Genomic Determinants of Outcome in Cardiogenic Shock (Goldilocs)

• ClinicalTrials.gov Identifier: NCT05728359
• Recruitment Status: Recruiting
• First Posted: February 15, 2023
• Last Update Posted: February 15, 2023
• Sponsor: Barts & The London NHS Trust
• Collaborator: University of Oxford
• Information provided by (Responsible Party): Barts & The London NHS Trust

Study Description

Brief Summary:

The aim of this project is to understand the heterogeneity of both the immune consequences and treatment responses in CS. We will explore this heterogeneity through identification of transcriptomic sub-phenotypes and their association with outcomes, including therapeutic responses.

Condition or disease	Intervention/treatment
Cardiogenic Shock	Other: Observational study

Detailed Description:

This is a prospective observational cohort study in 8-10 cardiac centres across Europe. We will recruit patients presenting with acute myocardial infarction (AMI) and CS who are supported medically (n=100); with extracorporeal membrane oxygenation (n=50); and with the Impella Device (n=50). We will also enrol patients who present with either AMI and no evidence of CS (n=50) or CS due to non-ischaemic pathologies (e.g. myocarditis: n=50) as comparators. The recruitment target is 300 patients.

Study Design

• Study Type: Observational [Patient Registry]
• Estimated Enrollment: 300 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Target Follow-Up Duration: 1 Month
• Official Title: Prospective Observational Study Investigating Genomic Determinants of Outcome From Cardiogenic Shock (GOlDilOCS)
• Actual Study Start Date: September 20, 2022
• Estimated Primary Completion Date: July 1, 2025
• Estimated Study Completion Date: July 1, 2025

Groups and Cohorts

Group/Cohort	Intervention/treatment
Cardiogenic shock and MI; Patients presenting with acute myocardial infarction and cardiogenic shock who are supported medically (ie. inotropes +/- intra aortic balloon pump only). N=50	Other: Observational study; Blood sampling and clinical data collection
Cardiogenic shock and MI wtih ECMO; Patients presenting with acute myocardial infarction and cardiogenic shock who are supported medically with ECMO (+/- LV unloading device). N=50	Other: Observational study; Blood sampling and clinical data collection
Cardiogenic shock and MI wtih Impella; Patients presenting with acute myocardial infarction and cardiogenic shock who are supported medically with Impella. N=50	Other: Observational study; Blood sampling and clinical data collection
MI without cardiogenic shock; Patients presenting with acute myocardial infarction and cardiogenic shock as a control comparator	Other: Observational study; Blood sampling and clinical data collection
Non ischemic Cardiogenic Shock ie myocarditis; Patients presenting with myocarditis and cardiogenic shock as a control comparator	Other: Observational study; Blood sampling and clinical data collection

Outcome Measures

Primary Outcome Measures :

1. The primary aim is to better understand the heterogeneity of the immune consequences and treatment responses in CS through identification of transcriptomic sub-phenotypes and their association with in-hospital mortality [ Time Frame: through study completion, an average of 5 days ]
   This will be achieved through bloods sample collection, analysis and linked to the patient's clinical diagnosis and outcome.

Secondary Outcome Measures :

1. Identify transcriptomic (and chemokine/cytokine) signatures at presentation that elucidate the pathobiology of CS and examine their subsequent evolution. [ Time Frame: through study completion, an average of 5 days ]
   Bloods samples will be collected from patients during their hospital stay and corresponding analysis performed.
2. Correlate recently identified clinical phenotypes of CS with transcriptomic and inflammatory mediator signatures. [ Time Frame: through study completion, an average of 5 days ]
   Bloods samples will be collected from patients during their hospital stay and corresponding analysis performed.
3. Identify transcriptomic and chemokine/cytokine signatures at presentation that improve prognostic accuracy in patients with CS [ Time Frame: through study completion, an average of 5 days ]
   Bloods samples will be collected from patients during their hospital stay and corresponding analysis performed.
4. Investigate inter-individual heterogeneity in the dynamic transcriptomic response to CS through an eQTL mapping approach and identify context- specific regulatory genetic variants involving gene networks central to the pathogenesis of CS. [ Time Frame: through study completion, an average of 5 days ]
   Bloods samples will be collected from patients during their hospital stay and corresponding analysis performed.
5. Identity novel therapeutic targets that might modulate the dysfunctional immune response to CS - "drug discovery" [ Time Frame: through study completion, an average of 5 days ]
   Bloods samples will be collected from patients during their hospital stay and corresponding analysis performed.
6. Determine the extent to which the signatures and drivers of a dysfunctional immune response in CS are shared with other critical illness syndromes. [ Time Frame: through study completion, an average of 5 days ]
   Bloods samples will be collected from patients during their hospital stay and corresponding analysis performed.

