Clinical Trials Logo

Clinical Trial Summary

To explore the efficacy of treatment of pulmonary cytokine storm induced by SARS-CoV2 with a monoclonal antibody to IL-2 (Basiliximab) in addition to current standard of care vs current standard of care with the primary efficacy endpoint being the proportion of subjects alive and free of ventilator support, defined as intubation and requiring mechanical ventilation, at Day 28 from time of randomization.


Clinical Trial Description

The current pandemic driven by SARS-CoV2 creating the COVID-19 disease state is creating enormous healthcare challenges globally with limited treatment paradigms outside of supportive medical, and intensive care measures. As the human population was entirely naïve to this viral pathogen, a particularly vigorous response of the immune cascade through cell-mediated mechanisms is a driving force behind the lethality of this disease in susceptible individuals. It is not presently understood why specific populations are at higher risk for disease state progression outside of traditional parameters such as age and pre-existing co-morbid health states. Furthermore, we lack a priori ways of identifying which SARS-COv2 infected patient may ultimately develop a "hyperactive" immune response that leads to the "cytokine storm" or "cytokine release syndrome", and the resultant cell, tissue, and organ system dysfunction.(1) Hypotheses in this area may include viral load phenomenon, aberration in immune/inflammatory regulatory check-points (JAK-STAT, JNK etc.), or underlying case dependent genetic factors (HLA etc.) influencing the immune system (2). Once the cytokine storm drives the clinical endpoint above, an affected patient who survives will become high risk for secondary pathogenic infection. Intravenous remdesivir (3) along with dexamethasone (4, 5) have become standard of care therapeutics. The FDA recently provided emergency use authorization (EUA) for a novel SARS-COV2 neutralizing monoclonal antibody cocktail targeting the spike protein that docks with the ACE2 receptor on susceptible cells (Regeneron) (5). Rapid development of robust viral treatment strategies and vaccine development are the key strategies to managing SARS-COV2 in the long term. To this end, the FDA will be reviewing an EUA application for Pfizer's mRNA vaccine in early December, with similar review expected for Moderna's mRNA vaccine. However, promising these developments are, thousands of patients are dying from cytokine storm mediated endpoints on a daily basis in the United States and across the world during the ongoing third wave/surge of COVID-19. There is broad recognition of this cytokine phenomenon, and in this era of targeted interleukin therapy for autoimmune disease states, a multitude of FDA approved monoclonal antibodies targeted to specific interleukins exist. Many institutions adopted IL-6 as a target for mitigation of the cytokine storm, and are utilizing tocilizumab (Actemra ®, Roche/Genentech) as a treatment (6) Sarilumab (Kevzara ®, Sanofi/Regeneron), another monoclonal Ab to IL-6, underwent rapid assessment for use in COVID-19(7). Both therapeutics did not meet primary specified endpoints in broader, Phase 2-3 studies. These studies targeted the Th2/Tfh cytokine IL-6, as it plays a role in cytokine mediated inflammation in the lungs (9, 10) There is evidence that Il-6 can be induced within several hours by certain viral species (11) perhaps providing another reason why this was chosen as a target. Finally, this cytokine may serve as a target based on existing protocols to treat macrophage activation syndrome (MAS), and based on early evidence of cytokine expression patterns in patients infected with SARS-COV2 in Wuhan, PRC (2, 12-14). Classically, however, Th2/Tfh related cytokines are associated with antibody mediated immune memory and response, and though Th2/Tfh cytokines play a crucial role in acute inflammation, we have not seen protocols that target differentiating cytokines that drive Th0 to Th1 maturation, or Th1 specific cytokines. The Th1 cytokine profile is more consistently demonstrated in almost all early viral infection, and therefore, we view these cytokines as potential targets for therapy to prevent or mitigate the cytokine storm (Figure 1) (2, 12). Cytokine storm is a downstream manifestation of the viral induced host response that represents either failure of the initial host response to mitigate viral load, an uncontrolled late cytotoxic T-cell activity, or both. There is no evidence that targeted therapy against Th1 cytokines impairs the host response with strong clinical evidence supporting use in other EBV mediated secondary HLH syndromes (15). The cytokine environment in which antigen primed T cells differentiate determines the subset that develops. In particular, IL-4 is essential for the development of Th2 response and IFN-gamma, IL-12 and IL-18 all are important in the development of Th1 cells. Th1 cells produce IL-2 and IFN-g, which in turn, promote the differentiation of fully cytotoxic T cells from CD8+ precursors. A recent report published in Nature Medicine by Long et al. demonstrated a multi-fold higher expression of Th-1 cytokines, in particular, TNF alpha and IL-2, and significant expression of the IL-2 receptor subunit alpha in symptomatic COVID 19 patients in Wuhan.(16) A subsequent report published in Science Immunology by Lee et al. (17) demonstrated similar results through transcriptional and immuno-profiling techniques, and most recently a report in Nature (18) did the same. Therefore, among all immunomodulatory therapies, we view that targeting the Th1 response to be a key strategy. We propose targeting the IL-2R with Basiliximab. Basiliximab (Simulect ®) is a monoclonal antibody against a subunit of IL-2 and is FDA approved for the treatment of acute renal transplant rejection, and is used off label in many other cases of transplant rejection mitigation.(2, 12) This agent has a long track record of safety and we believe among Th1 cytokine targets, to be a safe target for inhibition in SARS-COV2 induced cytokine storm. Additional novel methodologies, including treatment with orally approved FDA approved JAK-STAT inhibitors (2) sirolimus (19-21) or calcineurin inhibitors (12) may serve as a broader opportunity to maintain suppression of inflammation following acute phase cytokine storm intervention with Basilixamab. One new area of interest is in complement mitigation, and inhibitors (eciluzimab) targeting this more teleologically more primal cascade may have a role (12, 22). ;


