Primary Hypercholesterolemia
Conditions
Brief summary
The purpose of this study is to evaluate the efficacy and safety of atorvastatin 10 mg and ezetimibe 10 mg coadministration in Japanese participants with hypercholesterolemia whose low-density lipoprotein (LDL)-cholesterol levels have not reached the lipid management target value with atorvastatin 10 mg alone, versus increasing the dose of atorvastatin to 20 mg or changing to rosuvastatin 2.5 mg.
Interventions
DRUGEzetimibe
1 tablet of 10 mg daily for 12 weeks (Weeks 5-16)
DRUGAtorvastatin
1 tablet of 10 mg daily for 12 weeks (Weeks 5-16)
DRUGRosuvastatin
1 tablet of 2.5 mg daily for 12 weeks (Weeks 5-16)
Sponsors
Organon and Co
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* atorvastatin 10 mg monotherapy for 4 weeks or longer before the start of the 4-week washout and low density lipoprotein-cholesterol (LDL-C) levels that had not reached the following lipid management target values during treatment: Category I (low-risk group) with no other risk factors - LDL-C \<160 mg/dL; Category II (mid-risk group) with 1-2 risk factors other than LDL-C levels - LDL-C \<140 mg/dL; Category III (high-risk group) with 3 or more other risk factors - LDL-C \<120 mg/dL; and for participants with history of coronary artery disease - LDL-C \<100 mg/dL. * outpatient men or women, age 20 years and older
Exclusion criteria
* fasted triglyceride level at the start of washout or treatment period exceeding 400 mg/dL. * homozygous familial hypercholesterolemia. * creatine phosphokinase (CPK) \>2 times the upper limit of normal (X ULN) at start of washout or treatment period. * glycosylated hemoglobin (HbA1c) \>=8％ at start of washout or treatment period. * severe hepatic function disorder, or aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>2X ULN at start of washout or treatment period. * hypersensitivity to ezetimibe, atorvastatin, or rosuvastatin tablets. * pregnant or lactating * discontinued use of atorvastatin 10 mg for less than 4 weeks at start of treatment period (however, if participant had taken atorvastatin 10 mg before the test conducted at the start of the observation period, a period of discontinuation of 27 days is allowed.) * cyclosporine treatment * hyperlipidemia associated with hypothyroidism, obstructive gall bladder or biliary disease, chronic renal failure, and/or pancreatitis. * hyperlipidemia associated with drug administration that causes adverse serum lipid effects. * participation in a clinical study within 4 weeks of washout * cancer or cancer history within previous 5 years, except for successfully treated basal cell carcinoma of the skin.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Low-Density Lipoprotein - Cholesterol (LDL-C) Values | End of Week 4 to Week 16 or discontinuation | LDL-C was measured before group study drug administration (Week 4, end of atorvastatin single therapy) and at the end of study drug administration (after 12 weeks of study drug treatment, or at discontinuation). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in LDL-C | End of washout period to Week 16 or discontinuation | LDL-C was measured at the start of the atorvastatin 10 mg treatment period (end of the washout period) and at the end of administration of the study drug (Week 16 or discontinuation). |
| Number of Participants Whose LDL-C Levels Reached the Lipid Management Target Values | Week 16 or discontinuation | LDL-C was measured at the end of administration of the study drug (Week 16 or discontinuation). Target values: For participants with history of coronary artery disease: \<100 mg/dL; for participants with at least 3 cardiovascular (CV) risk factors: \<120 mg/dL; for participants with 1-2 CV risk factors: \<140 mg/dL; for participants with no CV risk factors: \<160 mg/dL. |
| Percent Change in Total Lipids and High Sensitivity C-reactive Protein (Hs-CRP) | End of Week 4 to Week 16 or discontinuation | Total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, and hs-CRP were measured at 4 weeks after the start of the treatment period (after completion of administration of atorvastatin 10 mg alone) and at Week 16 or at discontinuation. |
| Percent Change in Total Lipids and Hs-CRP | End of washout to Week 16 or discontinuation | Total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, and hs-CRP were measured at the start of the treatment period (at start of administration of atorvastatin 10 mg alone) and at the end of study drug (Week 16 or discontinuation). |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ezetimibe + Atorvastatin Participants with hypercholesterolemia receiving atorvastatin 10 mg and ezetimibe 10 mg for 12 weeks after a 4-week washout and 4 weeks of daily atorvastatin 10 mg | 47 |
| Atorvastatin Participants with hypercholesterolemia receiving atorvastatin 20 mg for 12 weeks after a 4-week washout and 4 weeks of daily atorvastatin 10 mg | 46 |
| Rosuvastatin Participants with hypercholesterolemia receiving rosuvastatin 2.5 mg for 12 weeks after a 4-week washout and 4 weeks of daily atorvastatin 10 mg | 32 |
| Total | 125 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Ezetimibe + Atorvastatin | Atorvastatin | Rosuvastatin | Total |
|---|---|---|---|---|
| Age, Continuous | 62.7 years STANDARD_DEVIATION 11.4 | 59.3 years STANDARD_DEVIATION 11.8 | 61.1 years STANDARD_DEVIATION 12 | 61.0 years STANDARD_DEVIATION 11.7 |
| Region of Enrollment Japan | 47 participants | 46 participants | 32 participants | 125 participants |
| Sex: Female, Male Female | 25 Participants | 22 Participants | 17 Participants | 64 Participants |
| Sex: Female, Male Male | 22 Participants | 24 Participants | 15 Participants | 61 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 / 47 | 5 / 46 | 9 / 32 |
| serious Total, serious adverse events | 4 / 47 | 1 / 46 | 0 / 32 |
Outcome results
Primary
Percent Change in Low-Density Lipoprotein - Cholesterol (LDL-C) Values
LDL-C was measured before group study drug administration (Week 4, end of atorvastatin single therapy) and at the end of study drug administration (after 12 weeks of study drug treatment, or at discontinuation).
