RIC as an Adjunct Therapy for Severe COVID-19 Disease: a Prospective Randomized Pilot Study

Study Overview
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Brief Summary
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This research aims to assess the use of an experimental and non-invasive procedure, Remote Ischemic Conditioning (RIC), as an adjunct therapy in attenuating severe COVID-19 disease. An excessive and counterproductive systemic inflammatory response is thought to be a major cause of severe disease and death in patients with COVID-19. Severe ICU cases frequently have markedly higher levels of inflammatory markers such as CRP, IL-6, IL and TNF-a; which is thought to be correlated with increasing disease severity. The relationship between dysregulated inflammatory processes and disease states such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are well understood. ALI is characterized by an acute exaggerated mononuclear/neutrophilic inflammatory response followed by progressive collagen deposition in the lung, and if severe enough, may progress to ARDS requiring ventilation.

Detailed Description
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This research aims to assess the use of an experimental and non-invasive procedure, Remote Ischemic Conditioning (RIC), as an adjunct therapy in attenuating severe COVID-19 disease. An excessive and counterproductive systemic inflammatory response is thought to be a major cause of severe disease and death in patients with COVID-19. Severe ICU cases frequently have markedly higher levels of inflammatory markers such as CRP, IL-6, IL-1 and TNF-a; which is thought to be correlated with increasing disease severity. The relationship between dysregulated inflammatory processes and disease states such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are well understood. ALI is characterized by an acute exaggerated mononuclear/neutrophilic inflammatory response followed by progressive collagen deposition in the lung, and if severe enough, may progress to ARDS requiring ventilation. Remote ischemic conditioning (RIC) is an experimental and non-invasive procedure that utilizes the body's natural defense against ischemia-reperfusion (IR) injury, which is believed to stimulate innate multiorgan protection against various systemic immunopathological processes. Although its mechanisms are not entirely understood, favorable outcomes have been demonstrated in multiple remote organs including the heart, kidneys, liver, and lungs. It consists of brief and repeated doses of non-lethal ischemia and reperfusion to a limb using a tourniquet, which is thought to modulate systemic inflammation by altering several inflammatory signaling pathways. Studies have demonstrated suppression of genes encoding proteins involved in leukocyte chemotaxis, adhesion, migration, and exocytosis, as well as innate immunity responses, cytokine synthesis, and upregulation of anti-inflammatory genes. Multiple human and animal studies have demonstrated its efficacy in decreasing inflammatory biomarkers such as IL-6, CRP, IL-1B, and TNF; inflammatory mediators correlated with increasing COVID-19 disease severity. With regards to safety, currently, over 10,000 patients worldwide have completed clinical trials involving RIC, and another 20,000 are enrolled in ongoing trials. RIC presents few risks in otherwise healthy patients. Theoretical risks are highest in those patients with risk factors for vascular compromise: previous vascular surgery, vascular trauma, or known vascular disease. Excluding such patients, the practise of RIC appears to be safe in human studies This clinical trial will be enrolling 30 COVID-19+, or presumed COVID-19+ ICU patients at St. Michael's Hospital in Toronto, Canada. Eligible patients with severe COVID-19 disease will be randomized to undergo RIC versus sham-RIC. RIC interventions will be applied to one of the extremities calibrated to induce four, ten-minute cycles of five-minutes-ischemia and five-minutes-perfusion for a total of 20 cumulative minutes of limb ischemia, at a pressure of 250 mmHg. All interventions will be performed within 6 hours upon ICU admission of a confirmed or suspected COVID+ patient, given that the patient is determined eligible and their physician deems it safe to enroll. The RIC procedure will be performed every 72 hours upon randomization, +/- 1 hour to accommodate caveats in performing the procedure at that time. Blood will be collected at various timepoints to assess RIC on biomarkers of inflammation and coagulation, and clinical metrics such as need for ventilation, LOS, presentation, and timing of symptoms will be tracked. Patients not in legal capacity and when an SDM cannot be identified or contacted will be enrolled on a deferred consent basis, and provided the option of withdrawing their study data should they regain capacity. With the current and evolving COVID-19 pandemic, ICU's are at risk of becoming overwhelmed; thus, there exists a need for a safe, rapid, and effective treatment. RIC is known to be a safe procedure that may have the potential to attenuate systemic immunopathological processes implicated in severe COVID-19 disease. If shown to be effective, it may help ameliorate the need for extensive and costly care in the ICU setting. It can theoretically be performed with any tourniquet-like device, which may be useful in a wide range of settings. Lastly, knowledge gained from this research may have the potential to inspire further work into the use of RIC in related conditions, such as viral pneumonia or sepsis.

