Methods

This clinical trial entitled A Randomized, Double-Blind, Active-Controlled, Multicenter Study of Patients with P rimary Hypercholesterolemia and High Cardiovascular Risk Who Are Not Adequately Controlled with A torvastatin 10 mg: A C omparison of the Efficacy and Safety of Switching to Coadministration E zetimibe and Atorvastatin Versus Doubling the Dose of Atorvastatin or Switching to Rosuvastatin (PACE), was conducted from September 29, 2010 to October 17, 2012 (study MK653C-162, http://clinicaltrials.gov , identifier NCT01154036 ) and included subjects evaluated from 296 research sites across 29 countries (Argentina [18], Belgium [2], Bulgaria [11], Canada [15], Chile [7], Columbia [5], Croatia [4], Czech Republic [19], Denmark [5], Estonia [4], Finland [5], France [7], Germany [9], Hungary [13], Israel [14], Italy [8], Lithuania [8], the Netherlands [4], Norway [4], Poland [14], Portugal [4], Romania [18], Slovakia [12], Slovenia [3], Spain [11], Sweden [6], Turkey [8], the United Kingdom [12], and the United States [46]). The study was conducted in accordance with principles of the ICH Good Clinical Practice and all local and/or national regulations and directives. The appropriate institutional review boards approved the protocol, and all subjects documented their agreement to participate by written informed consent.

Subjects included in the present study were men and women of nonchildbearing potential and aged ≥18 and <80 years with primary hypercholesterolemia. Subjects were required to be at high CVD risk and meet prespecified lipid entry criteria. The high CVD risk study entry criteria included subjects without CVD who had type 2 diabetes mellitus or ≥2 CVD risk factors and a 10-year risk for coronary heart disease >20% (as determined by the Framingham risk calculation) or subjects with known CVD, including patients with established coronary and other atherosclerotic vascular diseases. The lipid study entry criteria included subjects naive to lipid-lowering therapy (never treated or no therapy for ≥6 weeks before the prescreen visit) with an LDL-C level in the predetermined range of 166 to 190 mg/dl or subjects on a stable dose of statin, ezetimibe, or statin plus ezetimibe having LDL-C-lowering efficacy equivalent to or less than atorvastatin 10 mg and with historic lipid values within a range that might reasonably meet randomization lipid criteria (described later).

Main exclusion criteria included alanine aminotransferase or aspartate aminotransferase levels >2× the upper limit of normal (ULN); creatine kinase >3× the ULN; a history of significant myopathy or rhabdomyolysis with any statin or ezetimibe; hypersensitivity or intolerance to ezetimibe, atorvastatin, rosuvastatin, or any component of these medications; congestive heart failure (New York Heart Association class III or IV); previous myocardial infarction, coronary artery bypass surgery, angioplasty, or acute coronary syndrome within 3 months before screening; uncontrolled cardiac arrhythmias or recent significant changes on an electrocardiogram within 6 months before screening; homozygous familial hypercholesterolemia or LDL-C apheresis; partial ileal bypass, gastric bypass, or other significant intestinal malabsorption; uncontrolled hypertension; poorly controlled type 1 or 2 diabetes mellitus (defined by HbA1c ≥ 8.5%); estimated glomerular filtration rate <30 ml/min/1.73 m ² based on the 4-variable Modification of Diet in Renal Disease equation, nephrotic syndrome, or other clinically significant renal disease; active liver disease; uncontrolled endocrine or metabolic disease known to influence serum lipids or lipoproteins; disorders of the hematologic, digestive, or central nervous systems including cerebrovascular disease (e.g., stroke, transient ischemic attack) and degenerative disease that would limit study evaluation or participation.

After study entry, lipid-altering drug–naïve subjects were administered open-label atorvastatin 10 mg/day. For subjects previously treated with lipid-altering drugs, these lipid-altering drugs were discontinued, and the subjects were switched to open-label atorvastatin 10 mg/day. After 5 weeks of open-label atorvastatin 10 mg/day, subjects were required to meet a second set of randomization entry criteria which included LDL-C levels ≥100 and ≤160 mg/dl and triglyceride levels ≤400 mg/dl. Subjects meeting these criteria were randomized to 1 of 6 blinded treatment sequences in a 3:1:8:8:16:16 ratio based on sample size assumptions (see later), which determined treatment in period I (first 6 weeks) and period II (second 6 weeks) of the study ( Figure 1 ). Treatment during period I included (1) adding ezetimibe 10 mg to stable atorvastatin 10 mg therapy, (2) doubling atorvastatin to 20 mg, or (3) switching to rosuvastatin 10 mg. Subjects in the latter 2 groups who persisted with LDL-C levels ≥100 and ≤160 mg/dl at the end of period I entered period II; subjects on atorvastatin 20 mg received atorvastatin 20 mg plus ezetimibe 10 mg or atorvastatin uptitrated to 40 mg; those on rosuvastatin 10 mg were switched to atorvastatin 20 mg plus ezetimibe 10 mg or uptitrated to rosuvastatin 20 mg. Approximately 25% of those receiving atorvastatin 10 mg plus ezetimibe during period I continued into period II irrespective of LDL-C levels to maintain study blinding. Randomization was performed using a central interactive voice response system. All study personnel, including investigators, study site personnel, patients, monitors, and central laboratory personnel, remained blinded to treatment allocation throughout the study; the final database was not unblinded until medical/scientific review was performed, protocol violators were identified, and data were declared final and complete.

