MERS-CoV Infection tReated With A Combination of Lopinavir /Ritonavir and Interferon Beta-1b (MIRACLE)

MERS-CoV Infection tReated With A Combination of Lopinavir /Ritonavir and Interferon Beta-1b: a Multicenter, Placebo-controlled, Double-blind Randomized Trial

This is a placebo-controlled clinical trial to assess the efficacy and safety of a combination of lopinavir/ritonavir and Interferon beta-1b in hospitalized patients with MERS.

Study Overview

• Status: Completed
• Conditions: Middle East Respiratory Syndrome Coronavirus (MERS-CoV)
• Intervention / Treatment: Drug: Combination of Lopinavir /Ritonavir and Interferon beta-1b; Drug: Placebo

Detailed Description

The aim of this study is to investigate the efficacy and safety of lopinavir /ritonavir and recombinant Interferon beta-1b combination given with optimal supportive care compared to placebo with optimal supportive care for patients with laboratory-confirmed MERS-CoV infection requiring hospital admission.

• Study Type: Interventional
• Enrollment (Actual): 95
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Saudi Arabia
  • Riyadh, Saudi Arabia, 11426
    • Intensive Care Unit, King Abdulaziz Medical City, National Guard Health Affairs
  • Riyadh, Saudi Arabia, 22490
    • King Abdullah International Medical Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria at eligibility assessment

1. Adult (defined as ≥18 years of age);
2. Laboratory confirmation of MERS-CoV infection by reverse-transcription polymerase chain reaction (RT-PCR) from any diagnostic sampling source; and
3. New organ dysfunction that is judged to related to MERS including: hypoxia defined as requirement of supplemental oxygen to maintain oxygen saturations >90%, hypotension (systolic blood pressure<90 mmHg) or need for vasopressor/inotropic medication, renal impairment (increase of creatinine by 50% from baseline, glomerular filtration rate reduction by >25% from baseline or urine output of <0.5 ml/kg for 6 hours - Risk stage by RIFLE criteria), neurologic (reduction of Glasgow Coma Scale by 2 or more, i.e. 13 or lower of 15 points), thrombocytopenia (<150,000 platelets/mm3) or gastrointestinal symptoms that requires hospitalization (e.g. severe nausea, vomiting, diarrhea or/and abdominal pain).

Exclusion criteria at eligibility assessment

1. Suicidal ideation based on history (contraindication to interferon (IFN)-β1b);
2. Known allergy or hypersensitivity reaction to lopinavir/ritonavir or to recombinant IFN-β1b, including, but not limited to, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, urticaria or angioedema;
3. Elevated alanine aminotransferase (ALT) >5 fold the upper limit in the hospital's laboratory;
4. Use of medications that are contraindicated with lopinavir/ritonavir and that cannot be replaced or stopped during the study period, such as CYP3A inhibitors;
5. Pregnancy - eligible and consenting female participants in childbearing age will be tested for pregnancy before enrollment in the study;
6. Known HIV infection, because of concerns about the development of resistance to lopinavir/ritonavir if used without combination with other anti-HIV drugs; or
7. Patient likely to be transferred to a non-participating hospital within 72 hours.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Combination of Lopinavir /Ritonavir and IntErferon Beta 1B; Lopinavir /Ritonavir 400mg +100 mg / ml twice daily for 14 days and Interferon beta-1b 0.25 mg subcutaneous every alternate day for 14 days	Drug: Combination of Lopinavir /Ritonavir and Interferon beta-1b; Lopinavir /Ritonavir 400mg +100 mg / ml twice daily for 14 days and Interferon beta-1b 0.25 mg subcutaneous every alternate day for 14 days
Placebo Comparator: Placebo; Same characteristics as Lopinavir /Ritonavir and Interferon beta-1b to maintain blinding	Drug: Placebo; Same characteristics as Lopinavir /Ritonavir and Interferon beta-1b to maintain blinding

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
90-day mortality	90-day

Secondary Outcome Measures

Outcome Measure	Time Frame
28-day mortality	28-day
Organ support-free days (e.g., supplemental O2, ventilator, extracorporeal membrane oxygenation (ECMO), renal replacement and vasopressors)	28 days
RT-PCR cycle threshold value in the lower respiratory samples	At randomization and every 3 days afterwards, until 2 consecutive samples are negative or reaching a maximum of 90 days
Sequential organ failure assessment (SOFA) scores	Days 0, 3, 7, 14, 21 and 28
ICU-free days	Number of days in which patients are not being cared for in the ICU during the first 28 days after enrollment
Length of stay in hospital	Up to one year from enrollment
Number of Patients with Adverse drug reactions related to the treatment	From enrollment to 28 day
Karnofsky Performance Scale	90-day
ICU mortality	Up to one year from enrollment
Hospital mortality	Up to one year from enrollment

