Statins lower low‐density lipoprotein cholesterol (LDL‐C) by inhibiting 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase and consistently reduce cardiovascular disease (CVD) risk by 30% to 40%.1, 2, 3 Therefore, statin therapy is currently the recommended standard‐of‐care treatment for lowering LDL‐C in patients at increased CVD risk.2, 3 In contrast to all major randomized controlled trials, which have found comparable rates of muscle adverse events (AEs) between statin and placebo arms,4, 5, 6 observational studies reported higher rates of statin‐associated muscle symptoms (SAMS) in 7% to 29% of patients.7 As a consequence, patients with SAMS often receive a suboptimal statin dose or no statin therapy.7 A substantial proportion of these, often high‐risk, patients have persistently elevated LDL‐C levels (>190 mg/dL),8, 9, 10 placing them at a correspondingly high CVD risk.3, 11
Proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of cholesterol homeostasis, is a novel and attractive therapeutic target for lowering LDL‐C levels via a 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase‐independent pathway. Alirocumab, a fully human monoclonal antibody that specifically binds to PCSK9, has been shown to significantly lower LDL‐C levels across a range of dosing regimens, whether as monotherapy12 or on a background of statin±other lipid‐lowering therapies.13, 14, 15, 16 A monthly dosing regimen may be convenient and effective,17, 18 with different doses being appropriate when used as monotherapy compared with background statin therapy. This is because statins are known to increase PCSK9 levels,19 which reduce duration of alirocumab effect in the setting of every 4 weeks (Q4W) dosing.
Alirocumab 150 mg Q4W monotherapy demonstrated a 47.4% reduction in LDL‐C levels from baseline in a phase 1 study.17 However, in an early phase 2 study of patients with heterozygous familial hypercholesterolemia on statin, there was only an incremental LDL‐C reduction of 28.9% at week 12 with alirocumab 150 Q4W.18 The use of higher doses (200‐300 mg Q4W) resulted in greater incremental LDL‐C reductions (42.5‐47.7% at week 12) when added to stable statin therapy.18, 20
In this phase 3, placebo‐controlled study (ODYSSEY CHOICE II, NCT02023879), we evaluated the efficacy and safety of alirocumab 150 mg Q4W (with possible adjustment to 150 mg Q2W; referred to as “150Q4W”) as a therapeutic option for patients with hypercholesterolemia not receiving statin. This study also employed an alirocumab dosing regimen of 75 mg every 2 weeks (Q2W; with possible dose adjustment to 150 mg Q2W; referred to as “75Q2W”) as a calibrator arm, a dose that has been extensively investigated across the phase 3 ODYSSEY clinical trials program.12, 13, 14, 15, 16 CHOICE II followed a “treat‐to‐target” dosing strategy, based on the LDL‐C reduction needed to provide best achievement of target LDL‐C level at the lowest alirocumab dose.
ODYSSEY CHOICE II was a randomized, double‐blind, placebo‐controlled, phase 3 multinational study including 233 patients from 43 study sites from Australia (n=3), Belgium (n=3), Canada (n=6), Denmark (n=5), the Netherlands (n=9), New Zealand (n=2), Spain (n=7), and the United States (n=8). The study was initiated on December 16, 2013 (first patient screened) with the first patient randomized on January 2, 2014 and the last patient randomized on May 12, 2014. The study was conducted in accordance with the ethical principles in the Declaration of Helsinki and applicable amendments, and the International Conference on Harmonisation guidelines for Good Clinical Practice. The protocol was approved by the relevant institutional review boards or independent ethics committees. All participating patients provided written informed consent.
