Hypercholesterolemia
Conditions
Keywords
LDL-C Apheresis, Hypercholesterolemia, Elevated Cholesterol, High Cholesterol, PCSK9 mutations, Severe Familial Hypercholesterolemia, evolocumab, Repatha
Brief summary
To evaluate the efficacy of subcutaneous (SC) evolocumab, compared to regularly scheduled low-density lipoprotein cholesterol (LDL-C) apheresis, on reducing the need for future apheresis.
Interventions
BIOLOGICALEvolocumab
Administered by subcutaneous injection once every 2 weeks
PROCEDURELow-density Lipoprotein Cholesterol (LDL-C) Apheresis
Participants received apheresis for LDL-C according the their physician's prescription and local custom.
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female, ≥ 18 years of age * Subject has been receiving regular apheresis for LDL-C lowering for at least 3 months immediately prior to lipid screening and has a treatment goal of LDL-C \< 100 mg/dL (2.6 mmol/L), and has been receiving LDL-C apheresis during the last ≥ 4 weeks prior to lipid screening at regular QW or Q2W schedule and with no changes in apheresis type * Subject is receiving lipid-lowering pharmacological background therapy which includes a high-intensity statin dose (moderate-intensity statin dose with attestation that a higher dose is not appropriate for the subject) unless the subject has a history of statin intolerance * Lipid-lowering therapy status (ie, any therapy for lowering lipids, including apheresis type and frequency) must be unchanged for ≥ 4 weeks prior to LDL-C screening * Pre-apheresis LDL-C is ≥ 100 mg/dL (≥ 2.6 mmol/L) and ≤ 190 mg/dL (≤ 4.9 mmol/L) at screening * Fasting triglycerides ≤ 400 mg/dL (4.5 mmol/L) at screening.
Exclusion criteria
* Known homozygous familial hypercholesterolemia * Missing any apheresis session is medically contraindicated or inappropriate * Stopping apheresis would be inappropriate in the opinion of the investigator even if LDL-C is controlled to \< 100 mg/dL with other therapies * Myocardial infarction, unstable angina, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) or stroke within 3 months prior to randomization. * Uncontrolled hypertension
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Apheresis Avoidance at the End of Randomized Therapy | Week 5 and week 6 | Avoidance of apheresis at end of randomized therapy was defined as no apheresis at week 5 and week 6. Aperesis at weeks 5 or 6 was based on LDL-C level at week 4: participants with LDL-C ≥ 100 mg/dL at week 4 received apheresis at week 5 (participants who received apheresis QW before study entry) or week 6 (participants who received apheresis Q2W prior to study entry). If LDL-C was \< 100 mg/dL at week 4, no apheresis was performed at week 5 or week 6, irrespective of assigned treatment group. Participants who ended the study prior to week 6 were considered as not achieving apheresis avoidance. |
Secondary
| Measure | Time frame |
|---|---|
| Percent Change From Baseline in Low-density Lipoprotein Cholesterol | Baseline and week 4 |
| Percent Change From Baseline in Non-high-density Lipoprotein-Cholesterol | Baseline and Week 4 |
| Percent Change From Baseline in Total Cholesterol/High-density Lipoprotein Cholesterol Ratio | Baseline and Week 4 |
Countries
Australia, Czechia, France, Germany, Italy, Spain, United Kingdom, United States
Participant flow
Recruitment details
This study was conducted at 15 centers in the following 8 countries: Australia, Czech Republic, France, Germany, Italy, Spain, the United Kingdom, and the United States. Participants were enrolled from 21 December 2015 to 21 July 2016.
Pre-assignment details
Participants were randomized in a 1:1 ratio to continue apheresis on the same schedule as before study entry, or to stop apheresis and receive evolocumab. Randomization was stratified by screening low-density lipoprotein cholesterol (LDL-C) (\< 160 mg/dL \[4.1 mmol/L\] vs ≥ 160 mg/dL).
