Hypercholesterolemia
Conditions
Keywords
10020603
Brief summary
Primary Objective: To evaluate the effect of alirocumab (SAR236553/REGN727) on low-density lipoprotein cholesterol (LDL-C) levels compared with placebo when co-administered with 80 mg of atorvastatin after 8 weeks of treatment in participants with LDL-C ≥ 100mg/dL (≥ 2.59 mmol/L) on atorvastatin 10 mg. Secondary Objectives: * To evaluate the effects of alirocumab on other lipid levels in comparison with placebo, when co-administered with 80 mg of atorvastatin after 8 weeks of treatment. * To evaluate the efficacy of alirocumab when co-administered with a high dose of atorvastatin (80 mg) versus atorvastatin 10 mg. * To evaluate the safety and tolerability of alirocumab when co-administered with 2 different doses of atorvastatin. * To evaluate the development of anti-alirocumab antibodies. * To evaluate the pharmacokinetics of alirocumab.
Detailed description
The duration of study participation depended on the status of the patient at screening: * For participants receiving atorvastatin 10 mg at stable dose for at least 6 weeks prior to screening, the study participation was to be approximately 17 weeks including a screening period of 1 week, a double-blind treatment period of 8 weeks and a follow-up period of 8 weeks. * For participants receiving a lipid lowering treatment other than atorvastatin/ or not at stable dose of atorvastatin 10 mg for at least 6 weeks prior to screening, or drug naive participants, the study participation was to be approximately 23 weeks with a screening period of 1 week, a run-in treatment period with atorvastatin 10 mg of 6 weeks, a double-blind treatment period of 8 weeks and a follow-up period of 8 weeks.
Interventions
DRUGAlirocumab
One subcutaneous (SC) injection in the abdomen only.
One SC injection in the abdomen only.
DRUGAtorvastatin
Over-encapsulated tablet orally once daily in the evening with dinner.
One over-encapsulated tablet of placebo for atorvastatin orally once daily in the evening with dinner.
Sponsors
Regeneron Pharmaceuticals
Sanofi
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 75 Years
Healthy volunteers
No
Inclusion criteria
\- Participants receiving a lipid-lowering treatment other than atorvastatin/ or not at stable dose of atorvastatin 10 mg for at least 6 weeks prior to screening, or drug naive participants with primary hypercholesterolemia if they are likely to have low-density lipoprotein cholesterol (LDL-C) ≥ 100 mg/dL (≥ 2.59 mmol/L) at the end of the 6-week run-in treatment period on atorvastatin therapy OR \- Participants with primary hypercholesterolemia treated with stable dose of atorvastatin 10 mg for at least 6 weeks prior to screening and likely to have low-density lipoprotein cholesterol (LDL-C) ≥ 100 mg/dL (≥ 2.59 mmol/L) at the screening visit.
Exclusion criteria
1. LDL-C \< 100 mg/dL (\< 2.59 mmol/L) at Week -1 (V1): * After the run-in period on atorvastatin 10 mg for participants receiving a lipid lowering treatment other than atorvastatin/ or not at stable dose of atorvastatin 10 mg for at least 6 weeks prior to the screening period, or drug naive participants. OR * At the first visit for participants who are being treated with atorvastatin 10 mg at stable dose for at least 6 weeks prior to screening visit. 2. Participants not previously instructed on a cholesterol-lowering diet. 3. Participants with type 1 diabetes. 4. Participants with type 2 diabetes treated with insulin. 5. Participants with type 2 diabetes and with an HbA1c ≥ 8.5% at screening visit (considered poorly controlled). 6. Laboratory findings measured before randomization: * Triglycerides (TG) \> 350 mg/dL (\> 3.95 mmol/L) at screening visit. * Positive serum or urine pregnancy test in females of childbearing potential. 7. Pregnant or breast-feeding women. 8. Women of childbearing potential with no effective contraceptive method. The above information is not intended to contain all considerations relevant to a Participant's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Calculated LDL-C at Week 8 - On-treatment Analysis | From Baseline to Week 8 (LOCF) | Calculated LDL-C values were obtained using the Friedewald formula. Baseline adjusted least squares (LS) means and standard errors were estimated using an analysis of covariance (ANCOVA) model including available post-baseline data on treatment from first investigational product (IP) injection up to 21 days after last IP injection (on-treatment analysis). Missing Week 8 data were imputed by last observation carried forward \[LOCF\] method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Baseline in Calculated LDL-C (mg/dL) at Week 8 - On-treatment Analysis | From baseline to Week 8 (LOCF) | Adjusted LS means and standard errors were estimated using the same ANCOVA model as for primary endpoint. |
