Subjects With Hyperlipidemia, Dyslipidemia and HIV Infection
Conditions
Keywords
Hyperlipidemia, Dyslipidemia, Proprotein convertase subtilisin/kexin type 9 (PCSK9), Inhibition, HIV infection, Cluster of differentiation, Viral load
Brief summary
The study is divided into 2 parts. The first part of the study will be double-blinded and will last for 24 weeks. During this time, participants will be randomized in a ratio of 2:1 to receive either evolocumab once monthly (QM) or placebo QM. The second part of the study is a 24-week open label extension period. During this time all participants will receive evolocumab QM. The clinical hypothesis is that subcutaneous evolocumab QM will be well tolerated and will result in greater reduction of low density lipoprotein cholesterol (LDL-C), defined as percent change from baseline at Week 24, compared with placebo QM in human immunodeficiency virus (HIV)-positive participants with hyperlipidemia or mixed dyslipidemia.
Interventions
DRUGEvolocumab
Dose of subcutaneous evolocumab QM
DRUGPlacebo
Dose of matching placebo QM
Sponsors
Amgen
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
* Male or female ≥ 18 years of age * Known HIV infection with stable HIV therapy for ≥ 6 months * Cluster of differentiation 4 (CD4) ≥ 250 cells/mm\^3 for ≥ 6 months * HIV viral load ≤ 50 copies/mL at screening and ≤ 200 copies/mL for ≥ 6 months * Subject on stable lipid-lowering therapy for ≥ 4 weeks prior to randomization and not expected to change during the duration of study * For subjects with known clinical atherosclerotic cardiovascular disease (ASCVD), fasting LDL-C of ≥ 70 mg/dL or non-high density lipoprotein cholesterol (non-HDL-C) ≥ 100 mg/dL. For subjects without known clinical ASCVD: fasting LDL-C of ≥ 100 mg/dL or non-HDL-C of ≥ 130 mg/dL * Fasting triglycerides ≤ 600 mg/dL (6.8 mmol/L)
Exclusion criteria
* Taking a combination of background lipid-lowering therapy and HIV therapy known to have significant drug-drug interaction * New York Heart Association (NYHA) III or IV heart failure, or last known left ventricular ejection fraction (LVEF) \< 30% * Known opportunistic infection/acquired immunodeficiency syndrome (AIDS) defining illness within 1 year prior to randomization * Myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass graft or stroke within 3 months * Type 1 diabetes, new-onset or poorly controlled type 2 diabetes * Uncontrolled hypertension * Taken a cholesteryl ester transfer protein inhibitor in the last 12 months * Moderate to severe renal dysfunction * Persistent active liver disease or hepatic dysfunction (Stable chronic hepatitis C of at least 1 year duration prior to randomization is allowed) * Malignancy (except non-melanoma skin cancers, cervical in-situ carcinoma, breast ductal carcinoma in-situ, or stage 1 prostate carcinoma) within the last 5 years prior to randomization Other
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in LDL-C at Week 24 | Baseline, Week 24 | Least squares mean is from the repeated measures model which includes treatment group, statin stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates. (Hepatitis C stratification factor is not included in the model due to low participant numbers.) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Acheiving LDL-C < 70 mg/dL (1.8 mmol/L) at Week 24 | Week 24 | — |
| Percentage of Participants With an LDL-C Response (50% Reduction of LDL-C From Baseline) at Week 24 | Baseline, Week 24 | — |
| Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol (HDL-C) at Week 24 | Baseline, Week 24 | Least squares mean is from the repeated measures model which includes treatment group, statin stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates. (Hepatitis C stratification factor is not included in the model due to low participant numbers.) |
| Percent Change From Baseline in Apolipoprotein B (ApoB) at Week 24 | Baseline, Week 24 | Least squares mean is from the repeated measures model which includes treatment group, statin stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates. (Hepatitis C stratification factor is not included in the model due to low participant numbers.) |
| Change From Baseline in LDL-C at Week 24 | Baseline, Week 24 | Least squares mean is from the repeated measures model which includes treatment group, statin stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates. (Hepatitis C stratification factor is not included in the model due to low participant numbers.) |
| Percent Change From Baseline in Lipoprotein(a) (Lp[a]) at Week 24 | Baseline, Week 24 | Least squares mean is from the repeated measures model which includes treatment group, statin stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates. (Hepatitis C stratification factor is not included in the model due to low participant numbers.) |
