Platform Adaptive Embedded Trial for Acute Respiratory Distress Syndrome

Study Overview
=================
Brief Summary
-----------------
Platform adaptive embedded trial for acute respiratory distress syndrome (PETARDS) is a randomized, embedded, multifactorial, adaptive platform trial for ARDS. The study aimed to assess the impact of multiple interventions on outcomes in patients with ARDS admitted to the ICU.

Detailed Description
-----------------
Mortality is significantly higher in ARDS patients requiring intensive care unit (ICU) admission. ARDS patients admitted to the ICU typically receive multiple (as many as 10 or 20) treatments that work together to fight infection, reduce pulmonary exudation, improve oxygenation, and support systemic organ function. Clinicians are often willing to choose the exact or considered safe and effective regimen from the therapies mentioned above. Still, there are individual differences in ARDS patients, and it is difficult to confirm the optimal treatment plan. It is inevitable to choose treatment without evidence-based medicine based on experience. The primary purpose of this study was to help physicians select the best-effective approach among existing ARDS therapies, and secondly to provide a rationale for specific empirical or emerging ARDS treatments. Clinical evidence to guide optimal management is best obtained from randomized controlled trials (RCTs); however, ARDS is a multi-causal, clinically and therapeutically heterogeneous clinical syndrome with rapid disease progression and complex clinical manifestations, in fact, difficult to organize RCT trials. In cases where the timing of onset and the pathophysiological mechanism cannot be determined, the initial treatment is the selection of protective ventilation/controlled infusion as the first-line standard therapy according to the Berlin classification of ARDS, and some second-line treatments with potential clinical benefit. It is difficult to conduct objective, scientific and timely evaluation, and the overall treatment plan is inevitably blind and empirical. This clinical operation mode is likely related to ARDS-related RCT research results. The results are unsatisfactory, the treatment response heterogeneity is high, and the outcome events vary greatly. closely related to the clinical status. The adaptive platform trial PETARDS is ideal for evaluating the effects of highly heterogeneous ARDS treatment strategies. This clinical research design (adaptive platform trial, APT) can use the information of patients who are participating in the study to guide the clinical treatment of subsequent newly enrolled patients. The APT trial randomized patients into multiple domains for multiple interventions to assess their effectiveness in different patients. The term domain refers to a common treatment unit (eg, steroid therapy) within which patients can be randomly assigned to several interventional (dose) groups (including controls, such as no steroids, as appropriate). Certainly). All trial procedures consist of a primary or core protocol and multiple secondary protocols, and the standard protocols, clinical treatment adaptations, and trial management and practices for specific treatment units are managed in a unified manner for each treatment unit. The core protocol, secondary protocols, and Statistical Analysis Plan (SAP) of this trial are presented in the appendix; the study required approval from the relevant ethics committees of all participating hospitals and was conducted by good clinical practice guidelines and principles described in the Declaration of Helsinki.

Official Title
-----------------
Platform Adaptive Embedded Trial for Acute Respiratory Distress Syndrome

