RANDOMIZED COMPARISON OF VORICONAZOLE AND AMPHOTERICIN B IN PRIMARY THERAPY OF INVASIVE ASPERGILLOSIS. A COLLABORATIVE STUDY OF THE EORTC INVASIVE FUNGAL INFECTIONS GROUP AND THE GLOBAL ASPERGILLUS STUDY GROUP (studies 307 and 602)

Principal investigators: David W. Denning, Raoul Herbrecht, Thomas F. Patterson, John E. Bennett The criteria were drafted by David Denning in 1996 and modified by consultation with many experts over the following 12 months prior to the study start in 1997. These discussions were made possible by Pfizer who have invested hugely in these successful studies. They preceded the new definitions proposed by the EORTC IFIG and Mycoses Study Group which were developed between 1998-2000. Two protocols were run with the criteria below, laid out slightly differently between the 2 protocols. All enrolled cases were analysed subsequently by Data Review Committee (blinded to drug received and unblinding side effects), and all radiographs and scans by 4 radiologists all working to common carefully predefined standards for inclusion criteria and response. The table at the end is intended as an ‘aide memoire’ and should be read from the top down. In the protocols it was an appendix summary.The results of the study will be presented at ICAAC 2001 and submitted for publication late in 2001.

Inclusion Criteria

Adult males and females  µ12 years of age, immunocompromised as a result of any of the following conditions:

A)    Proven (definite) acute invasive aspergillosis

  1. Positive histopathologic evidence (septate hyaline hyphae that branch at acute angles with evidence of tissue invasion) in tissue specimens obtained by aspiration or biopsy with isolation of Aspergillus spp. from culture from the same site.
  2. Isolation of Aspergillus spp. from otherwise sterile body fluid or tissue obtained by an invasive procedure [e.g. transbronchial biopsy, percutaneous or fine needle aspirate, sinus aspirate, urine, cerebrospinal fluid, blood, tympanocentesis, bone aspiration, liver biopsy, aspirate of a brain lesion, vitreous aspirate, skin biopsy, (not including bronchoalveolar lavage)] in the presence of a clinically compatible illness.
  3. Bronchoscopic evidence of tracheal or bronchial ulceration or plaques (but not merely inflammation) with biopsy or brushing or bronchoalveolar lavage culture positive for Aspergillus spp.  (These patients will need follow up bronchoscopy to assess response).
  4. In patients with allogeneic bone marrow/peripheral stem cell transplant or any of the following conditions with recent neutropenia*:

Autologous bone marrow/peripheral haematopoetic stem cell transplant, hematological malignancy (including lymphoma), aplastic anemia or myelodysplastic syndrome

The following findings support a diagnosis of definite aspergillosis:

and

and

*3  within 14 days prior to enrollment 

B) Probable invasive aspergillosis

  1. Positive histopathologic evidence (acutely branching septate hyalinehyphae with evidence of tissue invasion) in tissue specimens obtained by aspiration or biopsy without isolation of Aspergillus species from the same site.
  2. In patients following an allogeneic bone marrow (BMT) or peripheral stem cell transplant with leukaemia, lymphoma, aplastic anaemia, myelodysplastic syndrome or following autologous bone marrow or stem cell transplantation with present or recent neutropenia*

and

or

and

   or

and

3. In patients with allogeneic bone marrow/peripheral stem cell transplant or any of the following conditions with recent neutropenia*:- autologous bone marrow/peripheral stem cell transplant, hematological malignancy (including lymphoma), aplastic anemia or myelodysplastic syndrome the following findings support a diagnosis of probable sinus aspergillosis:

and

and

  1. In patients with HIV infection/AIDS, solid organ transplantation (except lung transplant**), or prolonged corticosteroid/ immunosuppressive therapy, the following findings support a diagnosis of probable aspergillosis:

and

and

Note: All diagnostic procedures, including histopathology, mycology, and radiological investigations should be performed within 14 days prior to study enrollment.

