Hypercholesterolemia
Conditions
Brief summary
The primary objective of the study is to assess the pharmacodynamic (PD) effect of alirocumab on serum low density lipoprotein cholesterol (LDL-C) during 14 weeks of subcutaneous (SC) administered alirocumab in patients with autosomal dominant hypercholesterolemia (ADH) and gain-of-function mutation (GOFm) in 1 or both alleles of the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene or with loss-of-function mutation (LOFm) in 1 or more alleles of the apolipoprotein (ApoB) gene.
Interventions
DRUGAlirocumab
SC injection in the abdomen
DRUGPlacebo
SC injection in the abdomen
Sponsors
Sanofi
Regeneron Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
Inclusion criteria include, but are not limited to the following: 1. Between the ages of 18 and 70 years, inclusive 2. A history of molecularly confirmed PCSK9 GOFm for cohort 1 and a history of molecularly confirmed PCSK9 GOFm or ApoB LOFm 3. Plasma LDL-Cholesterol levels ≥70 mg/dL at the screening visit on a lipid-lowering therapy (LLT) regimen stable for at least 28 days
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Measured Serum Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 15 | Baseline to Day 15 | By day 15, participants in groups A and C had received 1 subcutaneous (SC) dose of 150 mg alirocumab and participants in group B and D had received 1 SC dose of placebo. \[Baseline adjusted least squares (LS) means and standard errors were obtained using analysis of covariance (ANCOVA) model specifying the treatment arm as the fixed effect and the baseline measured LDL-C value as a covariate.\] |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Apolipoprotein (Apo) B100 From Baseline to Day 15 | Baseline to Day 15 | Baseline adjusted LS means and standard errors were obtained using the same ANCOVA model as for primary endpoint specifying the treatment arm as the fixed effect and the parameter value as a covariate. |
| Percent Change in Non High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Day 15 | Baseline to Day 15 | — |
| Percent Change in Total Cholesterol (Total-C) From Baseline to Day 15 | Baseline to Day 15 | — |
| Percent Change in Apolipoprotein (Apo) B100/ ApoA-1 Ratio From Baseline to Day 15 | Baseline to Day 15 | — |
Countries
France, United States
Participant flow
Recruitment details
This study was conducted at 4 sites, 3 in France & 1 in the United States. Twenty-eight participants were screened between Feb 2012 & Apr 2013. A total of 23 participants were enrolled: 13 in cohort 1 & 10 in cohort 2. Recruitment for cohort 2 occurred after the un-blinding of cohort 1 & analyses of the double-blind study data for cohort 1.
Pre-assignment details
Eligible participants entered a 2-wk, single-blind, placebo run-in period. Participants in cohort 1 were randomized in a 1:1 ratio (group A or B); Participants in cohort 2 were also randomized in a 1:1 ratio (group C or D).
Participants by arm
| Arm | Count |
|---|---|
| PCSK9 GOFm: Alirocumab From Day 1 (Cohort 1: Group A) Participants with a gain-of-function mutation (GOFm) in the PCSK9 gene (Cohort 1: Group A) received 150 mg alirocumab subcutaneously (SC) on days 1, 15, 29, 43, and 71 and matching placebo SC on days 57, 85, and 99 during the double-blind period. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years. | 6 |
| PCSK9 GOFm: Alirocumab From Day 15 (Cohort 1: Group B) Participants with a GOFm in PCSK9 gene (Cohort 1: Group B) received 150 mg alirocumab SC on days 15, 29, 43, 57, and 85 and matching placebo SC on days 1, 71, and 99 during the double-blind period. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years. | 7 |
| PCSK9 GOFm/ApoB LOFm: Alirocumab From Day1 (Cohort 2: Group C) Participants with a GOFm in the PCSK9 gene or a LOFm in the Apo B gene (Cohort 2: Group C) received 150 mg alirocumab SC on days 1, 15, 29, 43, and 71 and matching placebo SC on days 57, 85, and 99. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years. | 5 |
| PCSK9GOFm/ApoB LOFm: Alirocumab From Day 15(Cohort 2: Group D) Participants with a GOFm in PCSK9 gene or LOFm in Apo B gene (Cohort 2: Group D) received 150 mg alirocumab SC on days 15, 29, 43, 57, and 85 and matching placebo SC on days 1, 71, and 99 during the double-blind period. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years. | 5 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Open-label Extension (OLE) Period | Chose not to enter OLE Period | 0 | 0 | 0 | 0 | 2 | 0 |
| Open-label Extension (OLE) Period | Refused to come into office | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | PCSK9 GOFm: Alirocumab From Day 15 (Cohort 1: Group B) | Total | PCSK9 GOFm: Alirocumab From Day 1 (Cohort 1: Group A) | PCSK9GOFm/ApoB LOFm: Alirocumab From Day 15(Cohort 2: Group D) | PCSK9 GOFm/ApoB LOFm: Alirocumab From Day1 (Cohort 2: Group C) |
|---|---|---|---|---|---|
| Age, Continuous | 46.4 years STANDARD_DEVIATION 13.24 | 44.2 years STANDARD_DEVIATION 11.15 | 42.3 years STANDARD_DEVIATION 14.72 | 42.0 years STANDARD_DEVIATION 10.84 | 45.6 years STANDARD_DEVIATION 3.21 |
| Age, Customized 85 years and over | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Adolescents (12-17 years) | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Adults (18-64 years) | 7 Participants | 23 Participants | 6 Participants | 5 Participants | 5 Participants |
