Chronic Pulmonary Aspergillosis and Ambisome Aerosol With Itraconazole

Overview

This study compares the therapeutic (clinical and radiological) efficacy of a six-month treatment by itraconazole and nebulised Ambisome® (liposomal amphotericin B = LAmB) versus treatment by itraconazole alone, in non - or mildly - immunocompromised patients affected by Chronic Pulmonary Aspergillosis (single aspergilloma excluded).

• Control arm: Itraconazole 200 mg x 2/day associated with inactive nebulised treatment twice a week during 24 weeks.

• Experimental arm: Itraconazole 200 mg x 2/day associated with nebulised LAmB, at 25 mg twice a week during 24 weeks.

Follow up duration for the patients will be 24 months (12 months minimum) after discontinuation of the treatment being studied.

Eligibility

Inclusion Criteria:

        All adult patients affected with Chronic Pulmonary Aspergillosis (CPA) "de novo" or in
        relapse (without any history of resistance to itraconazole) combining the following
        criteria are eligible:
          1. Patient with an Aspergillus bronchopulmonary infection, be it cavitary, fibrotic,
             necrotizing (SIA/Semi Invasive Aspergillosis) or nodular and documented by compatible
             thoracic CT-scan images ;
          2. Associated with one of the following criteria:
               -  positive detection of anti-Aspergillus IgG and/or precipitating anti-aspergillus
                  antibodies, according to the positivity threshold of the laboratory performing
                  the technique,
               -  positive direct examination of Aspergillus or positive culture, from
                  bronchopulmonary samples (expectoration or endoscopic aspiration),
               -  revealing aspergillar hyphae/filaments on histological samples
          3. Men or women age ≥ 18 years;
          4. For the women of childbearing age: women having a negative serum pregnancy test,
             having a contraception highly effective and accepting to pursue it during at least the
             first 12 months of the study;
          5. Patient legally free and not subject to any custody, guardianship, tutelage or
             subordination measures;
          6. Participants must be affiliated to France's Health Care Regime (" Sécurité Sociale ");
          7. Free and informed consent signed by each participating patient.
        Exclusion Criteria:
          1. - Patient affected with single aspergilloma
          2. - Patient presenting a contraindication to itraconazole (including all contraindicated
             co-administrated medications as listed in the itraconazole SmPc, including notably
             medications with potential to prolong theQT interval)
          3. - Patient presenting a contraindication to voriconazole or posaconazole (including all
             contraindicated coadministrated medications as listed in the SmPc)
          4. - Intolerance to beta2-agonists
          5. - Notion of relapse with isolation of an Aspergillus resistant to itraconazole
          6. - History of hypersensitivity reaction to liposomal amphotericin B or to itraconazole
             or to any other constituent
          7. - Patient having presented complications related to a previous treatment by nebulised
             LAmB
          8. - Patient received an oral (excepted oral Amphotericin B), parenteral or intra-cavity
             antifungal treatment within the last 2 months
          9. - Severe renal failure (clearance <30 ml / min).
         10. - Hepatic failure with transaminase and alkaline phosphatase values > 5 times normal
         11. - Significant abnormality of the blood cell and platelet counts (at the discretion of
             the investigator)
         12. - Concomitant use of one or several of treatments contra-indicated with the
             experimental or non-experimental treatment
         13. - Ventricular dysfunction such as congestive cardiac failure or history of congestive
             cardiac failure or patients with risk(s) factors of cardiac arrhythmia or symptomatic
             arrhythmia with a prolongation of the corrected QT interval > 450 msec in men and 470
             msec in women or treated by medication known to prolong QT interval, or prolongation
             of the corrected QT interval > 450 msec in men and 470 msec in women.
         14. - Invasive pulmonary Aspergillosis, Allergic Bronchopulmonary Aspergillosis
         15. - Chronic Pulmonary Aspergillosis with indication for surgical intervention within 6
             months from the start
         16. - Patients with Cystic Fibrosis
         17. - Immunocompromised patients
         18. - Threatening hemoptysis, with impossibility to defer surgical procedures (but
             patients contraindicated to surgery may be included after resolution of the
             hemoptysis)
         19. - Tuberculosis or progressive non-tuberculous mycobacteria
         20. - Respiratory infection aggravating the underlying CPA (patient may be included after
             eradication of infection)
         21. - Patient refusing to participate
         22. - Protected majors in the meaning of the law, non affiliated persons or with no social
             security scheme, persons deprived of liberty by a judicial or administrative decision,
             persons staying in a health or social institution, adults under legal protection, and
             finally patients in emergencies.
         23. - Patient in exclusion period following participation in another interventional study
             evaluating antifungals or medicines
         24. - Women at age to procreate and not using highly effective contraception, pregnant or
             breastfeeding women