Clinical trial NCT01576315: ATCF (Azole Therapy in Cystic Fibrosis)
Official title: Efficacy of Itraconazole and of Voriconazole in Patients With Cystic Fibrosis and Presenting With Persistent Positive Sputums for Aspergillus.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cystic Fibrosis
Aspergillus Infections
Keywords: cystic fibrosis
Aspergillus
itraconazole
voriconazole
Lead sponsor: Rennes University Hospital
Sponsor class: OTHER
First posted: 2012-04-12
Enrollment: 11
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Aspergillus infection is an infectious complication which frequently occurs in cystic fibrosis. The efficacy of azole therapy in patients with cystic fibrosis with persistent positive sputums for Aspergillus is still unknown. Furthermore, the efficacy of itraconazole and voriconazole in this indication has never been evaluated in a large prospective controlled clinical trial, even though many teams already use it. The ATCF study aims to assess in patients with cystic fibrosis with persistent Aspergillus positive cultures the efficacy of itraconazole and voriconazole on the negativisation of the sputum cultures for Aspergillus.

Detailed description: Aspergillus infection is an infectious complication which frequently occurs in cystic fibrosis. The efficacy of azole therapy in patients with cystic fibrosis with persistent positive sputums for Aspergillus is still unknown. Furthermore, the efficacy of itraconazole and voriconazole in this indication has never been evaluated in a large prospective controlled clinical trial, even though many teams already use it.

The ATCF study is a prospective, multicenter, randomized, open-label, controlled phase II trial, performed in patients with cystic fibrosis with persistent Aspergillus positive cultures.

The primary outcome is to assess the efficacy of itraconazole and voriconazole on the course and outcome of the negativisation of the sputum cultures for Aspergillus on two consecutive cultures.

Secondary objectives include the effects of azole therapy on quality of life, FEV1, co-prescription of antibiotic and steroids, plasma concentrations of antifungal agents, speed of negativisation of sputum culture for Aspergillus, outcome of other diagnostic criteria (Aspergillus detection by PCR, precipiting antibodies, total and specific IgE, eosinophilia), and the safety profiles of the two products. Mycological failures, and impact of anti-fungal treatments on lung and systemic inflammation will also be assessed.

Eligibility criteria: Inclusion Criteria:

* Patient with cystic fibrosis,
* men or women,
* age equal greater to 12 years,
* presenting with a positive sputum culture for Aspergillus confirmed twice within 6 months before study entry and at initial visit,
* written informed consent.

Exclusion Criteria:

* patients with a contraindication to one of the antifungal agents evaluated,
* pregnant women or nursing mothers,
* absence of an effective method of contraception in women of child-bearing potential,
* patients with signs or symptoms of invasive aspergillosis,
* patients with signs or symptoms of aspergilloma,
* patients with an infection caused by Burkholderia complex Cepacia or to mycobacteria,
* lung transplant patients, registered on a transplantation waiting list or whose registration is imminent,
* patients who received systemic antifungal therapy for more than 5 days within 2 months prior to inclusion,
* patients currently enrolled in another clinical drug trial,
* ongoing treatment with medicinal products contraindicated with itraconazole and voriconazole or with major interactions which reduce azole concentrations,
* patients treated by medication known to prolong QT interval, or with known prolongation of QTc interval \> 450 msec in men and \> 470 msec in women,
* Inability to follow or to understand the study procedures.

Primary outcomes:
measure: Change in percentage of patients with a negativisation of sputum cultures in 2 successive samples
timeFrame: Change from baseline in persentage of patients with a negativisation of sputum cultures at 4, 8, 16, 24 weeks after initiation of therapy
Secondary outcomes:
measure: plasma concentrations of antifungal agents
timeFrame: at 2 weeks after initiation of therapy
measure: safety of AFs including measurement of hepatic transaminases
timeFrame: at 2 weeks after initiation of therapy
measure: number of courses of steroids and antibiotics recording
timeFrame: at 2 weeks after initiation of therapy
measure: quality of life
timeFrame: at 4, 8, 16 and 24 weeks after initiation of therapy
measure: laboratory test indicators
timeFrame: at 4, 8, 16 and 24 weeks after initiation of therapy
measure: safety profiles of the antifungal agents
timeFrame: at 4, 8, 16 and 24 weeks after initiation of therapy
measure: mycological failures
timeFrame: after 1 month
measure: number of adverse events recording
timeFrame: at 2 weeks after initiation of therapy
Other outcomes:
Locations:
city: Amiens
country: France
facility: CRCM Adulte et Pédiatrie - Hôpital Nord
city: Angers
country: France
facility: CRCM adulte - Centre Robert Debré
city: Angers
country: France
facility: Pediatry - Centre Robert Debré
city: Bordeaux
country: France
facility: Pediatric penumologic - Groupe hospitalier de Pellegrin
city: Bron
country: France
facility: Pneumology pediatric - Hôpital Femme-Mère-Enfants
city: Créteil
country: France
facility: CRCM - Pediatry - CHI Créteil
city: Lille
country: France
facility: Service de Pneumologie-Immuno-Allergologie / Hôpital Calmette
city: Marseille
country: France
facility: Hôpital Nord - Pneumology
city: Nancy
country: France
facility: Pneumologie Infantile - Hôpital des enfants
city: Rennes
country: France
facility: CRCM - Hôpital Sud
city: Rennes
country: France
facility: Pneumology - Hôpital Pontchaillou
city: Strasbourg
country: France
facility: CRCM Pédiatrique - Hôpital de Hautepierre
city: Toulouse
country: France
facility: Pédiatrie - Pneumologie, Allergologie - Hôpital des enfants
city: Vannes
country: France
facility: Pneumology - CH Bretagne-Atlantique
city: Manchester
country: United Kingdom
facility: Manchester Adult Cystic Fibrosis Centre - University Hospital of South Manchester
Study officials:
affiliation: Service de parasito-mycologie - Rennes University Hospital
name: Jean-Pierre Gangneux, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gangneux JP, Godet C, Denning DW. Allergic diseases and fungal exposome: Prevention is better than cure. Allergy. 2022 Nov;77(11):3182-3184. doi: 10.1111/all.15436. No abstract available.
citation: Guegan H, Prat E, Robert-Gangneux F, Gangneux JP. Azole Resistance in Aspergillus fumigatus: A Five-Year Follow Up Experience in a Tertiary Hospital With a Special Focus on Cystic Fibrosis. Front Cell Infect Microbiol. 2021 Feb 18;10:613774. doi: 10.3389/fcimb.2020.613774. eCollection 2020.
citation: Guegan H, Poirier W, Ravenel K, Dion S, Delabarre A, Desvillechabrol D, Pinson X, Sergent O, Gallais I, Gangneux JP, Giraud S, Gastebois A. Deciphering the Role of PIG1 and DHN-Melanin in Scedosporium apiospermum Conidia. J Fungi (Basel). 2023 Jan 18;9(2):134. doi: 10.3390/jof9020134.