** patients with lung transplant must have a positive culture, cytology or histopathology from a transbronchial biopsy in order to enter the study; a positive result from a sputum or a specimen obtained by BAL is not adequate

C) General inclusion / exclusion criteria for acute invasive aspergillosis (but not subacute invasive, or chronic necrotising pulmonary aspergillosis)

  1. The fungal infection at baseline should represent a new episode of acute invasive aspergillosis.  Any course of systemic treatment with amphotericin B conventional or lipid formulation or itraconazole should have been completed at least 8 weeks prior to study entry.
  2. Patients with aspergilloma or allergic bronchopulmonary aspergillosis.
  3. Patients with chronic invasive aspergillosis defined as the duration of symptoms or radiological findings being present for more than 4 weeks prior to study entry.
  4. Patients who have received > 96 hours of systemic antifungal therapy at doses > 0.5 mg/kg/d for conventional or lipid formulations of amphotericin B or  >200 mg /d of itraconazole during the two weeks prior to study entry. 
  5. Patients who are taking any investigational drug (any unlicensed new chemical entity) with the exception of cytotoxics, antiretroviral agents and therapies for AIDS-related opportunistic infections.
  6. Patients who are receiving at baseline or are likely to receive the following medications or treatments in conjunction with study drug:
  7. G-CSF or GM-CSF other than for treatment of granulocytopenia.
  8. White blood cell transfusions
  9. Systemic antifungal agents active against Aspergillus spp. e.g. itraconazole, lipid formulations of amphotericin B, or 5-fluorocytosine (5FC).
  10. Patients with a life expectancy of less than 72 hours (all deaths in the first 72 hours were defined as failures by default) .
  11. Patients with any condition, which, in the opinion of the investigator, could affect patient safety, preclude evaluation of response, or render it unlikely that the contemplated course of therapy can be completed.
  12. Patients on artificial ventilation and unlikely to be extubated within 24 hours.
  13. Patients with sarcoidosis.
  14. Patients with a diagnosis of CMV pneumonia.

APPENDIX B - ASPERGILLOSIS inclusion criteria table

Sectn
Aspergillosis
Host Group
Clinical
Imaging
Specimen
Histo
Micros
Culture
Diagnosis
5.2.2.1
any site
any eligible disease
 
 
tissue biopsy or aspiration

+
+
-
+ / -


+
+
+
-
-
D
D
P
P
5.2.2.2
any site
any eligible disease
compatible illness
compatible imaging
otherwise sterile fluid or tissue
(not BAL)
NA
-
+
+
+
+
-
D
D
P
5.2.2.3
tracheal or  bronchial
any eligible disease (usually HIV/AIDS)
ulcers / plaques on bronchoscopynote: Follow-up bronchoscopy reqd for evaluation
 
tissue biopsy


BAL
+
+

NA


+ / -
+
+
-
+
-
D
P
D
P
5.2.2.4
pulmonary
allo BMT
or
haem malig / auto BMT + PMN<500 or within 2 weeks of PMN<500
any clinical features
new infiltrateshalo / aircrescent
BAL

sputum X1
NA



-
+ / -
+
+
-
-
+
-
-/+
+
-
D
P
P
P
P
5.2.2.5
pulmonary
HIV/AIDS
or
solid organ  (other than lung) transplant or high dose steroids
 
new infiltrates
BAL
NA
+ / -
+
+
-
P
P
5.2.2.6
sinus / nose
allo BMT
or
haem malig / auto BMT + PMN<500 or within 2 weeks of PMN<500
infectious sinusitis or nasal disease
sinus opacification
culture from abnormal nasal or sinus site
ND
+/-
+
P

D=definite, P=probable, PMN=neutrophils, BAL=bronchoalveolar lavage, BMT=bone marrow transplant, + =positive, - =negative, NA=not applicable, ND=not done

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