Clinical trial NCT03656081: Chronic Pulmonary Aspergillosis and Ambisome Aerosol with Itraconazole
Official title: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Chronic Pulmonary Aspergillosis
Lead sponsor: Poitiers University Hospital
Sponsor class: OTHER
First posted: 2018-09-04
Enrollment: 224
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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 criteria: 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 and 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

Primary outcomes:
measure: Composite efficacy criterion defined by the association of clinical improvement/stability and radiological improvement evaluated at 6 months
timeFrame: 6 months
Secondary outcomes:
measure: major events during follow-up period
timeFrame: month 6 to month 30
measure: relapse
timeFrame: month 6 to month 30
measure: mycological response
timeFrame: after 3 months and 6 months
Other outcomes:
Locations:
city: Poitiers
country: France
facility: CHU Poitiers
Study officials:
affiliation: Bichat Hospital, AP-HP
name: Cendrine GODET, MD
role: PRINCIPAL_INVESTIGATOR
References: