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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Middle East Respiratory Syndrome Coronavirus (MERS-CoV)

Intervention / Treatment
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* Drug: Combination of Lopinavir /Ritonavir and Interferon beta-1b
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria at eligibility assessment Adult (defined as ≥18 years of age); Laboratory confirmation of MERS-CoV infection by reverse-transcription polymerase chain reaction (RT-PCR) from any diagnostic sampling source; and 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 Suicidal ideation based on history (contraindication to interferon (IFN)-β1b); 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; Elevated alanine aminotransferase (ALT) >5 fold the upper limit in the hospital's laboratory; Use of medications that are contraindicated with lopinavir/ritonavir and that cannot be replaced or stopped during the study period, such as CYP3A inhibitors; Pregnancy - eligible and consenting female participants in childbearing age will be tested for pregnancy before enrollment in the study; Known HIV infection, because of concerns about the development of resistance to lopinavir/ritonavir if used without combination with other anti-HIV drugs; or Patient likely to be transferred to a non-participating hospital within 72 hours.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a 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 (n=34). The second two-stage component is designed to determine efficacy stopping and possibly readjustment of sample size.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combination of Lopinavir /Ritonavir and IntErferon Beta 1B<br>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<br>* 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<br>|
| Placebo Comparator: Placebo<br>Same characteristics as Lopinavir /Ritonavir and Interferon beta-1b to maintain blinding | Drug: Placebo<br>* Same characteristics as Lopinavir /Ritonavir and Interferon beta-1b to maintain blinding<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 90-day mortality |  | 90-day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 28-day mortality |  | 28-day | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Middle East Respiratory Syndrome Coronavirus, MERS-CoV, Clinical trial, Lopinavir, Ritonavir, Interferon beta