Extracorporeal Photopheresis as a Possible Therapeutic Approach to Adults With Severe and Critical COVID-19

Study Overview
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Brief Summary
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Optimal approach for adult patients hospitalized with severe and critical COVID-19 non-responsive to antiviral and immunomodulatory drugs is not well established. The study aim is to evaluate feasibility and safety of extracorporeal photopheresis (ECP) in this setting.

Detailed Description
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A prospective, single-center investigational study is olanned to be performed at a tertiary referral center for COVID-19. Patients with COVID-19 are screened, and severe or critical COVID-19 cases fulfilling pre-defined clinical and biochemical criteria of non-response for >5 days despite remdesivir, dexamethasone and immunomodulation (tocilizumab, baricitinib, ruxolitinib) are consecutively enrolled. After inclusion, two ECP sessions on two consecutive days per week for 2 weeks are applied. Patients are followed up per protocol from study inclusion, and clinical, virological and radiological outcomes are assessed at end-of-treatment (EOT)+28 days.

Official Title
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Extracorporeal Photopheresis as a Possible Therapeutic Approach to Adults With Severe and Critical COVID-19 Non-responsive to Remdesivir, Dexamethasone and Pharmacological Immunomodulation: an Investigational Study

Conditions
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COVID-19

Intervention / Treatment
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* Procedure: Extracorporeal photopheresis


Participation Criteria
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Eligibility Criteria
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Hospitalized adult (≥18 years at diagnosis) patients with diagnosed COVID-19 of any illness duration are eligible, and screened for inclusion during daily on-site investigator visits. Patients are consecutively enrolled. Inclusion criteria: severe or critical COVID-19, clinical and biochemical non-response for >5 consecutive days, despite remdesivir, dexamethasone and immunomodulatory therapies (tocilizumab, baricitinib or ruxolitinib), with or without COVID-19 reconvalescent plasmatherapy, in absence of other causes. Exclusion criteria: pregnancy or breastfeeding, allergy or contraindications to 8-methoxypsoralen, pre-COVID-19 ECP, written informed consent was not obtainable. Clinical non-response is defined when ≥2 of the following are met, compared to baseline: persistent fever (non-contact tympanal measurement of >38.0°C) for ≥48 hours, despite antipyretics, persistent or failing COVID-19 severity, according to World Health Organization criteria, by ≥1 stratum after ≥48 hours, persistent or failing partial arterial oxygen tension (PaO2) / inspired oxygen fraction (FiO2), by ≥10% after ≥48 hours, despite respiratory support, radiological progression by infiltrate extension on chest computed tomography (CT), by ≥10% after ≥48 hours, novel requirement of invasive mechanical ventilation, as deemed necessary by an intensive care unit (ICU) team. Biochemical non-response is defined when ≥2 of the following analytes show persistent or increasing levels by ≥20% after ≥48 hours, compared to baseline: serum lactate dehydrogenase (LDH), serum C-reactive protein (CRP), serum ferritin plasma interleukin-6 (IL-6), D-dimer.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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
Intervention Model: Single Group Assignment
Interventional Model Description: ECP is initiated on study inclusion day by Therakos Cellex system, according to manufacturers' instructions. Each patient receives two ECP cycles for 2 weeks, each consisting of two sessions on consecutive days per week (alltogether four sessions), through a peripheral or central venous route. Cycles 1 and 2 are separated by 5 consecutive days. One ECP session takes  3 hours, and is separated into 4 phases. On priming, the system performes a series of calibrations to ensure proper operation. During collection, 1500 ml of whole blood is processed to collect a concentrated buffy coat containing white blood cells, while other cells and plasma are reinfused. During the photoactive phase, a prescribed dose of 8-methoxypsoralen is added to the buffy coat, which is then circulated through ultraviolet-A photoactivation. During reinfusion phase, treated cells are automatically reinfused to the patient.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Extracorporeal photopheresis arm<br>Patients will receive extracorporeal photopheresis on this arm, in conjucntion to standard COVID-19 treatments (remdesivir, dexamethasone, IL-6- and/or JAK-inhibition). | Procedure: Extracorporeal photopheresis<br>* ECP is initiated on study inclusion day by Therakos Cellex system, according to manufacturers' instructions. Each patient receives two ECP cycles for 2 weeks, each consisting of two sessions on consecutive days per week (alltogether four sessions), through a peripheral or central venous route. Cycles 1 and 2 are separated by 5 consecutive days. One ECP session takes  3 hours, and is separated into 4 phases. On priming, the system performes a series of calibrations to ensure proper operation. During collection, 1500 ml of whole blood is processed to collect a concentrated buffy coat containing white blood cells, while other cells and plasma are reinfused. During the photoactive phase, a prescribed dose of 8-methoxypsoralen is added to the buffy coat, which is then circulated through ultraviolet-A photoactivation. During reinfusion phase, treated cells are automatically reinfused to the patient.<br>* Other names: Therakos Cellex system;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical outcomes | Clinical outcomes are all-cause death, invasive mechanical ventilation and ICU admittance requirement. | All outcomes are assessed at EOT+28 days and compared to data at inclusion. | 
| Virological outcomes | Virological outcomes are respiratory and blood SARS-CoV-2 RT-PCR positivity. | All outcomes are assessed at EOT+28 days and compared to data at inclusion. | 
| Radiological outcomes | Radiological outcomes are radiological progression/regression or fixed infiltration on chest CT scan. | All outcomes are assessed at EOT+28 days and compared to data at inclusion. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19