Conditions
-----------------
Acute Respiratory Distress Syndrome

Intervention / Treatment
-----------------
* Device: protective ventilation
* Behavioral: prone position ventilation
* Drug: glucocorticoid therapy
* Other: restrictive fluid resuscitation
* Biological: Thymosin Alpha
* Drug: Muscle relaxant therapy
* Other: Integrated Chinese and Western Medicine Treatment
* Drug: statin therapy
* Combination Product: anti-infective treatment
* Device: Extracorporeal Membrane Oxygenation（ECMO）
* Genetic: stem cell therapy
* Drug: Sedative analgesia/muscle relaxant therapy
* Drug: inotropes therapy
* Drug: Vasoactive drug therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adult patients (18 years and older, regardless of gender) admitted to the ICU with ARDS; Intubation and mechanical ventilation; Moderate/severe ARDS defined by Berlin criteria (PaO2/FiO2 ≤200mmHg, PEEP ≥5cmH20); Moderate/severe ARDS less than 48 hours before randomization. Exclusion Criteria: Pregnancy or breastfeeding; Known allergy to the intervention drug; Daily use of an intervention drug or measure within the past 15 days; Intervention drugs or measures primarily intended to treat other conditions (eg, septic shock); Patients using the intervention drug or standard for two or more days during hospitalization; Patients are expected to die within the next 24 hours; Other: Participated in PETARDS in the past 90 days.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: protective ventilation<br>For ARDS patients with moderate to severe mechanical ventilation(MAQUET), give 6-8ml/kg (ideal body weight PBW), and control the plateau pressure to <30cmH2O; In patients with respiratory distress, the tidal volume can be increased to 7-8ml/kg (PBW), while the plateau pressure is <30cmH2O. Adjust breathing rate according to CO2 level, up to 35 breaths/min. PBW, male: 50+0.91 (height cm-152.4); female: 45.5+0.91 (height cm-152.4). | Device: protective ventilation<br>* Patients with moderate to severe ARDS received ventilation treatment according to predicted body weight(PBW) and controlled plateau pressure.<br>|
| Experimental: prone position ventilation (including awake state)<br>For patients with moderate to severe ARDS who have no contraindications to prone ventilation, protective lung ventilation is given and prone ventilation is performed; the duration is more than 12 hours/time. | Behavioral: prone position ventilation<br>* patients with moderate to severe ARDS who don't have contraindications were given prone ventilation for over 12 hours.<br>|
| Experimental: glucocorticoid therapy<br>Glucocorticoids are used for ARDS patients, with small doses and short courses of treatment in the acute phase (within 14 days). There is no clear recommendation for patients with ARDS from other causes. At present, the main research methods are methylprednisolone program(Solu-Medrol®), dexamethasone program, and hydrocortisone program | Drug: glucocorticoid therapy<br>* Dexamethasone: Patients received intravenous dexamethasone 20 mg daily from days 1 to 5, reduced to 10 mg daily from days 6 to 10. Hydrocortisone：For septic ARDS patients, 50 mg of hydrocortisone was given as an intravenous bolus every 6 hours for 7 days; For patients with COVID-19-related ARDS, The corticosteroid field randomized participants to a fixed 7-day period of intravenous hydrocortisone (50 mg or 100 mg every 6 hours).<br>* Other names: Hydrocortisone;|
| Experimental: restrictive fluid resuscitation<br>ARDS patients with circulatory or organ hypoperfusion problems should use as little fluid as possible to maintain treatment and circulation; other ARDS patients should focus on stabilizing circulation during the resuscitation phase, with controlled fluid replacement combined with early vasoactive drugs; ultrasound, Central venous pressure measurement, mixed central venous oxygen saturation, alveolar-arterial oxygen difference, blood lactate, etc. guide fluid resuscitation therapy; stop using vasoactive drugs for more than 12 hours, and use diuretics or diuretics combined with albumin to achieve fluid balance. | Other: restrictive fluid resuscitation<br>* without other organ dysfunction patients: Minimize fluid was given; other ARDS patients: In the resuscitation phase, controlled fluid replacement combined with vasoactive drugs was given; multiple measures were taken, like lactate and so on, to utilizedto guide fluid resuscitation therapy; diuretics or diuretics in combination with albumin to achieve fluid balance.<br>|
| Experimental: Immunomodulatory therapy<br>Thymosin Alpha（Thymalfasin for Injection） 1.6mg subcutaneously twice a week. | Biological: Thymosin Alpha<br>* People received thymosin Alpha subcutaneous injections, twice a week.<br>|
| Experimental: Muscle relaxant therapy<br>For patients with moderate to severe ARDS, if light sedation cannot achieve protective lung ventilation strategy and prone position ventilation, deep sedation combined with intermittent bolus injection of muscle relaxants（Vecuronium Bromide for Injection） is used; if protective lung ventilation strategy and prone position ventilation still cannot be achieved, deep sedation combined with continuous Inject muscle relaxants. | Drug: Muscle relaxant therapy<br>* Deep sedation combined with intermittent bolus injection of muscle relaxant or deep sedation combined with continuous infusion of muscle relaxant<br>* Other names: Succinylcholine;|
| Experimental: Integrated Chinese and Western Medicine Treatment<br>Mechanical ventilation + conventional western medicine + Dachengqi Decoction/Rhubarb-Salvia Injection/Tanreqing/Xuanbai Chengqi Decoction(Drugs determined by syndrome differentiation and treatment) | Other: Integrated Chinese and Western Medicine Treatment<br>* ventilation; conventional western medicine treatment； Chinese herbal medicine（Determining medication based on syndrome differentiation）<br>|