| Percent Change From Baseline in Triglycerides at Week 24 | Baseline, Week 24 | Least squares mean is from the repeated measures model which includes treatment group, statin stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates. (Hepatitis C stratification factor is not included in the model due to low participant numbers.) |
| Percent Change From Baseline in HDL-C at Week 24 | Bseline, Week 24 | Least squares mean is from the repeated measures model which includes treatment group, statin stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates. (Hepatitis C stratification factor is not included in the model due to low participant numbers.) |
| Percent Change From Baseline in Very Low-Density Lipoprotein Cholesterol (VLDL-C) at Week 24 | Baseline, Week 24 | Least squares mean is from the repeated measures model which includes treatment group, statin stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates. (Hepatitis C stratification factor is not included in the model due to low participant numbers.) |
| Percent Change From Baseline in Total Cholesterol (TC) at Week 24 | Baseline, Week 24 | Least squares mean is from the repeated measures model which includes treatment group, statin stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates. (Hepatitis C stratification factor is not included in the model due to low participant numbers.) |
Countries
Australia, Belgium, Brazil, Canada, France, Greece, Italy, Poland, Portugal, Romania, South Africa, Spain, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
This study was conducted at 72 centers in Australia, Belgium, Brazil, Canada, France, Greece, Italy, Poland, Portugal, Romania, South Africa, Spain, Switzerland, United Kingdom, and United States. The first participant was enrolled on 22 May 2017, and the last participant was enrolled on 23 January 2019.
Pre-assignment details
Participants were randomized in a 2:1 ratio to evolocumab or placebo, respectively, in a double-blind manner. Randomization was stratified by entry statin treatment and hepatitis C status.
Participants by arm
| Arm | Count |
|---|---|
| Double-Blind Placebo Double-blind placebo SC injection QM for 24 weeks in the double-blind period. | 157 |
| Double-Blind Evolocumab Double-blind evolocumab SC injection QM for 24 weeks in the double-blind period. | 310 |
| Total | 467 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-Blind Period | Protocol Violation | 0 | 4 |
| Double-Blind Period | Withdrawal by Subject | 2 | 3 |
| Open-Label Period | Death | 0 | 2 |
| Open-Label Period | Lost to Follow-up | 1 | 0 |
| Open-Label Period | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Double-Blind Placebo | Double-Blind Evolocumab | Total |
|---|---|---|---|
| Age, Continuous | 56.2 years STANDARD_DEVIATION 8 | 56.5 years STANDARD_DEVIATION 9.1 | 56.4 years STANDARD_DEVIATION 8.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 21 Participants | 41 Participants | 62 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 136 Participants | 269 Participants | 405 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Low-Density Lipoprotein Cholesterol (LDL-C) | 133.26 mg/dL STANDARD_DEVIATION 39.97 | 133.25 mg/dL STANDARD_DEVIATION 40.25 | 133.25 mg/dL STANDARD_DEVIATION 40.11 |
| Race/Ethnicity, Customized Asian | 3 Participants | 3 Participants | 6 Participants |
| Race/Ethnicity, Customized Black or African American | 25 Participants | 54 Participants | 79 Participants |
| Race/Ethnicity, Customized Multiple Races | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other, Not Specified | 3 Participants | 7 Participants | 10 Participants |
| Race/Ethnicity, Customized White | 125 Participants | 246 Participants | 371 Participants |
| Sex: Female, Male Female | 37 Participants | 45 Participants | 82 Participants |
| Sex: Female, Male Male | 120 Participants | 265 Participants | 385 Participants |
| Stratification Factor: Hepatitis C Virus (HCV) Status at Baseline HCV= No | 150 Participants | 300 Participants | 450 Participants |
| Stratification Factor: Hepatitis C Virus (HCV) Status at Baseline HCV = Yes | 7 Participants | 10 Participants | 17 Participants |
| Stratification Factor: Statin Use at Baseline Statin Use = No | 29 Participants | 54 Participants | 83 Participants |
| Stratification Factor: Statin Use at Baseline Statin Use = Yes | 128 Participants | 256 Participants | 384 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 / 157 | 0 / 310 | 0 / 152 | 2 / 303 |
| other Total, other adverse events | 41 / 157 | 78 / 307 | 23 / 152 | 50 / 299 |
| serious Total, serious adverse events | 8 / 157 | 10 / 307 | 8 / 152 | 14 / 299 |
Outcome results
Primary
Percent Change From Baseline in LDL-C at Week 24
Least squares mean is from the repeated measures model which includes treatment group, statin stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates. (Hepatitis C stratification factor is not included in the model due to low participant numbers.)
