Hypercholesterolemia and High Risk for Cardiovascular Events
Conditions
Keywords
Japanese, hypercholesterolemia, high risk for cardiovascular events
Brief summary
The primary objective is to evaluate the effect of 12 weeks of subcutaneous evolocumab every 2 weeks or every 4 weeks, compared with placebo, on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) when used in addition to statin therapy in Japanese adults with hypercholesterolemia and high cardiovascular risk.
Interventions
BIOLOGICALEvolocumab
Administered by subcutaneous injection
OTHERPlacebo
Administered by subcutaneous injection
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Japanese adult, on statin, with or without ezetimibe, with stable dose(s) for at least 4 weeks, fasting LDL-C greater than or equal to 115 mg/dL (3.0 mmol/L), fasting triglycerides less than or equal to 400 mg/dL (4.5 mmol/L);
Exclusion criteria
New York Heart Association (NYHA) class III or IV, poorly controlled hypertension, recently diagnosed or poorly controlled type 2 diabetes, last known left ventricular ejection fraction \< 30%, myocardial infarction, unstable angina, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG), stroke, planned cardiac surgery or revascularization within 6 months of randomization, uncontrolled cardiac arrhythmia.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12 | Baseline and Week 12 | LDL-C was measured using ultracentrifugation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12 | Baseline and Week 12 | LDL-C was measured using ultracentrifugation. |
| Percentage of Participants With an LDL-C Response at Week 12 | Week 12 | An LDL-C response was defined as LDL-C \< 70 mg/dL (1.8 mmol/L) at Week 12. LDL-C was measured using ultracentrifugation. |
| Percent Change From Baseline to Week 12 in Apolipoprotein B | Baseline and Week 12 | — |
| Percent Change From Baseline to Week 12 in Non-HDL-C | Baseline and Week 12 | — |
| Percent Change From Baseline to Week 12 in Total Cholesterol/HDL-C Ratio | Baseline and Week 12 | — |
| Percent Change From Baseline to Week 12 in Apolipoprotein B/Apolipoprotein A-1 Ratio | Baseline and Week 12 | — |
| Percent Change From Baseline to Week 12 in VLDL-C | Baseline and Week 12 | — |
Countries
Japan
Participant flow
Recruitment details
Japanese men or women ≥ 20 to ≤ 80 years of age and who were at high risk for cardiovascular events, on a stable dose of an approved statin (with or without ezetimibe) and fasting low-density lipoprotein cholesterol (LDL-C) ≥ 115 mg/dL. First patient enrolled on 10 July 2012; last patient enrolled 19 February 2013.
Pre-assignment details
Randomization was stratified by screening LDL-C level (\< 130 mg/dL \[3.4 mmol/L\] vs ≥ 130 mg/dL) and by diagnosis of heterozygous familial hypercholesterolemia (HeFH) (yes vs no).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Q2W Participants received placebo subcutaneous injection once every 2 weeks (Q2W) for 12 weeks. | 52 |
| Placebo Q4W Participants received placebo subcutaneous injection once every 4 weeks (Q4W) for 12 weeks. | 50 |
| Evolocumab 70 mg Q2W Participants received 70 mg evolocumab by subcutaneous injection once every 2 weeks for 12 weeks. | 49 |
| Evolocumab 140 mg Q2W Participants received 140 mg evolocumab by subcutaneous injection once every 2 weeks for 12 weeks. | 52 |
| Evolocumab 280 mg Q4W Participants received 280 mg evolocumab by subcutaneous injection once every 4 weeks for 12 weeks. | 51 |
| Evolocumab 420 mg Q4W Participants received 420 mg evolocumab by subcutaneous injection once every 4 weeks for 12 weeks. | 53 |
| Total | 307 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Other | 0 | 0 | 0 | 1 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 3 | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo Q4W | Total | Evolocumab 420 mg Q4W | Evolocumab 280 mg Q4W | Evolocumab 140 mg Q2W | Placebo Q2W | Evolocumab 70 mg Q2W |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 60.9 years STANDARD_DEVIATION 9.8 | 61.5 years STANDARD_DEVIATION 9.7 | 61.3 years STANDARD_DEVIATION 9.9 | 61.6 years STANDARD_DEVIATION 9.6 | 60.8 years STANDARD_DEVIATION 9.2 | 60.2 years STANDARD_DEVIATION 10.1 | 64.1 years STANDARD_DEVIATION 9.7 |
