Platform Adaptive Embedded Trial for Acute Respiratory Distress Syndrome

Acute Respiratory Distress Syndrome Clinical Trial

— PETARDS  

Official title:

Platform Adaptive Embedded Trial for Acute Respiratory Distress Syndrome

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05658692
• Other study ID #: 2022-0770
• Status: Recruiting
• Phase: Phase 4
• Start date: October 1, 2022
• Est. completion date: December 2023

Study information

• Verified date: November 2022
• Source: Second Affiliated Hospital, School of Medicine, Zhejiang University
• Contact: Zhaocai Zhang, Doctor
• Phone: +86-13758131998
• Email: 2313003[@]zju.edu.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1000
• Est. completion date: December 2023
• Est. primary completion date: October 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Acute Lung Injury
• Acute Respiratory Distress Syndrome
• Respiratory Distress Syndrome
• Respiratory Distress Syndrome, Newborn
• Syndrome

Intervention

Device:
• protective ventilation
Patients with moderate to severe ARDS received ventilation treatment according to predicted body weight(PBW) and controlled plateau pressure.

Behavioral:
• prone position ventilation
patients with moderate to severe ARDS who don't have contraindications were given prone ventilation for over 12 hours.

Drug:
• glucocorticoid therapy
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).

Other:
• restrictive fluid resuscitation
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.

Biological:
• Thymosin Alpha
People received thymosin Alpha subcutaneous injections, twice a week.

Drug:
• Muscle relaxant therapy
Deep sedation combined with intermittent bolus injection of muscle relaxant or deep sedation combined with continuous infusion of muscle relaxant

Other:
• Integrated Chinese and Western Medicine Treatment
ventilation; conventional western medicine treatment; Chinese herbal medicine(Determining medication based on syndrome differentiation)

Drug:
• statin therapy
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.

Combination Product:
• anti-infective treatment
According to "Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021".

Device:
• Extracorporeal Membrane Oxygenation(ECMO)
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.

Genetic:
• stem cell therapy
A single injection of bone marrow stem cells, doses of 1, 5, 10*106 cells/kg was taken according to the previous clinical studies.

Drug:
• Sedative analgesia/muscle relaxant therapy
Deep sedation combined with intermittent bolus injection of muscle relaxant or deep sedation combined with continuous infusion of muscle relaxant
• inotropes therapy
According to "Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021".
• Vasoactive drug therapy
According to "Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021".

Locations

Country	Name	City	State
China	Peking Union Medical College Hospital	Beijing
China	West China Hospital,Sichuan University	Chengdu
China	Guangdong Provincial People's Hospital	Guangdong
China	The Second Affiliated Hospital of Harbin Medical University	Harbin
China	Lanxi People's Hospital	Lanxi
China	Ningbo First Hospital	Ningbo
China	Zhognshang hospital, Fudan University	Shanghai
China	Taizhou Hosptial of Zhejiang Province	Taizhou
China	Union Hospital, Tongji Medical College, Huazhong University of Science and Technology	Wuhan
China	Wuhan University Renmin Hospital	Wuhan
China	The First Affiliated Hospital of Zhengzhou University	Zhengzhou

Sponsors (11)

Lead Sponsor

Collaborator

Second Affiliated Hospital, School of Medicine, Zhejiang University

Fudan University, Guangdong Provincial People's Hospital, Ningbo No. 1 Hospital, Peking Union Medical College Hospital, Renmin Hospital of Wuhan University, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, The First Affiliated Hospital of Zhengzhou University, The Second Affiliated Hospital of Harbin Medical University, West China Hospital, Wuhan Union Hospital, China

Country where clinical trial is conducted

China, 

References & Publications (19)

Acute Respiratory Distress Syndrome Network, Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT, Wheeler A. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000 May 4;342(18):1301-8. doi: 10.1056/NEJM200005043421801. — View Citation

Alhazzani W, Belley-Cote E, Moller MH, Angus DC, Papazian L, Arabi YM, Citerio G, Connolly B, Denehy L, Fox-Robichaud A, Hough CL, Laake JH, Machado FR, Ostermann M, Piraino T, Sharif S, Szczeklik W, Young PJ, Gouskos A, Kiedrowski K, Burns KEA. Neuromuscular blockade in patients with ARDS: a rapid practice guideline. Intensive Care Med. 2020 Nov;46(11):1977-1986. doi: 10.1007/s00134-020-06227-8. Epub 2020 Oct 26. — View Citation

