Hypercholesterolemia
Conditions
Brief summary
The purpose of this study is to determine whether ezetimibe/atorvastatin 10 mg/40 mg combination tablet is equivalent to the coadministration of ezetimibe 10 mg and atorvastatin 40 mg in lowering low-density-lipoprotein-cholesterol (LDL-C) after 6 weeks of treatment.
Interventions
DRUGAtorvastatin
40 mg tablet administered orally once daily
DRUGEzetimibe
10 mg tablet administered orally once daily
Ezetimibe/atorvastatin 10 mg/40 mg combination tablet administered orally once daily
Administered orally once daily
Administered orally once daily
Administered orally once daily
Sponsors
Organon and Co
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 79 Years
Healthy volunteers
No
Inclusion criteria
* At low, moderate, or moderately high cardiovascular risk (according to National Cholesterol Education Program adult treatment panel III \[NCEP ATP III\] guidelines) and either statin-naïve with LDL-C ≥130 mg/dL for low risk or ≥100 mg/dL for moderate or moderately high risk OR on an allowable statin with on-therapy LDL-C ≥100 mg/dL in acceptable range and can safely discontinue and switch to study medication. * Is willing to maintain a cholesterol-lowering diet throughout the study. * Female of reproductive potential agrees to remain abstinent or to use (or have their partner use) 2 acceptable methods of birth control throughout the study. * Female receiving non-cyclical hormone therapy, if maintained on a stable dose and regimen for at least 8 weeks prior to the study and if willing to continue the same regimen throughout the study. * Off-therapy LDL-C levels are: for low risk patients, ≥130 mg/dL and ≤300 mg/dL; for moderate risk patients, ≥100 mg/dL and ≤300 mg/dL; for moderately high risk patients, ≥100 mg/dL and ≤275 mg/dL. * Has liver transaminases ≤2 X upper limit of normal (ULN) with no active liver disease. * Has creatine kinase (CK) levels ≤3 X ULN. * Has triglyceride (TG) concentrations ≤400 mg/dL.
Exclusion criteria
* Hypersensitivity or intolerance to ezetimibe, atorvastatin, the ezetimibe/atorvastatin combination tablet, or any component of these medications, or a history of myopathy or rhabdomyolysis with ezetimibe or any statin. * Routinely consumes more than 2 alcoholic drinks per day (average \>14 alcoholic drinks per week). * Is pregnant or lactating. * Has been treated with any other investigational drug within 30 days of the study. * Is high risk (according to NCEP ATP III guidelines), including but not limited to one or more of the following: diabetes mellitus (Type I or II), myocardial infarction, coronary artery bypass surgery, angioplasty, stable or unstable angina. * Has any of the following medical conditions: congestive heart failure; uncontrolled cardiac arrhythmias or recent significant changes in an electrocardiogram (ECG); homozygous familial hypercholesterolemia or has undergone LDL apheresis; partial ileal bypass, gastric bypass, or other significant intestinal malabsorption; uncontrolled hypertension; kidney disease; disease known to influence serum lipids or lipoproteins; hematologic, digestive, or central nervous system disorder; known to be human immunodeficiency virus (HIV) positive; history of malignancy ≤5 years prior to the study, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer; mental instability, drug/alcohol abuse within the past 5 years, or major psychiatric illness not adequately controlled and stable on pharmacotherapy. \- Taking prohibited medications/foods including: systemic azole antifungals (e.g., fluconazole, ketoconazole), erythromycin or clarithromycin, and cyclosporine; ritonavir and saquinavir or lopinavir; \>5 cups of grapefruit juice per day; combination therapies of ezetimibe + atorvastatin (10/80 mg) or ezetimibe + rosuvastatin (10/20 mg or 10/40 mg); non-statin lipid-lowering agents including fish oils containing \>900 mg/day of eicosapentaenoic acid and docosahexaenoic acid (EPA+DHA), red yeast extract, Cholestin™, bile acid sequestrants, other cholesterol-lowering agents, niacin (\>200 mg/day), or fibrates; systemic corticosteroids; psyllium, other fiber-based laxatives, phytosterol margarines, and/or over the counter (OTC) therapies known to affect serum lipid levels; orlistat or other anti-obesity medications and not maintained on a stable dose; any cyclical hormones; warfarin treatment without a stable dose or a stable International Normalized Ratio (INR).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) After 6 Weeks of Treatment | Baseline and Week 6 | Serum LDL-C calculated using Friedewald formula at baseline and after 6 weeks of treatment in each of the 2 treatment periods. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Total Cholesterol (TC) After 6 Weeks of Treatment | Baseline and Week 6 | Serum TC measured at baseline and after 6 week of treatment in each of the 2 treatment periods. |