| Apolipoprotein B/Apolipoprotein A-1 Ratio | 0.741 ratio STANDARD_DEVIATION 0.177 | 0.732 ratio STANDARD_DEVIATION 0.162 | 0.714 ratio STANDARD_DEVIATION 0.158 | 0.725 ratio STANDARD_DEVIATION 0.151 | 0.722 ratio STANDARD_DEVIATION 0.163 | 0.750 ratio STANDARD_DEVIATION 0.15 | 0.743 ratio STANDARD_DEVIATION 0.177 |
| Apolipoprotein B Concentration | 112.5 mg/dL STANDARD_DEVIATION 16.6 | 111.5 mg/dL STANDARD_DEVIATION 16.7 | 109.8 mg/dL STANDARD_DEVIATION 15.9 | 109.6 mg/dL STANDARD_DEVIATION 16.9 | 109.4 mg/dL STANDARD_DEVIATION 16 | 114.6 mg/dL STANDARD_DEVIATION 15.4 | 113.1 mg/dL STANDARD_DEVIATION 19.2 |
| LDL-C Concentration | 141.8 mg/dL STANDARD_DEVIATION 23.4 | 141.8 mg/dL STANDARD_DEVIATION 20.9 | 139.7 mg/dL STANDARD_DEVIATION 18.8 | 141.0 mg/dL STANDARD_DEVIATION 21.2 | 140.7 mg/dL STANDARD_DEVIATION 23.3 | 144.4 mg/dL STANDARD_DEVIATION 18.1 | 143.6 mg/dL STANDARD_DEVIATION 20.6 |
| Non-High-Density Lipoprotein Cholesterol (non-HDL-C) Concentration | 168.7 mg/dL STANDARD_DEVIATION 26.1 | 168.2 mg/dL STANDARD_DEVIATION 25 | 166.7 mg/dL STANDARD_DEVIATION 23.5 | 165.5 mg/dL STANDARD_DEVIATION 24.4 | 166.3 mg/dL STANDARD_DEVIATION 26.2 | 171.3 mg/dL STANDARD_DEVIATION 23 | 170.6 mg/dL STANDARD_DEVIATION 27.2 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 50 participants | 307 participants | 53 participants | 51 participants | 52 participants | 52 participants | 49 participants |
| Race/Ethnicity, Customized Black or African American | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized White | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Sex: Female, Male Female | 14 Participants | 114 Participants | 17 Participants | 23 Participants | 20 Participants | 16 Participants | 24 Participants |
| Sex: Female, Male Male | 36 Participants | 193 Participants | 36 Participants | 28 Participants | 32 Participants | 36 Participants | 25 Participants |
| Stratification Factor: Diagnosis of Heterozygous Familial Hypercholesterolemia (HeFH) No | 47 participants | 287 participants | 49 participants | 47 participants | 49 participants | 48 participants | 47 participants |
| Stratification Factor: Diagnosis of Heterozygous Familial Hypercholesterolemia (HeFH) Yes | 3 participants | 20 participants | 4 participants | 4 participants | 3 participants | 4 participants | 2 participants |
| Stratification Factor: LDL Level < 130 mg/dL | 17 participants | 98 participants | 17 participants | 15 participants | 17 participants | 17 participants | 15 participants |
| Stratification Factor: LDL Level ≥ 130 mg/dL | 33 participants | 209 participants | 36 participants | 36 participants | 35 participants | 35 participants | 34 participants |
| Total Cholesterol/HDL-C Ratio | 4.317 ratio STANDARD_DEVIATION 1.075 | 4.300 ratio STANDARD_DEVIATION 1.026 | 4.210 ratio STANDARD_DEVIATION 0.955 | 4.228 ratio STANDARD_DEVIATION 0.993 | 4.302 ratio STANDARD_DEVIATION 1.039 | 4.380 ratio STANDARD_DEVIATION 0.949 | 4.366 ratio STANDARD_DEVIATION 1.177 |
| Very Low-Density Lipoprotein Cholesterol (VLDL-C) Concentration | 27.1 mg/dL STANDARD_DEVIATION 10.7 | 26.4 mg/dL STANDARD_DEVIATION 11.3 | 27.0 mg/dL STANDARD_DEVIATION 12 | 24.6 mg/dL STANDARD_DEVIATION 10.5 | 25.6 mg/dL STANDARD_DEVIATION 10.8 | 26.9 mg/dL STANDARD_DEVIATION 10.5 | 26.9 mg/dL STANDARD_DEVIATION 13.3 |
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 | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 52 | 6 / 50 | 10 / 49 | 9 / 52 | 12 / 51 | 8 / 53 |
| serious Total, serious adverse events | 0 / 52 | 0 / 50 | 0 / 49 | 1 / 52 | 1 / 51 | 2 / 53 |
Outcome results
Primary
Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12
LDL-C was measured using ultracentrifugation.
