Improving antifungal Stewardship in hAemato-oncology using a biomarker-guided algorithm Versus Empirical treatment (I-SAVE)

Chief Investigator: Dr Samir Agrawal Sponsor: Queen Mary University of LondonFunder: HTA – 20-26 Antifungal Stewardship in Haemato-Oncology

Duration: 01/11/2021 to 31/10/2024 (36 months)CTU: Warwick

Background: Audits in haemato-oncology units in the UK have shown the incidence rate of proven invasive fungal disease (IFD) being 6.5%, while over 50% of patients are treated with antifungals during febrile neutropenia episodes. The overuse of antifungals is of major concern in terms of toxicity to patients, emerging antifungal resistance, limited antifungal drug classes and the huge costs for the NHS. The NIHR-HTA has recognised the need for “Rapid tests for fungal infection” in high-risk groups for IFD (HTA no. 15/116) with the A-STOP study (invasive candidiasis in ICU). The current NIHR-HTA call is for a national study addressing the clinical and cost-effectiveness of antifungal stewardship (based on rapid laboratory tests) in patients with haematological cancer. However, a practical limitation to the clinical use of fungal biomarkers in the UK is poor access to testing and/or delayed time-to-results being available. Therefore, the potential benefits of the optimal use of these biomarker assays remain unanswered and UK physicians remain unsure of their clinical utility. Both the Scottish SPAG and NHS England have identified antifungal stewardship in Haemato-Oncology as an area for attention.

We propose a multi-centre randomised controlled trial to determine the safety (mortality), efficacy (reduced antifungal therapy) and cost-effectiveness of a diagnostic-guided management strategy using galactomannan (GM), PCR for Aspergillus (A-PCR), (1,3)-beta-d-glucan (BDG) and lateral flow assays for Aspergillus in Haemato-Oncology patients at high-risk of IFD. The two arms are (a) standard-of-care (SoC) at each centre; (b) biomarker-guided antifungal management (see study schematic below and attached documentation). Biomarker testing will be done in real-time using centralised laboratories.

Design: Multicentre two-arm randomised controlled trial with an internal pilot. (This study has been assessed by the MHRA to not be a CTIMP).Setting: Paediatric and adult bone marrow transplant and Haemato-Oncology Units in tertiary and secondary care.Target population and Enrolment:1) patients aged greater than 2 years old2) a. patients starting chemotherapy for AML/MDS/ALL or conditioning for allogeneic HSCT are enrolled on admission for twice weekly biomarker screening during periods of neutropenia b. patients who have persistent neutropenic fever (>72/96 hours) not responding to broad-spectrum antibiotics can be enrolled prior to starting treatment antifungal drugsProcedures: (see attached study schematic)- blood samples twice weekly – biomarker results are only made available in the biomarker arm- CT chest for persistent neutropenic fever (>72/96 hours) is mandatory in both study arms- SoC empirical management as per centre policy, while management in the biomarker arm is according to the study algorithmKey outcomes:cost-effectiveness of the two arms, efficacy (antifungal usage, incidence of IFD), safety (all-cause mortality at day 30/180/365) and compliance with a biomarker-guided strategy to enable antifungal stewardship.

The deadline for our full application to the NIHR is November 19th - we really do need your input for this short survey!

Many thanks in advance for your help.

If you have any questions or comments, please contact:Dr Samir Agrawal, Barts Health NHS Trust, Samir.agrawal@nhs.netDr Varun MEHRA, King’s College Hospital, Varun.mehra@nhs.netProf Adilia Warris, MRC Centre for Medical Mycology, A.warris@exeter.ac.uk

Antifungal stewardship. NHIR: 20-26. Feasibility Form v5.0, September 2020

Feasibility Survey

Study schematic

For a schematic of the study sampling, biomarker-guided management and explanatory notes, see the attached document.

1.0 Centre Demographics

Name of Hospital:

Name of Investigator(s):

How many patients are diagnosed annually at your centre with:

Adults - Paediatrics (cross out as appropriate)

ALL - ............ patients

AML - ............ patients

MDS - ............ patientsHow many allografts do you perform annually?

Please estimate the number of weekly episodes of febrile neutropenia

(include patients with any disease type and autografting)

Please estimate how many patients had probable/proven invasive fungal disease during the past 12 months? ________ patients

Please estimate how many patients had antifungal treatment for suspected infection (regardless of probable/proven or not) during the past 12 months?

________ patients

Antifungal stewardship. NHIR: 20-26. Feasibility Form v5.0, September 2020

How many patients do you estimate your site could recruit to the study per year? ________ patients

2.0 Antifungal PROPHYLAXIS policy at your institution (Tick one in each row):

Prophylaxis FLU ITRA POSA VORI MICA OtherAML Chemo (induction)

AML Chemo (consolidation)

AML Chemo (in relapse)

MDS Chemo (induction)

MDS chemo (other)

ALL Chemo (induction)

ALL Chemo (other)High-risk ALL chemo (induction)High-risk ALL chemo (consolidation)Relapsed ALL chemo (induction)Relapsed ALL chemo (consolidationAllo transplant

a) Matched sibling

b) Matched Unrelated

c) Mismatched donor

d) Haplo-identical donor

e) Cord blood

Graft Versus Host disease

Autologous transplant

3.0 MANAGEMENT – what is your usual approach for initiating antifungal treatment:

Please tick one optionEmpirical (persistent fevers – no biomarkers or CT)

“Empirical” (persistent fevers with CT – no biomarkers)

Pre-emptive (based on biomarkers with or without CT evidence)

Targeted (only if probable/proven infection)

Antifungal stewardship. NHIR: 20-26. Feasibility Form v5.0, September 2020

4.0 DIAGNOSTICS for fungal infections at your institution:

Used routinely(Yes/No)

(reply ‘No’ if only used on an ad hoc basis)

Test available on site

(yes/no)

Frequency of testing(eg, once weekly)

Average time to get results

CT Chest scan --- Not applicable ---GalactomannanBeta-D-GlucanAspergillus PCRLateral flow assay

5.0 BRONCHOSCOPY at your institution:

Do you have on-site access to bronchoscopy? Yes/NoDo you routinely consider bronchoscopy for suspected fungal chest infections?

Yes/No

If no, what are the main concerns/limitations you face?

What is average time to perform bronchoscopy once requested.Will you be able to request bronchoscopy tests for patients included in the study protocol, where clinically appropriate?

Yes/No/Not sure

6.0 STUDY COMPLIANCE – is this likely to be a problem at your centre for patients randomised to the diagnostic arm of the study – ie, withholding antifungal treatment if multiple tests are negative? Yes/No

7.0 PARTICIPATION – is your department interested in taking part in the study? Yes/ No

If not, what changes would allow your participation?

8.0 Do you have any additional comments about the study?

PLEASE RETURN BY EMAIL TO: Dr Samir Agrawal, Barts Health NHS Trust, Samir.agrawal@nhs.net

Antifungal stewardship. NHIR: 20-26. Feasibility Form v5.0, September 2020