Treatment of Middle East respiratory syndrome with a combination of lopinavir/ritonavir and interferon-ß1b (MIRACLE trial): statistical analysis plan for a recursive two-stage group sequential randomized controlled trial

Arabi, Yaseen M.; Asiri, Ayed Y.; Assiri, Abdullah M.; Aziz Jokhdar, Hani A.; Alothman, Adel; Balkhy, Hanan H.; AlJohani, Sameera; Al Harbi, Shmeylan; Kojan, Suleiman; Al Jeraisy, Majed; Deeb, Ahmad M.; Memish, Ziad A.; Ghazal, Sameeh; Al Faraj, Sarah; Al-Hameed, Fahad; AlSaedi, Asim; Mandourah, Yasser; Al Mekhlafi, Ghaleb A.; Sherbeeni, Nisreen Murad; Elzein, Fatehi Elnour; Almotairi, Abdullah; Al Bshabshe, Ali; Kharaba, Ayman; Jose, Jesna; Al Harthy, Abdulrahman; Al Sulaiman, Mohammed; Mady, Ahmed; Fowler, Robert A.; Hayden, Frederick G.; Al-Dawood, Abdulaziz; Abdelzaher, Mohamed; Bajhmom, Wail; Hussein, Mohamed A.

With the exception of the analysis of the primary outcome, all other analyses will be tested using regular statistical methods and will be two-sided. A secondary adjusted analysis will be conducted using multiple logistic regression analysis, in which death within 90 days will be modeled as the dependent variable, and a set of baseline variables that are strongly believed to affect the outcome of MERS will be included as independent variables. Those variables will include at minimum the following: age, community-acquired versus hospital-acquired infection, mechanical ventilation, center, and Sequential Organ Failure Assessment score. Ninety-day median survival time will be summarized and reported using Kaplan-Meier curves and will be compared between the study groups using the log-rank test (Additional file 1: Figure S1 ). Analysis of secondary outcomes will be compared in the intention-to-treat cohort only. Subgroup analyses will be conducted if patient numbers permit (e.g., no fewer than five patients in subgroups of interest) in a priori defined subgroups (Additional file 1: Table S5 ). Multivariable logistic regression will be used to report the results of tests of interactions for these subgroups.