Time frame: End of Week 4 to Week 16 or discontinuation
Population: Randomized participants
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ezetimibe + Atorvastatin | Percent Change in Low-Density Lipoprotein - Cholesterol (LDL-C) Values | -25.8 Percent change |
| Atorvastatin | Percent Change in Low-Density Lipoprotein - Cholesterol (LDL-C) Values | -15.1 Percent change |
| Rosuvastatin | Percent Change in Low-Density Lipoprotein - Cholesterol (LDL-C) Values | 0.8 Percent change |
p-value: <0.000195% CI: [-15.4, -5.8]Hochberg's method
p-value: <0.000195% CI: [-31.8, -21.2]Hochberg's method
Secondary
Number of Participants Whose LDL-C Levels Reached the Lipid Management Target Values
LDL-C was measured at the end of administration of the study drug (Week 16 or discontinuation). Target values: For participants with history of coronary artery disease: \<100 mg/dL; for participants with at least 3 cardiovascular (CV) risk factors: \<120 mg/dL; for participants with 1-2 CV risk factors: \<140 mg/dL; for participants with no CV risk factors: \<160 mg/dL.
Time frame: Week 16 or discontinuation
Population: Randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ezetimibe + Atorvastatin | Number of Participants Whose LDL-C Levels Reached the Lipid Management Target Values | 37 Participants |
| Atorvastatin | Number of Participants Whose LDL-C Levels Reached the Lipid Management Target Values | 19 Participants |
| Rosuvastatin | Number of Participants Whose LDL-C Levels Reached the Lipid Management Target Values | 1 Participants |
Secondary
Percent Change in LDL-C
LDL-C was measured at the start of the atorvastatin 10 mg treatment period (end of the washout period) and at the end of administration of the study drug (Week 16 or discontinuation).
Time frame: End of washout period to Week 16 or discontinuation
Population: Randomized participants
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ezetimibe + Atorvastatin | Percent Change in LDL-C | -49.6 Percent change |
| Atorvastatin | Percent Change in LDL-C | -41.1 Percent change |
| Rosuvastatin | Percent Change in LDL-C | -30.5 Percent change |
p-value: 0.0003Hochberg's method
p-value: <0.0001Hochberg's method
Secondary
Percent Change in Total Lipids and High Sensitivity C-reactive Protein (Hs-CRP)
Total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, and hs-CRP were measured at 4 weeks after the start of the treatment period (after completion of administration of atorvastatin 10 mg alone) and at Week 16 or at discontinuation.