Collaborators and Investigators

• Sponsor: King Abdullah International Medical Research Center

Publications and helpful links

General Publications

• Arabi YM, Asiri AY, Assiri AM, Abdullah ML, Aljami HA, Balkhy HH, Al Jeraisy M, Mandourah Y, AlJohani S, Al Harbi S, Jokhdar HAA, Deeb AM, Memish ZA, Jose J, Ghazal S, Al Faraj S, Al Mekhlafi GA, Sherbeeni NM, Elzein FE, Hayden FG, Fowler RA, AlMutairi BM, Al-Dawood A, Alharbi NK. Heterogeneity of treatment effect of interferon-beta1b and lopinavir-ritonavir in patients with Middle East respiratory syndrome by cytokine levels. Sci Rep. 2022 Oct 28;12(1):18186. doi: 10.1038/s41598-022-22742-8.
• Arabi YM, Asiri AY, Assiri AM, Balkhy HH, Al Bshabshe A, Al Jeraisy M, Mandourah Y, Azzam MHA, Bin Eshaq AM, Al Johani S, Al Harbi S, Jokhdar HAA, Deeb AM, Memish ZA, Jose J, Ghazal S, Al Faraj S, Al Mekhlafi GA, Sherbeeni NM, Elzein FE, Al-Hameed F, Al Saedi A, Alharbi NK, Fowler RA, Hayden FG, Al-Dawood A, Abdelzaher M, Bajhmom W, AlMutairi BM, Hussein MA, Alothman A; Saudi Critical Care Trials Group. Interferon Beta-1b and Lopinavir-Ritonavir for Middle East Respiratory Syndrome. N Engl J Med. 2020 Oct 22;383(17):1645-1656. doi: 10.1056/NEJMoa2015294. Epub 2020 Oct 7.
• Arabi YM, Asiri AY, Assiri AM, Aziz Jokhdar HA, Alothman A, Balkhy HH, AlJohani S, Al Harbi S, Kojan S, Al Jeraisy M, Deeb AM, Memish ZA, Ghazal S, Al Faraj S, Al-Hameed F, AlSaedi A, Mandourah Y, Al Mekhlafi GA, Sherbeeni NM, Elzein FE, Almotairi A, Al Bshabshe A, Kharaba A, Jose J, Al Harthy A, Al Sulaiman M, Mady A, Fowler RA, Hayden FG, Al-Dawood A, Abdelzaher M, Bajhmom W, Hussein MA; and the Saudi Critical Care Trials group. Treatment of Middle East respiratory syndrome with a combination of lopinavir/ritonavir and interferon-beta1b (MIRACLE trial): statistical analysis plan for a recursive two-stage group sequential randomized controlled trial. Trials. 2020 Jan 3;21(1):8. doi: 10.1186/s13063-019-3846-x.
• Arabi YM, Alothman A, Balkhy HH, Al-Dawood A, AlJohani S, Al Harbi S, Kojan S, Al Jeraisy M, Deeb AM, Assiri AM, Al-Hameed F, AlSaedi A, Mandourah Y, Almekhlafi GA, Sherbeeni NM, Elzein FE, Memon J, Taha Y, Almotairi A, Maghrabi KA, Qushmaq I, Al Bshabshe A, Kharaba A, Shalhoub S, Jose J, Fowler RA, Hayden FG, Hussein MA; And the MIRACLE trial group. 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 Jan 30;19(1):81. doi: 10.1186/s13063-017-2427-0.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2016
• Primary Completion (Actual): May 1, 2020
• Study Completion (Actual): May 1, 2020

Study Registration Dates

• First Submitted: June 20, 2016
• First Submitted That Met QC Criteria: July 23, 2016
• First Posted (Estimate): July 27, 2016

Study Record Updates

• Last Update Posted (Actual): May 20, 2020
• Last Update Submitted That Met QC Criteria: May 18, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: Clinical trial; Ritonavir; MERS-CoV; Lopinavir; Interferon beta; Middle East Respiratory Syndrome Coronavirus
• Additional Relevant MeSH Terms: Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Coronavirus Infections; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antineoplastic Agents; Immunologic Factors; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Adjuvants, Immunologic; HIV Protease Inhibitors; Viral Protease Inhibitors; Interferons; Ritonavir; Lopinavir; Interferon-beta; Interferon beta-1b
• Other Study ID Numbers: KingAbdullahIMRC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED