Treatment of Middle East respiratory syndrome with a combination of lopinavir/ritonavir and interferon-β1b (MIRACLE trial): statistical analysis plan for a recursive two-stage group sequential randomized controlled trial

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

Abstract

The MIRACLE trial (MERS-CoV Infection tReated with A Combination of Lopinavir/ritonavir and intErferon-β1b) investigates the efficacy of a combination therapy of lopinavir/ritonavir and recombinant interferon-β1b provided with standard supportive care, compared to placebo provided with standard supportive care, in hospitalized patients with laboratory-confirmed MERS. The MIRACLE trial is designed as a recursive, two-stage, group sequential, multicenter, placebo-controlled, double-blind randomized controlled trial. The aim of this article is to describe the statistical analysis plan for the MIRACLE trial. The primary outcome is 90-day mortality. The primary analysis will follow the intention-to-treat principle. The MIRACLE trial is the first randomized controlled trial for MERS treatment. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02845843. Registered on 27 July 2016.

Keywords: Antiviral; Clinical trial; Coronavirus; Interferon-β1b; Lopinavir/ritonavir; MERS; Protocol; Statistical analysis plan.

Conflict of interest statement

The authors declare that they have no competing interests. YA and FGH are unpaid consultants on antivirals active for MERS for Gilead Sciences, SAB Biotherapeutics, and Regeneron.

Figures

Fig. 1
Fig. 1
CONSORT flow chart for the MIRACLE trial

References

    1. Arabi YM, Balkhy HH, Hayden FG, Bouchama A, Luke T, Baillie JK, Al-Omari A, Hajeer AH, Senga M, Denison MR, et al. Middle East respiratory syndrome. N Engl J Med. 2017;376:584–594. doi: 10.1056/NEJMsr1408795.
    1. Arabi Y, Shalhoub S, Mandourah Y, Al-Hameed F, Al-Omari A, Al Qasim E, Jose J, Alraddadi B, Almotairi A, Al Khatib K, Abdulmomen A, Qushmaq I, Sindi AA, Mady A, Solaiman O, Al-Raddadi R, Maghrabi K, Ragab A, Al Mekhlafi GA, Balkhy HH, Al Harthy A, Kharaba A, Gramish JA, Al-Aithan AM, Al-Dawood A, Merson L, Hayden FG, Fowler R, Saudi Critical Care Trials Group. Ribavirin and interferon therapy for critically ill patients with the Middle East respiratory syndrome: a multicenter observational study, Clin Infect Dis 2019; ciz544. doi: 10.1093/cid/ciz544.
    1. Arabi YM, Alothman A, Balkhy HH, Al-Dawood A, AlJohani S, Al Harbi S, Kojan S, Al Jeraisy M, Deeb AM, Assiri AM, et al. Treatment of Middle East respiratory syndrome with a combination of lopinavir-ritonavir and interferon-beta1b (MIRACLE trial): study protocol for a randomized controlled trial. Trials. 2018;19:81. doi: 10.1186/s13063-017-2427-0.
    1. Chang M. Adaptive design theory and implementation using SAS and R. 2. Boca Raton: Chapman & Hall/CRC; 2014. pp. 153–180.
    1. Liu Q, Anderson KM, Pledger GW. Benefit–risk evaluation of multi-stage adaptive designs. Seq Anal. 2004;23:317–331. doi: 10.1081/SQA-200027049.
    1. US Food and Drug Administration (FDA) Draft guidance for industry on enrichment strategies for clinical trials to support approval of human drugs and biological products; availability. 2012.
    1. Wassmer G, Eisebitt R, Coburger S. Flexible interim analyses in clinical trials using multistage adaptive test designs. Drug Inf J. 2001;35:1131–1146. doi: 10.1177/009286150103500410.
    1. Schafer H, Muller HH. Modification of the sample-size and the schedule of interim analyses in survival trials based on data inspections. Stat Med. 2001;20:3741–3751. doi: 10.1002/sim.1136.
    1. Moher D, Hopewell S, Schulz KF, Montori V, Gotzsche PC, Devereaux PJ, Elbourne D, Egger M, Altman DG. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340:c869. doi: 10.1136/bmj.c869.
    1. Schulz KF, Altman DG, Moher D, Group C CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340:c332. doi: 10.1136/bmj.c332.
    1. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use: Good Clinical Practice (GCP) guideline. .
    1. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH): statistical principles for clinical trials. .
    1. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use: E3 - structure and content of clinical study reports. .
    1. Gamble C, Krishan A, Stocken D, Lewis S, Juszczak E, Dore C, Williamson PR, Altman DG, Montgomery A, Lim P, et al. Guidelines for the content of statistical analysis plans in clinical trials. JAMA. 2017;318:2337–2343. doi: 10.1001/jama.2017.18556.
    1. Srivastava DK, Rai SN, Pan J. Robustness of an odds-ratio test in a stratified group sequential trial with a binary outcome measure. Biom J. 2007;49:351–364. doi: 10.1002/bimj.200610265.
    1. Rubin DB. Multiple imputation after 18+ years. J Am Stat Assoc. 1996;91:473–489. doi: 10.1080/01621459.1996.10476908.
    1. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B Methodol. 1995;57:289–300.

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj