Hypercholesterolemia
Conditions
Brief summary
This study will evaluate the EZ/Ator fixed-dose combination (FDC) tablet (MK-0653C) as second line Low-Density Lipoprotein - Cholesterol (LDL-C) treatment in Chinese participants. The primary hypothesis is that MK-0653C 10/10 mg is superior to atorvastatin 20 mg in percent change from baseline in LDL-C to 12 weeks after treatment.
Interventions
COMBINATION_PRODUCTEZ 10 mg/Ator 10 mg
FDC of EZ10 mg/Ator 10mg
COMBINATION_PRODUCTEZ 10 mg/Ator 20 mg
FDC of EZ10 mg/Ator 20mg
DRUGAtorvastatin
Atorvastatin administered orally QD, either as two 10 mg tablets or as two 20 mg tablets
DRUGPlacebo for FDC EZ/Ator
A single placebo tablet administered orally QD for 84 days
Two placebo tablets matching atorvastatin administered orally QD for 84 days
Sponsors
Organon and Co
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Has hypercholesterolemia diagnosed by investigator according to Chinese Guidelines on Prevention and Treatment of Dyslipidemia in Adults (2016 Edition). * Has been stabilized on atorvastatin treatment at 10 mg or 20 mg (or other statins with LDL-C lowering efficacy equivalent to atorvastatin) for at least 4 weeks prior to Visit 1. * If female, is not pregnant or breastfeeding, and is either not a woman of childbearing potential (WOCBP), or is a WOCBP who has used a contraceptive consistent with local regulations. * If male, has used a contraceptive consistent with local regulations. * Agrees to maintain a stable diet and stable exercise during the study.
Exclusion criteria
* Has uncontrolled hypertriglyceridemia which needs drug intervention or a fasting triglyceride (TG) value ≥500 mg/dL (4.52 mmol/L). * Is currently treated with statin at dose of equivalent LDL-C lowering effect \>20 mg atorvastatin. * Has active liver disease * Has New York Heart Association (NYHA) Class III or IV symptomatic congestive heart failure at Visit 1. * Has had uncontrolled cardiac arrhythmias, myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft, unstable angina, or stroke within 3 months (12 weeks) prior to Visit 1. * Has homozygous familial hypercholesterolemia or has undergone LDL apheresis. * Has endocrine or metabolic disease known to influence serum lipids or lipoproteins (i.e., secondary causes of hyperlipidemia, e.g., hyper or hypothyroidism, Cushing's syndrome). * Has had a gastrointestinal tract bypass, or other significant intestinal malabsorption. * Has a history of cancer within the past 5 years from Visit 1 (except for successfully treated dermatological basal cell or squamous cell carcinoma or in situ cervical cancer). * Is known to be human immunodeficiency virus (HIV) positive. * Has hypersensitivity or intolerance to ezetimibe, atorvastatin, the ezetimibe/atorvastatin combination tablet, or any component of these medications or has a condition or situation, which is described as a contraindication in labeling of EZETROL or Lipitor or may interfere with participation in the study. * Has disorders of the hematologic, digestive, or central nervous systems including cerebrovascular disease and degenerative disease that would limit study evaluation or participation. * Has a history of mental instability, drug/alcohol abuse within the past 5 years, or major psychiatric illness not adequately controlled and stable on pharmacotherapy. * Has a history of myopathy or rhabdomyolysis with ezetimibe or any statin. * Is a WOCBP who has had a positive urine pregnancy test within 24 hours before the first dose of study intervention. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. * Is currently taking medications that are potent modulators of cytochrome P-450 3A4 (CYP3A4) including: cyclosporine, systemically administered azole antifungals (e.g., ketoconazole, fluconazole, and itraconazole), macrolide antibiotics (e.g., clarithromycin, and erythromycin), protease inhibitors (e.g., ritonavir, saquinavir, and lopinavir), grapefruit or juice of grapefruit (200 ml/day for \>3 times per week) * Is taking any cyclical hormones (e.g., cyclical oral contraceptives, cyclical hormone replacement), including the combination of ethinyl estradiol and norethisterone, or non-cyclical hormones, including non-cyclical hormone replacement therapy (HRT) or any estrogen antagonist/agonist within 8 weeks. * Note: If participant has been treated with a stable regimen of non-cyclical HRT for \> 8 weeks and agree to continue this regimen for the duration of the trial, concomitant therapy is acceptable. * Is receiving treatment with systemic corticosteroids (intravenous, intramuscular and oral steroids). * Is treated with psyllium, other fiber-based laxatives, phytosterol margarine, and herbal medicine and/or over the counter (OTC) therapies that are known to affect serum lipids. * Note: If participant has been treated with a stable regimen for \> 8 weeks