Treatment of Middle East Respiratory Syndrome with a combination of lopinavir-ritonavir and interferon-β1b (MIRACLE trial): study protocol for a randomized controlled trial

Abstract

Background: It had been more than 5 years since the first case of Middle East Respiratory Syndrome coronavirus infection (MERS-CoV) was recorded, but no specific treatment has been investigated in randomized clinical trials. Results from in vitro and animal studies suggest that a combination of lopinavir/ritonavir and interferon-β1b (IFN-β1b) may be effective against MERS-CoV. The aim of this study is to investigate the efficacy of treatment with a combination of lopinavir/ritonavir and recombinant IFN-β1b provided with standard supportive care, compared to treatment with placebo provided with standard supportive care in patients with laboratory-confirmed MERS requiring hospital admission.

Methods: The protocol is prepared in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines. Hospitalized adult patients with laboratory-confirmed MERS will be enrolled in this recursive, two-stage, group sequential, multicenter, placebo-controlled, double-blind randomized controlled trial. The trial is initially designed to include 2 two-stage components. The first two-stage component is designed to adjust sample size and determine futility stopping, but not efficacy stopping. The second two-stage component is designed to determine efficacy stopping and possibly readjustment of sample size. The primary outcome is 90-day mortality.

Discussion: This will be the first randomized controlled trial of a potential treatment for MERS. The study is sponsored by King Abdullah International Medical Research Center, Riyadh, Saudi Arabia. Enrollment for this study began in November 2016, and has enrolled thirteen patients as of Jan 24-2018.

Trial registration: ClinicalTrials.gov, ID: NCT02845843 . Registered on 27 July 2016.

Keywords: Antiviral; Clinical trial; Coronavirus; Interferon-β1b; Lopinavir/ritonavir; MERS; Saudi Arabia.

Fig. 1

Schedule of enrollment, intervention and assessment for the MIRACLE trial according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) template [27]. Arrows indicate periods of continuous or daily collection or assessment, whereas “X” indicates collection on specific days. * ± 2 days except D0 and D3. ^‡Assessed by the clinical pharmacist. ^§Tests on sputum, tracheal aspirate, broncheoalveolar lavage and nasopharyngeal swab to be continued twice weekly until two consecutive tests are negative. ^||Mandatory for intubated patients, optional for non-intubated patients. ^¶Hemoglobin, white blood cells, neutrophils, lymphocytes and platelets. ^#Blood urea nitrogen, creatinine, potassium, sodium, chloride, bicarbonate, glucose and albumin. ∞Serum bilirubin, gamma-glutamyl transferase, alanine transaminase and aspartate aminotransferase. **Serum thyroxine, triiodothyronine and thyroid-stimulating hormone. Abbreviations: ACTH adrenocorticotropic hormone, MERS-CoV Middle East Respiratory Syndrome coronavirus, SOFA Sequential Organ Failure Assessment

Fig. 2

Schematic illustration of the MIRACLE trial design with 2 two-stage components with two interim analyses and one final analysis. Raw p values are obtained from the one-sided chi-square for difference in proportion at each interim analysis