Fort Worth Clinical Sciences Working Group (FWCSWG) for COVID-19: Exploratory Regimen of Basiliximab for Treatment of Pulmonary Cytokine Storm in SARS-CoV-2 Hospitalized Adult Patients
试验速览
- 阶段
- 2 期
- 发起方
- 入组人数
- 300
- 主要终点
- Primary Efficacy Endpoint
研究概览
简要总结
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.
详细描述
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subject Inclusion Criteria
- •Patient or legally authorized representative (LAR) willing and able to provide written or electronic or otherwise FDA-acceptable informed consent based on current FDA regulations.
- •Hospitalized male or non-pregnant female
- •RT-PCR confirmed SARS-CoV-2 using WHO consensus or validated primers
- •Meet the Following Criteria:
- •Deficiency in Oxygenation as defined by the Berlin ARDS Criteria (27):
- •Timing: Within 1 week of onset of symptoms Imaging: Bilateral pulmonary infiltrates
- •Oxygenation (any):
- •Mild: 200 mmHg < PaO2/FiO2 ≤ 300 mmHg Moderate: 100 mmHg < PaO2/FiO2 ≤ 200 mmHg Severe: PaO2/FiO2 ≤ 100 mmHg and
- •Requiring oxygen support in the form of High Flow Nasal Cannula (HFNC), non-invasive positive pressure ventilation, intubation and mechanical ventilation, or initiation of ECMO and
- •Any one or more of the following:
- •Elevated CRP (>10 gm/dL)
- •Elevated Ferritin (>1000)
- •Neutrophil/lymphocyte ratio >3.3
- •Patient will receive current clinical standard of care. This includes inpatient use of remdesivir, dexamethasone, convalescent plasma, or pre-hospitalization outpatient treatment with casirivimab and imdevima
- •Age ≥ 18 years
排除标准
- •Off label use of other drugs
- •WOCBP unwilling to use acceptable birth control for 5 weeks, or male partner of a WOCBP unwilling to use male barrier method (condom) plus effective second method birth control for partner
- •Pregnant women
- •Pancytopenia
- •Hgb< 8 g/dL (male) or < 7 g/dL (female)
- •WBC<2.0 x 109/L
- •PLT< 50 x 109/L
- •Enrollment in any study using immunomodulatory therapies (monoclonal antibodies, small molecule inhibitors etc. to interleukins or interleukin-receptor) 5) Any subjects who have received treatment with immunomodulators or immunosuppressant drugs, including but not limited to IL-6 inhibitors, TNF inhibitors, anti-IL-1 agents, and JAK inhibitors within 5 half-lives or 30 days (whichever is longer) prior to randomization.
- •Known/established systemic bacteremia (empiric antibiotics are allowed), uncontrolled viral infection besides the SARS-CoV-2 study disease, significant abscess in the opinion of the investigator, or any other finding that, in the opinion of the investigator, poses undue risk for treatment with basiliximab.
- •Any patient with multi-organ system failure or on intravenous vasopressor support 8) Do-not-resuscitate status at time of consent, or any contraindication to invasive mechanical ventilation
研究组 & 干预措施
Placebo (Current Standard of Care)
Current Standard of Care for SARS-CoV2 hypoxemic pulmonary diease
干预措施: Placebo (Drug)
Basiliximab
Basiliximab in addition to Current Standard of Care for SARS-CoV2 hypoxemic pulmonary diease
干预措施: Basiliximab Injection (Drug)
结局指标
主要结局
Primary Efficacy Endpoint
时间窗: From time of randomization to Day 28
1. Proportion of subjects alive and free of ventilator support, defined as intubation and requiring mechanical ventilation, at Day 28 from time of randomization
次要结局
- Overall Survival(From time of randomization to Day 28)
- ECMO Free Survival(From time of randomization to Day 28)
- Overall Survival at 90 days(From time of randomization to Day 90)
- Avoidance of escalation of O2 therapy(From time of randomization to Day 28)
- ICU Free Survival(From time of randomization to Day 28)
- Ventilator-free survival at 90 days(From time of randomization to Day 90)
研究者
Mohanakrishnan Sathyamoorthy MD
Chair
Fort Worth Clinical Sciences Working Group