The study enrolled adult patients (≥18 years of age) with hypercholesterolemia receiving fenofibrate or ezetimibe or diet alone. Only patients not receiving a statin were eligible for the study, which corresponded to patients who (1) had SAMS (which was defined as statin intolerance in the protocol) with moderate, high, or very high cardiovascular risk or (2) were not receiving a statin but who did not fulfill the SAMS definition: only patients at moderate cardiovascular risk were included in this stratum. SAMS, as well as moderate, high, and very high cardiovascular risk, were defined as previously described.21
SAMS, defined as statin intolerance in the study protocol, was defined as the inability to tolerate at least 2 statins, consistent with other studies in the ODYSSEY clinical trial program21: 1 statin at the lowest daily starting dose (defined as rosuvastatin 5 mg, atorvastatin 10 mg, simvastatin 10 mg, lovastatin 20 mg, pravastatin 40 mg, fluvastatin 40 mg, or pitavastatin 2 mg), and another statin at any dose, due to SAMS, other than those due to strain or trauma, such as pain, aches, weakness, or cramping, that began or increased during statin therapy and stopped when statin therapy was discontinued.
The aim was for two‐thirds of randomized patients to be receiving fenofibrate/ezetimibe, and for ≥50% of patients to fulfill the SAMS definition. Patients were instructed to maintain a stable diet (National Cholesterol Education Program Adult Treatment Panel III Therapeutic Lifestyle Changes diet or equivalent) throughout the entire study duration, including the screening period.22 Use of fibrates (other than fenofibrate), niacin, bile acid‐binding sequestrants, or red yeast rice products was not allowed during the study. A list of exclusion criteria is given in Table S1.
Hypercholesterolemia was defined based on cardiovascular risk: LDL‐C ≥70 mg/dL if very high cardiovascular risk, or LDL‐C ≥100 mg/dL if high or moderate risk. In addition, for those patients not fulfilling the SAMS definition, or who were being treated with diet alone, LDL‐C also had to be ≥100 and <160 mg/dL.
The study comprised a 3‐week screening period, followed by 24 weeks of double‐blind treatment and 8 weeks of follow‐up (off treatment) for those patients who did not enter the open‐label treatment period (Figure 1). After screening, the planned randomization was to follow a 2:1:1 treatment ratio for alirocumab 150Q4W, alirocumab 75Q2W (calibrator arm), and placebo Q2W, respectively. Randomization was stratified by SAMS status and by either ezetimibe/fenofibrate therapy or diet alone. However, owing to a systematic error in the algorithm managing treatment allocation at the study setup (where alirocumab 75Q2W was allocated to patients randomized to alirocumab 150Q4W during the entire double‐blind period and vice versa), patients were actually randomized in a 1:2:1 ratio to receive alirocumab 150Q4W, 75Q2W, or placebo in a blinded manner. The blinding was maintained for patients randomized to alirocumab 150Q4W by alternating active and placebo injections; each patient received 12 injections during the study period. Each treatment was administered subcutaneously by 1‐mL prefilled pen.
CHOICE II study design. *Patients were to be randomized to 2:1:1 alirocumab 150Q4W: alirocumab 75Q2W: placebo. However, a systematic randomization error occurred in alirocumab treatment allocation. †Blind was maintained in all patients, including those receiving dose adjustments, by giving the study treatment as a single 1‐mL subcutaneous injection Q2W in all groups. 75Q2W indicates 75 mg every 2 weeks (with possible dose adjustment to 150 mg every 2 weeks); 150Q4W, 150 mg every 4 weeks (with possible dose adjustment to 150 mg every 2 weeks); LDL‐C, low‐density lipoprotein cholesterol; NCEP ATP III TLC, National Cholesterol Education Program Adult Treatment Panel III Therapeutic Lifestyle Changes; Q2W, every 2 weeks; Q4W, every 4 weeks; R, randomization; W, week.
On‐site visits took place during the double‐blind period at weeks 0 (baseline, ie, the randomization visit), 4, 8, 9, 10, 11, 12, 16, and 24.
