PRAETORIAN-COVID: A Double-blind, Placebo-controlled Randomized Clinical Trial With Valsartan for PRevention of Acute rEspiraTORy dIstress Syndrome in hospitAlized patieNts With SARS-COV-2 (COVID-19) Infection Disease
试验速览
- 阶段
- 4 期
- 状态
- 终止
- 入组人数
- 23
- 试验地点
- 7
- 主要终点
- first occurrence of intensive care unit admission, mechanical ventilation or death
研究概览
简要总结
Rationale: The current SARS-CoV-2 pandemic has a high burden of morbidity and mortality due to development of the so-called acute respiratory distress syndrome (ARDS). The renin-angiotensin-system (RAS) plays an important role in the development of ARDS.
ACE2 is one of the enzymes involved in the RAS cascade. Virus spike protein binds to ACE2 to form a complex suitable for cellular internalization. The downregulation of ACE2 results in the excessive accumulation of angiotensin II, and it has been demonstrated that the stimulation of the angiotensin II type 1a receptor (AT1R) increases pulmonary vascular permeability, explaining the increased lung pathology when activity of ACE2 is decreased. Currently available AT1R blockers (ARBs) such as valsartan, have the potential to block this pathological process mediated by angiotensin II. There are presently two complementary mechanisms suggested: 1) ARBs block the excessive angiotensin-mediated AT1R activation, and 2) they upregulate ACE2, which reduces angiotensin II concentrations and increases the production of the protective vasodilator angiotensin 1-7. In light of the above, ARBs may prevent the development of ARDS and avert morbidity (admission to intensive care unit (ICU) and mechanical ventilation) and mortality.
Objective: To investigate the effect of the ARB valsartan in comparison to placebo on the occurrence of one of the following items, within 14 days of randomization:1) ICU admission; 2) Mechanical ventilation; 3) Death.
Study design: A double-blind, placebo-controlled 1:1 randomized clinical trial Study population: Adult hospitalized SARS-CoV-2-infected patients (n=651). Intervention: The active-treatment arm will receive valsartan in a dosage titrated to blood pressure up to a maximum of 160mg b.i.d. and the placebo arm will receive a matching placebo also titrated to blood pressure. Treatment duration will be 14 days or up to hospital discharge < 14 days or occurrence of the primary endpoint if < 14 days.
Main study endpoint: The primary study endpoint is the occurrence within 14 days of randomization of either: 1) ICU admission; 2) Mechanical ventilation; 3) Death.
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
- 未提供
排除标准
- •Admitted to ICU prior to randomization
- •Currently taking an ARB or angiotensin-receptor-neprilysin-inhibitor (ARNI)
- •Use of other investigational drugs at the time of enrollment
- •Prior reaction or intolerance to an ARB or ARNI; or severe intolerance to an ACEi, defined as angio-oedema requiring medical intervention
- •Systolic blood pressure < 105mmHg or diastolic blood pressure <65mmHg
- •Potassium greater than 5.5 mEq/L within 4 weeks of study enrollment.
- •Estimated Glomerular Filtration Rate (eGFR) of < 30ml/min/1.73 m2 within 4 weeks of study initiation
- •A known history of renal artery stenosis
- •AST and/or ALT > 3 times the upper limit of normal within 4 weeks of study enrollment. In case of mild to moderate liver dysfunction valsartan dosage will be limited to a maximum of 80mg
- •Severe liver dysfunction, biliary cirrhosis or cholestasis
- •Severe volume depletion or severe acute kidney injury that, in the opinion of the investigator, would preclude administration of valsartan
- •Concurrent treatment with Aliskiren
- •Inability to obtain informed consent
- •Pregnancy or breastfeeding
- •In females of childbearing age, unwillingness to use birth control or to be sexually abstinent for the duration of the study
研究组 & 干预措施
Active treatment arm
Valsartan at a dosage and frequency titrated to blood pressure with 80mg or 160mg tablets up to a maximum dose of 160mg b.i.d.
干预措施: Valsartan (Diovan) (Drug)
Placebo arm
Matching 80mg or 160mg placebo tablets at a dosage and frequency titrated to systolic blood pressure
干预措施: Placebo oral tablet (Drug)
结局指标
主要结局
first occurrence of intensive care unit admission, mechanical ventilation or death
时间窗: within 14 days
Death is defined as all-cause mortality
次要结局
- Intensive care unit admission(within 14 days)
- Death(Within 14 days, 30 days, 90 days and at 1 year)
- Mechanical ventilation(within 14 days)
- Occurrence of acute kidney injury(Within 14 days)