| Percentage of Participants Achieving Calculated LDL-C <100 mg/dL (2.59 mmol/L) and < 70 mg/dL (1.81 mmol/L) at Week 8 - On-treatment Analysis | Week 8 (LOCF) | — |
| Absolute Change From Baseline in Calculated LDL-C (mmol/L) at Week 8 - On-treatment Analysis | From baseline to Week 8 (LOCF) | Adjusted LS means and standard errors were estimated using the same ANCOVA model as for primary endpoint. |
| Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Week 8 - On-treatment Analysis | From Baseline to Week 8 (LOCF) | Adjusted LS means and standard errors were estimated using the same ANCOVA model as for primary endpoint. |
| Absolute Change in the Ratio Apolipoprotein B/Apolipoprotein A-1 (ApoB/ApoA-1) From Baseline to Week 8 - On-treatment Analysis | From Baseline to Week 8 (LOCF) | Adjusted LS means and standard errors were estimated using the same ANCOVA as for primary endpoint. |
| Percent Change From Baseline in Total Cholesterol, Fasting Triglycerides, Non-high-Density Lipoprotein Cholesterol (Non-HDL-C), Apolipoprotein B (Apo-B) and Lipoprotein(a) at Week 8 - On-treatment Analysis | From baseline to Week 8 (LOCF) | Since the assumptions of normal distribution and equality of variances were not verified for the lipid parameters, percent changes were expressed as median (interquartile range). |
Countries
United States
Participant flow
Recruitment details
The study was conducted at 20 centers in the United States of America. Overall, 214 participants were screened between January 2011 and April 2011. Screen failures were mainly due to exclusion criteria met.
Pre-assignment details
Assignment to treatment arms was done centrally using an Interactive Voice/Web Response System in a 1:1:1 ratio after confirmation of selection criteria. 92 participants were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Placebo + Atorvastatin 80 mg Placebo (for alirocumab) SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks. | 31 |
| Alirocumab + Atorvastatin 10 mg Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 10 mg orally once daily for 8 weeks. | 31 |
| Alirocumab + Atorvastatin 80 mg Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks. | 30 |
| Total | 92 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 1 | 1 |
| Overall Study | Consent withdrawn by subject | 1 | 1 | 1 |
| Overall Study | Exclusion criteria finally met | 1 | 0 | 0 |
| Overall Study | Participant Moved | 1 | 0 | 0 |
| Overall Study | Poor compliance to protocol | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo + Atorvastatin 80 mg | Alirocumab + Atorvastatin 10 mg | Alirocumab + Atorvastatin 80 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 55.3 years STANDARD_DEVIATION 10.3 | 57.9 years STANDARD_DEVIATION 10 | 57.6 years STANDARD_DEVIATION 9.3 | 56.9 years STANDARD_DEVIATION 9.8 |
| LDL-C in mg/dL | 121.2 mg/dL STANDARD_DEVIATION 18.1 | 119.7 mg/dL STANDARD_DEVIATION 15.5 | 126.9 mg/dL STANDARD_DEVIATION 21.8 | 122.6 mg/dL STANDARD_DEVIATION 18.7 |
| Low-Density Lipoprotein Cholesterol (LDL-C) in mmol/L | 3.138 mmol/L STANDARD_DEVIATION 0.469 | 3.101 mmol/L STANDARD_DEVIATION 0.402 | 3.288 mmol/L STANDARD_DEVIATION 0.564 | 3.174 mmol/L STANDARD_DEVIATION 0.484 |
| Sex: Female, Male Female | 18 Participants | 17 Participants | 20 Participants | 55 Participants |
| Sex: Female, Male Male | 13 Participants | 14 Participants | 10 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 13 / 31 | 4 / 31 | 10 / 30 |
| serious Total, serious adverse events | 0 / 31 | 0 / 31 | 1 / 30 |
Outcome results
Primary
Percent Change From Baseline in Calculated LDL-C at Week 8 - On-treatment Analysis
Calculated LDL-C values were obtained using the Friedewald formula. Baseline adjusted least squares (LS) means and standard errors were estimated using an analysis of covariance (ANCOVA) model including available post-baseline data on treatment from first investigational product (IP) injection up to 21 days after last IP injection (on-treatment analysis). Missing Week 8 data were imputed by last observation carried forward \[LOCF\] method.
