-background Ratio Missing | 2 Participants | 1 Participants | 3 Participants |
| Location of the Index Vessel Used for Calculation of Maximum Target-to-background Ratio Right common carotid | 11 Participants | 8 Participants | 19 Participants |
| Low-density Lipoprotein Cholesterol (LDL-C) Concentration | 146.2 mg/dL STANDARD_DEVIATION 43.5 | 141.7 mg/dL STANDARD_DEVIATION 35.7 | 144.0 mg/dL STANDARD_DEVIATION 39.7 |
| Maximum Target-to-background Ratio (TBR) in the Most Diseased Section of the Index Vessel | 2.29667 ratio STANDARD_DEVIATION 0.46063 | 2.28765 ratio STANDARD_DEVIATION 0.41284 | 2.29216 ratio STANDARD_DEVIATION 0.43566 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 3 Participants | 5 Participants |
| Race/Ethnicity, Customized Black or African American | 4 Participants | 2 Participants | 6 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 58 Participants | 58 Participants | 116 Participants |
| Sex: Female, Male Female | 39 Participants | 30 Participants | 69 Participants |
| Sex: Female, Male Male | 26 Participants | 34 Participants | 60 Participants |
| Stratification Factor: Baseline Statin Therapy No | 31 Participants | 31 Participants | 62 Participants |
| Stratification Factor: Baseline Statin Therapy Yes | 34 Participants | 33 Participants | 67 Participants |
| Stratification Factor: Screening Lipoprotein(a) (Lp[a]) Level < 175 mg/dL | 61 Participants | 60 Participants | 121 Participants |
| Stratification Factor: Screening Lipoprotein(a) (Lp[a]) Level ≥ 175 mg/dL | 4 Participants | 4 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 64 | 0 / 65 |
| other Total, other adverse events | 47 / 64 | 49 / 65 |
| serious Total, serious adverse events | 0 / 64 | 2 / 65 |
Outcome results
Primary
Percent Change From Baseline in Maximum Target-to-background Ratio in the Most Diseased Segment of the Index Vessel at Week 16
Arterial inflammation was assessed using 18F-fluoro-deoxyglucose positron-emission tomography/computed tomography (18F-FDG PET/CT). Arterial 18F-FDG uptake is correlated with arterial macrophage content and predicts cardiovascular events. Images were analyzed by an experienced radiologist blinded to all patient characteristics. The maximum standardized uptake value was calculated as a time- and dose- corrected tissue radioactivity divided by body weight in the index and the target-to-background ratio (TBR) was calculated from the ratio of the standardized uptake value of the artery compared to mean background venous activity. The average maximum TBR for the most diseased segment (MDS) was calculated from a group of 3 contiguous slices (approximately 1.5 cm), centered on the slice with the highest maximum TBR in the index vessel. The index vessel was defined as the vessel (either the right or left carotid or aorta) with the highest mean TBR at baseline.
Time frame: Baseline and week 16
Population: Participants who received at least 1 dose of study drug with available data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Maximum Target-to-background Ratio in the Most Diseased Segment of the Index Vessel at Week 16 | -5.31 percent change | Standard Error 1.67 |
| Evolocumab 420 mg QM | Percent Change From Baseline in Maximum Target-to-background Ratio in the Most Diseased Segment of the Index Vessel at Week 16 | -8.31 percent change | Standard Error 1.67 |
Comparison: A multivariate regression was modelled on the primary endpoint as well as three other response variables (percent change in Lp\[a\] at Weeks 8 and 16, baseline MDS TBR, and baseline Lp\[a\]). The primary endpoint was regressed on the treatment group and statin stratification factor; baseline MDS TBR and Lp(a) were regressed on the statin stratification factor, and percent changes in Lp(a) were regressed on the treatment group, statin stratification factor, visit, and treatment group by visit.p-value: 0.1895% CI: [-7.4, 1.39]Multivariate regression model
Secondary
Percent Change From Baseline in Apolipoprotein B Concentration at Week 16
Time frame: Baseline and week 16
Population: Participants who received at least 1 dose of study drug with available data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Apolipoprotein B Concentration at Week 16 | 3.29 percent change | Standard Error 1.53 |
| Evolocumab 420 mg QM | Percent Change From Baseline in Apolipoprotein B Concentration at Week 16 | -48.30 percent change | Standard Error 1.51 |
p-value: <0.000195% CI: [-55.85, -47.33]Repeated measures linear effects model
Secondary
Percent Change From Baseline in Lipoprotein(a) Concentration at Week 16
Time frame: Baseline and week 16
Population: Participants who received at least 1 dose of study drug with available data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Lipoprotein(a) Concentration at Week 16 | 1.06 percent change | Standard Error 1.94 |
| Evolocumab 420 mg QM | Percent Change From Baseline in Lipoprotein(a) Concentration at Week 16 | -12.83 percent change | Standard Error 1.92 |
p-value: <0.000195% CI: [-19.29, -8.49]Repeated measures linear effects model
Secondary
Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) Concentration at Week 16
Time frame: Baseline and week 16
Population: Participants who received at least 1 dose of study drug with available data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) Concentration at Week 16 | 1.64 percent change | Standard Error 1.86 |
| Evolocumab 420 mg QM | Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) Concentration at Week 16 | -59.02 percent change | Standard Error 1.82 |
p-value: <0.000195% CI: [-65.81, -55.51]Repeated measures linear effects model