Biospecimen Retention:   Samples With DNA

We will collect blood samples (18ml per time-point) at research-specific time points Plasma will be extracted from spun blood in appropriate blood collection tubes (EDTA, 2x3mL), aliquoted and stored at -80°C.

DNA will be extracted from the Buffy Layer of spun whole human blood. RNA from human whole blood (1x3ml) will be collected into a Tempus tube. Whole blood will be added to Cytodelics to allow cellular fixation and subsequent analysis.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Sampling Method: Probability Sample

Study Population

All patients presenting to recruiting sites who fulfil study inclusion criteria and have no exclusion, will be considered. The majority of patients will be present through the heart attack centres and pathways. Some patients will, however, develop cardiogenic shock (CS) during their admission. These patients will be recruited from the coronary care units, intensive care units or cardiology wards and will be identified by clinicians who will alert research staff.

Criteria

Inclusion Criteria:

• All of the following are required for inclusion following screening:

  • Willing to provide informed consent or appropriate consent from a nominated consultee or personal consultee
  • Presentation within 24 hours of onset of ACS symptoms.
  • CS can only be secondary to ACS (Type 1 MI STEMI or N-STEMI) or myocarditis
  • Planned or completed revascularisation of culprit coronary artery

CS will be defined by:

• Systolic blood pressure <90 mmHg for at least 30 minutes
• A requirement for a continuous infusion of vasopressor or inotropic therapy to maintain systolic blood pressure > 90 mmHg.

• Clinical signs of pulmonary congestion, plus signs of impaired organ perfusion with at least one of the following manifestations:

  • altered mental status.
  • cold and clammy skin and limbs.
  • oliguria with a urine output of less than 30 ml per hour.
  • elevated arterial lactate level of >2.0 mmol per litre.

Exclusion Criteria:

• Any of the inclusion criteria not met and:

  1. Unwilling to provide informed consent.
  2. Echocardiographic evidence (recorded within 90 mins of end of PCI procedure) of mechanical cause for CS: eg ventricular septal defect, LV-free wall rupture, ischaemic mitral regurgitation.
  3. Age <18 and ≥80 years.
  4. Shock from another cause (sepsis, haemorrhagic/hypovolaemic shock, anaphylaxis, etc).
  5. Significant systemic illness
  6. Known dementia of any severity
  7. Comorbidity with life expectancy <12 months.

  8. Out-of-hospital cardiac arrest (OHCA) and any of the following:

     1. No return of spontaneous circulation (ongoing resuscitation effort)
     2. pH <7
     3. Without bystander CPR within 10 minutes of collapse
  9. Arterial lactate level of <2.0 mmol per litre.

Contacts and Locations

Contacts

Contact: Alastair Proudfoot; 02037658707; alastair.proudfoot1@nhs.net

Contact: Mervyn Andiapen; 02037658707; mervyn.andiapen@nhs.net

Locations

United Kingdom

Barts Health NHS trust; Recruiting

London, United Kingdom

Contact: Dan Jones dan.jones8@nhs.net

Sponsors and Collaborators

Barts & The London NHS Trust

University of Oxford

Investigators

• Principal Investigator: Alastair Proudfoot; Barts Heath NHS trust

More Information

Publications:

Maslove DM, Tang B, Shankar-Hari M, Lawler PR, Angus DC, Baillie JK, Baron RM, Bauer M, Buchman TG, Calfee CS, Dos Santos CC, Giamarellos-Bourboulis EJ, Gordon AC, Kellum JA, Knight JC, Leligdowicz A, McAuley DF, McLean AS, Menon DK, Meyer NJ, Moldawer LL, Reddy K, Reilly JP, Russell JA, Sevransky JE, Seymour CW, Shapiro NI, Singer M, Summers C, Sweeney TE, Thompson BT, van der Poll T, Venkatesh B, Walley KR, Walsh TS, Ware LB, Wong HR, Zador ZE, Marshall JC. Redefining critical illness. Nat Med. 2022 Jun;28(6):1141-1148. doi: 10.1038/s41591-022-01843-x. Epub 2022 Jun 17.

