Study Design and Oversight

Table 1. Table 1. Features of the Parent Trials.

The OSLER-1 trial was an open-label, randomized, controlled study conducted at 190 centers that participated in at least one of five phase 2 studies of evolocumab.14-19 Analogously, the OSLER-2 trial was an open-label, randomized, controlled study conducted at 305 centers that participated in at least one of seven phase 3 studies of evolocumab (Table 1).9-13,20,21

The protocols for the OSLER-1 and OSLER-2 trials were approved by the relevant ethics committee at each participating site and are available with the full text of this article at NEJM.org. Amgen sponsored and designed the two trials and was responsible for data collection and analysis. The first draft of the manuscript was written by the first and last authors. All the coauthors participated in subsequent revisions of the manuscript. The academic authors had full access to the data and vouch for their accuracy and completeness and for the analyses as presented and for the fidelity of this report to the trial protocols. The first and last authors made the decision to submit the manuscript for publication.

Patients

There was variation in the clinical characteristics of the patients enrolled in the 12 parent studies (Table 1). Patients who had completed one of the parent studies could enroll in one of the OSLER extension studies, provided that they did not have an adverse event that led to the discontinuation of a study drug during the parent trial, did not have an unstable medical condition (in the judgment of the investigator), and were not expected to need unblinded lipid measurements or adjustment of background lipid-regulating therapy during the first 12 weeks of participation in the OSLER trials. All patients provided written informed consent before enrollment in the extension study.

Randomization, Study Treatment, and Follow-up

Regardless of the study-group assignment in the parent study, eligible patients were randomly assigned at the last visit in the parent study, or as soon as possible thereafter, to receive either evolocumab plus standard therapy (evolocumab group) or standard therapy alone (standard-therapy group) in a 2:1 ratio. Randomization was performed centrally with the use of an interactive voice-response or Web-response system, with stratification in OSLER-1 according to the study-group assignment in the parent trial and in OSLER-2 according to the parent trial and study-drug dose frequency in the parent trial.

Evolocumab was administered subcutaneously at a dose of 420 mg once a month in OSLER-1 and, on the basis of patient choice, at a dose of either 140 mg every 2 weeks or 420 mg once a month in OSLER-2. Both regimens have been shown to reduce LDL cholesterol levels by approximately 60% in this patient population.9-13 All patients, investigators, and care providers were aware of the randomized treatment assignments; no placebo was used for the standard-therapy group. Standard-of-care background therapy in the two groups was based on local guidelines for the treatment of LDL cholesterol.

To avoid inadvertent unblinding of the parent study, lipid results from the central laboratory were unblinded only after the week 12 visit in the OSLER trials. Adjustments to background lipid-lowering therapies were discouraged. The study-visit schedules were similar in OSLER-1 and OSLER-2. Common to the two trials, patients were to have in-person clinic visits on day 1 and then quarterly at weeks 12, 24, 36, and 48. At other time points, patients in the evolocumab group had in-person visits, whereas patients in the standard-therapy group had telephone contact only.

The trial protocols specified that randomized treatment was to conclude at week 56 in OSLER-1 and at week 48 in OSLER-2. After the end of randomized treatment, all patients were to receive open-label evolocumab for longer-term, nonrandomized assessment of efficacy and safety.

End Points

The primary end point in the two trials was the incidence of adverse events. Additional safety end points included serious adverse events, adverse events leading to the discontinuation of the study drug (for patients in the evolocumab group), abnormalities in creatine kinase levels and liver-function testing, and the development of binding and neutralizing antibodies against evolocumab, which were assayed as reported previously.22

The secondary end point was the percent change in the LDL cholesterol level. Other efficacy lipid measurements included non–high-density lipoprotein (HDL) cholesterol, total cholesterol, triglycerides, HDL cholesterol, apolipoproteins A1 and B, and lipoprotein(a). Lipids were measured at a central laboratory (Medpace Reference Laboratories, Cincinnati, and Leuven, Belgium) after a fast of at least 9 hours. The LDL cholesterol level was calculated with the use of the Friedewald formula.23

A prespecified exploratory outcome was the incidence of adjudicated cardiovascular events, which was ascertained over the course of the study. (Definitions are provided in the Methods section in the Supplementary Appendix, available at NEJM.org.) Cardiovascular events included death, coronary events (myocardial infarction, unstable angina requiring hospitalization, or coronary revascularization), cerebrovascular events (stroke or transient ischemic attack), and heart failure requiring hospitalization. Potential cardiovascular events were adjudicated by the central clinical-events committee at the Thrombolysis in Myocardial Infarction (TIMI) Study Group in Boston, whose members were unaware of treatment assignments. All cardiovascular events were combined in an exploratory composite analysis that was based on the events that were prespecified in the trial protocols. In addition, all cardiovascular end points except for heart failure were combined into a post hoc composite of major adverse cardiovascular events.

Statistical Analysis

The timing of the analysis in this report was triggered by a planned submission of a biologics license application to the Food and Drug Administration. The authors decided to present these data to the scientific community at the next major scientific meeting. In anticipation of that meeting, the data were updated with cardiovascular outcomes that were based on adjudicated data through January 21, 2015, along with demographic, lipid, and safety data that were based on cleaned data through October 31, 2014.

The data from the OSLER-1 and OSLER-2 trials were combined into a single analysis set. Data for patients were censored at the start of the uncontrolled period in each study. Lipid measurements were summarized with the use of means or medians, and treatment differences were tested with the use of the Wilcoxon rank-sum test without adjustment for multiplicity. We used the Kaplan–Meier method to estimate time-to-event cumulative incidence on an intention-to-treat basis. Safety was described according to the incidence of adverse events. The minimum LDL cholesterol category for a patient was determined by the minimum value observed in the randomized, controlled period of the studies. We used the log-rank test to analyze the difference in cumulative incidence curves for cardiovascular events. Hazard ratios were estimated with the use of Cox proportional-hazard models without stratification. Statistical analyses were performed with the use of SAS software, version 9.3, and R software, version 3.0.3.