Time frame: Baseline and Week 12
Population: Full analysis set; missing ultracentrifugation (UC) LDL-C at Week 12 was imputed using last observation carried forward (LOCF) and calculated LDL-C.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12 | -2.71 percent change | Standard Error 2.16 |
| Placebo Q4W | Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12 | 0.05 percent change | Standard Error 2.32 |
| Evolocumab 70 mg Q2W | Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12 | -55.56 percent change | Standard Error 2.23 |
| Evolocumab 140 mg Q2W | Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12 | -71.32 percent change | Standard Error 2.16 |
| Evolocumab 280 mg Q4W | Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12 | -58.10 percent change | Standard Error 2.33 |
| Evolocumab 420 mg Q4W | Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12 | -63.89 percent change | Standard Error 2.27 |
Comparison: The null hypothesis was that there was no mean difference in the percent change from Baseline at Week 12 in LDL-C between evolocumab and placebo, and the alternative hypothesis was that a mean difference did exist.p-value: <0.00195% CI: [-74.51, -62.71]ANCOVA
Comparison: The null hypothesis was that there was no mean difference in the percent change from Baseline at Week 12 in LDL-C between evolocumab and placebo, and the alternative hypothesis was that a mean difference did exist.p-value: <0.00195% CI: [-58.84, -46.86]ANCOVA
Comparison: The null hypothesis was that there was no mean difference in the percent change from Baseline at Week 12 in LDL-C between evolocumab and placebo, and the alternative hypothesis was that a mean difference did exist.p-value: <0.00195% CI: [-70.23, -57.66]ANCOVA
Comparison: The null hypothesis was that there was no mean difference in the percent change from Baseline at Week 12 in LDL-C between evolocumab and placebo, and the alternative hypothesis was that a mean difference did exist.p-value: <0.00195% CI: [-64.51, -51.81]ANCOVA
Secondary
Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12
LDL-C was measured using ultracentrifugation.
Time frame: Baseline and Week 12
Population: Full analysis set; missing data were imputed using LOCF.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12 | -1.8 mg/dL | Standard Error 3.6 |
| Placebo Q4W | Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12 | 0.8 mg/dL | Standard Error 3.4 |
| Evolocumab 70 mg Q2W | Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12 | -77.2 mg/dL | Standard Error 3.7 |
| Evolocumab 140 mg Q2W | Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12 | -98.0 mg/dL | Standard Error 3.6 |
| Evolocumab 280 mg Q4W | Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12 | -79.9 mg/dL | Standard Error 3.4 |
| Evolocumab 420 mg Q4W | Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12 | -87.4 mg/dL | Standard Error 3.3 |
p-value: <0.00195% CI: [-106, -86.5]ANCOVA
p-value: <0.00195% CI: [-85.4, -65.5]ANCOVA
p-value: <0.00195% CI: [-97.4, -79]ANCOVA
p-value: <0.00195% CI: [-90, -71.4]ANCOVA
Secondary
Percentage of Participants With an LDL-C Response at Week 12
An LDL-C response was defined as LDL-C \< 70 mg/dL (1.8 mmol/L) at Week 12. LDL-C was measured using ultracentrifugation.