Study design. Atorva = atorvastatin; EZ = ezetimibe; Rosuva = rosuvastatin.

The primary efficacy end point variable was the percent change from treated baseline in LDL-C levels at the end of period I. Key secondary end point variables included percent change from treated baseline in LDL-C at the end of period II; percentage of subjects achieving LDL-C <100 or <70 mg/dl at the end of periods I and II; percent change from treated baseline in other lipids, lipoproteins, and high-sensitivity C-reactive protein (hs-CRP) at the end of periods I and II; assessment of safety and tolerability.

Primary and secondary efficacy end point variables were evaluated using the full analysis set population, including all randomized subjects receiving ≥1 dose of blinded study treatment with baseline and ≥1 postbaseline measurement. Because normality was rejected (at the alpha = 0.001 level) for the primary end point of percent change from baseline in LDL-C levels after period I, the analysis used a prespecified 2-step multiple imputation method followed by a robust regression approach that included terms for treatment and baseline LDL-C. The robust regression provided iteratively reweighted-least-square means and associated p values to determine within- and between-treatment effects. Evaluation of the percentage of patients reaching LDL-C targets <100 or <70 mg/dl used a logistic regression model with terms for treatment and baseline LDL-C categories (3 categories based on tertiles). Odds ratio estimates and 95% confidence intervals were used to quantify treatment effects. The percent change from baseline in other lipid and lipoprotein parameters (except triglycerides and hs-CRP) was evaluated using the robust regression approach as described previously. The percent change from baseline in log-transformed data for triglycerides and hs-CRP was assessed using a constrained longitudinal data analysis method because of the non-normal distribution seen in previous studies. As this study design employed the use of serial treatment assessments, a parallel gatekeeping testing approach was applied to control the overall type-I error rate at an α value of 0.05 for comparisons of percent change from baseline in LDL-C after periods I and II. For other evaluations, the false discovery rate was controlled at 5%. Analysis of prespecified subgroups provided least squares means and 95% confidence intervals by fitting an analysis of covariance repeated measure model with terms for treatment and baseline LDL-C.

For the primary and secondary efficacy end points, with a sample size of approximately 1,500 patients planned for randomization, the study was anticipated to have at least 90% power to demonstrate a difference between ezetimibe coadministered with atorvastatin and the comparative atorvastatin or rosuvastatin monotherapy, assuming a drop-out rate of ∼8%, a SD of 20% (α-level of 0.045 [period I] or 0.050 [period II], 2 sided), and an anticipated number of patients not adequately controlled on atorvastatin 20 mg/day (50%) or rosuvastatin 10 mg/day (40%) after period I. These sample size assumptions account for the differences in n values planned for the various treatment arms.

Safety was evaluated using the all-patients-as-treated population, including all randomized subjects who received ≥1 dose of study treatment. Prespecified safety end points of special interest for this study were subject to inferential testing, with p values and 95% confidence intervals determined for between-group comparisons using a stratified Miettinen and Nurminen method. Confidence intervals (95%) for between-group differences were provided for adverse experience (AE) categories including ≥1 AE, serious AEs, drug-related AEs, serious drug-related AEs, and discontinuations due to an AE. Assessment of drug causality was determined by the investigator during blinded study treatment, using the criteria of definitely, probably, possibly, probably not, and definitely not related to study drug. An AE was defined as “drug related” if the investigator reported the AE as being possibly, probably, or definitely due to study drug.

Results

Of the 1,547 patients randomized, 1,460 (94%) completed period I. Afterward, 718 subjects with LDL-C levels high enough to be eligible to participate proceeded to period II. Of these, 689 (96%) completed period II ( Figure 2 ). Study subject discontinuations were 5.6% during period I (range, 2.5%–5.9%) and 4.0% during period II (range, 2.9%–6.5%). Baseline characteristics ( Table 1 ) and lipid and lipoprotein levels ( Table 2 ) were generally similar across treatment regimens within each period. Patients randomized to period I had a mean age of 60 years, 53% were women, 95% were white, 50% had CVD, and 47% had diabetes mellitus (0.4% with type 1, 32.4% with type 2, and 14.6% with unknown type). The overall mean baseline LDL-C level was ∼120 mg/dl. Baseline characteristics and lipid and lipoprotein levels for uncontrolled patients who continued into period II were similar to those for patients in period I. Overall, mean compliance at the >95% level of the prescribed dose was 94% during atorvastatin 10 mg run-in, 91% during period I, and 92% during period II.

