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.

The MIRACLE trial is a recursive, two-stage, group sequential, multicenter, randomized, placebo-controlled, double-blind trial. The trial includes hospitalized patients who are 18 years old or older with laboratoryconfirmed MERS in addition to evidence of acute organ dysfunction that is judged related to MERS. Inclusion and exclusion criteria have been detailed in a previously published protocol manuscript [3] . Patients are randomized to receive lopinavir/ritonavir and recombinant interferon-β1b or placebo. Randomization is stratified according to center and according to whether the patients require mechanical ventilation (invasive or noninvasive) at the time of enrollment, as mechanical ventilation is a major, but pragmatic, surrogate for severity of illness. The study interventions continue for 14 days or until hospital discharge. Patients are followed up daily until day 28 or hospital discharge and then at day 90.