Back to resultsMERS-CoV Infection tReated With A Combination of Lopinavir /Ritonavir and Interferon Beta-1b (MIRACLE)
Primary Purpose
Middle East Respiratory Syndrome Coronavirus (MERS-CoV)
Status
Completed
Phase
Phase 2
Locations
Saudi Arabia
Study Type
Interventional
Intervention
Combination of Lopinavir /Ritonavir and Interferon beta-1b
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Middle East Respiratory Syndrome Coronavirus (MERS-CoV) focused on measuring Middle East Respiratory Syndrome Coronavirus, MERS-CoV, Clinical trial, Lopinavir, Ritonavir, Interferon beta
Eligibility Criteria
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.
Sites / Locations
- Intensive Care Unit, King Abdulaziz Medical City, National Guard Health Affairs
- King Abdullah International Medical Research Center
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Combination of Lopinavir /Ritonavir and IntErferon Beta 1B
Placebo
Arm Description
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
Same characteristics as Lopinavir /Ritonavir and Interferon beta-1b to maintain blinding
Outcomes
Primary Outcome Measures
90-day mortality
Secondary Outcome Measures
Organ support-free days (e.g., supplemental O2, ventilator, extracorporeal membrane oxygenation (ECMO), renal replacement and vasopressors)
RT-PCR cycle threshold value in the lower respiratory samples
Sequential organ failure assessment (SOFA) scores
ICU-free days
Length of stay in hospital
Number of Patients with Adverse drug reactions related to the treatment
Karnofsky Performance Scale
ICU mortality
Hospital mortality
28-day mortality
Full Information
NCT ID
NCT02845843
First Posted
June 20, 2016
Last Updated
May 18, 2020
Sponsor
King Abdullah International Medical Research Center
1. Study Identification
Unique Protocol Identification Number
NCT02845843
Brief Title
MERS-CoV Infection tReated With A Combination of Lopinavir /Ritonavir and Interferon Beta-1b
Acronym
MIRACLE
Official Title
MERS-CoV Infection tReated With A Combination of Lopinavir /Ritonavir and Interferon Beta-1b: a Multicenter, Placebo-controlled, Double-blind Randomized Trial
Study Type
Interventional
2. Study Status
Record Verification Date
May 2020
Overall Recruitment Status
Completed
Study Start Date
July 2016 (Actual)
Primary Completion Date
May 2020 (Actual)
Study Completion Date
May 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
King Abdullah International Medical Research Center
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Middle East Respiratory Syndrome Coronavirus (MERS-CoV)
Keywords
Middle East Respiratory Syndrome Coronavirus, MERS-CoV, Clinical trial, Lopinavir, Ritonavir, Interferon beta
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
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
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
95 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Combination of Lopinavir /Ritonavir and IntErferon Beta 1B
Arm Type
Experimental
Arm Description
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
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Same characteristics as Lopinavir /Ritonavir and Interferon beta-1b to maintain blinding
Intervention Type
Drug
Intervention Name(s)
Combination of Lopinavir /Ritonavir and Interferon beta-1b
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Same characteristics as Lopinavir /Ritonavir and Interferon beta-1b to maintain blinding
Primary Outcome Measure Information:
Title
90-day mortality
Time Frame
90-day
Secondary Outcome Measure Information:
Title
Organ support-free days (e.g., supplemental O2, ventilator, extracorporeal membrane oxygenation (ECMO), renal replacement and vasopressors)
Time Frame
28 days
Title
RT-PCR cycle threshold value in the lower respiratory samples
Time Frame
At randomization and every 3 days afterwards, until 2 consecutive samples are negative or reaching a maximum of 90 days
Title
Sequential organ failure assessment (SOFA) scores
Time Frame
Days 0, 3, 7, 14, 21 and 28
Title
ICU-free days
Time Frame
Number of days in which patients are not being cared for in the ICU during the first 28 days after enrollment
Title
Length of stay in hospital
Time Frame
Up to one year from enrollment
Title
Number of Patients with Adverse drug reactions related to the treatment
Time Frame
From enrollment to 28 day
Title
Karnofsky Performance Scale
Time Frame
90-day
Title
ICU mortality
Time Frame
Up to one year from enrollment
Title
Hospital mortality
Time Frame
Up to one year from enrollment
Title
28-day mortality
Time Frame
28-day
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Facility Information:
Facility Name
Intensive Care Unit, King Abdulaziz Medical City, National Guard Health Affairs
City
Riyadh
ZIP/Postal Code
11426
Country
Saudi Arabia
Facility Name
King Abdullah International Medical Research Center
City
Riyadh
ZIP/Postal Code
22490
Country
Saudi Arabia
12. IPD Sharing Statement
Plan to Share IPD
Undecided
Citations:
PubMed Identifier
36307462
Citation
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.
Results Reference
derived
PubMed Identifier
33026741
Citation
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.
Results Reference
derived
PubMed Identifier
31900204
Citation
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.
Results Reference
derived
PubMed Identifier
29382391
Citation
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.
Results Reference
derived
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MERS-CoV Infection tReated With A Combination of Lopinavir /Ritonavir and Interferon Beta-1b
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