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

Study Overview
=================
Brief Summary
-----------------
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.

Official Title
-----------------
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

Conditions
-----------------
Invasive Aspergillosis

Intervention / Treatment
-----------------
* Other: Culture and histology
* Other: Aspergillus galactomannan and PCR


Participation Criteria
=================
Eligibility Criteria
-----------------
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. - 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 -

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard diagnostic strategy of culture and histology<br>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<br> <br> |
| Experimental: Aspergillus galactomannan and PCR directed<br>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<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | 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 |