Time frame: From Baseline to Week 8 (LOCF)
Population: Modified Intent-To-Treat (mITT) population: all randomized and treated participants with one baseline and at least one post-baseline calculated LDL-C value on-treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Atorvastatin 80 mg | Percent Change From Baseline in Calculated LDL-C at Week 8 - On-treatment Analysis | -17.3 percent change | Standard Error 3.5 |
| Alirocumab + Atorvastatin 10 mg | Percent Change From Baseline in Calculated LDL-C at Week 8 - On-treatment Analysis | -66.2 percent change | Standard Error 3.5 |
| Alirocumab + Atorvastatin 80 mg | Percent Change From Baseline in Calculated LDL-C at Week 8 - On-treatment Analysis | -73.2 percent change | Standard Error 3.5 |
Comparison: Throughout the ANCOVA model, the Alirocumab + atorvastatin 80 mg group was compared to the placebo + atorvastatin 80 mg group using appropriate contrast and the 95% confidence interval (CI) of the difference was provided.p-value: <0.000195% CI: [-65.62, -46.03]ANCOVA
Secondary
Absolute Change From Baseline in Calculated LDL-C (mg/dL) at Week 8 - On-treatment Analysis
Adjusted LS means and standard errors were estimated using the same ANCOVA model as for primary endpoint.
Time frame: From baseline to Week 8 (LOCF)
Population: mITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Atorvastatin 80 mg | Absolute Change From Baseline in Calculated LDL-C (mg/dL) at Week 8 - On-treatment Analysis | -21.5 mg/dL | Standard Error 4.2 |
| Alirocumab + Atorvastatin 10 mg | Absolute Change From Baseline in Calculated LDL-C (mg/dL) at Week 8 - On-treatment Analysis | -80.7 mg/dL | Standard Error 4.2 |
| Alirocumab + Atorvastatin 80 mg | Absolute Change From Baseline in Calculated LDL-C (mg/dL) at Week 8 - On-treatment Analysis | -89.3 mg/dL | Standard Error 4.1 |
Secondary
Absolute Change From Baseline in Calculated LDL-C (mmol/L) at Week 8 - On-treatment Analysis
Adjusted LS means and standard errors were estimated using the same ANCOVA model as for primary endpoint.
Time frame: From baseline to Week 8 (LOCF)
Population: mITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Atorvastatin 80 mg | Absolute Change From Baseline in Calculated LDL-C (mmol/L) at Week 8 - On-treatment Analysis | -0.56 mmol/L | Standard Error 0.11 |
| Alirocumab + Atorvastatin 10 mg | Absolute Change From Baseline in Calculated LDL-C (mmol/L) at Week 8 - On-treatment Analysis | -2.09 mmol/L | Standard Error 0.11 |
| Alirocumab + Atorvastatin 80 mg | Absolute Change From Baseline in Calculated LDL-C (mmol/L) at Week 8 - On-treatment Analysis | -2.31 mmol/L | Standard Error 0.11 |
Secondary
Absolute Change in the Ratio Apolipoprotein B/Apolipoprotein A-1 (ApoB/ApoA-1) From Baseline to Week 8 - On-treatment Analysis
Adjusted LS means and standard errors were estimated using the same ANCOVA as for primary endpoint.
Time frame: From Baseline to Week 8 (LOCF)
Population: Participants of the mITT population with one baseline and at least one post-baseline on treatment value for lipid parameter analyzed
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Atorvastatin 80 mg | Absolute Change in the Ratio Apolipoprotein B/Apolipoprotein A-1 (ApoB/ApoA-1) From Baseline to Week 8 - On-treatment Analysis | -0.03 ratio |
| Alirocumab + Atorvastatin 10 mg | Absolute Change in the Ratio Apolipoprotein B/Apolipoprotein A-1 (ApoB/ApoA-1) From Baseline to Week 8 - On-treatment Analysis | -0.34 ratio |
| Alirocumab + Atorvastatin 80 mg | Absolute Change in the Ratio Apolipoprotein B/Apolipoprotein A-1 (ApoB/ApoA-1) From Baseline to Week 8 - On-treatment Analysis | -0.36 ratio |
Secondary
Percentage of Participants Achieving Calculated LDL-C <100 mg/dL (2.59 mmol/L) and < 70 mg/dL (1.81 mmol/L) at Week 8 - On-treatment Analysis
Time frame: Week 8 (LOCF)