Official Title
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Remote Ischemic Conditioning as an Adjunct Therapy for Severe COVID-19 Disease: a Prospective Randomized Pilot Study

Conditions
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COVID, Corona Virus Infection, Acute Lung Injury, Ischemia Limb, Acute Respiratory Distress Syndrome

Intervention / Treatment
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* Device: Remote Ischemic Conditioning


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 16 years old Admission to ICU Either confirmed positive, or presumed, COVID-19 disease Radiological evidence of COVID-related pneumonia (CXR or CT abnormalities indicating COVID-19 pneumonia; such as, ground-glass opacities) Able to safely undergo conditioning of the arm No peripheral vascular disease No evidence of prior arm surgery No evidence of prior radiation or lymph node dissection Clinical staff deems it safe to proceed (Yes/No: signed by MRP) Exclusion Criteria: Age <16 years Unable to safely undergo conditioning Known peripheral vascular disease Evidence of prior arm surgery Evidence of prior radiation or lymph node dissection Clinical staff deems it unsafe (Yes/No: signed by MRP) No radiological evidence of COVID-related pneumonia Hemodynamically unstable: Patients with SBP 90 or SBP 180 excluded until hemodynamically stabilized, then reassessed for inclusion Anti-coagulation drug use

Ages Eligible for Study
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Minimum Age: 16 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: Crossover Assignment
Interventional Model Description: Single-centre, randomized controlled pilot study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Remote Ischemic Conditioning<br>RIC interventions will be applied to the upper extremity for a total of 20 cumulative minutes of limb ischemia, at a pressure of 250 mmHg. | Device: Remote Ischemic Conditioning<br>* RIC interventions will be applied to the upper extremity calibrated to induce four, ten-minute cycles of five-minutes-ischemia and five-minutes-perfusion for a total of 20 cumulative minutes of limb ischemia, at a pressure of 250 mmHg.<br>|
| Sham Comparator: Sham Remote Ischemic Conditioning<br>RIC sham interventions will be applied to the upper extremity for a total of 20 cumulative minutes. For sham, inflation will occur. | Device: Remote Ischemic Conditioning<br>* RIC interventions will be applied to the upper extremity calibrated to induce four, ten-minute cycles of five-minutes-ischemia and five-minutes-perfusion for a total of 20 cumulative minutes of limb ischemia, at a pressure of 250 mmHg.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Interleukin 1-Beta (IL-1B) (pg/mL) | Serum concentration, to be collected immediately before RIC treatment, treatment plus 6 hours, treatment plus 12 hours, treatment plus 24 hours, and treatment plus 48 hours (+/- 1 hour at each 0+ time point) | Through study completion - up to 12 months | 
| Interleukin 6 (IL-6) (pg/mL) | Serum concentration, to be collected immediately before RIC treatment, treatment plus 6 hours, treatment plus 12 hours, treatment plus 24 hours, and treatment plus 48 hours (+/- 1 hour at each 0+ time point) | Through study completion - up to 12 months | 
| C-reactive protein (CRP) (mg/mL) | Serum concentration, to be collected immediately before RIC treatment, treatment plus 6 hours, treatment plus 12 hours, treatment plus 24 hours, and treatment plus 48 hours (+/- 1 hour at each 0+ time point) | Through study completion - up to 12 months | 
| Tumour Necrosis Factor Alpha (TNFa) (pg/mL) | Serum concentration, to be collected immediately before RIC treatment, treatment plus 6 hours, treatment plus 12 hours, treatment plus 24 hours, and treatment plus 48 hours (+/- 1 hour at each 0+ time point) | Through study completion - up to 12 months | 
| Neutrophil to Lymphocyte Ratio (NLR) (absolute neutrophils/lymphocytes) | Serum concentration, to be collected immediately before RIC treatment, treatment plus 6 hours, treatment plus 12 hours, treatment plus 24 hours, and treatment plus 48 hours (+/- 1 hour at each 0+ time point) | Through study completion - up to 12 months | 
| Serum Ferritin (ng/mL) | Serum concentration, to be collected immediately before RIC treatment, treatment plus 6 hours, treatment plus 12 hours, treatment plus 24 hours, and treatment plus 48 hours (+/- 1 hour at each 0+ time point) | Through study completion - up to 12 months | 
| International Normalized Ratio (INR) | Standard coagulation parameter, to be collected immediately before RIC treatment, treatment plus 6 hours, treatment plus 12 hours, treatment plus 24 hours, and treatment plus 48 hours (+/- 1 hour at each 0+ time point) | Through study completion - up to 12 months | 
| Prothrombin Time (PTT) | Standard coagulation parameter, to be collected immediately before RIC treatment, treatment plus 6 hours, treatment plus 12 hours, treatment plus 24 hours, and treatment plus 48 hours (+/- 1 hour at each 0+ time point) | Through study completion - up to 12 months | 
| Rotational Thromboelastometry (ROTEM) | ROTEM coagulation assessment using the commercial ROTEM device traditionally used for the assessment of coagulopathy, to be collected immediately before RIC treatment, treatment plus 6 hours, treatment plus 12 hours, treatment plus 24 hours, and treatment plus 48 hours (+/- 1 hour at each 0+ time point). | Through study completion - up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total duration of mechanical ventilation (number of days) | Number of continuous calendar days or partial calendar days including treatment with invasive ventilation. | Through study completion - up to 12 months | 
| Intensive Care Unit Length of Stay (number of days) | Number of continuous calendar days or partial calendar days admitted to an acute care hospital. | Through study completion - up to 12 months | 
| Hospital Length of Stay (number of days) | Number of continuous calendar days or partial calendar days admitted to an acute care hospital. | Through study completion - up to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Remote Ischemic Conditioning, Inflammatory response