A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of EB05 + SOC Vs. Placebo + SOC in Adult Hospitalized Patients with COVID-19
试验速览
- 阶段
- 2 期
- 状态
- 暂停
- 入组人数
- 644
- 试验地点
- 20
- 主要终点
- Mortality rate at Day 28 from IP administration.
研究概览
简要总结
COVID-19 patients who develop severe disease often develop acute respiratory distress syndrome (ARDS) as a result of a dysregulated immune response. This in turn stimulates a pro-inflammatory cascade ("cytokine storm") as well as emergency myelopoiesis.
This proinflammatory cascade is activated when viral-mediated cell damage occurs in the lungs, resulting in the release of damage-signaling alarmin molecules such as S100A8/A9 (Calprotectin), HMGB1, Resistin, and oxidized phospholipids. These damage-associated molecular patterns (DAMPs) are recognized by the pattern recognition receptor Toll-Like Receptor 4 (TLR4) found on macrophages, dendritic cells and other innate immune cells and result in additional release of pro-inflammatory molecules. Several recent studies have shown that S100A8/A9 serum levels in hospitalized COVID-19 patients positively correlate with both neutrophil count and disease severity. Taken together the DAMP-TLR4 interaction forms a central axis in the innate immune system and is a key driver of the pathological inflammation observed in COVID-19. We hypothesis that targeting the initial step in the signalling pathways of these DAMPs in innate immunity offers the best hope for controlling the exaggerated host response to SARS-CoV-2 infection.
EB05 has demonstrated safety in two clinical studies (>120 patients) and was able to block LPS-induced (TLR4 agonist) IL-6 release in humans. Given, this extensive body of evidence we believe EB05 could ameliorate ARDS due to COVID-19, significantly reducing ventilation rates and mortality.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
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
- •Men and women ≥18 years of age at the time of consent.
- •Laboratory-confirmed diagnosis of COVID-
- •Hospitalized for COVID-19 related respiratory disease.
- •Patient belongs to one of the following two categories in the nine-point COVID-19 severity scale:
- •Hospitalized, requiring intubation and mechanical ventilation - Level 6 of the nine-point COVID-19 severity scale.
- •Hospitalized and intubated with additional organ support - pressors, RRT, ECMO - Level 7 of the nine-point COVID-19 severity scale.
- •For women of childbearing potential involved in any sexual intercourse that could lead to pregnancy: Negative pregnancy test and willingness to use contraceptive (consistent with local regulations) during the study period.
- •Signed informed consent obtained by any patient capable of giving consent, or, when the patient is not capable of giving consent, from his or her legal/authorized representatives.
排除标准
- •The subject is a female who is breastfeeding or pregnant.
- •Known hypersensitivity to EB05 or its excipients.
- •In the opinion of the investigator, death is imminent and inevitable or patient will be discharged within the next 48 - 72 hours, irrespective of the provision of treatment.
- •Experiencing cardiac arrest while hospitalized with COVID-
- •Active participation in other immunomodulator or immunosuppressant drug clinical trials.
- •a. Participation in COVID-19 antiviral, anticoagulant and convalescent plasma trials may be permitted; however, the decision to enroll a patient who is participating in other clinical trials will be dealt with on a case-by-case basis.
- •Treatment with immunomodulator or immunosuppressant drugs, including but not limited to TNF inhibitors and anti-IL-1 agents within 5 half-lives or 30 days (whichever is longer) before randomization. Except for the following, which are permitted:
- •Treatment with immunomodulator, or immunosuppressant drugs, such as corticosteroids, as part of SOC for COVID-19
- •Transplant patients
- •Known other clinical conditions that contraindicate EB05 and cannot be treated or solved according to the judgment of the clinician.
- •Patient has been intubated or mechanically ventilated for more than 72 hours prior to administration of the investigational product.
- •Patient has been intubated and then extubated during the current hospitalization prior to administration of the investigational product.
- •Patient has experienced meaningful clinical improvement in the severity of disease prior to administration of the investigational product.
研究组 & 干预措施
Stage 1
Stage 1 (Phase II Study) For 80% power (β = 0.20), at a significance level of 5% (α =0.05) and a 1:1 randomization ratio, a total of 316 (EB05: 158, SOC: 158) evaluable patients will be required. Allowing for 20% attrition a total of 396 patients will be recruited.
干预措施: SOC plus 15mg/kg EB05 IV (Biological)
Stage 1
Stage 1 (Phase II Study) For 80% power (β = 0.20), at a significance level of 5% (α =0.05) and a 1:1 randomization ratio, a total of 316 (EB05: 158, SOC: 158) evaluable patients will be required. Allowing for 20% attrition a total of 396 patients will be recruited.
干预措施: SOC plus Placebo IV (Other)
Stage 2
Stage 2 (Phase III Study) For a 1:1 ratio of patients treated with EB05 vs. Placebo, a cumulative one-sided alpha of 2.5% and 90% power, to detect an Odds Ratio of 2.00, a total of 586 evaluable patients will be required for Stage 2 (Phase III study). 293 of these will be treated with EB05 + SOC and 293 treated with Placebo + SOC. Allowing for 10% attrition, a total of 644 patients will be enrolled in this Stage.
干预措施: SOC plus 15mg/kg EB05 IV (Biological)
Stage 2
Stage 2 (Phase III Study) For a 1:1 ratio of patients treated with EB05 vs. Placebo, a cumulative one-sided alpha of 2.5% and 90% power, to detect an Odds Ratio of 2.00, a total of 586 evaluable patients will be required for Stage 2 (Phase III study). 293 of these will be treated with EB05 + SOC and 293 treated with Placebo + SOC. Allowing for 10% attrition, a total of 644 patients will be enrolled in this Stage.
干预措施: SOC plus Placebo IV (Other)
结局指标
主要结局
Mortality rate at Day 28 from IP administration.
时间窗: 28 days
For the current study, the primary efficacy outcome measure will be the mortality rate from IP administration. Mortality is the most clinically relevant therapeutic endpoint for this population that is on IMV. The primary endpoint will be assessed at 28-days after treatment initiation.
次要结局
- Proportion of patients with clinical improvement at Day 28(28 days)
- Proportion of patients with clinical improvement at Day 60(60 days)
- Mortality rate at Day 60(60 days)