Precision Medicine Adaptive Network Platform Trial in Hypoxemic Acute Respiratory Failure
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 300
- 主要终点
- 28 day organ support free days
研究概览
简要总结
The goal of this trial is to accelerate the development of pharmacological therapies for critical illness by identifying biological sub phenotypes in patients with acute respiratory distress syndrome (ARDS). The trial will stratify participants by biological markers into different sub phenotypes, then randomized 1:1:1 to active treatment 1, active treatment 2, or usual care. Initial stratification will be into hyperinflammatory and hypoinflammatory sub phenotypes in ARDS based on plasma biomarker profiles. Regular adaptive analyses will enable efficient identification of treatment effects within each sub phenotype, stopping interventions where there is evidence of efficacy or futility, and bringing in new interventions and potentially new sub phenotypes.
详细描述
The primary objective of this trial is to accelerate the development of pharmacological therapies for critical illness by establishing an adaptive platform trial to test the efficacy of prioritized pharmacological interventions in patients with acute respiratory distress syndrome (ARDS). Participants will be recruited from multiple sites within the United States.
ARDS is defined by:
A known acute clinical insult or new or worsening respiratory dysfunction, and Receipt of respiratory support via invasive mechanical ventilation or non-invasive ventilation including continuous positive airway pressure, or high-flow nasal oxygen ≥30L/min, and
Within the same 24-hour time period:
Bilateral opacities on chest imaging not fully explained by effusions, lobar/lung collapse/atelectasis, or nodules, and Respiratory failure not fully explained by cardiac failure, fluid overload, pulmonary embolism, acute airways disease, or interstitial lung disease and Pa02/Fi02 ration <40 kPa from arterial blood gases, or Sp02/Fi02 <315 from pulse oximetry where Sp02 <97.
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
- None
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
- •Critically ill patients in hospital and at least 1 of the following:
- •Acute respiratory distress syndrome (ARDS). ARDS as defined by:
- •a known acute clinical insult or new or worsening respiratory dysfunction
- •receiving respiratory support via invasive mechanical ventilation or non- invasive mechanical ventilation including continuous positive airway pressure, or high flow nasal oxygen greater than or equal to 30L/min
- •within the same 24-hour time period:
- •i. bilateral opacities on chest imaging not fully explained by effusion, lobar/lung collapse/atelectasis, or nodules ii. respiratory failure not fully explained by cardiac failure, fluid overload, pulmonary embolism, acute airway disease iii. Pa02/Fi02 ration <40 kPa from arterial blood gases, or Sp02 <315 from pulse oximetry where Sp02 <97
- •A pandemic associated syndrome
排除标准
- •Simvastatin:
- •More than 48 hours from the diagnosis of AHRF
- •Patient is known to be pregnant
- •Liver transaminases >8 times the upper limit of the normal range
- •Creatine kinase >10 times the upper limit of the normal range
- •Currently receiving ongoing treatment with any of the following: itraconazole, ketoconazole, HIV protease inhibitors, nefazodone, cyclosporine, amiodarone, verapamil, or diltiazem.
- •Severe renal impairment (eGFR < 30mL/min and not receiving renal replacement therapy).
- •Current or recent treatment (within 2 weeks) with statins
- •Physician decision that a statin is required for proven indication
- •Contraindication to enteral drug administration, e.g., patients with mechanical bowel obstruction. Patients with high gastric aspirates due to an ileus are not excluded.
- •Known hypersensitivity to simvastatin
- •Baricitinib
- •More than 48 hours from the diagnosis of AHRF
- •Patient is known to be pregnant
- •Liver transaminases >8 times the upper limit of the normal range
- •Absolute neutrophil count less than 0.5x10 9/L
- •Currently receiving ongoing immunosuppressants (high dose corticosteroids, B and T cell targeted therapies, interferon, or JAK inhibitors)
- •Severe renal impairment (eGFR < 15mL/min) or receiving renal replacement therapy
- •Known active tuberculosis infection or, if known, latent TB treated for less than 4 weeks with appropriate anti-tuberculosis therapy per local guidelines.
- •Contraindication to enteral drug administration, e.g., patients with mechanical bowel obstruction. Patients with high gastric aspirates due to an ileus are not excluded.
- •Known hypersensitivity to baricitinib
研究组 & 干预措施
Baricitinib
Baricitinib will be administered at a dose of 4 mg once daily by the enteral route for up to 10 days.Baricitinib will be prescribed on the participants' in-patient drug administration chart (or equivalent) and administered to the participant by appropriately trained clinical staff with appropriate competencies in accordance with local practice. These staff do not need to be on the study delegation log.
The dosing regimen below will be used in the setting of renal impairment:
eGFR 30 to <60 mL/min Baricitinib Dose: 2mg
eGFR15 to <30 mL/min Baricitinib Dose:1mg
eGFR <15 mL/min (or receiving RRT) Baricitinib Dose withheld
干预措施: Baricitinib (Drug)
Usual Care
Usual care of ICU patients with ARDS. Patients randomized to the control arm or usual care will not receive simvastatin or baricitinib for 28 days or discharge from the ICU.
Simvastatin
Simvastatin will be administered at a dose of 80 mg once daily by the enteral route for up to 28 days
干预措施: Simvastatin (Drug)
结局指标
主要结局
28 day organ support free days
时间窗: in- hospital through day 28
Number of days alive and free of organ support, which is defined as needing either respiratory or cardiovascular support. Respiratory support is defined as invasive mechanical ventilation or non-invasive ventilation including continuous positive airway pressure or high-flow nasal oxygen with a Fraction of inspired oxygen (FiO2) ≥ 0.4 and a flow rate ≥30L/min. Cardiovascular support is defined as the continuous infusion of any vasopressor or inotrope medication
次要结局
- 28 day vasopressor free days(in-hospital through day 28)
- 28-day respiratory support free days(28 days)
- Receiving new renal replacement therapy(in-hospital through day 28)
- ICU length of stay(in-hospital through day 90)
- Hospital length of stay(In-hospital through day 90)
- All-cause mortality(In-hospital through Day 28 and day 90)
- Elevated Creatine Kinase more than 10 times the upper limit of normal(28 days)
- Alanine Transaminase or Aspartate Transaminase more than 8 times the upper limit of normal(28 days)
- Severe thrombocytopenia, out of keeping with clinical disease(28 days)
- Severe neutropenia, out of keeping with clinical disease(28 days)
- Serious infection defined as a positive blood cultures requiring treatment.(28 days)
- Venous thromboembolism(28 days)
- Stroke(28 days)
- Myocardial infarction(28 days)
- Ischemic bowel(28 days)
- Gastrointestinal perforation(28 days)
- Clinically important gastrointestinal bleeding.(28 days)
- Serious adverse events(90 days)
- Physical function (SPPB) at hospital discharge(Hospital discharge)
- Cognitive function Montreal Cognitive Assessment (MoCA)(Hospital discharge, day 90, day 180)
- Progression to invasive mechanical ventilation, extracorporeal membrane oxygenation (ECMO) or death among those not receiving that support at baseline(In-hospital through day 90)