ATCF (Azole Therapy in Cystic Fibrosis) (ATCF)

Efficacy of Itraconazole and of Voriconazole in Patients With Cystic Fibrosis and Presenting With Persistent Positive Sputums for Aspergillus.

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.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis; Aspergillus Infections
• Intervention / Treatment: Drug: Itraconazole/voriconazole

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.

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Amiens, France, 80054
    • CRCM Adulte et Pédiatrie - Hôpital Nord
  • Angers, France, 49033
    • CRCM adulte - Centre Robert Debré
  • Angers, France, 49033
    • Pediatry - Centre Robert Debré
  • Bordeaux, France, 33000
    • Pediatric penumologic - Groupe hospitalier de Pellegrin
  • Bron, France, 69500
    • Pneumology pediatric - Hôpital Femme-Mère-Enfants
  • Créteil, France, 94000
    • CRCM - Pediatry - CHI Créteil
  • Lille, France, 59037
    • Service de Pneumologie-Immuno-Allergologie / Hôpital Calmette
  • Marseille, France, 13015
    • Hôpital Nord - Pneumology
  • Nancy, France, 54577
    • Pneumologie Infantile - Hôpital des enfants
  • Rennes, France, 35000
    • CRCM - Hôpital Sud
  • Rennes, France, 35000
    • Pneumology - Hôpital Pontchaillou
  • Strasbourg, France, 67098
    • CRCM Pédiatrique - Hôpital de Hautepierre
  • Toulouse, France, 31059
    • Pédiatrie - Pneumologie, Allergologie - Hôpital des enfants
  • Vannes, France, 56017
    • Pneumology - CH Bretagne-Atlantique
• United Kingdom
  • Manchester, United Kingdom, M23 9LT
    • Manchester Adult Cystic Fibrosis Centre - University Hospital of South Manchester

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: itraconazole; itraconazole 10 mg/mL oral solution; patients > 40 kg body weight : 200 mg morning and evening.; patients < 40 kg body weight : 100 mg morning and evening.; dosage out of meal.; Without a loading dose	Drug: Itraconazole/voriconazole; The two treatments will be administered orally for 6 months One doage of treatment permitted based on plasma levels will be performed after two weeks of treatment.; Other Names: Non applicable.
Experimental: voriconazole; voriconazole 40 mg/mL oral suspension :; patients > 40 kg body weight : 200 mg morning and evening.; patients < 40 kg body weight : 100 mg morning and evening.; dosage out of meal.; Without a loading dose	Drug: Itraconazole/voriconazole; The two treatments will be administered orally for 6 months One doage of treatment permitted based on plasma levels will be performed after two weeks of treatment.; Other Names: Non applicable.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in percentage of patients with a negativisation of sputum cultures in 2 successive samples	The primary evaluation criterion is the percentage of patients with a negativisation of sputum cultures in 2 successive samples, according to a standardised technique	Change from baseline in persentage of patients with a negativisation of sputum cultures at 4, 8, 16, 24 weeks after initiation of therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
plasma concentrations of antifungal agents	measurement of plasma concentrations of antifungal agents and testing at 4 weeks in case of dose adjustment.	at 2 weeks after initiation of therapy
safety of AFs including measurement of hepatic transaminases	safety of AFs including measurement of hepatic transaminases	at 2 weeks after initiation of therapy
number of courses of steroids and antibiotics recording	number of courses of steroids and antibiotics	at 2 weeks after initiation of therapy
quality of life	quality of life self-questionnaire scores, dyspnoea scale scores, 6 minute walking test, FEV1 value, and number of courses of steroids and antibiotics	at 4, 8, 16 and 24 weeks after initiation of therapy
laboratory test indicators	course of different laboratory test indicators (sputum culture and PCR, IgG, total and specific IgE, eosinophilia)	at 4, 8, 16 and 24 weeks after initiation of therapy
safety profiles of the antifungal agents	safety profiles of the antifungal agents : impact of anti-fungal treatments on lung and systemic inflammation	at 4, 8, 16 and 24 weeks after initiation of therapy
mycological failures	analysis of mycological failures (defined as persistence of a positive culture) by a study over time of the course and outcome of fungal biodiversity of isolates (sequential study of chemosensitivity to different antifungal agents and molecular typing)	after 1 month
number of adverse events recording	number of adverse events recording	at 2 weeks after initiation of therapy

Collaborators and Investigators

• Sponsor: Rennes University Hospital
• Investigators: Principal Investigator: Jean-Pierre Gangneux, MD, PhD, Service de parasito-mycologie - Rennes University Hospital

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: June 1, 2014
• Primary Completion (Actual): October 1, 2015
• Study Completion (Actual): November 1, 2015

Study Registration Dates

• First Submitted: March 29, 2012
• First Submitted That Met QC Criteria: April 11, 2012
• First Posted (Estimate): April 12, 2012

Study Record Updates

• Last Update Posted (Actual): May 24, 2023
• Last Update Submitted That Met QC Criteria: May 22, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: cystic fibrosis; voriconazole; Aspergillus; itraconazole
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Infections; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Bacterial Infections and Mycoses; Mycoses; Pancreatic Diseases; Fibrosis; Cystic Fibrosis; Aspergillosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Itraconazole; Voriconazole
• Other Study ID Numbers: 2011-005799-41