Efficacy of Itraconazole as Secondary Prophylaxis in Patients Undergoing Allogeneic Stem Cell Transplantation or Chemotherapy With Prior Invasive Fungal Infection

Invasive fungal infections (IFI) remain the major cause of death among neutropenic patients receiving chemotherapy for leukemia, or submitted to stem cell transplantation. Patients with a history of invasive fungal infection (IFI) are at high risk of developing relapse and fatal complications.

Prompt intensive antifungal therapy, have improved responses and survival, allowing an increase of antifungal treatments, including secondary antifungal prophylaxis.

Few studies have addressed the role of previous IFI in the feasibility of stem cell transplant, or the secondary prophylaxis with antifungal drugs in preventing recurrence of infection after transplantation. However, given the lack of prospective studies, the role of secondary antifungal prophylaxis remains unclear.

Itraconazole is a wide-spectrum triazole antifungal agent active against Candida albicans, non-albicans, Aspergillus spp., Blastomyces dermatitidis, Blastomyces coccidioides, Cryptococcus neoformans, Sporothrix schenkii, Paracoccidioides brasiliensis, Histoplasma spp. and various kinds of yeast fungi and mycetes.

The role of itraconazole IFI prophylaxis treatment has been proved by many interventional studies. In this prospective, multicentric study of secondary prophylaxis, itraconazole will be given at standard dose to patients undergoing allogeneic stem cell transplantation or chemotherapy with prior invasive fungal infection, to assess the efficacy and safety of itraconazole secondary prophylaxis.

Study Overview

• Status: Completed
• Conditions: Invasive Fungal Infection
• Intervention / Treatment: Drug: Itraconazole

• Study Type: Interventional
• Enrollment (Actual): 150
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310003
      • The First Hospital of Zhejiang Medical Colleage Zhejiang University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Man or woman between 18 and 65 years of age, inclusive.
• Patients who affected by hematological malignancies, receiving chemotherapy, or submitted to stem cell transplantation.
• Patients with previous proven or probable invasive fungal infections, with residual or absent lesions on CT scan or X-ray and the absence of clinical signs of fungal infection at the time of enrollment. Or, possible IFI patients without microbiological evidence but with effective anti-fungal therapy history.

(The diagnosis is according to the definitions of Chinese guideline for the diagnosis and treatment of invasive fungal infections in immunocompromised patients with cancer cancer and hematopoietic stem cell transplant.)

• Subjects (or their legally acceptable representatives) must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.
• Lack of clinical symptoms of invasive fungal infection

Exclusion Criteria:

• Patient has no response to the previous intravenous itraconazole antifungal therapy.
• Currently taking the contra-indicated medications such as teldane, astemizol, cisapride and HMG-CoA reductase inhibitor（e.g. Simvastatin, ovastatin, oral Midazolam and Triazolam）
• History of allergy or intolerance to imidazole or azoles anti-fungal agents（e.g. Fluconazol, Itraconazole, Ketoconazole, Miconazole, Clotrimazole）
• Pregnant women, lactating women or women of child bearing potential without applying valid contraceptive measures
• Patients with current cardiac dysfunction (especially with congestive heart failure) or with the history of congestive heart failure
• Patients with severe liver dysfunction (aminotransferase levels ≥5 times the upper limit of normal and total bilirubin level ≥3mg/dL(51.3 μmol/L); or the severity of liver dysfunction does not match this criteria but the patient is in bad condition and not suitable for this trial( doctors make the decision);
• Patients with renal insufficiency having serum Ccr level <30ml/min, calculated from the following formula:

Male: Ccr (ml/min)=(140-age)×weight (kg) /(0.8136×Crea (μmol/L) ) Female:Ccr (ml/min)=(140-age)×weight (kg) ×0.85/(0.8136× Crea (μmol/L) )

• Patients received any experimental drug within 10 days before the planned start of treatment.
• Patients with bad whole body status and not suitable for the trial (doctors make the decision)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
successful prophylaxis rate	The rate of patients without documented relapse of the fungal infection and the absence of new proven, probable or possible IFI at the end of secondary prophylaxis treatment and 7 days later.	more than 7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
rate of patients who developed persistent fever or pulmonary infiltrates of unknown etiology	The rate of patients who developed persistent fever or pulmonary infiltrates of unknown etiology. For those neutropenic patients with persistent fever, antibiotics should be used according to the International anti-infection guideline in order to exclude the possibility of bacterial infection. If the fever persists after 5-6 days' combination use of itraconazole and antibiotics, this case would be regarded as "secondary prophylaxis failure" and the trial is terminated , while doctors should search for further clinical therapy to save the patient.	at least 7 days

Collaborators and Investigators

• Sponsor: Zhejiang University
• Collaborators: Guangdong Provincial People's Hospital; Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine; First Affiliated Hospital of Wenzhou Medical University; Zhejiang Provincial Hospital of TCM
• Investigators: Principal Investigator: He Huang, MD, The First Hopspital of Zhejiang Medical Colleage, Zhejiang University

Publications and helpful links

General Publications

• Cordonnier C, Maury S, Pautas C, Bastie JN, Chehata S, Castaigne S, Kuentz M, Bretagne S, Ribaud P. Secondary antifungal prophylaxis with voriconazole to adhere to scheduled treatment in leukemic patients and stem cell transplant recipients. Bone Marrow Transplant. 2004 May;33(9):943-8. doi: 10.1038/sj.bmt.1704469.
• de Fabritiis P, Spagnoli A, Di Bartolomeo P, Locasciulli A, Cudillo L, Milone G, Busca A, Picardi A, Scime R, Bonini A, Cupelli L, Chiusolo P, Olivieri A, Santarone S, Poidomani M, Fallani S, Novelli A, Majolino I. Efficacy of caspofungin as secondary prophylaxis in patients undergoing allogeneic stem cell transplantation with prior pulmonary and/or systemic fungal infection. Bone Marrow Transplant. 2007 Aug;40(3):245-9. doi: 10.1038/sj.bmt.1705720. Epub 2007 May 28.

Study record dates

Study Major Dates

• Study Start: July 1, 2008
• Primary Completion (Actual): September 1, 2010
• Study Completion (Actual): November 1, 2010

Study Registration Dates

• First Submitted: September 9, 2010
• First Submitted That Met QC Criteria: September 9, 2010
• First Posted (Estimate): September 10, 2010

Study Record Updates

• Last Update Posted (Estimate): October 14, 2011
• Last Update Submitted That Met QC Criteria: October 13, 2011
• Last Verified: October 1, 2011

More Information

Terms related to this study

• Keywords: hematological malignancy; previous proven or probable invasive fungal infection
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Bacterial Infections and Mycoses; Infections; Communicable Diseases; Mycoses; Invasive Fungal Infections; 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
• Other Study ID Numbers: SpoIV-CHA-IIS-0802; ITRFUN4044 (Other Grant/Funding Number: Xi'an-Janssen pharmaceutical Ltd.)