| Experimental: statin therapy<br>There are currently two options: 1) Simvastatin （Simvastatin Tablets）80 mg QD orally for up to 28 days in patients with acute lung injury. 2) Rosuvastatin （Rosuvastatin Calcium Tablets）40 mg for the first time, followed by 20 mg orally daily for 28 days, or 3 days after being transferred out of the ICU, or after the patient died. | Drug: statin therapy<br>* Simvastatin: 80mg qd po for not more than 28days; Rosuvastatin: 20mg qd po (40mg for the first time) for 28days or 3 days after transfer out of the ICU, or the patient died.<br>* Other names: Rosuvastatin;|
| Experimental: anti-infective treatment<br>Refer to the Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. recommendations. | Combination Product: anti-infective treatment<br>* According to Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021.<br>|
| Experimental: Extracorporeal Membrane Oxygenation（ECMO）<br>ECMO (Medtronic) is chosen as rescue therapy for severe ARDS patients with refractory hypoxemia within 7 days of onset. (Oxygenation index < 50 mmHg for 3 hours, or oxygenation index < 80 mmHg for 6 hours, or arterial pH < 7.25, arterial partial pressure of carbon dioxide [Paco2] ≥ 60 mmHg > 6 hours, and respiratory rate increased to every minute 35 breaths, adjusting mechanical ventilation settings to maintain plateau pressure ≤32 cmH2O) despite ventilator optimization (defined as inspired oxygen concentration) ≥ 0.80, tidal volume 6 ml/kg (PBW), and positive end-expiratory pressure [PEEP] ≥ 10 cmH2O). V-V mode is preferred. | Device: Extracorporeal Membrane Oxygenation（ECMO）<br>* For severe ARDS patients with refractory hypoxemia within 7 days of onset; (Inspiratory oxygen concentration) ≥ 0.80, tidal volume 6ml/kg (PBW), positive end-expiratory pressure [PEEP] ≥ 10 cmH2O; V-V Model.<br>|
| Experimental: stem cell therapy<br>Previous clinical studies have found that stem cell therapy is safe, using a single injection of bone marrow stem cells at a dose of 1, 5, 10*106 cells/kg; START trial, ClinicalTrials.gov NCT02097641, for patients with moderate to severe ARDS, a single intravenous injection of bone marrow stem cells 10* 106 cells/kg intervention protocol. | Genetic: stem cell therapy<br>* A single injection of bone marrow stem cells, doses of 1, 5, 10*106 cells/kg was taken according to the previous clinical studies.<br>|
| Experimental: Sedative analgesia/muscle relaxant therapy<br>For patients with moderate to severe ARDS, if light sedation cannot achieve protective lung ventilation strategy and prone position ventilation, deep sedation（Propofol Injectable Emulsion or Midazolam Injection） combined with intermittent bolus injection of muscle relaxants is used; if protective lung ventilation strategy and prone position ventilation still cannot be achieved, deep sedation combined with continuous Inject muscle relaxants（Vecuronium Bromide for Injection）. | Drug: Sedative analgesia/muscle relaxant therapy<br>* Deep sedation combined with intermittent bolus injection of muscle relaxant or deep sedation combined with continuous infusion of muscle relaxant<br>* Other names: dexmedetomidine;|
| Experimental: inotropes therapy<br>For unconventional medication, according toSurviving sepsis campaign: international guidelines for the management of sepsis and septic shock 2021. | Drug: inotropes therapy<br>* According to Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021.<br>* Other names: Levosimendan;|
| Experimental: Vasoactive drug therapy<br>According toSurviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. | Drug: Vasoactive drug therapy<br>* According to Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021.<br>* Other names: isoproterenol;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ventilator-free days | Ventilator-free days 28 days after randomization, definition: Survival without mechanical ventilation | within 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical status assessment | Patients' clinical status (6-point scale score) was assessed on day 15 after randomization, Definition: This scale ranges from 1 (no hospitalization) to 6 (death), with higher scores indicating worse outcomes. | 15 days | 
| All-Cause Mortality | All-cause mortality 28 days after randomization | within 28 days | 
| Duration of mechanical ventilation | days of mechanical ventilation | within 28 days | 
| Sequential Organ Failure Assessment (SOFA) Score | SOFA Score for different times, from 0 to 24 points | at 48 hours, 72 hours, and 7 days after randomization | 
| ICU stay time | The time for patients staying in ICU when they were in the hospital. | within 90 days | 
| Hospital stay | The whole time patients lived in the hospital, including the time when they lived in the ICU | within 90 days | 
| Organ failure free days | Patients got ARDS, but the other organs were not injury. | within 28 days | 
| Health-related quality of life assessment, EQ5D-5L and WHODAS 2.0 | Patient's life quality was assessed according to EQ5D-5L. If the patient had severe impairment of organ function within 6 months, evaluated the patient's quality of life according to WHODAS 2.0 | within 6 months | 
| Proportion of intubated patients undergoing tracheostomy | ARDS patients received tracheostomy. | 28 days | 
| Where the patient went after discharge | Home, rehabilitation hospital, nursing home or long-term care facility, or other emergency hospital | No recurrence within 90 days | 
| Re-admission to ICU during readmission | Patients were sent to the hospital and sent to the ICU again, | within 90 days | 
| Days not in intensive care unit | ICU transfer and discharge 28 days after randomization | 28 days after randomization | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ARDS, ICU, domain, platform adaptive embedded trial