A Multicentre Randomised Controlled Trial Comparing Two Strategies for the Diagnosis of Invasive Aspergillosis in High-risk Haematology Patients

A Multicentre Randomised Controlled Trial Comparing the Current Standard Diagnostic Strategy for Invasive Aspergillosis to the New Diagnostic Strategy for Invasive Aspergillosis in High-Risk Haematology Patients in Order to Determine Which Strategy Results in the Lower Rates of Use of Empiric Antifungal Therapy

Aspergillus is a fungus found in soil, on farms and on construction sites. In those whose immune system is impaired it causes severe infection. The people who are particularly at high-risk of infection with Aspergillus (which is called Invasive Aspergillosis)are those with acute leukaemia who are having chemotherapy and those post bone marrow transplantation. Currently 15% of those at high-risk develop Invasive Aspergillosis and 60-90% of those with Invasive Aspergillosis die.

The main reason for this high death rate is that our current diagnostic tests are not good at detecting infection or often only detect the infection at advanced stages when treatment is ineffective. Because of the limitations of current diagnostic tests the current practice is to give empiric antifungal therapy (EAFT) early to treat suspected Invasive Aspergillosis. However studies have demonstrated that this therapy has only resulted in a minor reduction in the mortality rates and it also causes significant drug toxicity. It is a suboptimal treatment modality.

New tests have recently been developed to diagnose Invasive Aspergillosis. These tests are for the detection of an Aspergillus protein in blood and for the detection of Aspergillus DNA in blood. Available data suggests that these new tests make an early diagnosis and seem to be able to monitor responses to treatment. However no study has been reported to date which demonstrates that the use of these tests can impact on important patient outcomes. This trial is being performed to determine whether the use of the new diagnostic tests to guide antifungal therapy will help improve treatment of Invasive Aspergillosis, reduce drug toxicity and reduce the death rate in the high-risk patients as compared with the current standard method of diagnosis and treatment with EAFT.

Study Overview

• Status: Completed
• Conditions: Invasive Aspergillosis
• Intervention / Treatment: Other: Culture and histology; Other: Aspergillus galactomannan and PCR

• Study Type: Interventional
• Enrollment (Actual): 240
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2145
      • Westmead Hospital
    • Sydney, New South Wales, Australia, 2010
      • St. Vincent's Hospital
  • South Australia
    • Adelaide, South Australia, Australia
      • Royal Adelaide Hospital
  • Victoria
    • Melbourne, Victoria, Australia, 3052
      • Royal Melbourne Hospital
    • Melbourne, Victoria, Australia, 3004
      • Alfred Hospital
    • Melbourne, Victoria, Australia, 3002
      • Peter MacCallum Cancer Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Patients fulfilling all the following criteria will be eligible for enrolment 1. Aged 18-80 years 2. Undergoing allogeneic haematopoietic stem cell transplantation (HSCT) for any reason OR Undergoing intensive combination chemotherapy for acute myeloid leukaemia (AML) or acute lymphoblastic leukaemia (ALL) 3. Has given written informed consent.

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Exclusion Criteria:

Patients with any of the following will be ineligible for enrolment 1. Other immunocompromised states (e.g. HIV infection, solid organ transplantation, autoimmune conditions treated with immunosuppressants etc.) besides those outlined in the inclusion criteria above 2. Currently enrolled in an antifungal treatment trial (not an antifungal prophylaxis trial) 3. Past history of proven or probable IA (as per standardized definitions) during a previous cycle of chemotherapy 4. Currently have active IA or other active invasive fungal infection 5. Prior enrolment in this study

