Changes from Version 1.0 Highlighted in Yellow

PIMDA Study Design. 29 May 2012 Version 1.1

Changes from Version 1.0 highlighted in yellow.

Study design

1. Primary aim

To estimate the rate of occurrence of possible, probable and proven invasive mould disease (IMD) in patients who are expected to develop neutropenia of at least 7 days duration after receiving chemotherapy to induce or maintain remission of acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS), and recipients of allogeneic stem cell transplantation.

Study design

Patients at risk of IMD will be recruited during a 12-week enrolment period and then followed up during a 12-week exposure period to see whether or not they develop an IMD (Figure 1). Patients can be recruited once only so there will be one episode per patient. Each participating centre will be expected to follow their normal standard of care. No change in treatment regimen is required.

2. Secondary aims

Outcome

The outcome of each category of IMD (see Table 1) will be determined depending upon whether or not antifungal therapy is given.

2.1 Survival (all categories)

Comparison of the survival rate of patients with and without possible, probable or proven IMD for up to 6 months.

2.2 Therapy if given (categories B and CI, CII, CIII, CIV)

a) The treatment outcome 12 weeks after starting antifungal therapy for probable and proven IMD (category D and E, Table 1) will be evaluated according to EORTC/MSG definitions of Segal et al. 2008, (see Appendix A).

b) The treatment outcome 12 weeks after starting antifungal therapy for IMD categories CI, CII, CIII, CIV (see Table 1) will be considered successful if all signs and symptoms associated with IMD have resolved and there is no evidence of recurrence.

c) The treatment outcome 12 weeks after starting antifungal therapy for persistent unexplained fever (IMD category B, Table 1) will be considered successful if there is resolution of fever by the end of therapy and there is no evidence for IMD.

d) Progression of categories B and CI, CII, CIII and CIV to probable or proven IMD.

e) Exploration of the feasibility of adopting a diagnostic-driven approach to initiating antifungal therapy as detailed in Figure 2.

3. Eligible patients

Patient inclusions

a) Patients aged ≥18 years.

b) Patients about to receive either

1. chemotherapy to induce or maintain remission of AML or MDS (Appendix B), or
2. conditioning treatment for allogeneic stem cell transplantation (Appendix C)

c) Patients expected to develop neutropenia (<0.5 x 109/litre granulocytes) of at least 7 days duration.

d) Patients who have given written informed consent (dependent on local regulations).

Patient exclusions

a) Patients aged <18 years.

b) Patients with AML or MDS for whom there is no intention to treat their underlying disease.

c) Patients receiving an autologous haematopoietic stem cell transplant (HSCT).

4. Enrolment period

a) All eligible patients who are admitted to hospital during the 12-week enrolment period should be registered within 3 working days of starting chemotherapy or conditioning regimen.

b) The first day of enrolment (day 1 of the observation period) is the first day of starting chemotherapy or conditioning therapy.

5. Follow-up

a) All enrolled patients will be followed for a fixed observational period of 12 weeks.

b) Those patients who are treated for IMD during the observational period will be followed for 12 weeks after starting antifungal therapy to assess the outcome of treatment of the IMD (Figure 1).

1. Treatment outcome will be defined according to EORTC/MSG definitions (Segal et al. 2008) see Appendix A.

6. Survival

a) All enrolled patients will be assessed at 6 months after enrolment to determine survival.

• No active follow-up should be made

7. Definitions of IMD

a) The EORTC 2008 definitions of possible, probable and proven will be strictly applied.

• De Pauw B, Walsh TJ, Donnelly JP, et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 2008;46:1813–21.

b) The EORTC 2008 definitions of ‘Radiological Signs and Clinical Symptoms’ will be used (Appendix D).

c) Probable or proven IMD will be considered to be a genuine case. However all cases recruited will be classified according to the pattern of IMD (Table 1, Patterns of IMD).

d) The ‘non-specific’ or ‘uncertain’ EORTC Group II group will include patients with ‘non-specific new pulmonary infiltrates on CT scan +/- mycological evidence (positive galactomannan (GM) biomarker)’ i.e. CII (IMD cannot be excluded) and CIII (IMD cannot be excluded) in Table 1, Patterns of IMD.