Annane D, Pastores SM, Rochwerg B, Arlt W, Balk RA, Beishuizen A, Briegel J, Carcillo J, Christ-Crain M, Cooper MS, Marik PE, Umberto Meduri G, Olsen KM, Rodgers S, Russell JA, Van den Berghe G. Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Intensive Care Med. 2017 Dec;43(12):1751-1763. doi: 10.1007/s00134-017-4919-5. Epub 2017 Sep 21. Erratum In: Intensive Care Med. 2018 Feb 23;: — View Citation

Brodie D, Bacchetta M. Extracorporeal membrane oxygenation for ARDS in adults. N Engl J Med. 2011 Nov 17;365(20):1905-14. doi: 10.1056/NEJMct1103720. — View Citation

Combes A, Hajage D, Capellier G, Demoule A, Lavoue S, Guervilly C, Da Silva D, Zafrani L, Tirot P, Veber B, Maury E, Levy B, Cohen Y, Richard C, Kalfon P, Bouadma L, Mehdaoui H, Beduneau G, Lebreton G, Brochard L, Ferguson ND, Fan E, Slutsky AS, Brodie D, Mercat A; EOLIA Trial Group, REVA, and ECMONet. Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome. N Engl J Med. 2018 May 24;378(21):1965-1975. doi: 10.1056/NEJMoa1800385. — View Citation

Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, Machado FR, Mcintyre L, Ostermann M, Prescott HC, Schorr C, Simpson S, Wiersinga WJ, Alshamsi F, Angus DC, Arabi Y, Azevedo L, Beale R, Beilman G, Belley-Cote E, Burry L, Cecconi M, Centofanti J, Coz Yataco A, De Waele J, Dellinger RP, Doi K, Du B, Estenssoro E, Ferrer R, Gomersall C, Hodgson C, Moller MH, Iwashyna T, Jacob S, Kleinpell R, Klompas M, Koh Y, Kumar A, Kwizera A, Lobo S, Masur H, McGloughlin S, Mehta S, Mehta Y, Mer M, Nunnally M, Oczkowski S, Osborn T, Papathanassoglou E, Perner A, Puskarich M, Roberts J, Schweickert W, Seckel M, Sevransky J, Sprung CL, Welte T, Zimmerman J, Levy M. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021 Nov;47(11):1181-1247. doi: 10.1007/s00134-021-06506-y. Epub 2021 Oct 2. No abstract available. — View Citation

Guerin C, Reignier J, Richard JC, Beuret P, Gacouin A, Boulain T, Mercier E, Badet M, Mercat A, Baudin O, Clavel M, Chatellier D, Jaber S, Rosselli S, Mancebo J, Sirodot M, Hilbert G, Bengler C, Richecoeur J, Gainnier M, Bayle F, Bourdin G, Leray V, Girard R, Baboi L, Ayzac L; PROSEVA Study Group. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013 Jun 6;368(23):2159-68. doi: 10.1056/NEJMoa1214103. Epub 2013 May 20. — View Citation

Malbrain MLNG, Van Regenmortel N, Saugel B, De Tavernier B, Van Gaal PJ, Joannes-Boyau O, Teboul JL, Rice TW, Mythen M, Monnet X. Principles of fluid management and stewardship in septic shock: it is time to consider the four D's and the four phases of fluid therapy. Ann Intensive Care. 2018 May 22;8(1):66. doi: 10.1186/s13613-018-0402-x. — View Citation

Matthay MA, Calfee CS, Zhuo H, Thompson BT, Wilson JG, Levitt JE, Rogers AJ, Gotts JE, Wiener-Kronish JP, Bajwa EK, Donahoe MP, McVerry BJ, Ortiz LA, Exline M, Christman JW, Abbott J, Delucchi KL, Caballero L, McMillan M, McKenna DH, Liu KD. Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial. Lancet Respir Med. 2019 Feb;7(2):154-162. doi: 10.1016/S2213-2600(18)30418-1. Epub 2018 Nov 16. — View Citation

McAuley DF, Laffey JG, O'Kane CM, Cross M, Perkins GD, Murphy L, McNally C, Crealey G, Stevenson M; HARP-2 investigators; Irish Critical Care Trials Group. Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in acute lung injury to reduce pulmonary dysfunction (HARP-2) trial: study protocol for a randomized controlled trial. Trials. 2012 Sep 17;13:170. doi: 10.1186/1745-6215-13-170. — View Citation