Time frame: End of Week 4 to Week 16 or discontinuation
Population: Randomized participants
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Ezetimibe + Atorvastatin | Percent Change in Total Lipids and High Sensitivity C-reactive Protein (Hs-CRP) | High-Density Lipoprotein Cholesterol (HDL-C) | 4.5 Percent change |
| Ezetimibe + Atorvastatin | Percent Change in Total Lipids and High Sensitivity C-reactive Protein (Hs-CRP) | Non-HDL-C | -25.0 Percent change |
| Ezetimibe + Atorvastatin | Percent Change in Total Lipids and High Sensitivity C-reactive Protein (Hs-CRP) | Triglycerides | -0.8 Percent change |
| Ezetimibe + Atorvastatin | Percent Change in Total Lipids and High Sensitivity C-reactive Protein (Hs-CRP) | High Sensitivity C-Reactive Protein (Hs-CRP) | 49.0 Percent change |
| Ezetimibe + Atorvastatin | Percent Change in Total Lipids and High Sensitivity C-reactive Protein (Hs-CRP) | Total Cholesterol | -18.0 Percent change |
| Atorvastatin | Percent Change in Total Lipids and High Sensitivity C-reactive Protein (Hs-CRP) | Triglycerides | 0.2 Percent change |
| Atorvastatin | Percent Change in Total Lipids and High Sensitivity C-reactive Protein (Hs-CRP) | High-Density Lipoprotein Cholesterol (HDL-C) | 0.5 Percent change |
| Atorvastatin | Percent Change in Total Lipids and High Sensitivity C-reactive Protein (Hs-CRP) | Total Cholesterol | -10.3 Percent change |
| Atorvastatin | Percent Change in Total Lipids and High Sensitivity C-reactive Protein (Hs-CRP) | Non-HDL-C | -13.7 Percent change |
| Atorvastatin | Percent Change in Total Lipids and High Sensitivity C-reactive Protein (Hs-CRP) | High Sensitivity C-Reactive Protein (Hs-CRP) | 9.9 Percent change |
| Rosuvastatin | Percent Change in Total Lipids and High Sensitivity C-reactive Protein (Hs-CRP) | High Sensitivity C-Reactive Protein (Hs-CRP) | 25.7 Percent change |
| Rosuvastatin | Percent Change in Total Lipids and High Sensitivity C-reactive Protein (Hs-CRP) | Non-HDL-C | 2.0 Percent change |
| Rosuvastatin | Percent Change in Total Lipids and High Sensitivity C-reactive Protein (Hs-CRP) | Triglycerides | 14.7 Percent change |
| Rosuvastatin | Percent Change in Total Lipids and High Sensitivity C-reactive Protein (Hs-CRP) | High-Density Lipoprotein Cholesterol (HDL-C) | 2.5 Percent change |
| Rosuvastatin | Percent Change in Total Lipids and High Sensitivity C-reactive Protein (Hs-CRP) | Total Cholesterol | 1.9 Percent change |
Secondary
Percent Change in Total Lipids and Hs-CRP
Total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, and hs-CRP were measured at the start of the treatment period (at start of administration of atorvastatin 10 mg alone) and at the end of study drug (Week 16 or discontinuation).
Time frame: End of washout to Week 16 or discontinuation
Population: Randomized participants
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Ezetimibe + Atorvastatin | Percent Change in Total Lipids and Hs-CRP | Non-HDL-C | -50.1 Percent change |
| Ezetimibe + Atorvastatin | Percent Change in Total Lipids and Hs-CRP | High-Density Lipoprotein Cholesterol (HDL-C) | 10.3 Percent change |
| Ezetimibe + Atorvastatin | Percent Change in Total Lipids and Hs-CRP | Total Cholesterol | -39.9 Percent change |
| Ezetimibe + Atorvastatin | Percent Change in Total Lipids and Hs-CRP | Triglycerides | -25.3 Percent change |
| Ezetimibe + Atorvastatin | Percent Change in Total Lipids and Hs-CRP | High Sensitivity C-reactive Protein (Hs-CRP) | 73.0 Percent change |
| Atorvastatin | Percent Change in Total Lipids and Hs-CRP | High-Density Lipoprotein Cholesterol (HDL-C) | 7.4 Percent change |
| Atorvastatin | Percent Change in Total Lipids and Hs-CRP | Total Cholesterol | -32.8 Percent change |
| Atorvastatin | Percent Change in Total Lipids and Hs-CRP | Triglycerides | -18.8 Percent change |
| Atorvastatin | Percent Change in Total Lipids and Hs-CRP | Non-HDL-C | -41.4 Percent change |
| Atorvastatin | Percent Change in Total Lipids and Hs-CRP | High Sensitivity C-reactive Protein (Hs-CRP) | -2.9 Percent change |
| Rosuvastatin | Percent Change in Total Lipids and Hs-CRP | High Sensitivity C-reactive Protein (Hs-CRP) | -13.6 Percent change |
| Rosuvastatin | Percent Change in Total Lipids and Hs-CRP | Non-HDL-C | -31.3 Percent change |
| Rosuvastatin | Percent Change in Total Lipids and Hs-CRP | Total Cholesterol | -24.4 Percent change |
| Rosuvastatin | Percent Change in Total Lipids and Hs-CRP | High-Density Lipoprotein Cholesterol (HDL-C) | 9.9 Percent change |
| Rosuvastatin | Percent Change in Total Lipids and Hs-CRP | Triglycerides | -12.0 Percent change |