Population: mITT population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo + Atorvastatin 80 mg | Percentage of Participants Achieving Calculated LDL-C <100 mg/dL (2.59 mmol/L) and < 70 mg/dL (1.81 mmol/L) at Week 8 - On-treatment Analysis | LDL-C < 100 mg/dL (2.59 mmol/L) | 51.7 percentage of participants |
| Placebo + Atorvastatin 80 mg | Percentage of Participants Achieving Calculated LDL-C <100 mg/dL (2.59 mmol/L) and < 70 mg/dL (1.81 mmol/L) at Week 8 - On-treatment Analysis | LDL-C < 70 mg/dL (1.81 mmol/L) | 17.2 percentage of participants |
| Alirocumab + Atorvastatin 10 mg | Percentage of Participants Achieving Calculated LDL-C <100 mg/dL (2.59 mmol/L) and < 70 mg/dL (1.81 mmol/L) at Week 8 - On-treatment Analysis | LDL-C < 100 mg/dL (2.59 mmol/L) | 100.0 percentage of participants |
| Alirocumab + Atorvastatin 10 mg | Percentage of Participants Achieving Calculated LDL-C <100 mg/dL (2.59 mmol/L) and < 70 mg/dL (1.81 mmol/L) at Week 8 - On-treatment Analysis | LDL-C < 70 mg/dL (1.81 mmol/L) | 96.6 percentage of participants |
| Alirocumab + Atorvastatin 80 mg | Percentage of Participants Achieving Calculated LDL-C <100 mg/dL (2.59 mmol/L) and < 70 mg/dL (1.81 mmol/L) at Week 8 - On-treatment Analysis | LDL-C < 100 mg/dL (2.59 mmol/L) | 100.0 percentage of participants |
| Alirocumab + Atorvastatin 80 mg | Percentage of Participants Achieving Calculated LDL-C <100 mg/dL (2.59 mmol/L) and < 70 mg/dL (1.81 mmol/L) at Week 8 - On-treatment Analysis | LDL-C < 70 mg/dL (1.81 mmol/L) | 90.0 percentage of participants |
Secondary
Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Week 8 - On-treatment Analysis
Adjusted LS means and standard errors were estimated using the same ANCOVA model as for primary endpoint.
Time frame: From Baseline to Week 8 (LOCF)
Population: Participants of the mITT population with one baseline and at least one post-baseline on treatment HDL-C value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Atorvastatin 80 mg | Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Week 8 - On-treatment Analysis | -3.6 percent change | Standard Error 2.3 |
| Alirocumab + Atorvastatin 10 mg | Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Week 8 - On-treatment Analysis | 2.6 percent change | Standard Error 2.3 |
| Alirocumab + Atorvastatin 80 mg | Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Week 8 - On-treatment Analysis | 5.8 percent change | Standard Error 2.3 |
Secondary
Percent Change From Baseline in Total Cholesterol, Fasting Triglycerides, Non-high-Density Lipoprotein Cholesterol (Non-HDL-C), Apolipoprotein B (Apo-B) and Lipoprotein(a) at Week 8 - On-treatment Analysis
Since the assumptions of normal distribution and equality of variances were not verified for the lipid parameters, percent changes were expressed as median (interquartile range).
Time frame: From baseline to Week 8 (LOCF)
Population: Participants of the mITT population with one baseline and at least one post-baseline on treatment value for lipid parameters analyzed. Here, n signifies number of participants analysed for each lipid parameter.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo + Atorvastatin 80 mg | Percent Change From Baseline in Total Cholesterol, Fasting Triglycerides, Non-high-Density Lipoprotein Cholesterol (Non-HDL-C), Apolipoprotein B (Apo-B) and Lipoprotein(a) at Week 8 - On-treatment Analysis | Lipoprotein(a) (n= 29, 28, 29) | -2.7 percent change |
| Placebo + Atorvastatin 80 mg | Percent Change From Baseline in Total Cholesterol, Fasting Triglycerides, Non-high-Density Lipoprotein Cholesterol (Non-HDL-C), Apolipoprotein B (Apo-B) and Lipoprotein(a) at Week 8 - On-treatment Analysis | Non-HDL-C (n= 29, 29, 30) | -22.3 percent change |