Patients in the alirocumab 150 mg Q4W or 75 mg Q2W treatment groups who did not achieve their target LDL‐C levels (<70 or <100 mg/dL, depending on CVD risk), or who did not achieve a reduction of ≥30% in LDL‐C level from baseline at week 8, had their alirocumab regimen changed to 150 mg Q2W at week 12 in a blinded fashion.
Patients also had the option of entering an open‐label treatment period after completion of the double‐blind treatment period. In this treatment period all patients received alirocumab 150Q4W at week 36 based on the investigator's judgment.
The primary efficacy endpoint was the percentage change in LDL‐C (calculated using the Friedewald equation) from baseline to week 24 in the intent‐to‐treat (ITT) population, using all LDL‐C values within 1 of the analysis windows up to week 24 regardless of adherence to treatment (ie, ITT approach). Efficacy endpoints were also assessed using an on‐treatment approach, using all LDL‐C values during the efficacy treatment period.
A hierarchical procedure was used to control type I error and handle multiple key secondary endpoints. Those endpoints included the percentage change in calculated LDL‐C from baseline to week 24 using the on‐treatment approach, the percentage change in calculated LDL‐C from baseline to week 12 (also averaged for weeks 9‐12), the proportion of patients achieving predefined LDL‐C targets of <70 or <100 mg/dL, depending on cardiovascular risk, at weeks 12 and 24, and the percentage change in other lipid parameters such as apolipoprotein B, non‐high‐density lipoprotein cholesterol, total cholesterol, lipoprotein(a) (Lp[a]), fasting triglycerides, high‐density lipoprotein cholesterol, and apolipoprotein A1 from baseline to weeks 12 and 24. All comparisons with the alirocumab 75 mg Q2W treatment arm were classed as other secondary endpoints.
Analyses of lipid samples were conducted by a central laboratory. Lp(a) was analyzed using an immunoturbidimetric assay on a Siemens BNII analyzer (Siemens, Erlangen, Germany), with a reference range of 1 to 30 mg/dL. If triglyceride values exceeded 400 mg/dL (4.52 mmol/L), LDL‐C was measured via β‐quantification rather than by calculation. (LDL‐C ultracentrifugation was performed using a Beckman Ultracentrifuge with an ultracentrifuge rotor, Type 50.4; LDL‐C concentration was assessed using a Beckman Coulter chemistry analyzer.) LDL‐C was also measured via the β‐quantification method at weeks 0 and 24 in all patients.
Safety was assessed primarily from the reporting of treatment‐emergent AEs (TEAEs), defined as those occurring during the period from first to last study drug injection plus 70 days or up to the first open‐label injection, whichever came first.
Certain events were classed as safety events of interest, requiring completion of a special electronic case report form (e‐CRF), including general allergic reactions, cardiovascular events, injection‐site reactions, hemolytic anemia, neurologic events, ophthalmologic events, and increased alanine aminotransferase (ALT) levels. See Appendix S1 for further details on safety events of interest and preferred terms for the adverse events categories.
To assess development of antidrug antibodies to alirocumab, blood samples were collected before study drug administration at baseline and scheduled clinic visits at weeks 4, 8, 12, 16, 24, and at the follow‐up visit. These samples were analyzed using a validated nonquantitative, titer‐based bridging immunoassay by Regeneron Pharmaceuticals, Inc (Tarrytown, NY), using a tiered approach involving 3 potential steps: initial screen, confirmation, and a titer measurement. Assay sensitivity was ~5.6 ng/mL based on the positive control monoclonal antibody, and the drug tolerance limit was 191 μg/mL of alirocumab for 500 ng/mL of monoclonal antibody positive control. Positive samples were tested for the presence of antidrug antibody using a validated, nonquantitative, competitive ligand‐binding assay with sensitivity based on a monoclonal positive control neutralizing antibody of 470 ng/mL. Drug tolerance limit was 547 ng/mL of alirocumab in neat serum for 500 ng/mL of monoclonal antibody positive control. Free PCSK9 levels were determined using a specific validated enzyme‐linked immunosorbent assay (Regeneron Pharmaceuticals, Tarrytown, NY). The lower limits of detection were 31.2 ng/mL.