1

PIMDA Study Design. 29 May 2012 Version 1.1

Changes from Version 1.0 highlighted in yellow.

Table 1. Patterns of IMD

1

PIMDA Study Design. 29 May 2012 Version 1.1

Changes from Version 1.0 highlighted in yellow.

8. Centre requirements

a) Employing a diagnostic work up that includes

1. CT scanning (centres will be asked to provide details on the type of CT scan they perform)
2. Platelia EIA test for galactomannan (GM) to diagnose IMD
3. No more than 7 days between the CT scan and GM test for each case.

9. Ethics committee approvals

a) When required, centres will be responsible for obtaining local ethics committee approval for the study.

b) Relevant documentation will be provided to assist with this.

10. Statistical evaluation and sample size

a) The primary aim is to estimate the rate of occurrence of probable or proven IMD as defined by the EORTC/MSG criteria. To achieve this, there will be no distinction made between proven and probable disease. The final conclusive diagnosis will be used to classify the patients rather than the initial diagnosis made at the start of antifungal treatment, as this may evolve during the 12-week follow-up period from unclassified (category CIIII) to possible, probable or even proven IMD. Confidence limits at 95% will be provided using the exact binomial distribution.

b) A total of 1,000 patients will be registered. With this sample size, assuming that (a) 70% of patients will be given induction or maintenance chemotherapy for AML or MDS and the remaining 30% will be receiving conditioning therapy to prepare them for an allogeneic transplant, and (b) the corresponding expected rates of occurrence of IMD are 5% and 10% respectively, then the half length of the confidence interval (CI) will be around 1.5%

c) All eligible patients will be included in the analysis whatever the true duration of neutropenia will be. However, a central review of patient's eligibility will be performed in order to validate the investigator's assessment about the expected duration of neutropenia that has to be ≥ 7 days. The reviewers will make use of data available at registration as the planned chemotherapy regimen, underlying disease and patients characteristics as age and will be blinded of patients outcomes (true neutropenia duration, IMD development, survival). Patients assessed as ineligible after central review will be excluded from the analysis.

d) Subgroup analysis will be done according to the treatment setting and the underlying disease i.e. AML, MDS and allogeneic HSCT.

e) Descriptive analysis will be done on the whole observed distribution of IMD from unclassified through to proven (Table 1).

f) Time to final conclusive diagnosis will be assessed using KaplanMeier's estimates.

g) The response to antifungal treatment given empirically or pre-emptively will be assessed after 12 weeks following the start of treatment.

h) Calculating specific survival rates will not be possible since the cause of death will not be known with any certainty owing to the low rate of autopsy. However, survival estimates of patients with IMD (cases) and those without IMD (controls) will be compared by matching cases and controls on the basis of the number of days between registration and survival at 6 months after enrolment. The survival rate estimate will be calculated using the KaplanMeier method after accounting for losses to follow-up. A 95% CI will be provided. This analysis will be broken down by type of IMD and by first therapeutic antifungal treatment.

i) The investigations performed for diagnosing IMD will be used to assess whether it would have been feasible to have used the diagnosis-driven approach to initiate antifungal therapy as detailed in Figure 2. The feasibility rate will be estimated together with calculation of a 95% CI.

j) A detailed statistical analysis plan (SAP) will be prepared before locking the database.

11. Publications policy

a) It is intended to publish results in a peer-reviewed journal. The Steering Committee will be the authors of the main publications on behalf of the PIMDA Study Group and the contributors of cases will be duly acknowledged by name and affiliation (the PI in each Centre will be named, together with the number of cases contributed).

