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

Study design: A multicentre, randomised parallel-group trial which compares 2 strategies for the diagnosis of Invasive Aspergillosis (IA) in patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) and in patients undergoing intensive combination chemotherapy for acute leukaemia. Eligible patients will be stratified by centre and randomised 1:1 to the either the current standard diagnostic strategy (comparator or control arm) or the new diagnostic strategy (intervention arm) for IA. The study will not be blinded to enrolled patients or participating clinicians. However the assessment of the endpoints/outcomes will be by the Outcome Committee who will be blinded to the patients randomisation status.Experimental Protocol:Comparator arm: The current standard diagnostic work-up for IA will be implemented in patients with persistent or recurrent neutropenic fevers despite broad-spectrum antibiotics. The diagnostic components of this arm include serial blood cultures and serial urine, faeces, sputum and mouth swill samples for fungal culture; chest x-ray, high resolution computerised tomographic (HRCT) scan of thorax; bronchoscopy and culture of bronchoalveolar lavage (BAL) fluid; biopsy for histological examination etc. The results of the tests will determine the type of antifungal therapy given namely, empiric antifungal therapy or fungal therapy for proven or probable IA as per the predefined treatment protocol.New diagnostic strategy (index arm): Screening will be performed with Aspergillus galactomannan enzyme-linked immunosorbent assay (GM-ELISA) and an Aspergillus nested polymerase chain reaction (PCR) assay twice weekly for inpatients and weekly for outpatients. The results of the tests will determine if antifungal therapy is administered as per the same predefined treatment protocol, the timing of HRCT scan and what other procedures (e.g. bronchoscopy and culture of bronchoalveolar lavage (BAL) fluid etc.) are performed to further investigate persistent or recurrent neutropenic fevers. Duration on study:Each patient will be followed using the trial protocol for 26 weeks or until death, if earlier Sample size calculation and duration of study: 300 patients per arm are required to detect a 12% absolute reduction (i.e. from 40% to 28%) in the proportion of patients treated with empiric antifungal therapy. An interim analysis is planned. The expected accrual rate is 240 patients per year, thus the expected duration of the trial including follow-up will be 3 years.