| Percent Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C) After 6 Weeks of Treatment | Baseline and Week 6 | Serum HDL-C measured at baseline and after 6 weeks of treatment in each of the 2 treatment periods. |
| Percent Change From Baseline in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) After 6 Weeks of Treatment | Baseline and Week 6 | Non-HDL-C calculated at baseline and after 6 weeks of treatment in each of the 2 treatment periods. |
| Percent Change From Baseline in Apolipoprotein (Apo) B After 6 Weeks of Treatment | Baseline and Week 6 | Serum Apo B measured at baseline and after 6 weeks of treatment in each of the 2 treatment periods. |
| Percent Change From Baseline in Triglycerides (TG) After 6 Weeks of Treatment | Baseline and Week 6 | Serum TG measured at baseline and after 6 weeks of treatment in each of the 2 treatment periods. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Co-administration/Combination Sequence Co-administration Ezetimibe 10 mg and Atorvastatin 40 mg then Ezetimibe/Atorvastatin 10 mg/40 mg fixed-dose combination | 164 |
| Combination/Co-administration Sequence Ezetimibe/Atorvastatin 10 mg/40 mg fixed-dose combination then Co-administration Ezetimibe 10 mg and Atorvastatin 40 mg | 164 |
| Total | 328 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Crossover Washout | Adverse Event | 2 | 1 |
| Crossover Washout | Lost to Follow-up | 2 | 0 |
| Crossover Washout | Non-compliance with Study Drug | 0 | 2 |
| Crossover Washout | Protocol Violation | 1 | 0 |
| Crossover Washout | Withdrawal by Subject | 4 | 1 |
| Period 1 | Adverse Event | 5 | 3 |
| Period 1 | Lost to Follow-up | 2 | 0 |
| Period 1 | Protocol Violation | 2 | 2 |
| Period 1 | Withdrawal by Subject | 5 | 5 |
| Period 2 | Adverse Event | 1 | 4 |
| Period 2 | Lost to Follow-up | 1 | 0 |
| Period 2 | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Co-administration/Combination Sequence | Combination/Co-administration Sequence | Total |
|---|---|---|---|
| Age, Customized 30 to 39 years | 10 Participants | 9 Participants | 19 Participants |
| Age, Customized 40 to 49 years | 35 Participants | 29 Participants | 64 Participants |
| Age, Customized 50 to 59 years | 74 Participants | 61 Participants | 135 Participants |
| Age, Customized 60 to 64 years | 20 Participants | 35 Participants | 55 Participants |
| Age, Customized ≥ 65 years | 25 Participants | 30 Participants | 55 Participants |
| Sex: Female, Male Female | 94 Participants | 92 Participants | 186 Participants |
| Sex: Female, Male Male | 70 Participants | 72 Participants | 142 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 303 | 0 / 313 |
| serious Total, serious adverse events | 3 / 303 | 2 / 313 |
Outcome results
Primary
Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) After 6 Weeks of Treatment
Serum LDL-C calculated using Friedewald formula at baseline and after 6 weeks of treatment in each of the 2 treatment periods.
Time frame: Baseline and Week 6
Population: Per-Protocol (PP) population, which excluded participants due to important deviations from the protocol that may have substantially affected the results of the primary efficacy endpoint(s). A participant may have been a protocol violator in 1 treatment period and not in the other treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ezetimibe/Atorvastatin Fixed Dose Combination | Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) After 6 Weeks of Treatment | -58.9 Percentage Change |
| Co-Administration Ezetimibe and Atorvastatin | Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) After 6 Weeks of Treatment | -58.7 Percentage Change |
Comparison: It was anticipated that 85% of the enrolled participants would be evaluable to achieve 95% power in order to establish equivalence between the Ezetimibe/Atorvastatin Fixed Dose Combination and the co-administration of Ezetimibe and Atorvastatin with respect to percent change from baseline in LDL-C after 6 weeks of treatment using two one-sided tests each at 2.5% α-level, assuming the underlying true treatment difference is ±1.08% and that the standard deviation of the difference is 12.8%.97.5% CI: [-1.9, 1.4]ANCOVA
Secondary
Percent Change From Baseline in Apolipoprotein (Apo) B After 6 Weeks of Treatment
Serum Apo B measured at baseline and after 6 weeks of treatment in each of the 2 treatment periods.