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Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard diagnostic strategy of culture and histology; The standard-diagnostic strategy was designed to be consistent with the 2002 guidelines for antimicrobial use in neutropenic patients with cancer. When an invasive fungal infection was suspected (e.g. persistent fevers) cultures of blood, urine, sputum (if available) and faeces (if clinically indicated), and HRCT scans of chest were performed. Bronchoscopy and biopsies were performed according to institutional protocols. Empiric antifungal therapy was recommended whilst undergoing these investigations and was continued, de-escalated to prophylaxis, or changed to treatment of invasive aspergillosis or other IFD according to test results.	Other: Culture and histology
Experimental: Aspergillus galactomannan and PCR directed; Results of once to twice weekly testing with Aspergillus galactomannan and PCR directed the timing of CT scan performance and whether antifungal therapy was given	Other: Aspergillus galactomannan and PCR

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The proportion of patients treated with at least 1 course of empiric antifungal therapy as per protocol definition at 26 weeks following randomisation	26 weeks of follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Invasive Aspergillosis related mortality rates		26 weeks of follow-up
Other invasive fungal infection-related (IFI) mortality rates		26 weeks of follow-up
All-cause mortality rates		26 weeks of follow-up
Nephrotoxicity rates		26 weeks of follow-up
Hepatotoxicity rates		26 weeks of follow-up
Total number of courses of empiric antifungal therapy		26 weeks of follow-up
Cost data associated with treatment and complications.	To include number of hospital admissions, hospital length of stay, total duration of antifungal therapy and number of invasive procedures to diagnose invasive aspergillosis	26 weeks of follow-up
Incidence of proven, probable and possible invasive aspergillosis		26 weeks of follow-up
Incidence of proven, probable and possible other invasive fungal disease besides invasive aspergillosis		26 weeks of follow-up

Other Outcome Measures

Outcome Measure	Time Frame
Sub-group analysis according to type of antifungal prophylaxis, underlying disease and centre	26 weeks of follow-up

Collaborators and Investigators

• Sponsor: Bayside Health
• Collaborators: National Health and Medical Research Council, Australia
• Investigators: Principal Investigator: Monica Slavin, MB BS FRACP, Infectious Diseases Unit, Peter MacCallum Cancer Centre, St. Andrew's Place, East Melbourne, Victoria, Australia; Principal Investigator: Orla Morrissey, MB BCh FRACP, Infectious Diseases Unit, Alfred Hospital, Level 2, Burnet Institute, Commercial Road, Melbourne, Victoria, 3004, Australia

Publications and helpful links

General Publications

• Morrissey CO, Chen SC, Sorrell TC, Milliken S, Bardy PG, Bradstock KF, Szer J, Halliday CL, Gilroy NM, Moore J, Schwarer AP, Guy S, Bajel A, Tramontana AR, Spelman T, Slavin MA; Australasian Leukaemia Lymphoma Group and the Australia and New Zealand Mycology Interest Group. Galactomannan and PCR versus culture and histology for directing use of antifungal treatment for invasive aspergillosis in high-risk haematology patients: a randomised controlled trial. Lancet Infect Dis. 2013 Jun;13(6):519-28. doi: 10.1016/S1473-3099(13)70076-8. Epub 2013 Apr 30.
• Morrissey CO, Chen SC, Sorrell TC, Bradstock KF, Szer J, Halliday CL, Gilroy NM, Schwarer AP, Slavin MA. Design issues in a randomized controlled trial of a pre-emptive versus empiric antifungal strategy for invasive aspergillosis in patients with high-risk hematologic malignancies. Leuk Lymphoma. 2011 Feb;52(2):179-93. doi: 10.3109/10428194.2010.542600.

Study record dates

Study Major Dates

• Study Start: September 1, 2005
• Primary Completion (Actual): January 1, 2011
• Study Completion (Actual): August 1, 2011

Study Registration Dates

• First Submitted: September 11, 2005
• First Submitted That Met QC Criteria: September 12, 2005
• First Posted (Estimate): September 14, 2005

Study Record Updates

• Last Update Posted (Estimate): February 20, 2013
• Last Update Submitted That Met QC Criteria: February 17, 2013
• Last Verified: September 1, 2005

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Bacterial Infections and Mycoses; Mycoses; Aspergillosis
• Other Study ID Numbers: 55/05; ALLG SC01; NHMRC Project Grant 331305