Time frame: Baseline, Week 24
Population: Full Analysis Set: randomized participants who received at least 1 dose of investigational product. Participants with an assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Double-Blind Placebo | Percent Change From Baseline in LDL-C at Week 24 | 1.68 percent change | Standard Error 2.03 |
| Double-Blind Evolocumab | Percent Change From Baseline in LDL-C at Week 24 | -55.23 percent change | Standard Error 1.52 |
p-value: <0.000195% CI: [-61.55, -52.28]repeated measures linear effects model
Secondary
Change From Baseline in LDL-C at Week 24
Least squares mean is from the repeated measures model which includes treatment group, statin stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates. (Hepatitis C stratification factor is not included in the model due to low participant numbers.)
Time frame: Baseline, Week 24
Population: Full Analysis Set: randomized participants who received at least 1 dose of investigational product. Participants with an assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Double-Blind Placebo | Change From Baseline in LDL-C at Week 24 | -2.3 mg/dL | Standard Error 3.1 |
| Double-Blind Evolocumab | Change From Baseline in LDL-C at Week 24 | -77.5 mg/dL | Standard Error 2.3 |
p-value: <0.000195% CI: [-82.1, -68.4]repeated measures linear effects model
Secondary
Percentage of Participants Acheiving LDL-C < 70 mg/dL (1.8 mmol/L) at Week 24
Time frame: Week 24
Population: Full Analysis Set: randomized participants who received at least 1 dose of investigational product. Participants with observed data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double-Blind Placebo | Percentage of Participants Acheiving LDL-C < 70 mg/dL (1.8 mmol/L) at Week 24 | 7.9 percentage of participants |
| Double-Blind Evolocumab | Percentage of Participants Acheiving LDL-C < 70 mg/dL (1.8 mmol/L) at Week 24 | 73.3 percentage of participants |
Comparison: Multiplicity adjustment was based on the combination of sequential testing, the fallback procedure, and the Hochberg procedure.p-value: <0.000195% CI: [57.8, 71.1]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With an LDL-C Response (50% Reduction of LDL-C From Baseline) at Week 24
Time frame: Baseline, Week 24
Population: Full Analysis Set: randomized participants who received at least 1 dose of investigational product. Participants with observed data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double-Blind Placebo | Percentage of Participants With an LDL-C Response (50% Reduction of LDL-C From Baseline) at Week 24 | 0.7 percentage of participants |
| Double-Blind Evolocumab | Percentage of Participants With an LDL-C Response (50% Reduction of LDL-C From Baseline) at Week 24 | 72.5 percentage of participants |
Comparison: Multiplicity adjustment was based on the combination of sequential testing, the fallback procedure, and the Hochberg procedure.p-value: <0.000195% CI: [65.7, 76.7]Cochran-Mantel-Haenszel
Secondary
Percent Change From Baseline in Apolipoprotein B (ApoB) at Week 24
Least squares mean is from the repeated measures model which includes treatment group, statin stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates. (Hepatitis C stratification factor is not included in the model due to low participant numbers.)
Time frame: Baseline, Week 24
Population: Full Analysis Set: randomized participants who received at least 1 dose of investigational product. Participants with an assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Double-Blind Placebo | Percent Change From Baseline in Apolipoprotein B (ApoB) at Week 24 | 2.59 percent change | Standard Error 1.5 |
| Double-Blind Evolocumab | Percent Change From Baseline in Apolipoprotein B (ApoB) at Week 24 | -45.14 percent change | Standard Error 1.13 |
p-value: <0.000195% CI: [-51.11, -44.35]repeated measures linear effects model
Secondary
Percent Change From Baseline in HDL-C at Week 24
Least squares mean is from the repeated measures model which includes treatment group, statin stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates. (Hepatitis C stratification factor is not included in the model due to low participant numbers.)
