Amarin Corporation plc (ADR) (NASDAQ:AMRN) announced that the U.S. Food and Drug Administration (FDA) agreed to an amendment of the company’s special protocol assessment (SPA) agreement for the REDUCE-IT cardiovascular outcomes study reaffirming concurrence on critical components of the revised study protocol and analysis plans and incorporating recommendations from the trial’s independent oversight committees.

Key new elements reflected in the company’s amendment include:

  • Finalized details of the statistical analysis plan covering both final and interim efficacy analyses;
  • Added a second pre-specified interim efficacy analysis at approximately 80% of the 1,612 primary cardiovascular events targeted for completion of the study; and
  • Expanded to over 30 the number of pre-specified secondary and tertiary endpoints in an effort to more fully capture the broad potential clinical effects of Vascepa® (icosapent ethyl) and the diversity of the patient population being studied.

The amendment does not change the primary endpoint or the overall size of the REDUCE-IT study or the company’s prior guidance on timing. Prospective study of additional endpoints could lead to improved patient care for specific groups within the diverse population studied in REDUCE-IT. The addition of a second interim efficacy analysis at approximately 80% completion is expected to facilitate the compilation of the final locked dataset at study end and potentially shorten the time needed to complete final analysis and final result reporting.

“This amendment reflects timely modification and fine tuning of an already robust clinical trial design and helps ensure that expectations are clear between all parties directly involved regarding the formalities of data presentation and analysis at trial completion and interim looks,” commented Steven Ketchum, Ph.D., chief scientific officer of Amarin. “Residual cardiovascular risk is high in the patient population being studied in REDUCE-IT. Because of this important unmet clinical need, the opportunity it presents and the years invested in this study, our goal is to promptly report and broadly publish the multiple findings anticipated from the study. We remain confident that REDUCE-IT is positioned for success.”

Statistical Analysis Plan Finalized

The primary endpoint of REDUCE-IT is the time from randomization to the first occurrence of a composite of adjudicated cardiovascular events (including cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina). Consistent with the protocol, patients in REDUCE-IT have been randomized in a 1:1 ratio to either the Vascepa plus statin treatment arm of the study or to the placebo plus statin treatment arm of the study. The time to the first occurrence of the composite endpoint will be compared between arms.

REDUCE-IT is designed to provide 90% power to detect a 15% relative risk reduction between arms. The final analysis for the comparison of the time to onset of the first primary cardiovascular event between the treatment and control groups will be considered significant if the two-sided p-value is less than 0.0422.

The planned interim analyses by the DMC are based on a group sequential design with classic O’Brien-Fleming boundaries generated using the typical Lan-DeMets alpha-spending function. The use of the spending function allows for possible deviations from the target event numbers at the times of the respective interim analyses. As is standard with similar statistical assessments and permitted by study protocol, should either the first or second planned interim efficacy analysis include slightly more or slightly fewer adjudicated events, the target p-value stopping boundaries will be adjusted accordingly. The statistical analysis plan for REDUCE-IT does not include futility analysis at either interim analysis.

Amarin will remain blinded to the interim and ongoing results of the REDUCE-IT study as well as to any interim p-values or other statistical information until after the study is stopped and the database is locked, either at the final analysis or, in the event of a determination by the independent DMC of overwhelming efficacy, at an interim analysis. Guidelines for the independent DMC to recommend stopping the study at an interim analysis for overwhelming efficacy require that the study achieve the applicable pre-specified statistical significance threshold for the primary endpoint for that interim analysis, and generate robust efficacy evidence on selected subgroup analyses for the primary endpoint and certain pre-specified secondary outcome measures, to support an overall favorable benefit/risk profile. Given the high thresholds of overwhelming efficacy required prior to a DMC recommending an early stop to a cardiovascular outcomes trial like REDUCE-IT, Amarin continues to expect that the DMC’s 60% and 80% interim analyses will each result in a recommendation to continue the REDUCE-IT study as planned.