Appendix A:

Responses to antifungal therapy in patients with probable or proven invasive mould disease

Reference:

Segal BH, Herbrecht R, Stevens DA et al. Defining responses to therapy and study outcomes in clinical trials of invasive fungal diseases: Mycoses Study Group and European Organization for Research and Treatment of Cancer Consensus Criteria. Clin Infect Dis 2008:47;674-83

Table 3. Responses to antifungal therapy in patients with invasive mold disease

NOTE

The minimum period of observation is at least 6 weeks in trials of primary therapy, but assessment of outcome at week 12 or later should be included as a secondary end point. For trials of salvage therapy, consider evaluation of the primary end point at least 12 weeks after enrolment.

a Clear evidence of a radiological response (reduction in diameter by at least 25% with no new sites of disease) should be given more weight than subjective, nonspecific, or difficult-to-quantify symptoms or signs of disease. Thus, in the scenario of fungal pneumonia, we suggest that radiological improvement with persistence of fever or cough should be scored as a partial response. Because radiological improvement often lags behind clinical improvement, especially if a short-term period of evaluation is employed (see Invasive Aspergillosis and Other Mold Diseases), we suggest that radiological stabilization and resolution of all attributable symptoms and signs of disease can also be equated with a partial response. See text for discussion of serum galactomannan index as a promising correlate of therapeutic outcome.

Appendix B:

Chemotherapy of AML and MDS

Phase of treatment:

• Remission-induction
• Consolidation
• Re-induction (for refractory or relapsed cases only).

Chemotherapy regimen:

• Cytosine-arabinoside plus anthracycline or anthracenedione-based regimen
• ICE-like regimen
• Cytosine-arabinoside monotherapy
• Other.

Appendix C: Standard intensity conditioning regimens for HSCT (established regimens) (source EBMT 2010)

1. Leukaemias

• Busulfan 16 mg/kg + cyclophosphamide 120200 mg/kg
• Cyclophosphamide 120 mg/kg fractionated, TBI 12 Gy (fractionated) ATG
• Etoposide 30-60 mg/kg, TBI 12 Gy (fractionated) or 10 Gy in single dose

2. Chronic lymphocytic leukaemia (CLL)

• TBI 10-14 Gy; busulfan 16 mg/kg; + other agent

3. Lymphomas

• BEAM, ATG
• BCNU (300 mg/m2)
• Etoposide (600800 mg/m2)
• AraC (8001600 mg/m2)
• Melphalan (100140 mg/m2)
• CBV, ATG
• Busulfan 16 mg/kg + cyclophosphamide 120200 mg/kg ATG
• Cyclophosphamide 120 mg/kg + TBI 12 Gy (fractionated) ATG

4. Myeloma

• Melphalan 200 mg/m2

5. Solid tumours

• Cyclophosphamide 60120 mg/kg
• Fludarabine 120 mg/kg

6. Aplastic anaemia (non-constitutional)

• Cyclophosphamide 200 mg/kg ATG

7. Congenital disorders

• Busulfan 1416 mg/kg + cyclophosphamide 120200 mg/kg ATG

8. Autoimmune diseases

• BEAM, ATG
• BCNU (300 mg/m2)
• Etoposide (600800 mg/m2)
• AraC (8001600 mg/m2)
• Melphalan (100140 mg/m2)

Others:

• Cyclophosphamide 200 mg/kg + ATG
• Busulfan 16 mg/kg + cyclophosphamide 120200 mg/kg + ATG
• Cyclophosphamide 120 mg/kg + fractionated TBI 12 Gy + AT

Appendix D:

Criteria for probable invasive fungal disease except for endemic mycoses

Reference:

Ben De Pauw, Thomas J. Walsh, J. Peter Donnelly et al. Revised Definitions of Invasive Fungal Disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clinical Infectious Diseases 2008; 46:1813–211.