Time frame: Bseline, Week 24
Population: Full Analysis Set: randomized participants who received at least 1 dose of investigational product. Participants with an assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Double-Blind Placebo | Percent Change From Baseline in HDL-C at Week 24 | 2.73 percent change | Standard Error 1.57 |
| Double-Blind Evolocumab | Percent Change From Baseline in HDL-C at Week 24 | 11.08 percent change | Standard Error 1.2 |
p-value: <0.000195% CI: [4.83, 11.89]repeated measures linear effects model
Secondary
Percent Change From Baseline in Lipoprotein(a) (Lp[a]) at Week 24
Least squares mean is from the repeated measures model which includes treatment group, statin stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates. (Hepatitis C stratification factor is not included in the model due to low participant numbers.)
Time frame: Baseline, Week 24
Population: Full Analysis Set: randomized participants who received at least 1 dose of investigational product. Participants with an assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Double-Blind Placebo | Percent Change From Baseline in Lipoprotein(a) (Lp[a]) at Week 24 | 10.35 percent change | Standard Error 3.34 |
| Double-Blind Evolocumab | Percent Change From Baseline in Lipoprotein(a) (Lp[a]) at Week 24 | -16.44 percent change | Standard Error 2.57 |
p-value: <0.000195% CI: [-34.17, -19.4]repeated measures linear effects model
Secondary
Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol (HDL-C) at Week 24
Least squares mean is from the repeated measures model which includes treatment group, statin stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates. (Hepatitis C stratification factor is not included in the model due to low participant numbers.)
Time frame: Baseline, Week 24
Population: Full Analysis Set: randomized participants who received at least 1 dose of investigational product. Participants with an assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Double-Blind Placebo | Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol (HDL-C) at Week 24 | 2.86 percent change | Standard Error 1.74 |
| Double-Blind Evolocumab | Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol (HDL-C) at Week 24 | -48.07 percent change | Standard Error 1.31 |
p-value: <0.000195% CI: [-54.88, -46.99]repeated measures linear effects model
Secondary
Percent Change From Baseline in Total Cholesterol (TC) at Week 24
Least squares mean is from the repeated measures model which includes treatment group, statin stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates. (Hepatitis C stratification factor is not included in the model due to low participant numbers.)
Time frame: Baseline, Week 24
Population: Full Analysis Set: randomized participants who received at least 1 dose of investigational product. Participants with an assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Double-Blind Placebo | Percent Change From Baseline in Total Cholesterol (TC) at Week 24 | 2.34 percent change | Standard Error 1.4 |
| Double-Blind Evolocumab | Percent Change From Baseline in Total Cholesterol (TC) at Week 24 | -35.78 percent change | Standard Error 1.06 |
p-value: <0.000195% CI: [-41.3, -34.94]repeated measures linear effects model
Secondary
Percent Change From Baseline in Triglycerides at Week 24
Least squares mean is from the repeated measures model which includes treatment group, statin stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates. (Hepatitis C stratification factor is not included in the model due to low participant numbers.)
Time frame: Baseline, Week 24
Population: Full Analysis Set: randomized participants who received at least 1 dose of investigational product. Participants with an assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Double-Blind Placebo | Percent Change From Baseline in Triglycerides at Week 24 | 13.21 percent change | Standard Error 3.8 |
| Double-Blind Evolocumab | Percent Change From Baseline in Triglycerides at Week 24 | -9.25 percent change | Standard Error 2.89 |
p-value: <0.000195% CI: [-31.03, -13.88]repeated measures linear effects model
Secondary
Percent Change From Baseline in Very Low-Density Lipoprotein Cholesterol (VLDL-C) at Week 24
Least squares mean is from the repeated measures model which includes treatment group, statin stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates. (Hepatitis C stratification factor is not included in the model due to low participant numbers.)
Time frame: Baseline, Week 24
Population: Full Analysis Set: randomized participants who received at least 1 dose of investigational product. Participants with an assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Double-Blind Placebo | Percent Change From Baseline in Very Low-Density Lipoprotein Cholesterol (VLDL-C) at Week 24 | 12.34 percent change | Standard Error 3.54 |
| Double-Blind Evolocumab | Percent Change From Baseline in Very Low-Density Lipoprotein Cholesterol (VLDL-C) at Week 24 | -9.81 percent change | Standard Error 2.65 |
p-value: <0.000195% CI: [-30.04, -14.26]repeated measures linear effects model