Clinical trial NCT02845843: MERS-CoV Infection tReated With A Combination of Lopinavir /Ritonavir and Interferon Beta-1b
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
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Middle East Respiratory Syndrome Coronavirus (MERS-CoV)
Keywords: Middle East Respiratory Syndrome Coronavirus
MERS-CoV
Clinical trial
Lopinavir
Ritonavir
Interferon beta
Lead sponsor: King Abdullah International Medical Research Center
Sponsor class: OTHER
First posted: 2016-07-27
Enrollment: 95
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: 90-day mortality
timeFrame: 90-day
Secondary outcomes:
measure: Organ support-free days (e.g., supplemental O2, ventilator, extracorporeal membrane oxygenation (ECMO), renal replacement and vasopressors)
timeFrame: 28 days
measure: RT-PCR cycle threshold value in the lower respiratory samples
timeFrame: At randomization and every 3 days afterwards, until 2 consecutive samples are negative or reaching a maximum of 90 days
measure: Sequential organ failure assessment (SOFA) scores
timeFrame: Days 0, 3, 7, 14, 21 and 28
measure: ICU-free days
timeFrame: Number of days in which patients are not being cared for in the ICU during the first 28 days after enrollment
measure: Length of stay in hospital
timeFrame: Up to one year from enrollment
measure: Number of Patients with Adverse drug reactions related to the treatment
timeFrame: From enrollment to 28 day
measure: Karnofsky Performance Scale
timeFrame: 90-day
measure: ICU mortality
timeFrame: Up to one year from enrollment
measure: Hospital mortality
timeFrame: Up to one year from enrollment
measure: 28-day mortality
timeFrame: 28-day
Other outcomes:
Locations:
city: Riyadh
country: Saudi Arabia
facility: Intensive Care Unit, King Abdulaziz Medical City, National Guard Health Affairs
city: Riyadh
country: Saudi Arabia
facility: King Abdullah International Medical Research Center
Study officials:
References:
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.
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.
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.
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.