Table 2. Criteria for probable invasive fungal disease except for endemic mycoses

Host factorsa

Recent history of neutropenia (<0.5 x 109 neutrophils/L [<500 neutrophils/mm3] for >10 days) temporally related to the onset of fungal disease

Receipt of an allogeneic stem cell transplant

Prolonged use of corticosteroids (excluding among patients with allergic bronchopulmonary aspergillosis) at a mean minimum dose of 0.3 mg/kg/day of prednisone equivalent for >3 weeks

Treatment with other recognized T cell immunosuppressants, such as cyclosporine, TNF-α blockers, specific monoclonal antibodies (such as alemtuzumab), or nucleoside analogues during the past 90 days

Inherited severe immunodeficiency (such as chronic granulomatous disease or severe combined immunodeficiency)

Clinical criteriab

Lower respiratory tract fungal diseasec

The presence of 1 of the following 3 signs on CT:

Dense, well-circumscribed lesion(s) with or without a halo sign

Air-crescent sign

Cavity

Tracheobronchitis

Tracheobronchial ulceration, nodule, pseudomembrane, plaque, or eschar seen on bronchoscopic analysis

Sinonasal infection

Imaging showing sinusitis plus at least 1 of the following 3 signs:

Acute localized pain (including pain radiating to the eye)

Nasal ulcer with black eschar

Extension from the paranasal sinus across bony barriers, including into the orbit

CNS infection

1 of the following 2 signs:

Focal lesions on imaging

Meningeal enhancement on MRI or CT

Disseminated candidiasisd

At least 1 of the following 2 entities after an episode of candidemia within the previous 2 weeks:

Small, target-like abscesses (bull’s-eye lesions) in liver or spleen

Progressive retinal exudates on ophthalmologic examination

Mycological criteria

Direct test (cytology, direct microscopy, or culture)

Mold in sputum, bronchoalveolar lavage fluid, bronchial brush, or sinus aspirate samples, indicated by 1 of the following:

Presence of fungal elements indicating a mold

Recovery by culture of a mold (e.g. Aspergillus, Fusarium, Zygomycetes, or Scedosporium species)

Indirect tests (detection of antigen or cell-wall constituentse

Aspergillosis

Galactomannan antigen detected in plasma, serum, bronchoalveolar lavage fluid or CSF

Invasive fungal disease other than cryptococcosis and zygomycoses

β-D-glucan detected in serum

NOTE

Probable IFD requires the presence of a host factor, a clinical criterion and a mycological criterion. Cases that meet the criteria for a host factor and a clinical criterion but for which mycological criteria are absent are considered possible IFD.

a Host factors are not synonymous with risk factors and are characteristics by which individuals predisposed to invasive fungal diseases can be recognized. They are intended primarily to apply to patients given treatment for malignant disease and to recipients of allogeneic hematopoietic stem cell and solid-organ transplants. These host factors are also applicable to patients who receive corticosteroids and other T cell suppressants as well as to patients with primary immunodeficiencies.

b Must be consistent with the mycological findings, if any, and must be temporarily related to current episode.

c Every reasonable attempt should be made to exclude an alternative etiology.

d The presence of signs and symptoms consistent with sepsis syndrome indicates acute disseminated disease, whereas their absence denotes chronic dissemination disease

e These tests are primarily applicable to aspergillosis and candidiasis and are not useful in diagnosing infections due to Cryptococcus species or Zygomycetes (e.g. Rhizopus, Mucor, or Absidia species). Detection of nucleic acid is not included, because there are as yet no validated or standardized methods.

PIMDA Steering Committee and General Contact Information

• Prof Catherine Cordonnier, Service d'Hématologie Clinique, Hôpital Henri Mondor, Créteil, France

• Dr Manuel Cuenca-Estrella, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda (Madrid), Spain.

• Dr J Peter Donnelly, Coordinator, Studies in Supportive Care, Department of Haematology
  Radboud University Nijmegen Medical Centre, The Netherlands [Principal Investigator]

• Dr Raoul Herbrecht, Département d’Hématologie et d’Oncologie, Hôpital de Hautepierre, Strasbourg, France

• Prof Christopher C Kibbler, Centre for Clinical Microbiology, University College London, and Department of Medical Microbiology, Royal Free Hampstead NHS Trust, London, UK

• Univ Prof Dr Cornelia Lass-Flörl, Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Austria [ECMM Treasurer]

• Prof Johan A Maertens, University Hospital Gasthuisberg, Department of Hematology, Acute Leukaemia and Stem Cell Transplantation Unit, Leuven, Belgium

MANAGEMENT NOTES FOR STEERING COMMITTEE: