Platform Adaptive Embedded Trial for Acute Respiratory Distress Syndrome

Phase 4

Recruiting

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

• Registration Number: NCT05658692
• Lead Sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University

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.

Study Timeline

• Study Start: 2022-10-01
• Status Verified: 2022-11
• Study First Submitted: 2022-11-22
• Study First Submitted QC: 2022-12-13
• Last Update Submitted: 2022-12-13
• Study First Posted: 2022-12-21
• Last Update Posted: 2022-12-21
• Primary Completion: 2023-10
• Study Completion: 2023-12

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 1000

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
prone position ventilation (including awake state)	prone position ventilation	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.
anti-infective treatment	anti-infective treatment	Refer to the "Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021." recommendations.
Sedative analgesia/muscle relaxant therapy	Sedative analgesia/muscle relaxant therapy	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）.
protective ventilation	protective ventilation	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).
Integrated Chinese and Western Medicine Treatment	Integrated Chinese and Western Medicine Treatment	Mechanical ventilation + conventional western medicine + Dachengqi Decoction/Rhubarb-Salvia Injection/Tanreqing/Xuanbai Chengqi Decoction(Drugs determined by syndrome differentiation and treatment)
Extracorporeal Membrane Oxygenation（ECMO）	Extracorporeal Membrane Oxygenation（ECMO）	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.
Immunomodulatory therapy	Thymosin Alpha	Thymosin Alpha（Thymalfasin for Injection） 1.6mg subcutaneously twice a week.
Muscle relaxant therapy	Muscle relaxant therapy	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.
stem cell therapy	stem cell therapy	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.
glucocorticoid therapy	glucocorticoid therapy	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
restrictive fluid resuscitation	restrictive fluid resuscitation	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.
statin therapy	statin therapy	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.
inotropes therapy	inotropes therapy	For unconventional medication, according to"Surviving sepsis campaign: international guidelines for the management of sepsis and septic shock 2021".
Vasoactive drug therapy	Vasoactive drug therapy	According to"Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021".

Primary Outcome Measures

Name	Time	Method
ventilator-free days	within 28 days	Ventilator-free days 28 days after randomization, definition: Survival without mechanical ventilation

Secondary Outcome Measures

Name	Time	Method
Organ failure free days	within 28 days	Patients got ARDS, but the other organs were not injury.
Where the patient went after discharge	No recurrence within 90 days	Home, rehabilitation hospital, nursing home or long-term care facility, or other emergency hospital
Health-related quality of life assessment, EQ5D-5L and WHODAS 2.0	within 6 months	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
ICU stay time	within 90 days	The time for patients staying in ICU when they were in the hospital.
Hospital stay	within 90 days	The whole time patients lived in the hospital, including the time when they lived in the ICU
Re-admission to ICU during readmission	within 90 days	Patients were sent to the hospital and sent to the ICU again,
Days not in intensive care unit	28 days after randomization	ICU transfer and discharge 28 days after randomization
All-Cause Mortality	within 28 days	All-cause mortality 28 days after randomization
Duration of mechanical ventilation	within 28 days	days of mechanical ventilation
Sequential Organ Failure Assessment (SOFA) Score	at 48 hours, 72 hours, and 7 days after randomization	SOFA Score for different times, from 0 to 24 points
Clinical status assessment	15 days	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.
Proportion of intubated patients undergoing tracheostomy	28 days	ARDS patients received tracheostomy.

Trial Locations

Locations (11)

Lanxi People's Hospital; 🇨🇳 Lanxi, China

Taizhou Hosptial of Zhejiang Province; 🇨🇳 Taizhou, China

West China Hospital，Sichuan University; 🇨🇳 Chengdu, China

The Second Affiliated Hospital of Harbin Medical University; 🇨🇳 Harbin, China

Peking Union Medical College Hospital; 🇨🇳 Beijing, China

Guangdong Provincial People's Hospital; 🇨🇳 Guangdong, China

Ningbo First Hospital; 🇨🇳 Ningbo, China

The First Affiliated Hospital of Zhengzhou University; 🇨🇳 Zhengzhou, China

Zhognshang hospital, Fudan University; 🇨🇳 Shanghai, China

Union Hospital, Tongji Medical College, Huazhong University of Science and Technology; 🇨🇳 Wuhan, China

Wuhan University Renmin Hospital; 🇨🇳 Wuhan, China