Study Design


Related Conditions & MeSH terms


NCT number NCT05013034
Study type Interventional
Source Fort Worth Clinical Sciences Working Group
Contact mohanakrishnan sathyamoorthy, md
Phone 817423-8585
Email m.sathyamoorthy@tcu.edu
Status Not yet recruiting
Phase Phase 2
Start date October 15, 2021
Completion date December 1, 2022

See also
  Status Clinical Trial Phase
Completed NCT04979858 - Reducing Spread of COVID-19 in a University Community Setting: Role of a Low-Cost Reusable Form-Fitting Fabric Mask N/A
Recruiting NCT05311410 - Viral Kinetics of SARS-CoV-2 in Patients With COVID-19 in the Intensive Care Unit Undergoing Dental Procedures N/A
Active, not recruiting NCT05073718 - SARS-CoV-2 and Acetylsalicylic Acid (SARA) Phase 3
Completed NCT05055492 - The School SPIT Study - Elementary Schools in High COVID-19 Incidence Regions N/A
Completed NCT05055505 - The School SPIT Study - Elementary Schools in Low COVID-19 Incidence Regions N/A
Completed NCT05060510 - The School SPIT Study - COVID-19 Testing in Secondary Schools N/A
Completed NCT05054218 - COVID-19 Immunogenicity of a Third Dose of mRNA-1273 Vaccine Among Cancer Patients
Completed NCT05449392 - Topical Antibacterial Agents for Prevention of COVID-19 Phase 1
Completed NCT05076253 - Efficacy of Ivermectin in COVID-19 Phase 1/Phase 2
Recruiting NCT05172024 - Understanding the Long-term Impact of COVID-19 in Adults (RECOVER)
Terminated NCT05593770 - International Sites: Novel Experimental COVID-19 Therapies Affecting Host Response Phase 2/Phase 3
Completed NCT05030974 - RECOVAC Repeated Vaccination Study Phase 4
Withdrawn NCT05067946 - Evaluation of Efficacy, Safety and Immunogenicity of GX-19N in Healthy Individuals Who Have Received COVID-19 Vaccines Phase 2/Phase 3
Withdrawn NCT05393999 - SABRE: A Single-arm Prospective Study Measuring Safety and Tolerability of SARS-CoV-2 Neutralising Antibodies in High-risk Populations Phase 2
Recruiting NCT05047783 - Masitinib in Patients With Symptomatic Mild to Moderate COVID-19 Phase 2
Not yet recruiting NCT05116657 - Obstructive Sleep Apnoea Post Covid 19: Role of the Upper Airway Microbiome
Recruiting NCT04590222 - Impact of a Monoamine Oxidase Inhibitor on the Phenotype of Blood Mononucleated Cells in Patients With COVID-19
Completed NCT04551911 - Safety and Efficacy of Rayaldee for Treating Mild to Moderate COVID-19 Phase 2
Completed NCT04953039 - Use of Saliva for COVID-19 Diagnosis
Active, not recruiting NCT06181292 - Safety and Immunogenicity of a Booster Vaccination With an Adapted Vaccine Phase 2/Phase 3