Time frame: Week 12
Population: Full analysis set
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percentage of Participants With an LDL-C Response at Week 12 | 0.0 percentage of participants | 3.6 |
| Placebo Q4W | Percentage of Participants With an LDL-C Response at Week 12 | 0.0 percentage of participants | 3.4 |
| Evolocumab 70 mg Q2W | Percentage of Participants With an LDL-C Response at Week 12 | 66.0 percentage of participants | 3.7 |
| Evolocumab 140 mg Q2W | Percentage of Participants With an LDL-C Response at Week 12 | 96.0 percentage of participants | 3.6 |
| Evolocumab 280 mg Q4W | Percentage of Participants With an LDL-C Response at Week 12 | 80.4 percentage of participants | 3.4 |
| Evolocumab 420 mg Q4W | Percentage of Participants With an LDL-C Response at Week 12 | 82.4 percentage of participants | 3.3 |
p-value: <0.00195% CI: [89.64, 42232.63]Regression, Logistic
p-value: <0.00195% CI: [14.74, 5360.92]Regression, Logistic
p-value: <0.00195% CI: [28.37, 10143.4]Regression, Logistic
p-value: <0.00195% CI: [31.11, 11402.67]Regression, Logistic
Secondary
Percent Change From Baseline to Week 12 in Apolipoprotein B
Time frame: Baseline and Week 12
Population: Full analysis set; missing data were imputed using LOCF.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline to Week 12 in Apolipoprotein B | -0.90 percent change | Standard Error 1.82 |
| Placebo Q4W | Percent Change From Baseline to Week 12 in Apolipoprotein B | 0.22 percent change | Standard Error 2.02 |
| Evolocumab 70 mg Q2W | Percent Change From Baseline to Week 12 in Apolipoprotein B | -47.65 percent change | Standard Error 1.88 |
| Evolocumab 140 mg Q2W | Percent Change From Baseline to Week 12 in Apolipoprotein B | -61.59 percent change | Standard Error 1.82 |
| Evolocumab 280 mg Q4W | Percent Change From Baseline to Week 12 in Apolipoprotein B | -47.16 percent change | Standard Error 2.03 |
| Evolocumab 420 mg Q4W | Percent Change From Baseline to Week 12 in Apolipoprotein B | -53.22 percent change | Standard Error 1.98 |
p-value: <0.00195% CI: [-65.67, -55.72]ANCOVA
p-value: <0.00195% CI: [-51.8, -41.7]ANCOVA
p-value: <0.00195% CI: [-58.91, -47.97]ANCOVA
p-value: <0.00195% CI: [-52.9, -41.85]ANCOVA
Secondary
Percent Change From Baseline to Week 12 in Apolipoprotein B/Apolipoprotein A-1 Ratio
Time frame: Baseline and Week 12
Population: Full analysis set; missing data were imputed using LOCF.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline to Week 12 in Apolipoprotein B/Apolipoprotein A-1 Ratio | -3.18 percent change | Standard Error 2.12 |
| Placebo Q4W | Percent Change From Baseline to Week 12 in Apolipoprotein B/Apolipoprotein A-1 Ratio | 1.44 percent change | Standard Error 2.21 |
| Evolocumab 70 mg Q2W | Percent Change From Baseline to Week 12 in Apolipoprotein B/Apolipoprotein A-1 Ratio | -50.71 percent change | Standard Error 2.19 |
| Evolocumab 140 mg Q2W | Percent Change From Baseline to Week 12 in Apolipoprotein B/Apolipoprotein A-1 Ratio | -64.53 percent change | Standard Error 2.12 |
| Evolocumab 280 mg Q4W | Percent Change From Baseline to Week 12 in Apolipoprotein B/Apolipoprotein A-1 Ratio | -50.79 percent change | Standard Error 2.22 |
| Evolocumab 420 mg Q4W | Percent Change From Baseline to Week 12 in Apolipoprotein B/Apolipoprotein A-1 Ratio | -56.31 percent change | Standard Error 2.16 |
p-value: <0.00195% CI: [-67.14, -55.56]ANCOVA
p-value: <0.00195% CI: [-53.41, -41.65]ANCOVA