and agrees to continue this regimen for the duration of the trial, concomitant therapy is acceptable. * Is treated with an anti-obesity drug (e.g. mazindol) within 12 weeks prior to Visit 1. * Is treated with warfarin or warfarin-like anticoagulants and has not been on a stable dose with a stable International Normalized Ratio (INR) for at least 6 weeks. weeks. * Has taken lipid-lowering agents (except probucol) including, Cholestin, bile acid sequestrants, ezetimibe, fibrates or niacin (\>200 mg/day), proprotein convertases subtilisin/kexin type 9 (PCSK9) inhibitors within 6 weeks prior to Visit 1. * Has taken probucol within 10 weeks prior to Visit 1. * Has been treated with any other investigational drug within 30 days. * Currently follows an excessive weight reduction diet. * Currently engages in a vigorous exercise regimen (e.g., marathon training, body building training) or intends to start training during the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in LDL-C at Week 12 | Baseline (Day 1) and Week 12 | Participants had LDL-C levels assessed at baseline and after 12 weeks of study drug administration. The change from baseline was calculated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With An Adverse Event (AE) | Up to approximately 17 weeks | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. |
| Number of Participants Who Discontinued From Study Treatment | Up to approximately 15 weeks | The number of participants who discontinued treatment over the 12-week treatment period was assessed. |
Countries
China
Participant flow
Recruitment details
Chinese participants with Hypercholesterolemia inadequately controlled with 10 mg or 20 mg atorvastatin (Ator) monotherapy were enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Atorvastatin 10 mg - Ezetimibe 10 mg/Ator 10 mg Participants had a 5-week run-in of atorvastatin 10 mg once daily (QD). They then received a single oral dose of ezetimibe (EZ) 10 mg/Ator 10 mg fixed dose combination (FDC) tablet QD, and 1 placebo tablet matched to active atorvastatin tablet QD for 84 days. | 88 |
| Atorvastatin 10mg - Atorvastatin 20 mg Participants had a 5-week run-in of atorvastatin 10 mg QD. They then received 2 atorvastatin 20 mg tablets QD, and 1 placebo tablet matched to active atorvastatin tablet QD for 84 days. | 89 |
| Atorvastatin 20 mg - EZ 10 mg/Ator 20 mg Participants had a 5-week run-in of atorvastatin 20 mg QD. They then received a single oral dose of EZ 10 mg/Ator 20 mg FDC tablet QD, and 1 placebo tablet matched to active atorvastatin tablet QD for 84 days. | 137 |
| Atorvastatin 20 mg - Atorvastatin 40 mg Participants had a 5-week run-in of atorvastatin 20 mg QD. They then received 2 atorvastatin 20 mg tablets administered orally, QD, and 1 placebo tablet matched to active atorvastatin tablet QD for 84 days. | 140 |
| Total | 454 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 0 | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 2 | 0 | 0 | 0 |
| Overall Study | Physician Decision | 3 | 2 | 4 | 4 |
| Overall Study | Withdrawal by Subject | 7 | 2 | 6 | 7 |
Baseline characteristics
| Characteristic | Atorvastatin 10 mg - Ezetimibe 10 mg/Ator 10 mg | Atorvastatin 10mg - Atorvastatin 20 mg | Atorvastatin 20 mg - EZ 10 mg/Ator 20 mg | Atorvastatin 20 mg - Atorvastatin 40 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 62.4 Years STANDARD_DEVIATION 7.4 | 62.4 Years STANDARD_DEVIATION 8.5 | 59.4 Years STANDARD_DEVIATION 9.3 | 60.6 Years STANDARD_DEVIATION 10.3 | 60.9 Years STANDARD_DEVIATION 9.2 |
| Baseline Low-Density Lipoprotein Cholesterol (LDL-C) | 95.5 mg/dL STANDARD_DEVIATION 24.6 | 96.8 mg/dL STANDARD_DEVIATION 25.9 | 96.2 mg/dL STANDARD_DEVIATION 25.2 | 88.4 mg/dL STANDARD_DEVIATION 21.9 | 91.9 mg/dL STANDARD_DEVIATION 24.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 88 Participants | 89 Participants | 137 Participants | 140 Participants | 454 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 88 Participants | 89 Participants | 137 Participants | 140 Participants | 454 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 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) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 43 Participants | 38 Participants | 34 Participants | 46 Participants | 161 Participants |
| Sex: Female, Male Male | 45 Participants | 51 Participants | 103 Participants | 94 Participants | 293 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 88 | 0 / 89 | 1 / 137 | 0 / 140 |
| other Total, other adverse events | 0 / 88 | 0 / 89 | 7 / 137 | 2 / 140 |
| serious Total, serious adverse events | 2 / 88 | 4 / 89 | 10 / 137 | 6 / 140 |
Outcome results
Primary
Percent Change From Baseline in LDL-C at Week 12
Participants had LDL-C levels assessed at baseline and after 12 weeks of study drug administration. The change from baseline was calculated.
