Study Design
ODYSSEY MONO was a randomized, double-blind, double-dummy, active-controlled (ezetimibe), parallel-group study to investigate the efficacy and safety of alirocumab over 24 weeks in 100 patients with hypercholesterolemia on no LLT. Inclusion criteria included patients with an LDL-C between 100 mg/dl (≥2.6 mmol/l) and 190 mg/dl (<4.9 mmol/l; inclusive) and not on LLT. In addition, patients needed to have moderate CV risk defined as a 10-year risk of fatal CV events ≥1% and <5% based on the European Systematic Coronary Risk Estimation (SCORE).[19] Key exclusion criteria were established coronary heart disease or coronary heart disease risk equivalents defined as manifestations of noncoronary forms of atherosclerotic disease (peripheral arterial disease, abdominal aortic aneurysm and carotid artery disease), use of any LLT within 4 weeks or a fibrate within 6 weeks of the screening visit, fasting serum triglycerides >400 mg/dl (>4.52 mmol/l) during the screening period and systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg at screening (week -2) or randomization (week 0) visits.[18]
Institutional Review Boards or Ethics Boards approved the study protocol at all participating research sites. The study complied with the International Conference on Harmonization Good Clinical Practice Guidelines and all applicable local regulations. All patients provided written informed consent.
Patients were randomized in a 1:1 ratio to alirocumab 75 mg sc. Q2W plus ezetimibe placebo po. q.d. (alirocumab group) or alirocumab placebo sc. Q2W plus ezetimibe 10 mg po. q.d. (ezetimibe group). The alirocumab dosing was continued from week 0 through to week 24 unless the week-8 LDL-C was ≥100 mg/dl (≥2.5 mmol/l), in which case the alirocumab dose was to be increased to 150 mg sc. Q2W from week 12 to week 24 (last injection at week 22 in both cases). Due to an administrative error, blinded uptitration actually occurred if week-8 LDL-C was ≥70 mg/dl (≥1.8 mmol/l). Both doses of alirocumab were self-administered by autoinjector. Blood samples for multiple parameters were obtained at weeks 0, 4, 8, 12, 16, 24 and 32 (Figure 1). The primary end point was the percentage change in LDL-C from baseline to week 24 and major secondary end points included the percentage change in LDL-C from baseline to week 12, the percentage change in ApoB, ApoA1, Lp(a), non-HDL-cholesterol (non-HDL-C), total cholesterol, HDL-C, triglycerides and HbA1c from baseline to weeks 12 and 24. Safety end points were adverse events (AEs; including adjudicated CV events), laboratory data, injection site reactions and vital signs assessed throughout the study. Other end points included serum alirocumab concentrations and antialirocumab antibodies also assessed throughout the study. Fifty-two patients were enrolled in the alirocumab group and 51 into the ezetimibe group at eight centers worldwide (USA, Belgium, Finland and The Netherlands). A total sample size of 90 patients (45 in each group) was calculated to have 95% power to detect a difference in mean percentage change in LDL-C of 20% with a 0.05 two-sided significance level assuming a common standard deviation of 25% and a 5% nonevaluable primary end point.
Figure 1.
Study protocol. Due to an error in the interactive voice responsive system, uptitration at week 12 occurred if LDL-C at W8 was ≥70 mg/dl, not the protocol-specified ≥100 mg/dl. EOT: End of treatment; EZE: Ezetimibe; LDL-C: LDL-cholesterol, NCEP-ATP III: National Cholesterol Education Program Adult Treatment Panel III; Q2W: Every 2 weeks; R: Randomization; W: Week. Adapted with permission from [18].
Data Analysis
The primary efficacy analysis population was the intent-to-treat (ITT) population, defined as the randomized population that actually received at least one dose or partial dose of investigational medicinal product (IMP) and had both the baseline and at least one subsequent LDL-C value. The ITT population included all patients and laboratory assessments regardless of whether the patient was on or off double-blind IMP or regardless of the timing of laboratory samples. The safety population consisted of the randomized population who actually received at least one dose or partial dose of IMP analyzed according to the treatment actually received. Safety analysis (AEs [including adjudicated CV events], laboratory parameters, injection site reactions and vital signs) was descriptive, based on the safety population. The safety analysis focused on the treatment-emergent AE (TEAE) period, defined as the time from the first double-blind dose of the IMP to the last double-blind dose of the IMP injection plus 70 days (10 weeks). The modified ITT (mITT) or 'on-treatment' population included all subjects with a baseline and postbaseline LDL-C that occurred within a prespecified time window of having received the study IMP.
Future Cardiol. 2015;11(1):27-37. © 2015 Future Medicine Ltd.