| Age, Customized Children (2-11 years) | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized From 65-84 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Infants and toddlers (28 days-23 months) | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized In utero | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Newborns (0-27 days) | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Preterm newborn infants (gestational age < 37 wks) | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Apolipoprotein (Apo) A1 | 131.4 mg/dL STANDARD_DEVIATION 30.02 | 142.7 mg/dL STANDARD_DEVIATION 25.65 | 136.3 mg/dL STANDARD_DEVIATION 29.75 | 154.8 mg/dL STANDARD_DEVIATION 20.36 | 154.0 mg/dL STANDARD_DEVIATION 10.98 |
| Apolipoprotein (Apo) B100 | 101.0 mg/dL STANDARD_DEVIATION 15.77 | 104.7 mg/dL STANDARD_DEVIATION 37.38 | 89.2 mg/dL STANDARD_DEVIATION 27.29 | 103.6 mg/dL STANDARD_DEVIATION 42.83 | 129.4 mg/dL STANDARD_DEVIATION 58.27 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 23 Participants | 6 Participants | 5 Participants | 5 Participants |
| Measured Low-Density Lipoprotein Cholesterol (LDL-C) | 144.3 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 68.39 | 145.9 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 72.82 | 108.8 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 33.84 | 151.0 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 82.7 | 187.4 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 98.12 |
| Non-high-density lipoprotein cholesterol (Non-HDL-C) | 165.9 mg/dL STANDARD_DEVIATION 75.59 | 159.6 mg/dL STANDARD_DEVIATION 74.97 | 124.3 mg/dL STANDARD_DEVIATION 49 | 163.4 mg/dL STANDARD_DEVIATION 86.88 | 189.4 mg/dL STANDARD_DEVIATION 93.43 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Other: Indian Ocean Islander | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Other: Mauritius | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 21 Participants | 5 Participants | 5 Participants | 5 Participants |
| Sex: Female, Male Female | 5 Participants | 15 Participants | 4 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 2 Participants | 8 Participants | 2 Participants | 3 Participants | 1 Participants |
| Total Cholesterol | 216.3 mg/dL STANDARD_DEVIATION 78.61 | 216.6 mg/dL STANDARD_DEVIATION 71.84 | 181.3 mg/dL STANDARD_DEVIATION 41.89 | 226.0 mg/dL STANDARD_DEVIATION 77.8 | 249.8 mg/dL STANDARD_DEVIATION 86.68 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 7 | 0 / 5 | 0 / 5 | 0 / 11 | 0 / 10 |
| other Total, other adverse events | 6 / 6 | 6 / 7 | 5 / 5 | 4 / 5 | 10 / 11 | 9 / 10 |
| serious Total, serious adverse events | 1 / 6 | 0 / 7 | 0 / 5 | 0 / 5 | 3 / 11 | 0 / 10 |
Outcome results
Primary
Percent Change in Measured Serum Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 15
By day 15, participants in groups A and C had received 1 subcutaneous (SC) dose of 150 mg alirocumab and participants in group B and D had received 1 SC dose of placebo. \[Baseline adjusted least squares (LS) means and standard errors were obtained using analysis of covariance (ANCOVA) model specifying the treatment arm as the fixed effect and the baseline measured LDL-C value as a covariate.\]
Time frame: Baseline to Day 15
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| PCSK9 GOFm: Alirocumab From Day 1 (Cohort 1: Group A) | Percent Change in Measured Serum Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 15 | -62.48 percent change | Standard Error 8.217 |
| PCSK9 GOFm: Alirocumab From Day 15 (Cohort 1: Group B) | Percent Change in Measured Serum Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 15 | -8.77 percent change | Standard Error 7.575 |
| PCSK9 GOFm/ApoB LOFm: Alirocumab From Day1 (Cohort 2: Group C) | Percent Change in Measured Serum Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 15 | -48.21 percent change | Standard Error 7.66 |
| PCSK9GOFm/ApoB LOFm: Alirocumab From Day 15(Cohort 2: Group D) | Percent Change in Measured Serum Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 15 | -4.93 percent change | Standard Error 7.66 |
p-value: =0.000995% CI: [-79.31, -28.12]ANCOVA
p-value: =0.005695% CI: [-69.21, 17.35]ANCOVA
Secondary
Percent Change in Apolipoprotein (Apo) B100/ ApoA-1 Ratio From Baseline to Day 15
Time frame: Baseline to Day 15
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| PCSK9 GOFm: Alirocumab From Day 1 (Cohort 1: Group A) | Percent Change in Apolipoprotein (Apo) B100/ ApoA-1 Ratio From Baseline to Day 15 | -55.26 percent change | Standard Error 7.188 |
| PCSK9 GOFm: Alirocumab From Day 15 (Cohort 1: Group B) | Percent Change in Apolipoprotein (Apo) B100/ ApoA-1 Ratio From Baseline to Day 15 | -5.53 percent change | Standard Error 6.647 |
| PCSK9 GOFm/ApoB LOFm: Alirocumab From Day1 (Cohort 2: Group C) | Percent Change in Apolipoprotein (Apo) B100/ ApoA-1 Ratio From Baseline to Day 15 | -48.34 percent change | Standard Error 8.09 |
| PCSK9GOFm/ApoB LOFm: Alirocumab From Day 15(Cohort 2: Group D) | Percent Change in Apolipoprotein (Apo) B100/ ApoA-1 Ratio From Baseline to Day 15 | 0.99 percent change | Standard Error 8.09 |
p-value: =0.000595% CI: [-71.71, -27.74]ANCOVA
p-value: =0.003795% CI: [-76.63, -22.03]ANCOVA
Secondary
Percent Change in Apolipoprotein (Apo) B100 From Baseline to Day 15
Baseline adjusted LS means and standard errors were obtained using the same ANCOVA model as for primary endpoint specifying the treatment arm as the fixed effect and the parameter value as a covariate.
