PET/CT Guided Antifungal Stewardship in Invasive Pulmonary Aspergillosis

Study Overview
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Brief Summary
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OPTIFIL is a pilot prospective multicenter study based over the hypothesis that the normalization of the functional imaging 18F-FDG-PET/CT during the Invasive pulmonary aspergillosis (IPA) could occur earlier than that of conventional imaging. This study evaluates the therapeutic response through a systematic 18F-FDG-PET/CT at week 6. The latter response will be correlated with the kinetics of selected biomarkers including antigens (galactomannan, β-D glucans), circulating Aspergillus DNA and anti-Aspergillus host response markers in addition to the conventional imaging tools obtained at weeks 6 and 12.

Detailed Description
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Invasive pulmonary aspergillosis (IPA) is the 3rd most frequent invasive mycosis in France with a rising incidence and 40% mortality (Bitar, 2014, Lortholary, 2011). Modern antifungals (AF) improved survival of IPA but lead to ecological, toxic and cost issues. In agreement with the  plan national de la bonne maîtrise des anti-infectieux , optimization of AF duration in IPA appears therefore challenging. Positron emission tomography using 2-deoxy-2-[fluorine-18] fluoro- D-glucose integrated with computed tomography (18F-FDG PET/CT) was reported to allow shortened AF duration (Hot, 2011, Chamilos, 2008) and is currently evaluated during chronic disseminated candidiasis {CANHPARI trial, PHRC 2012, NCT01916057}. The investigators raise the hypothesis that normalization of the functional imaging 18F-FDG-PET/CT during IPA could occur earlier than that of conventional imaging. However, due to the current lack of data, an intervention trial evaluating an early AF withdrawal based on 18F-FDG-PET/CT appears premature. In order to optimize IPA treatment duration, a two-step evaluation project has been designed. The first step consists in OPTIFIL prospective project. It will evaluate the therapeutic response through a systematic 18F-FDG-PET/CT at week 6 (crucial time point (Segal) used in recent IPA trials (Marr, 2015, Maertens, 2016). The latter response will be correlated with the kinetics of selected biomarkers including antigens (galactomannan, β-D glucans), circulating Aspergillus DNA and anti-Aspergillus host response markers in addition to the conventional imaging tools obtained at weeks 6 and 12. OPTIFIL project results will serve establishing a decision algorithm used during the second step intervention trial evaluating the accuracy of IPA AF interruption. Pilot prospective multicenter study of therapeutic follow-up of IPA in patients with hematological malignancy. Patients will have an inclusion visit (D0) and 8 or 9 follow up visits: D3, W1, W2, W4, W6, End of Treatment, W24 and W48. Each visit will include physical examination. Lung CT scan, 18F-FDG-PET/CT, samplings of blood will be performed at different visits in respective centers β-D-Glucan, Aspergillus fumigatus and Aspergillus spp. quantitative PCRs and host biomarkers such as Aspergillus Elispot will be performed and centralized Response evaluation will be assessed by an independent committee. CT response will be evaluated by a blinded radiologist. PET/CT response will be evaluated by 2 blinded nuclear medicine physicians.

Official Title
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PET/CT Guided Antifungal Stewardship in Invasive Pulmonary Aspergillosis

Conditions
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Aspergillosis and Haematological Malignancy

Intervention / Treatment
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* Device: imaging 18F-FDG-PET/CT
* Biological: Blood collection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients ≥18 years-old Patient with hematological malignancy Proven or probable invasive pulmonary aspergillosis according to EORTC/MSG modified criteria Inclusion ≤ 4 days (≤ 5 days in case of week end) after IPA diagnosis Possibility to perform 18F-FDG-PET/CT scanner within the 7 subsequent days following diagnosis Informed consent form signed Affiliation to French social insurance Exclusion Criteria: Pregnancy or breastfeeding women Life expectancy < 3 months Fungal or mycobacterial lung co infection at time of IPA diagnosis Haematological malignancy with lung location Proven or probable mold infection in 6 previous months Disseminated aspergillosis (lung and sinus aspergillosis can be included)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patient with invasive pulmonary aspergillosis<br>Blood collection and imaging 18F-FDG-PET/CT | Device: imaging 18F-FDG-PET/CT<br>* 18F-FDG PET Scan at Day 0, W6 and W12<br>Biological: Blood collection<br>* Blood collection at D0, D3, W1, W2, W4, W6, W12, end of treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate according to 18F-FDG-PET/CT (PET/CT response) |  | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate according to EORTC/MSG criteria (Segal response). |  | 6 weeks | 
| Response rate according to EORTC/MSG criteria (Segal response). |  | 12 weeks | 
| Response rate according to PET/CT |  | 12 weeks or at the end of treatment | 
| Number of patients for whom 18F-FDG-PET/CT has evidenced extra pulmonary attributable lesions |  | 6 weeks | 
| Number of patients for whom 18F-FDG-PET/CT has evidenced extra pulmonary attributable lesions |  | 12 weeks | 
| Number of patients for whom 18F-FDG-PET/CT has evidenced extra pulmonary attributable lesions in initial work-up |  | first day | 
| Patient mortality rate | overall mortality and relationship with Invasive Pulmonary Aspergillosis or Haematological Malignancies | 6 weeks | 
| Patient mortality rate | overall mortality and relationship with Invasive Pulmonary Aspergillosis or Haematological Malignancies | 12 weeks | 
| Patient mortality rate | overall mortality and relationship with Invasive Pulmonary Aspergillosis or Haematological Malignancies | 24 weeks | 
| Patient mortality rate | overall mortality and relationship with Invasive Pulmonary Aspergillosis or Haematological Malignancies | 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Aspergillosis, Haematological malignancy, 18F-FDG PET/CT, Biomarkers