Clinical trial NCT01160952: Long-term Versus Short-term Sequential Therapy (Intravenous Itraconazole Followed by Oral Solution) of Itraconazole as Primary Prophylaxis in Patients Undergoing Allogeneic Stem Cell Transplantation
Official title: Long-term Versus Short-term Sequential Therapy (Intravenous Itraconazole Followed by Oral Solution) of Itraconazole as Primary Prophylaxis in Patients Undergoing Allogeneic Stem Cell Transplantation
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Hematological Diseases
Allogeneic Stem Cell Transplantation
Keywords: primary prophylaxis
itraconazole
stem cell transplantation
Lead sponsor: Guangzhou General Hospital of Guangzhou Military Command
Sponsor class: OTHER
Collaborators: name: Nanfang Hospital, Southern Medical University
name: First Affiliated Hospital, Sun Yat-Sen University
name: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
name: Renmin Hospital of Zhongshan Guangdong
name: Zhujiang Hospital
First posted: 2010-07-13
Enrollment: 120
Sex: ALL
Minimum age (years): 14
Maximum age (years): 60
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: * The primary objective of this study is to evaluate the efficacy and safety profile of itraconazole as in primary prophylaxis
* The second objective of this study is to find the difference between long-term versus short-term sequential therapy of Itraconazole (intravenous followed by oral itraconazole) as primary prophylaxis of invasive fungal infections (IFI) in patients undergoing allogeneic stem cell transplantation (allo-SCT)
* also to explore the relationship between the incidence of IFI with plasma concentrations of itraconazole and hydroxy-itraconazole

Detailed description: Invasive fungal infections (IFI) remain the major cause of death among neutropenic patients receiving high dose chemotherapy or allo-SCT. Especially, patients undergoing allo-SCT generally receive intensive immunosuppressive therapy, which make those patients at high risk of developing IFI.

Prompt intensive antifungal therapy may increase the incidence rate of IFI and improved responses and survival. Antifungal prophylaxis has been recommended in patients undergoing allo-SCT by Infectious diseases society of America (IDSA) and Chinese guidelines for the diagnosis and management of IFI in patients with hematologic/malignant tumor (revised).

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 primary antifungal prevention and the course of treatment remain 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 in IFI prophylaxis has been proved by many interventional studies. However the optimal course of prophylaxis is still unknown，especially in China. In this prospective, multicentric study of primary antifungal prevention, long-term or short-term sequential therapy (intravenous followed by oral itraconazole) will be given at standard dose to patients undergoing allogeneic stem cell transplantation to assess the efficacy and safety of itraconazole in primary prophylaxis, and to analysis the relationship between the incidence rate of IFI with plasma concentrations of itraconazole and hydroxy-itraconazole.

Eligibility criteria: Inclusion Criteria:

* Man or woman between 14 and 60 years of age, inclusive
* Patients who affected by hematological diseases, receiving allo-SCT
* Patients with no previous proven or probable invasive fungal infections. Patients without microbiological evidence but with effective anti-fungal therapy history are inclusive
* 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

Exclusion Criteria:

* Currently taking the contra-indicated medications such as teldane, astemizol, cisapride and HMG-CoA reductase inhibitor（e.g. Simvastatin, lovastatin, 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 14 days before the planned start of treatment.
* Patients with bad whole body status and not suitable for the trial (doctors make the decision)

Primary outcomes:
measure: efficacy evaluation
timeFrame: 90 days
Secondary outcomes:
measure: group difference evaluation
timeFrame: 90 days
Other outcomes:
Locations:
city: Guangzhou
country: China
facility: Guangzhou General Hospital of Guangzhou Military Command
state: Guangdong
Study officials:
affiliation: Guangzhou General Hospital of Guangzhou Military Command
name: Yang Xiao, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Marr KA, Crippa F, Leisenring W, Hoyle M, Boeckh M, Balajee SA, Nichols WG, Musher B, Corey L. Itraconazole versus fluconazole for prevention of fungal infections in patients receiving allogeneic stem cell transplants. Blood. 2004 Feb 15;103(4):1527-33. doi: 10.1182/blood-2003-08-2644. Epub 2003 Oct 2.
citation: Winston DJ, Maziarz RT, Chandrasekar PH, Lazarus HM, Goldman M, Blumer JL, Leitz GJ, Territo MC. Intravenous and oral itraconazole versus intravenous and oral fluconazole for long-term antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant recipients. A multicenter, randomized trial. Ann Intern Med. 2003 May 6;138(9):705-13. doi: 10.7326/0003-4819-138-9-200305060-00006.
citation: Chinese guideline for the diagnosis and management of IFI in patients with hematologic/maliglant tumor (revised). Chinese journal of internal medicine 2007，46(7):607-610.
citation: Lin R, Xu X, Li Y, Sun J, Fan Z, Jiang Q, Huang F, Zhou H, Nie D, Guo Z, Mao Y, Xiao Y, Liu Q. Comparison of long-term and short-term administration of itraconazole for primary antifungal prophylaxis in recipients of allogeneic hematopoietic stem cell transplantation: a multicenter, randomized, open-label trial. Transpl Infect Dis. 2014 Apr;16(2):286-94. doi: 10.1111/tid.12192. Epub 2014 Mar 5.