Time frame: Baseline (Day 1) and Week 12
Population: All randomized participants who took at least one dose of study treatment, and have at least one post treatment observation of the respective endpoint (Baseline and Week 12) during the treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Atorvastatin 10 mg - Ezetimibe 10 mg/Ator 10 mg | Percent Change From Baseline in LDL-C at Week 12 | -24.7 Percent change | Standard Deviation 24.9 |
| Atorvastatin 10mg - Atorvastatin 20 mg | Percent Change From Baseline in LDL-C at Week 12 | -5.3 Percent change | Standard Deviation 22.5 |
| Atorvastatin 20 mg - EZ 10 mg/Ator 20 mg | Percent Change From Baseline in LDL-C at Week 12 | -23.3 Percent change | Standard Deviation 23.1 |
| Atorvastatin 20 mg - Atorvastatin 40 mg | Percent Change From Baseline in LDL-C at Week 12 | -9.1 Percent change | Standard Deviation 18.2 |
Comparison: This statistical analysis was performed by fitting a constrained longitudinal model adjusting for time and the interaction of time by treatment, and time by baseline disease risk category, including all participants with baseline data (88 participants in arm Atorvastatin 10 mg - ezetimibe 10 mg/Ator 10 mg and 89 participants in arm Atorvastatin 10mg - Atorvastatin 20 mg).p-value: <0.00195% CI: [-26.7, -12.3]Constrained longitudinal model
Comparison: This statistical analysis was performed by fitting a constrained longitudinal model adjusting for time and the interaction of time by treatment, and time by baseline disease risk category, including all participants with baseline data (137 participants in arm Atorvastatin 20 mg - EZ 10 mg/Ator 20 mg and 140 participants in arm Atorvastatin 20 mg - Atorvastatin 40 mg).p-value: <0.00195% CI: [-21, -10.7]Constrained longitudinal model
Secondary
Number of Participants Who Discontinued From Study Treatment
The number of participants who discontinued treatment over the 12-week treatment period was assessed.
Time frame: Up to approximately 15 weeks
Population: All randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Atorvastatin 10 mg - Ezetimibe 10 mg/Ator 10 mg | Number of Participants Who Discontinued From Study Treatment | 9 Number of Participants |
| Atorvastatin 10mg - Atorvastatin 20 mg | Number of Participants Who Discontinued From Study Treatment | 5 Number of Participants |
| Atorvastatin 20 mg - EZ 10 mg/Ator 20 mg | Number of Participants Who Discontinued From Study Treatment | 13 Number of Participants |
| Atorvastatin 20 mg - Atorvastatin 40 mg | Number of Participants Who Discontinued From Study Treatment | 15 Number of Participants |
Secondary
Percentage of Participants With An Adverse Event (AE)
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.
Time frame: Up to approximately 17 weeks
Population: All randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Atorvastatin 10 mg - Ezetimibe 10 mg/Ator 10 mg | Percentage of Participants With An Adverse Event (AE) | 31.8 Percentage of Participants |
| Atorvastatin 10mg - Atorvastatin 20 mg | Percentage of Participants With An Adverse Event (AE) | 34.8 Percentage of Participants |
| Atorvastatin 20 mg - EZ 10 mg/Ator 20 mg | Percentage of Participants With An Adverse Event (AE) | 55.5 Percentage of Participants |
| Atorvastatin 20 mg - Atorvastatin 40 mg | Percentage of Participants With An Adverse Event (AE) | 47.9 Percentage of Participants |