| Placebo + Atorvastatin 80 mg | Percent Change From Baseline in Total Cholesterol, Fasting Triglycerides, Non-high-Density Lipoprotein Cholesterol (Non-HDL-C), Apolipoprotein B (Apo-B) and Lipoprotein(a) at Week 8 - On-treatment Analysis | Fasting Triglycerides (n=29, 29, 30) | -11.9 percent change |
| Placebo + Atorvastatin 80 mg | Percent Change From Baseline in Total Cholesterol, Fasting Triglycerides, Non-high-Density Lipoprotein Cholesterol (Non-HDL-C), Apolipoprotein B (Apo-B) and Lipoprotein(a) at Week 8 - On-treatment Analysis | Apo-B (n = 29, 28, 29) | -12.0 percent change |
| Placebo + Atorvastatin 80 mg | Percent Change From Baseline in Total Cholesterol, Fasting Triglycerides, Non-high-Density Lipoprotein Cholesterol (Non-HDL-C), Apolipoprotein B (Apo-B) and Lipoprotein(a) at Week 8 - On-treatment Analysis | Total Cholesterol (n=29, 29, 30) | -16.6 percent change |
| Alirocumab + Atorvastatin 10 mg | Percent Change From Baseline in Total Cholesterol, Fasting Triglycerides, Non-high-Density Lipoprotein Cholesterol (Non-HDL-C), Apolipoprotein B (Apo-B) and Lipoprotein(a) at Week 8 - On-treatment Analysis | Apo-B (n = 29, 28, 29) | -54.4 percent change |
| Alirocumab + Atorvastatin 10 mg | Percent Change From Baseline in Total Cholesterol, Fasting Triglycerides, Non-high-Density Lipoprotein Cholesterol (Non-HDL-C), Apolipoprotein B (Apo-B) and Lipoprotein(a) at Week 8 - On-treatment Analysis | Lipoprotein(a) (n= 29, 28, 29) | -34.7 percent change |
| Alirocumab + Atorvastatin 10 mg | Percent Change From Baseline in Total Cholesterol, Fasting Triglycerides, Non-high-Density Lipoprotein Cholesterol (Non-HDL-C), Apolipoprotein B (Apo-B) and Lipoprotein(a) at Week 8 - On-treatment Analysis | Total Cholesterol (n=29, 29, 30) | -40.5 percent change |
| Alirocumab + Atorvastatin 10 mg | Percent Change From Baseline in Total Cholesterol, Fasting Triglycerides, Non-high-Density Lipoprotein Cholesterol (Non-HDL-C), Apolipoprotein B (Apo-B) and Lipoprotein(a) at Week 8 - On-treatment Analysis | Fasting Triglycerides (n=29, 29, 30) | -4.0 percent change |
| Alirocumab + Atorvastatin 10 mg | Percent Change From Baseline in Total Cholesterol, Fasting Triglycerides, Non-high-Density Lipoprotein Cholesterol (Non-HDL-C), Apolipoprotein B (Apo-B) and Lipoprotein(a) at Week 8 - On-treatment Analysis | Non-HDL-C (n= 29, 29, 30) | -58.3 percent change |
| Alirocumab + Atorvastatin 80 mg | Percent Change From Baseline in Total Cholesterol, Fasting Triglycerides, Non-high-Density Lipoprotein Cholesterol (Non-HDL-C), Apolipoprotein B (Apo-B) and Lipoprotein(a) at Week 8 - On-treatment Analysis | Total Cholesterol (n=29, 29, 30) | -47.2 percent change |
| Alirocumab + Atorvastatin 80 mg | Percent Change From Baseline in Total Cholesterol, Fasting Triglycerides, Non-high-Density Lipoprotein Cholesterol (Non-HDL-C), Apolipoprotein B (Apo-B) and Lipoprotein(a) at Week 8 - On-treatment Analysis | Apo-B (n = 29, 28, 29) | -58.0 percent change |
| Alirocumab + Atorvastatin 80 mg | Percent Change From Baseline in Total Cholesterol, Fasting Triglycerides, Non-high-Density Lipoprotein Cholesterol (Non-HDL-C), Apolipoprotein B (Apo-B) and Lipoprotein(a) at Week 8 - On-treatment Analysis | Non-HDL-C (n= 29, 29, 30) | -63.9 percent change |
| Alirocumab + Atorvastatin 80 mg | Percent Change From Baseline in Total Cholesterol, Fasting Triglycerides, Non-high-Density Lipoprotein Cholesterol (Non-HDL-C), Apolipoprotein B (Apo-B) and Lipoprotein(a) at Week 8 - On-treatment Analysis | Lipoprotein(a) (n= 29, 28, 29) | -31.0 percent change |
| Alirocumab + Atorvastatin 80 mg | Percent Change From Baseline in Total Cholesterol, Fasting Triglycerides, Non-high-Density Lipoprotein Cholesterol (Non-HDL-C), Apolipoprotein B (Apo-B) and Lipoprotein(a) at Week 8 - On-treatment Analysis | Fasting Triglycerides (n=29, 29, 30) | -24.7 percent change |