Inhaled ZYESAMI (Aviptadil Acetate) for the Treatment of Severe COVID-19 (AVICOVID-3)
试验速览
- 阶段
- 3 期
- 状态
- 撤回
- 发起方
- 主要终点
- Progression to Respiratory Failure
研究概览
简要总结
Brief Summary:
SARS-CoV-2 virus infection is known to cause Lung Injury that begins as dyspnea and exercise intolerance, but may rapidly progress to Critical COVID-19 with Respiratory Failure and the need for noninvasive or mechanical ventilation. Mortality rates as high as 80% have been reported among those who require mechanical ventilation, despite best available intensive care.
Patients with severe COVID-19 by FDA definition who have not developed respiratory failure be treated with nebulized ZYESAMI™ (aviptadil acetate, a synthetic version of Vasoactive Intestinal Polypeptide (VIP)) 100 μg 3x daily plus Standard of Care vs. placebo + Standard of Care using an FDA 501(k) cleared mesh nebulizer.
The primary outcome will be progression in severity of COVID-19 (i.e. critical OR severe progressing to critical) over 28 days. Secondary outcomes will include blood oxygenation as measured by pulse oximetry, dyspnea, exercise tolerance, and levels of TNFα IL-6 and other cytokines.
详细描述
Detailed Description:
Attack of the Alveolar Type II (ATII) cell via its ACE2 surface receptor by the SARS-CoV-2 virus leads to respiratory failure, morbidity, and frequently mortality in COVID-19. There is no approved treatment that specifically targets the pulmonary injury. Vasoactive Intestinal Peptide (VIP) is known to target the VPAC1 receptor of the ATII cell and to protect that cell against all manner of injuries, including smoke inhalation, exposure to stomach acid, and exposure to infectious agents. VIP prevents apoptosis, blocks cytokines, lowers TNFα levels, reverses CD4/CD8 ratio, and reduces cough and dyspnea in nonclinical and clinical studies. Aviptadil acetate, a synthetic form of Vasoactive Intestinal Polypeptide (VIP) has been awarded FDA Orphan Drug Designation for the treatment of ARDS and Pulmonary Hypertension and EMEA Orphan Drug Designation for the treatment of ARDS and Sarcoid. ZYESAMI™ (Aviptadil) has been granted FDA Fast Track Designation for the treatment of ARDS/Acute Lung Injury in COVID-19.
The objective of this study is to identify patients severe COVID-19 who have not yet developed respiratory failure and to treat them with inhaled ZYESAMI™ in the hope of preventing progression to Critical COVID-19 with Respiratory Failure.
Nonclinical studies demonstrate that VIP is 70% concentrated in the lung, where it binds primarily to ATII cells. VIP prevents NMDA-induced caspase-3 activation in the lung, inhibits IL6 and TNFα production, protects against HCl-induced pulmonary edema, These and other effects have been observed in numerous animal model systems of lung injury in mice, rats, guinea pigs, sheep, swine, and dogs. In these models, Aviptadil restores barrier function at the endothelial/alveolar interface and thereby protects the lung and other organs from failure.
Both intravenous and inhalation preclinical toxicology and safety pharmacology have been performed in four species, with a six-month trial of inhaled Aviptadil in primates.
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)
盲法说明
Only the study pharmacist will be aware of treatment assignment
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Severe COVID-19 , as defined by clinical signs indicative of severe systemic illness with COVID-19, being given oxygenation and meeting
- •ONE of the following:
- •Respiratory rate ≥ 30 per minute Heart rate ≥ 125 per minute SpO2 ≤ 93% on room air at sea level PaO2/FiO2 < 300 mmHg or SpO2/FiO2 < 315 mmHg
- •Positive test by standard RT-PCR assay or equivalent within last 7 days
- •Physician determination that patient is on SOC therapy, and will receive standard of care if patient progresses to Critical COVID-19, patient must be full CODE
排除标准
- •Evidence of Critical COVID-19
- •Inability to utilize nebulized drugs, or history of bronchospasm with inhaled medications
- •Age <12 years;
- •Mean arterial pressure < 65 mm Hg after initial hospital stabilization,
- •Non-COVID-19 irreversible underlying condition with projected fatal course within 6 months or with high risk of mortality;
- •Immunosuppressive treatment for transplant or other diseases associated with high mortality;
- •Stage IV cancer or cancer on active treatment with chemotherapy immunotherapy or checkpoint inhibitors; acute renal failure or chronic renal insufficiency with GFR less than 30; CHF New York Heart Association class III or IV, new neurologic disorder in the last 3 months or chronic neurologic disorder or other that would impact on assessing the resolution of severe COVID-19 respiratory failure
- •Myocardial Infarction in previous six months or troponin >0.5
- •Recent history of venous thrombotic events (PE / DVT) within the last 3 months.
- •New diagnosis of atrial fibrillation within the last 3 months. Acceptable if greater than 3 months and well controlled in the opinion of the investigator
- •Watery diarrhea requiring replacement of 1 liter or more of iv fluids and electrolytes
研究组 & 干预措施
Severe COVID-19 ZYESAMI™
Patients with Severe COVID-19 to be treated with inhaled ZYESAMI™ (aviptadil) by mesh nebulizer 100μg 3x daily
干预措施: Nebulized administration of ZYESAMI™ or Placebo (Device)
Severe COVID-19 ZYESAMI™
Patients with Severe COVID-19 to be treated with inhaled ZYESAMI™ (aviptadil) by mesh nebulizer 100μg 3x daily
干预措施: ZYESAMI™ (aviptadil acetate) (Drug)
Severe COVID-19 Placebo
Patients with Severe COVID-19 to be treated with inhaled placebo 3x daily
干预措施: Placebo (Drug)
Severe COVID-19 Placebo
Patients with Severe COVID-19 to be treated with inhaled placebo 3x daily
干预措施: Nebulized administration of ZYESAMI™ or Placebo (Device)
结局指标
主要结局
Progression to Respiratory Failure
时间窗: 28 days
Progression to Respiratory Failure is defined as the need for mechanical ventilation, non-invasive ventilation or high flow nasal oxygen
次要结局
- Blood oxygenation(28 days)
- RPD Dyspnea Scale(28 days)
- Distance walked in six minutes(28 days)