First Efficacy Analysis Anticipated Within 90 Days

As previously announced, late in the first quarter of 2016, the onset of approximately 60% of the target aggregate number of primary cardiovascular events triggered formal preparation for a protocol-specified interim efficacy and safety analysis by the DMC. The study has undergone multiple prior safety reviews by the DMC with each such review resulting in a DMC recommendation that REDUCE-IT continue as planned. The upcoming interim analysis in the September-October timeframe will include the first review of unblinded efficacy data by the DMC.

To be considered statistically significant at this interim look, based on the assumption that exactly 60% of target events are adjudicated and available for assessment by the DMC, the primary efficacy analysis must show that the two-sided p-value for relative risk reduction on the primary endpoint is less than 0.0076 in favor of the Vascepa plus statin treatment arm.

Second Efficacy Analysis Added

Preparations for the second planned interim efficacy analysis will be triggered by the onset of approximately 80% of the target aggregate number of primary cardiovascular events in the study. Based on historical event rates, Amarin anticipates that the onset of approximately 80% of events will occur in the first half of 2017, with the second pre-specified interim efficacy and safety analysis by the DMC expected around mid-2017.

Assuming that exactly 80% of the target primary events have been adjudicated and included in the second interim efficacy analysis by the DMC, the primary efficacy analysis must show that the two-sided p-value for relative risk reduction on the primary endpoint is less than 0.0220 in favor of the Vascepa plus statin treatment arm.

Final Efficacy Analysis Anticipated in 2018

The final analysis will be conducted from a locked database after notification that 1,612 primary cardiovascular events have been formally adjudicated. Amarin currently expects that the final event will occur in the second half of 2017, with top-line data announcement anticipated in 2018.

If the study is continued until the planned end, subsequent to the two interim efficacy analyses by the DMC, the final analysis for the comparison of the time to onset of first primary cardiovascular event between the treatment and control groups will be considered significant if the two-sided p-value is less than 0.0422. This final p-value reflects accepted statistical methodology for adjustment of multiple analyses.

Secondary and Tertiary Endpoints Expanded

Recognizing the potential to observe broad beneficial impact from treatment with Vascepa in REDUCE-IT, the study’s statistical analysis plan now includes more than 30 pre-specified secondary and tertiary endpoints designed to capture multiple potential drug effects in multiple additional sub-populations. Such pre-specified endpoints are designed to better assess the potential therapeutic benefits of Vascepa across multiple patient subpopulations and support a variety of related new publications. We anticipate these publications could help us improve patient care by supporting informed medical decisions in the treatment of cardiovascular disease.

“The data generated by this trial, if successful, could define how residual cardiovascular risk is treated in the studied patient population,” added Dr. Ketchum. “As a result, the comprehensive value of REDUCE-IT data could come not just from a statistically significant reduction in risk for the overall patient population, which is paramount, but also from the potential for consistent and robust REDUCE-IT data across multiple secondary outcome measures and patient subgroups. We seek efficacy and safety results that are unequivocal, robust, and consistent to provide the strongest foundation from which to seek expanded labeling for Vascepa.” (Original Source)

Shares of Amarin are down nearly 7% to $3.10 in early trading Thursday. AMRN has a 1-year high of $3.36 and a 1-year low of $1.24. The stock’s 50-day moving average is $2.29 and its 200-day moving average is $1.81.

On the ratings front, Amarin has been the subject of a number of recent research reports. In a report issued on July 7, Jefferies Co. analyst Hugo Ong reiterated a Buy rating on AMRN, with a price target of $3.50, which represents a potential upside of 5.4% from where the stock is currently trading. Separately, on May 27, Oppenheimer’s Carlos Solorzano assigned a Hold rating to the stock .

According to TipRanks.com, which ranks over 7,500 financial analysts and bloggers to gauge the performance of their past recommendations, Hugo Ong and Carlos Solorzano have a total average return of 22.9% and 25.3% respectively. Ong has a success rate of 75.0% and is ranked #488 out of 4085 analysts, while Solorzano has a success rate of 61.5% and is ranked #549.

Amarin Corp. Plc is a biopharmaceutical company, which engages in the commercialization and development of therapeutics to improve cardiovascular health. Its product, Vascepa capsules, is use as an adjunct to diet to reduce triglyceride levels in adult patients with severe hypertriglyceridemia.