Participants by arm
| Arm | Count |
|---|---|
| Apheresis Participants continued apheresis at the same schedule, every week (QW) or every two weeks (Q2W), as prior to study entry, for the first 6 weeks. Starting at week 6 (beginning of the post-primary period), participants received 140 mg evolocumab Q2W up to week 24. | 20 |
| Evolocumab Participants received 140 mg evolocumab every 2 weeks (Q2W) administered by subcutaneous injection for 6 weeks during the primary period of the study. Starting at week 6 (beginning of the post-primary period), participants received 140 mg evolocumab Q2W up to week 24. | 19 |
| Total | 39 |
Baseline characteristics
| Characteristic | Total | Apheresis | Evolocumab |
|---|---|---|---|
| Age, Continuous | 62.4 years STANDARD_DEVIATION 9.5 | 59.6 years STANDARD_DEVIATION 10 | 65.4 years STANDARD_DEVIATION 8.1 |
| Age, Customized < 65 years | 21 participants | 14 participants | 7 participants |
| Age, Customized ≥ 65 years | 18 participants | 6 participants | 12 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 37 Participants | 20 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| LDL-C Concentration | 151.5 mg/dL STANDARD_DEVIATION 23.3 | 150.6 mg/dL STANDARD_DEVIATION 25.6 | 152.4 mg/dL STANDARD_DEVIATION 21.2 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Black or African American | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized White | 38 participants | 20 participants | 18 participants |
| Sex: Female, Male Female | 16 Participants | 7 Participants | 9 Participants |
| Sex: Female, Male Male | 23 Participants | 13 Participants | 10 Participants |
| Stratification Factor: Screening LDL-C Level < 160 mg/dL | 22 participants | 11 participants | 11 participants |
| Stratification Factor: Screening LDL-C Level ≥ 160 mg/dL | 17 participants | 9 participants | 8 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 4 | 5 / 16 | 10 / 19 | 6 / 20 | 8 / 19 |
| serious Total, serious adverse events | 0 / 4 | 2 / 16 | 0 / 19 | 0 / 20 | 2 / 19 |
Outcome results
Primary
Percentage of Participants With Apheresis Avoidance at the End of Randomized Therapy
Avoidance of apheresis at end of randomized therapy was defined as no apheresis at week 5 and week 6. Aperesis at weeks 5 or 6 was based on LDL-C level at week 4: participants with LDL-C ≥ 100 mg/dL at week 4 received apheresis at week 5 (participants who received apheresis QW before study entry) or week 6 (participants who received apheresis Q2W prior to study entry). If LDL-C was \< 100 mg/dL at week 4, no apheresis was performed at week 5 or week 6, irrespective of assigned treatment group. Participants who ended the study prior to week 6 were considered as not achieving apheresis avoidance.
Time frame: Week 5 and week 6
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Apheresis | Percentage of Participants With Apheresis Avoidance at the End of Randomized Therapy | 10.0 percentage of participants |
| Evolocumab | Percentage of Participants With Apheresis Avoidance at the End of Randomized Therapy | 84.2 percentage of participants |
p-value: <0.000195% CI: [44.6, 86.8]Cochran-Mantel-Haenszel
Secondary
Percent Change From Baseline in Low-density Lipoprotein Cholesterol
Time frame: Baseline and week 4
Population: Randomized participants with non-missing data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Apheresis | Percent Change From Baseline in Low-density Lipoprotein Cholesterol | 2.61 percent change | Standard Error 3.97 |
| Evolocumab | Percent Change From Baseline in Low-density Lipoprotein Cholesterol | -50.13 percent change | Standard Error 4.03 |
p-value: <0.000195% CI: [-64.18, -41.3]Repeated measures linear effects model
Secondary
Percent Change From Baseline in Non-high-density Lipoprotein-Cholesterol
Time frame: Baseline and Week 4
Population: Randomized participants with non-missing data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Apheresis | Percent Change From Baseline in Non-high-density Lipoprotein-Cholesterol | 1.80 percent change | Standard Error 3.29 |
| Evolocumab | Percent Change From Baseline in Non-high-density Lipoprotein-Cholesterol | -44.58 percent change | Standard Error 3.34 |
p-value: <0.000195% CI: [-55.85, -36.9]Repeated measures linear effects model
Secondary
Percent Change From Baseline in Total Cholesterol/High-density Lipoprotein Cholesterol Ratio
Time frame: Baseline and Week 4
Population: Randomized participants with non-missing data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Apheresis | Percent Change From Baseline in Total Cholesterol/High-density Lipoprotein Cholesterol Ratio | 0.15 percent change | Standard Error 2.65 |
| Evolocumab | Percent Change From Baseline in Total Cholesterol/High-density Lipoprotein Cholesterol Ratio | -35.65 percent change | Standard Error 2.67 |
p-value: <0.000195% CI: [-43.39, -28.21]Repeated measures linear effects model