Impact of PCSK9 Inhibition on Clinical Outcome in Patients During the Inflammatory Stage of the COVID-19

Study Overview
=================
Brief Summary
-----------------
The IMPACT-SIRIO 5 is a randomized, double-blind, phase III clinical trial aimed to evaluate safety and efficacy of PCSK9 inhibition on clinical outcome in patients during the inflammatory stage of the COVID-19. During the hospitalization participants will be randomized in a 1:1 ratio to either receive PCSK9 inhibitor (evolocumab) or to receive placebo (saline solution). Furthermore, all people included in the study will be treated in accordance to the latest recommendations on the treatment of patients infected with SARS-CoV-2.

Official Title
-----------------
Impact of PCSK9 Inhibition on Clinical Outcome in Patients During the Inflammatory Stage of the COVID-19: the Randomized, Double-blind, Phase III IMPACT-SIRIO 5 Study.

Conditions
-----------------
Sars-CoV-2 Infection

Intervention / Treatment
-----------------
* Drug: Evolocumab
* Drug: Saline solution


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Written informed consent for participation in the study Male and female age 18 or more at the time of signing the informed consent SARS-CoV-2 infection confirmed by Real-Time Reverse Transcription Polymerase Chain Reaction (RT-PCR) COVID-19 pneumonia with a typical radiological changes PaO2/FIO2 ratio less than or equal to 300 COVID-19 Pneumonia in cytokine storm with elevated serum level of interleukin-6 Exclusion Criteria: Use of fibrates other than fenofibrate or fenofibric acid Known active infections or other clinical condition that contraindicate PCSK9 inhibitors Known systemic hypersensitivity to PCSK9 inhibitors Estimated glomerular filtration rate <30 ml/min/1.73 m2 Absolute neutrophil count (ANC) less than 2000/mm3 A platelet count less than 50000/mm3 Creatine kinase (CK) greater than 3x upper limit of normal (ULN) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 3x upper limit of normal (ULN) Not expected to survive for more than 48 hours from screening Unrelated co-morbidity with life expectancy <3 months. Pregnancy Any physical examination findings and/or history of any illness that, in the opinion of the study investigator, might confound the results of the study or pose an additional risk to the patient by their participation in the study Patient being treated with other immunomodulators (except for glucocorticoids). Patient included in any other interventional trial.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PCSK9 inhibitor (evolocumab)<br>140 mg of evolocumab as a single subcutaneous injection and standard of care accordance to the latest recommendations | Drug: Evolocumab<br>* A single subcutaneous administration of 140 mg evolocumab<br>|
| Placebo Comparator: Usual Care<br>1 ml of 0,9% saline solution as a single subcutaneous injection. Patients will be treated in accordance to the latest recommendations on caring for patients infected with SARS-CoV-2. | Drug: Saline solution<br>* A single subcutaneous injection of 1ml of 0,9% saline solution<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death from any cause or need for intubation | Indication for intubation determined individually for each patient and clinical status | during hospitalization, up to 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in serum interleukin-6 concentration from day 0 to day 7 and day 30 |  | 7 and 30 days from randomization | 
| Death from any cause | Death from any cause during hospitalization. | during hospitalization, up to 30 days | 
| Need for intubation | Indication for intubation determined individually for each patient and clinical status | during hospitalization, up to 30 days | 
| Duration of oxygen therapy | Defined as the number of days of oxygen therapy (including all methods of oxygen therapy) | during hospitalization, up to 30 days | 
| Duration of hospital stay | Defined as the number of days that pass between the day of hospital admission and discharge or death. | during hospitalization, up to 30 days | 
| Days of intubation | Defined as the number of days between intubation and extubation | during hospitalization, up to 30 days | 
| Time with Non-invasive mechanical ventilation (NIV) or High-flow nasal cannula (HFNC) | Defined as the number of days between initiation and cessation of Non-invasive mechanical ventilation (NIV) or High-flow nasal cannula (HFNC) | during hospitalization, up to 30 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
COVID-19, SARS-CoV-2 Pneumonia, PCSK9 inhibitor