Davenport EE, Burnham KL, Radhakrishnan J, Humburg P, Hutton P, Mills TC, Rautanen A, Gordon AC, Garrard C, Hill AV, Hinds CJ, Knight JC. Genomic landscape of the individual host response and outcomes in sepsis: a prospective cohort study. Lancet Respir Med. 2016 Apr;4(4):259-71. doi: 10.1016/S2213-2600(16)00046-1. Epub 2016 Feb 23.

Toma A, Dos Santos C, Burzynska B, Gora M, Kiliszek M, Stickle N, Kirsten H, Kosyakovsky LB, Wang B, van Diepen S, Epelman S, Szekely Y, Marshall JC, Billia F, Lawler PR. Diversity in the Expressed Genomic Host Response to Myocardial Infarction. Circ Res. 2022 Jun 24;131(1):106-108. doi: 10.1161/CIRCRESAHA.121.318391. Epub 2022 May 9. No abstract available.

Cano-Gamez E, Burnham KL, Goh C, Allcock A, Malick ZH, Overend L, Kwok A, Smith DA, Peters-Sengers H, Antcliffe D; GAinS Investigators; McKechnie S, Scicluna BP, van der Poll T, Gordon AC, Hinds CJ, Davenport EE, Knight JC, Webster N, Galley H, Taylor J, Hall S, Addison J, Roughton S, Tennant H, Guleri A, Waddington N, Arawwawala D, Durcan J, Short A, Swan K, Williams S, Smolen S, Mitchell-Inwang C, Gordon T, Errington E, Templeton M, Venatesh P, Ward G, McCauley M, Baudouin S, Higham C, Soar J, Grier S, Hall E, Brett S, Kitson D, Wilson R, Mountford L, Moreno J, Hall P, Hewlett J, McKechnie S, Garrard C, Millo J, Young D, Hutton P, Parsons P, Smiths A, Faras-Arraya R, Soar J, Raymode P, Thompson J, Bowrey S, Kazembe S, Rich N, Andreou P, Hales D, Roberts E, Fletcher S, Rosbergen M, Glister G, Cuesta JM, Bion J, Millar J, Perry EJ, Willis H, Mitchell N, Ruel S, Carrera R, Wilde J, Nilson A, Lees S, Kapila A, Jacques N, Atkinson J, Brown A, Prowse H, Krige A, Bland M, Bullock L, Harrison D, Mills G, Humphreys J, Armitage K, Laha S, Baldwin J, Walsh A, Doherty N, Drage S, Ortiz-Ruiz de Gordoa L, Lowes S, Higham C, Walsh H, Calder V, Swan C, Payne H, Higgins D, Andrews S, Mappleback S, Hind C, Garrard C, Watson D, McLees E, Purdy A, Stotz M, Ochelli-Okpue A, Bonner S, Whitehead I, Hugil K, Goodridge V, Cawthor L, Kuper M, Pahary S, Bellingan G, Marshall R, Montgomery H, Ryu JH, Bercades G, Boluda S, Bentley A, Mccalman K, Jefferies F, Knight J, Davenport E, Burnham K, Maugeri N, Radhakrishnan J, Mi Y, Allcock A, Goh C. An immune dysfunction score for stratification of patients with acute infection based on whole-blood gene expression. Sci Transl Med. 2022 Nov 2;14(669):eabq4433. doi: 10.1126/scitranslmed.abq4433. Epub 2022 Nov 2.

• Responsible Party: Barts & The London NHS Trust
• ClinicalTrials.gov Identifier: NCT05728359
• Other Study ID Numbers: 290406
• First Posted: February 15, 2023
• Last Update Posted: February 15, 2023
• Last Verified: July 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Barts & The London NHS Trust:

ACS,; Cardiogenic Shock; ECMO; Impella; Gene Expression; Endotype

Additional relevant MeSH terms:

Shock, Cardiogenic; Shock; Pathologic Processes; Myocardial Infarction; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Infarction; Ischemia; Necrosis