Time frame: Baseline and Week 6
Population: Per-Protocol (PP) population, which excluded participants due to important deviations from the protocol that may have substantially affected the results of the primary efficacy endpoint(s). A participant may have been a protocol violator in 1 treatment period and not in the other treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ezetimibe/Atorvastatin Fixed Dose Combination | Percent Change From Baseline in Apolipoprotein (Apo) B After 6 Weeks of Treatment | -48.7 Percentage Change |
| Co-Administration Ezetimibe and Atorvastatin | Percent Change From Baseline in Apolipoprotein (Apo) B After 6 Weeks of Treatment | -48.3 Percentage Change |
97.5% CI: [-1.9, 1]ANCOVA
Secondary
Percent Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C) After 6 Weeks of Treatment
Serum HDL-C measured at baseline and after 6 weeks of treatment in each of the 2 treatment periods.
Time frame: Baseline and Week 6
Population: Per-Protocol (PP) population, which excluded participants due to important deviations from the protocol that may have substantially affected the results of the primary efficacy endpoint(s). A participant may have been a protocol violator in 1 treatment period and not in the other treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ezetimibe/Atorvastatin Fixed Dose Combination | Percent Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C) After 6 Weeks of Treatment | 2.3 Percentage Change |
| Co-Administration Ezetimibe and Atorvastatin | Percent Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C) After 6 Weeks of Treatment | 2.6 Percentage Change |
97.5% CI: [-1.8, 1.2]ANCOVA
Secondary
Percent Change From Baseline in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) After 6 Weeks of Treatment
Non-HDL-C calculated at baseline and after 6 weeks of treatment in each of the 2 treatment periods.
Time frame: Baseline and Week 6
Population: Per-Protocol (PP) population, which excluded participants due to important deviations from the protocol that may have substantially affected the results of the primary efficacy endpoint(s). A participant may have been a protocol violator in 1 treatment period and not in the other treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ezetimibe/Atorvastatin Fixed Dose Combination | Percent Change From Baseline in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) After 6 Weeks of Treatment | -55.4 Percentage Change |
| Co-Administration Ezetimibe and Atorvastatin | Percent Change From Baseline in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) After 6 Weeks of Treatment | -55.2 Percentage Change |
97.5% CI: [-1.7, 1.4]ANCOVA
Secondary
Percent Change From Baseline in Total Cholesterol (TC) After 6 Weeks of Treatment
Serum TC measured at baseline and after 6 week of treatment in each of the 2 treatment periods.
Time frame: Baseline and Week 6
Population: Per-Protocol (PP) population, which excluded participants due to important deviations from the protocol that may have~substantially affected the results of the primary efficacy endpoint(s). A participant may have been a protocol violator in 1 treatment period and not in the other treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ezetimibe/Atorvastatin Fixed Dose Combination | Percent Change From Baseline in Total Cholesterol (TC) After 6 Weeks of Treatment | -43.0 Percentage Change |
| Co-Administration Ezetimibe and Atorvastatin | Percent Change From Baseline in Total Cholesterol (TC) After 6 Weeks of Treatment | -42.9 Percentage Change |
97.5% CI: [-1.4, 1.2]ANCOVA
Secondary
Percent Change From Baseline in Triglycerides (TG) After 6 Weeks of Treatment
Serum TG measured at baseline and after 6 weeks of treatment in each of the 2 treatment periods.
Time frame: Baseline and Week 6
Population: Per-Protocol (PP) population, which excluded participants due to important deviations from the protocol that may have substantially affected the results of the primary efficacy endpoint(s). A participant may have been a protocol violator in 1 treatment period and not in the other treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ezetimibe/Atorvastatin Fixed Dose Combination | Percent Change From Baseline in Triglycerides (TG) After 6 Weeks of Treatment | -36.2 Percentage Change |
| Co-Administration Ezetimibe and Atorvastatin | Percent Change From Baseline in Triglycerides (TG) After 6 Weeks of Treatment | -36.2 Percentage Change |
97.5% CI: [-4.9, 4.9]constrained Longitudinal Data Analysis