McAuley DF, Laffey JG, O'Kane CM, Perkins GD, Mullan B, Trinder TJ, Johnston P, Hopkins PA, Johnston AJ, McDowell C, McNally C; HARP-2 Investigators; Irish Critical Care Trials Group. Simvastatin in the acute respiratory distress syndrome. N Engl J Med. 2014 Oct 30;371(18):1695-703. doi: 10.1056/NEJMoa1403285. Epub 2014 Sep 30. Erratum In: N Engl J Med. 2016 Nov 17;375(20):2010. — View Citation

Meduri GU, Annane D, Confalonieri M, Chrousos GP, Rochwerg B, Busby A, Ruaro B, Meibohm B. Pharmacological principles guiding prolonged glucocorticoid treatment in ARDS. Intensive Care Med. 2020 Dec;46(12):2284-2296. doi: 10.1007/s00134-020-06289-8. Epub 2020 Nov 4. — View Citation

National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D, deBoisblanc B, Connors AF Jr, Hite RD, Harabin AL. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006 Jun 15;354(24):2564-75. doi: 10.1056/NEJMoa062200. Epub 2006 May 21. — View Citation

National Heart, Lung, and Blood Institute ARDS Clinical Trials Network, Truwit JD, Bernard GR, Steingrub J, Matthay MA, Liu KD, Albertson TE, Brower RG, Shanholtz C, Rock P, Douglas IS, deBoisblanc BP, Hough CL, Hite RD, Thompson BT. Rosuvastatin for sepsis-associated acute respiratory distress syndrome. N Engl J Med. 2014 Jun 5;370(23):2191-200. doi: 10.1056/NEJMoa1401520. Epub 2014 May 18. — View Citation

Papazian L, Forel JM, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, Jaber S, Arnal JM, Perez D, Seghboyan JM, Constantin JM, Courant P, Lefrant JY, Guerin C, Prat G, Morange S, Roch A; ACURASYS Study Investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010 Sep 16;363(12):1107-16. doi: 10.1056/NEJMoa1005372. — View Citation

Qin H, Zhao A. Mesenchymal stem cell therapy for acute respiratory distress syndrome: from basic to clinics. Protein Cell. 2020 Oct;11(10):707-722. doi: 10.1007/s13238-020-00738-2. Epub 2020 Jun 9. — View Citation

Vignon P, Evrard B, Asfar P, Busana M, Calfee CS, Coppola S, Demiselle J, Geri G, Jozwiak M, Martin GS, Gattinoni L, Chiumello D. Fluid administration and monitoring in ARDS: which management? Intensive Care Med. 2020 Dec;46(12):2252-2264. doi: 10.1007/s00134-020-06310-0. Epub 2020 Nov 9. — View Citation

Villar J, Ferrando C, Martinez D, Ambros A, Munoz T, Soler JA, Aguilar G, Alba F, Gonzalez-Higueras E, Conesa LA, Martin-Rodriguez C, Diaz-Dominguez FJ, Serna-Grande P, Rivas R, Ferreres J, Belda J, Capilla L, Tallet A, Anon JM, Fernandez RL, Gonzalez-Martin JM; dexamethasone in ARDS network. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med. 2020 Mar;8(3):267-276. doi: 10.1016/S2213-2600(19)30417-5. Epub 2020 Feb 7. — View Citation

Wick KD, Leligdowicz A, Zhuo H, Ware LB, Matthay MA. Mesenchymal stromal cells reduce evidence of lung injury in patients with ARDS. JCI Insight. 2021 Jun 22;6(12):e148983. doi: 10.1172/jci.insight.148983. — View Citation

* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	ventilator-free days	Ventilator-free days 28 days after randomization, definition: Survival without mechanical ventilation	within 28 days
Secondary	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
Secondary	All-Cause Mortality	All-cause mortality 28 days after randomization	within 28 days
Secondary	Duration of mechanical ventilation	days of mechanical ventilation	within 28 days
Secondary	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
Secondary	ICU stay time	The time for patients staying in ICU when they were in the hospital.	within 90 days
Secondary	Hospital stay	The whole time patients lived in the hospital, including the time when they lived in the ICU	within 90 days
Secondary	Organ failure free days	Patients got ARDS, but the other organs were not injury.	within 28 days
Secondary	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
Secondary	Proportion of intubated patients undergoing tracheostomy	ARDS patients received tracheostomy.	28 days
Secondary	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
Secondary	Re-admission to ICU during readmission	Patients were sent to the hospital and sent to the ICU again,	within 90 days
Secondary	Days not in intensive care unit	ICU transfer and discharge 28 days after randomization	28 days after randomization