A sample size of 39 patients (26 in alirocumab 150Q4W and 13 in placebo arms, respectively) was estimated to have 90% power to detect a between‐treatment‐group difference in mean percentage change in LDL‐C of 30%, with a 5% 2‐sided significance level and assuming a common standard deviation of 25%, and a 5% nonevaluable primary endpoint. To obtain additional safety data on the administration of a 150Q4W regimen in non‐statin‐treated patients, the total planned sample size was increased and rounded to 200 (100 for alirocumab 150Q4W, 50 for alirocumab 75Q2W, and 50 for placebo). Thus, the systematic allocation error was not anticipated to have an impact on the power of the study.
The primary efficacy analysis was conducted in the ITT population, which included all randomized patients with an evaluable primary endpoint. Analysis utilized a mixed‐effect model with repeated measures to account for missing data as used in previous alirocumab studies.23
Secondary lipid endpoints were analyzed as for the primary endpoint, except Lp(a) and triglycerides (analyzed by multiple imputation followed by a robust regression model) and LDL‐C goal achievement (analyzed by multiple imputation followed by logistic regression). The modified ITT population used for on‐treatment analyses included all randomized patients with an evaluable primary endpoint during the treatment period who had received at least 1 dose or part of a dose of study treatment.
The safety population included all randomized patients who had received at least 1 dose or part of a dose of study drug. Safety data were analyzed by descriptive statistics.
At weeks 0 and 12, an optional device‐handling questionnaire assessed experience of participants performing self‐injection using the alirocumab prefilled pen.
Participants rated 7 manipulations/steps to inject alirocumab/placebo (7‐point scale from “not easy at all”  to “extremely easy” ), how many clicks they heard during injection, satisfaction with duration of injection (7‐point scale from “extremely unsatisfied”  to “extremely satisfied” ), and the overall experience performing self‐injection (7‐point scale from “extremely unsatisfied”  to “extremely satisfied” ).
A total of 233 patients were randomly assigned to alirocumab 150Q4W (n=59), 75Q2W (n=116), and placebo (n=58) (Figure 1, Figure S1). The ITT, modified ITT, and safety populations comprised 230, 228, and 231 patients, respectively. A total of 158 (90.3%) randomized patients receiving alirocumab completed the 24‐week treatment period. Reasons for study discontinuation are given in Table S2.
Baseline characteristics and lipid parameters were generally balanced between groups (Table 1). A total of 90.1% of patients fulfilled the criteria for SAMS as the reason for statin discontinuation. The majority of patients with additional lipid‐lowering therapy received ezetimibe (60.1%) and/or fenofibrate (8.6%). Across the different treatment groups, 32.2% of patients received treatment with diet alone and 3.4% received nutraceuticals (Table 1).
Alirocumab (both dose regimens) maintained LDL‐C reductions from week 4 (first sampling point) until week 24 (Figure 2; Table 2).
Calculated LDL‐C mean (SE) absolute values from baseline (ITT analysis) (A) and free PCSK9 levels (B) over time (PK analysis). ΔW 9 to 12 defined as percentage change in calculated LDL‐C from baseline to averaged values from weeks 9 to 12 vs placebo in the ITT analysis; ΔW 24 defined as percentage change in calculated LDL‐C from baseline to week 24 vs placebo in the ITT analysis. 75Q2W indicates 75 mg every 2 weeks (with possible dose adjustment to 150 mg every 2 weeks); 150Q4W indicates150 mg every 4 weeks (with possible dose adjustment to 150 mg every 2 weeks); ITT, intent‐to‐treat; LDL‐C, low‐density lipoprotein cholesterol; LS, least‐squares; PCSK9, proprotein convertase subtilisin/kexin type 9; SE, standard error.
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