p-value: <0.00195% CI: [-63.73, -51.77]ANCOVA
p-value: <0.00195% CI: [-58.27, -46.18]ANCOVA
Secondary
Percent Change From Baseline to Week 12 in Non-HDL-C
Time frame: Baseline and Week 12
Population: Full analysis set; missing data were imputed using LOCF.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline to Week 12 in Non-HDL-C | -2.20 percent change | Standard Error 1.94 |
| Placebo Q4W | Percent Change From Baseline to Week 12 in Non-HDL-C | 0.55 percent change | Standard Error 2.17 |
| Evolocumab 70 mg Q2W | Percent Change From Baseline to Week 12 in Non-HDL-C | -51.66 percent change | Standard Error 2 |
| Evolocumab 140 mg Q2W | Percent Change From Baseline to Week 12 in Non-HDL-C | -64.76 percent change | Standard Error 1.94 |
| Evolocumab 280 mg Q4W | Percent Change From Baseline to Week 12 in Non-HDL-C | -53.00 percent change | Standard Error 2.17 |
| Evolocumab 420 mg Q4W | Percent Change From Baseline to Week 12 in Non-HDL-C | -57.53 percent change | Standard Error 2.12 |
p-value: <0.00195% CI: [-67.85, -57.27]ANCOVA
p-value: <0.00195% CI: [-54.83, -44.08]ANCOVA
p-value: <0.00195% CI: [-63.93, -52.22]ANCOVA
p-value: <0.00195% CI: [-59.46, -47.63]ANCOVA
Secondary
Percent Change From Baseline to Week 12 in Total Cholesterol/HDL-C Ratio
Time frame: Baseline and Week 12
Population: Full analysis set; missing data were imputed using LOCF.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline to Week 12 in Total Cholesterol/HDL-C Ratio | -4.82 percent change | Standard Error 1.91 |
| Placebo Q4W | Percent Change From Baseline to Week 12 in Total Cholesterol/HDL-C Ratio | 1.19 percent change | Standard Error 2.09 |
| Evolocumab 70 mg Q2W | Percent Change From Baseline to Week 12 in Total Cholesterol/HDL-C Ratio | -42.04 percent change | Standard Error 1.98 |
| Evolocumab 140 mg Q2W | Percent Change From Baseline to Week 12 in Total Cholesterol/HDL-C Ratio | -51.81 percent change | Standard Error 1.91 |
| Evolocumab 280 mg Q4W | Percent Change From Baseline to Week 12 in Total Cholesterol/HDL-C Ratio | -44.11 percent change | Standard Error 2.1 |
| Evolocumab 420 mg Q4W | Percent Change From Baseline to Week 12 in Total Cholesterol/HDL-C Ratio | -45.47 percent change | Standard Error 2.05 |
p-value: <0.00195% CI: [-52.21, -41.76]ANCOVA
p-value: <0.00195% CI: [-42.52, -31.91]ANCOVA
p-value: <0.00195% CI: [-52.32, -41]ANCOVA
p-value: <0.00195% CI: [-51.02, -39.58]ANCOVA
Secondary
Percent Change From Baseline to Week 12 in VLDL-C
Time frame: Baseline and Week 12
Population: Full analysis set; missing data were imputed using LOCF.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline to Week 12 in VLDL-C | 8.23 percent change | Standard Error 8.55 |
| Placebo Q4W | Percent Change From Baseline to Week 12 in VLDL-C | 7.26 percent change | Standard Error 6.87 |
| Evolocumab 70 mg Q2W | Percent Change From Baseline to Week 12 in VLDL-C | -16.02 percent change | Standard Error 8.74 |
| Evolocumab 140 mg Q2W | Percent Change From Baseline to Week 12 in VLDL-C | -26.26 percent change | Standard Error 8.44 |
| Evolocumab 280 mg Q4W | Percent Change From Baseline to Week 12 in VLDL-C | -13.56 percent change | Standard Error 6.8 |
| Evolocumab 420 mg Q4W | Percent Change From Baseline to Week 12 in VLDL-C | -22.56 percent change | Standard Error 6.71 |
p-value: 0.00495% CI: [-57.71, -11.26]ANCOVA
p-value: 0.04495% CI: [-47.83, -0.68]ANCOVA
p-value: 0.00295% CI: [-48.32, -11.32]ANCOVA
p-value: 0.02895% CI: [-39.41, -2.22]ANCOVA