Time frame: Baseline to Day 15
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| PCSK9 GOFm: Alirocumab From Day 1 (Cohort 1: Group A) | Percent Change in Apolipoprotein (Apo) B100 From Baseline to Day 15 | -53.33 percent change | Standard Error 8.678 |
| PCSK9 GOFm: Alirocumab From Day 15 (Cohort 1: Group B) | Percent Change in Apolipoprotein (Apo) B100 From Baseline to Day 15 | -3.78 percent change | Standard Error 8.008 |
| PCSK9 GOFm/ApoB LOFm: Alirocumab From Day1 (Cohort 2: Group C) | Percent Change in Apolipoprotein (Apo) B100 From Baseline to Day 15 | -47.73 percent change | Standard Error 7.547 |
| PCSK9GOFm/ApoB LOFm: Alirocumab From Day 15(Cohort 2: Group D) | Percent Change in Apolipoprotein (Apo) B100 From Baseline to Day 15 | -3.09 percent change | Standard Error 7.547 |
Comparison: LS means (SE), mean difference, 95% CI, and p-values were derived from ANCOVA with treatment group as factor and baseline as covariate.p-value: =0.002195% CI: [-76.39, -22.7]ANCOVA
Comparison: LS means (SE), mean difference, 95% CI, and p-values were derived from ANCOVA with treatment group as factor and baseline as covariate.p-value: =0.004595% CI: [-70.36, 18.92]ANCOVA
Secondary
Percent Change in Non High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Day 15
Time frame: Baseline to Day 15
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| PCSK9 GOFm: Alirocumab From Day 1 (Cohort 1: Group A) | Percent Change in Non High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Day 15 | -56.87 percent change | Standard Error 8.217 |
| PCSK9 GOFm: Alirocumab From Day 15 (Cohort 1: Group B) | Percent Change in Non High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Day 15 | -7.50 percent change | Standard Error 7.575 |
| PCSK9 GOFm/ApoB LOFm: Alirocumab From Day1 (Cohort 2: Group C) | Percent Change in Non High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Day 15 | -44.40 percent change | Standard Error 7.357 |
| PCSK9GOFm/ApoB LOFm: Alirocumab From Day 15(Cohort 2: Group D) | Percent Change in Non High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Day 15 | -4.04 percent change | Standard Error 7.357 |
p-value: =0.001695% CI: [-74.96, -23.77]ANCOVA
p-value: =0.006395% CI: [-65.12, 15.6]ANCOVA
Secondary
Percent Change in Total Cholesterol (Total-C) From Baseline to Day 15
Time frame: Baseline to Day 15
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| PCSK9 GOFm: Alirocumab From Day 1 (Cohort 1: Group A) | Percent Change in Total Cholesterol (Total-C) From Baseline to Day 15 | -36.94 percent change | Standard Error 5.203 |
| PCSK9 GOFm: Alirocumab From Day 15 (Cohort 1: Group B) | Percent Change in Total Cholesterol (Total-C) From Baseline to Day 15 | -6.18 percent change | Standard Error 4.802 |
| PCSK9 GOFm/ApoB LOFm: Alirocumab From Day1 (Cohort 2: Group C) | Percent Change in Total Cholesterol (Total-C) From Baseline to Day 15 | -29.40 percent change | Standard Error 4.422 |
| PCSK9GOFm/ApoB LOFm: Alirocumab From Day 15(Cohort 2: Group D) | Percent Change in Total Cholesterol (Total-C) From Baseline to Day 15 | -7.18 percent change | Standard Error 4.422 |
p-value: =0.001795% CI: [-46.85, -14.66]ANCOVA
p-value: =0.009695% CI: [-37.11, -7.34]ANCOVA