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

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

doi:10.1186/s13063-019-3846-x

Cited by 120 publications

(103 citation statements)

References 15 publications

(20 reference statements)

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“…Moreover, screening of a compound library of Food and Drug Administration-approved drugs revealed that the HIV type 1 (HIV-1) protease inhibitor lopinavir is active against MERS-CoV (21). This drug is currently tested in a clinical trial for the treatment of MERS-CoV in combination with interferon-␤ and ritonavir (22), which is used for pharmacological…”

Section: Discussionmentioning

confidence: 99%

The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus

Gordon

Tchesnokov

Feng

et al. 2020

Journal of Biological Chemistry

723

742

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Antiviral drugs for managing infections with human coronaviruses are not yet approved, posing a serious challenge to current global efforts aimed at containing the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Remdesivir (RDV) is an investigational compound with a broad spectrum of antiviral activities against RNA viruses, including SARS-CoV and Middle East respiratory syndrome (MERS-CoV). RDV is a nucleotide analog inhibitor of RNA-dependent RNA polymerases (RdRps).Here, we co-expressed the MERS-CoV nonstructural proteins nsp5, nsp7, nsp8, and nsp12 (RdRp) in insect cells as a part a polyprotein to study the mechanism of inhibition of MERS-CoV RdRp by RDV. We initially demonstrated that nsp8 and nsp12 form an active complex. The triphosphate form of the inhibitor (RDV-TP) competes with its natural counterpart ATP. Of note, the selectivity value for RDV-TP obtained here with a steady-state approach suggests that it is more efficiently incorporated than ATP and two other nucleotide analogues. Once incorporated at position i, the inhibitor caused RNA synthesis arrest at position i+3. Hence, https://www.jbc.org/cgi/

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Section: Discussionmentioning

confidence: 99%

The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus

Gordon

Tchesnokov

Feng

et al. 2020

Journal of Biological Chemistry

723

742

View full text Add to dashboard Cite

show abstract

“…Scientists previously confirmed that the protease inhibitors lopinavir and ritonavir, used to treat infection with human immunodeficiency virus (HIV) [83], could improve the outcome of MERS-CoV [84] and SARS-CoV [85] patients. It has reported that β-coronavirus viral loads of a COVID-19 patient in Korea significantly decreased after lopinavir/ritonavir (Kaletra®, AbbVie, North Chicago, IL, USA) treatment [86].…”

Section: Antiviral Treatmentsmentioning

confidence: 99%

The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak – an update on the status

et al. 2020

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An acute respiratory disease, caused by a novel coronavirus (SARS-CoV-2, previously known as 2019-nCoV), the coronavirus disease 2019 (COVID-19) has spread throughout China and received worldwide attention. On 30 January 2020, World Health Organization (WHO) officially declared the COVID-19 epidemic as a public health emergency of international concern. The emergence of SARS-CoV-2, since the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, marked the third introduction of a highly pathogenic and large-scale epidemic coronavirus into the human population in the twenty-first century. As of 1 March 2020, a total of 87,137 confirmed cases globally, 79,968 confirmed in China and 7169 outside of China, with 2977 deaths (3.4%) had been reported by WHO. Meanwhile, several independent research groups have identified that SARS-CoV-2 belongs to β-coronavirus, with highly identical genome to bat coronavirus, pointing to bat as the natural host. The novel coronavirus uses the same receptor, angiotensin-converting enzyme 2 (ACE2) as that for SARS-CoV, and mainly spreads through the respiratory tract. Importantly, increasingly evidence showed sustained human-to-human transmission, along with many exported cases across the globe. The clinical symptoms of COVID-19 patients include fever, cough, fatigue and a small population of patients appeared gastrointestinal infection symptoms. The elderly and people with underlying diseases are susceptible to infection and prone to serious outcomes, which may be associated with acute respiratory distress syndrome (ARDS) and cytokine storm. Currently, there are few specific antiviral strategies, but several potent candidates of antivirals and repurposed drugs are under urgent investigation. In this review, we summarized the latest research progress of the epidemiology, pathogenesis, and clinical characteristics of COVID-19, and discussed the current treatment and scientific advancements to combat the epidemic novel coronavirus.

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“…In an animal model of MERS-CoV infection, treatment with lopinavir/ritonavir or IFN-β1b was associated with virologic, histologic and clinical improvement versus placebo [191]. Lopinavir/ritonavir in combination with interferon beta 1-b is being tested in an RCT in MERS-CoV patients [192]. This combination was considered the second candidate in a WHO research prioritization list of therapeutic agents [193].…”

Section: Rationalementioning

confidence: 99%

Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19)

et al. 2020

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Background: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a rapidly spreading illness, Coronavirus Disease 2019 (COVID-19), affecting thousands of people around the world. Urgent guidance for clinicians caring for the sickest of these patients is needed. Methods:We formed a panel of 36 experts from 12 countries. All panel members completed the World Health Organization conflict of interest disclosure form. The panel proposed 53 questions that are relevant to the management of COVID-19 in the ICU. We searched the literature for direct and indirect evidence on the management of COVID-19 in critically ill patients in the ICU. We identified relevant and recent systematic reviews on most questions relating to supportive care. We assessed the certainty in the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, then generated recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. Recommendations were either strong or weak, or in the form of best practice recommendations. Results:The Surviving Sepsis Campaign COVID-19 panel issued 54 statements, of which 4 are best practice statements, 9 are strong recommendations, and 35 are weak recommendations. No recommendation was provided for 6 questions. The topics were: (1) infection control, (2) laboratory diagnosis and specimens, (3) hemodynamic support, (4) ventilatory support, and (5) COVID-19 therapy.Recommendation 9. For the acute resuscitation of adults with COVID-19 and shock, we suggest using a conservative over a liberal fluid strategy. Weak recommendation, low-quality evidence.

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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

Cited by 120 publications

References 15 publications

The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus

The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus

The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak – an update on the status

Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19)

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