Chronic Pulmonary Aspergillosis and Ambisome Aerosol With Itraconazole

Study Overview
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Brief Summary
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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.

Official Title
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Therapeutic Efficacy Comparison of a Six-month Treatment by Itraconazole and Nebulised Ambisome® Versus Treatment by Itraconazole Alone in Non- or Mildly- Immunocompromised Patients With Chronic Pulmonary Aspergillosis: a Prospective, Randomized, Single Blind Study, (Single Aspergilloma Excluded)

Conditions
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Chronic Pulmonary Aspergillosis

Intervention / Treatment
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* Drug: inhaled Ambisome®
* Drug: inhaled placebo
* Drug: Itraconazole


Participation Criteria
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Eligibility Criteria
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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: 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 ; 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 Men or women age ≥ 18 years; 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; Patient legally free and not subject to any custody, guardianship, tutelage or subordination measures; Participants must be affiliated to France's Health Care Regime ( Sécurité Sociale ); Free and informed consent signed by each participating patient. Exclusion Criteria: - Patient affected with single aspergilloma - 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) - Patient presenting a contraindication to voriconazole or posaconazole (including all contraindicated coadministrated medications as listed in the SmPc) - Intolerance to beta2-agonists - Notion of relapse with isolation of an Aspergillus resistant to itraconazole - History of hypersensitivity reaction to liposomal amphotericin B or to itraconazole or to any other constituent - Patient having presented complications related to a previous treatment by nebulised LAmB - Patient received an oral (excepted oral Amphotericin B), parenteral or intra-cavity antifungal treatment within the last 2 months - Severe renal failure (clearance <30 ml / min). - Hepatic failure with transaminase and alkaline phosphatase values > 5 times normal - Significant abnormality of the blood cell and platelet counts (at the discretion of the investigator) - Concomitant use of one or several of treatments contra-indicated with the experimental or non-experimental treatment - 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. - Invasive pulmonary Aspergillosis, Allergic Bronchopulmonary Aspergillosis - Chronic Pulmonary Aspergillosis with indication for surgical intervention within 6 months from the start - Patients with Cystic Fibrosis - Immunocompromised patients - Threatening hemoptysis, with impossibility to defer surgical procedures (but patients contraindicated to surgery may be included after resolution of the hemoptysis) - Tuberculosis or progressive non-tuberculous mycobacteria - Respiratory infection aggravating the underlying CPA (patient may be included after eradication of infection) - Patient refusing to participate - 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. - Patient in exclusion period following participation in another interventional study evaluating antifungals or medicines - Women at age to procreate and not using highly effective contraception, pregnant or breastfeeding women

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Itraconazole & inhaled placebo<br>Itraconazole 200 mg x 2/day associated with inactive nebulised treatment (isotonic saline) twice a week during 24 weeks. | Drug: inhaled placebo<br>* inhaled isotonic saline<br>* Other names: placebo (for Ambisome®);Drug: Itraconazole<br>* Itraconazole tablet<br>* Other names: Sporanox®;|
| Experimental: Itraconazole & inhaled Ambisome®<br>Itraconazole 200 mg x 2/day associated with inhaled liposomal amphotericin B (Ambisome®) at 25 mg twice a week during 24 weeks | Drug: inhaled Ambisome®<br>* inhaled liposomal amphotericin B = inhaled LAmB<br>Drug: Itraconazole<br>* Itraconazole tablet<br>* Other names: Sporanox®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite efficacy criterion defined by the association of clinical improvement/stability and radiological improvement evaluated at 6 months | • Clinical improvement or stability is evaluated using the Respiratory Symptom Score based on 6 items (cough, expectoration, dyspnea, hemoptysis, chest pain, and nocturnal awakening ) quoted with a 10 cm visual analogical scale). Stability is defined by a score variation between -25 and +25%, while improvement is defined by a decrease in score greater than 25%. • Radiological improvement is based on the analysis of CT-scan parameters (a committee consisting on two chest radiologists wil perform centrally and parallel analyses of each CT-scan blinded to the study treatment allocation to reach a final decision by consensus) The radiological improvement (binary variable) is defined by a consensual score based on the evolution of the various radiological parameters (cavity, fungus ball, alveolar condensation, nodules) according to validated thresholds. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| major events during follow-up period |  | month 6 to month 30 | 
| relapse |  | month 6 to month 30 | 
| mycological response |  | after 3 months and 6 months |