Participant distribution. Atorva = atorvastatin; EZ = ezetimibe; FAS = full analysis set (includes all randomized patients with baseline and at least 1 valid postbaseline evaluation); Rosuva = rosuvastatin.

For patients with LDL-C levels ≥100 and ≤160 mg/dl after atorvastatin 10 mg run-in, the addition of ezetimibe to atorvastatin 10 mg produced a significantly greater reduction in LDL-C than doubling the atorvastatin dose to 20 mg or switching to rosuvastatin 10 mg ( Table 3 ). Furthermore, the addition of ezetimibe to atorvastatin 10 mg produced significantly greater attainment of LDL-C <100 or <70 mg/dl ( Figure 3 ) and significantly greater reductions in total cholesterol, non–high-density lipoprotein cholesterol (HDL-C), apolipoprotein B, and LDL-C/HDL-C, total/HDL-C, and non-HDL-C/HDL-C ratios ( Table 3 ) than atorvastatin 20 mg or rosuvastatin 10 mg. The change from baseline in HDL-C, triglycerides, apolipoprotein AI, and hs-CRP were similar among treatments ( Table 3 ). Treatment effects were similar for percent change from baseline in LDL-C across all prespecified subgroups of age, gender, race, and diabetic status ( Figure 4 ).

Table 3

Percent change from treated baseline in assessed parameters (full analysis set population)

Parameter	Period I					Period II
	Percent Change from Baseline †			Treatment Difference		Percent Change from Baseline †				Treatment Difference
	E10 + A10 (n = 120) ‡	A20 (n = 480) ‡	R10 (n = 939) ‡	E10 + A10 vs A20	E10 + A10 vs R10	A20→		R10→		E10 + A20 vs A40	E10 + A20 vs R20
						E10 + A20 (n = 124) ‡	A40 (n = 124) ‡	E10 + A20 (n = 231) ‡	R20 (n = 205) ‡
LDL-C	−22.2	−9.5	−13.0	−12.7***	−9.1***	−17.4	−6.9	−17.1	−7.5	−10.5***	−9.5***
Total cholesterol	−13.5	−6.4	−7.7	−7.1***	−5.8***	−10.7	−3.8	−11.8	−4.5	−6.8***	−7.4***
Non-HDL-C	−18.3	−8.1	−10.6	−10.1***	−7.6***	−15.1	−5.8	−16.2	−6.4	−9.3***	−9.8***
HDL-C	0.6	−1.1	1.1	1.7	−0.6	0.7	1.7	0.1	0.8	−1.0	−0.7
Triglycerides §	−6.0	−3.9	−1.1	−2.1	−4.9	−5.9	−3.1	−10.2	−3.2	−2.8	−7.1*
Apolipoprotein B	−11.3	−6.0	−6.9	−5.3**	−4.3*	−9.8	−5.4	−11.9	−4.1	−4.3	−7.7***
Apolipoprotein AI	0.2	−1.4	1.0	1.6	−0.9	1.2	0.7	0.0	1.0	0.5	−1.0
LDL-C/HDL-C	−21.7	−8.0	−13.9	−13.7***	−7.8***	−19.0	−8.7	−16.5	−8.2	−10.4***	−8.3***
Total/HDL-C	−13.5	−5.5	−8.7	−8.1***	−4.8**	−12.4	−5.5	−11.3	−4.9	−6.9***	−6.4***
Non-HDL-C/HDL-C	−17.6	−7.0	−11.4	−10.6***	−6.2**	−16.7	−7.3	−15.1	−6.7	−9.3***	−8.4***
Apolipoprotein B/apolipoprotein AI	−11.5	−5.3	−8.0	−6.3***	−3.5	−11.3	−5.5	−11.5	−5.4	−5.8*	−6.1**
Hs-CRP (mg/L) §	−10.5	−6.6	−9.0	−3.9	−1.5	−19.5	−6.4	−10.9	0.7	−13.1	−11.6

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related

Related posts:

1. Relation of Conjugated Bilirubin Concentrations to the Presence of Coronary Artery Calcium
2. Outcomes of Adolescents and Adults Undergoing Primary Fontan Procedure
3. Diagnostic Performance of High-Sensitive Troponin T in Patients With Renal Insufficiency
4. Remote Ischemic Conditioning for Patients With Heart Failure?

Stay updated, free articles. Join our Telegram channel

Join