ITRAG: Evaluation of Antifungal Prophylaxis on Graft-versus-host Disease (GVHD) Patients

Sponsor

Samsung Medical Center (Other)

Overall Status

Terminated

CT.gov ID

NCT01282879

Collaborator

Janssen, LP (Industry)

Enrollment

Locations

Arm

Duration (Months)

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Antifungal prophylaxis should be used in patients being treated with glucocorticoids for graft-versus-host disease (GVHD) following allogeneic hematopoietic stem-cell transplantation (HSCT). Although fluconazole has been widely used as an antifungal prophylactic agent after allogeneic HSCT, fluconazole prophlaxis only shows a limited protective role against IFIs, is not effective against invasive aspergillosis. In addition, NCCN guideline of the prevention and treatment of cancer-related infections recommends antifungal prophylaxis in patients with significant GVHD until resolution of GVHD using Posaconazole, Voriconazole, Echinocandin, or Amphotericin B. However, under the National Health Insurance System, none of the drug can be given prophylactically except itraconazole oral solution against IFIs. Itraconazole oral solution shows excellent bioavailability and good efficacy against aspergillus and fluconazole resistant candida infection.Based on these findings, we will perform prospective multicenter study evaluating the efficacy, safety and long-term outcomes of itraconazole oral solution prophylaxis against IFIs in patients treated with systemic corticosteroids for GVHD after allogeneic HSCT.

Condition or Disease	Intervention/Treatment	Phase
Graft vs Host Disease	Drug: Itraconazole	Phase 4

Detailed Description

Eligible patients who provided an informed consent form will be administered itraconazole oral solution (200mg bid initially, swash and swallow) in either an in patient or outpatient setting. Treatment can be initiated at the same time of or within 10 days after starting systemic immunosuppressive therapy.

Itraconazole oral solution dose can be adjusted according to the liver function test: 1) in case of - AST/ALT level 5-10 times UNL or bilirubin/ALP level 2-5 times UNL, itraconazole dose can be reduced to half (i.e. itraconazole 200mg po once daily or 100mg bid); 2) in case of - AST/ALT level > 10 times UNL or bilirubin/ALP level > 5 times UNL, itraconazole can be stopped.

GVHD treatment can be given per center's policy: With respect to acute GVHD, prednisone (1-2mg/Kg/day) oral or iv can be given on top of calcineurin inhibitor (CNI) GVHD prophylaxis. For chronic GVHD, various type of frontline regimen can be permitted including CNI+prednisone (PD), PD alone, CNI+PD+mycophenolate mofetil (MMF), or MMF+PD. Various dose of PD will be accepted if it is at least from 0.5mg/Kg/day. For example, at SMC, in case of mild grade cGVHD with high risk feature, or of moderate grade cGVHD, CNI plus PD, 0.5mg/kg/day can be given initially. In case of severe grade cGVHD, CNI plus PD, 1.0mg/Kg/day will be given.

Itraconazole will be maintained until PD is tapered to 10mg/day in case of PD alone therapy group, or until PD is stopped in case of CNI+PD or CNI+PD+MMF or MMF+PD group, etc. In addition, patients will receive itraconazole oral suspension until: 1) Development of proven or probable IFIs, 2) Severe toxicity (such as liver function abnormality - AST/ALT level > 10 times UNL or bilirubin/ALP level > 5 times UNL, 3) Worsening GVHD that requires second line therapy for steroid refractory GVHD (in this situation, investigator could stop itraconazole oral solution if there is a potential drug interaction between itraconazole oral solution and 2nd line GVHD drug or prolonged use of itraconazole oral solution could be hazardous to the patient), 4) Need to switch antifungal agent for the treatment of prolonged febrile episode related to systemic infection, thus requiring systemic antifungal treatment, 6) Withdrawal from study participation (patient's decision), or 7) Death.

Study Design

Study Type:

Interventional

Actual Enrollment :

36 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Prevention

Official Title:

Evaluation of Antifungal Prophylaxis Against Invasive Fungal Infections During Corticosteroid Containing Therapy for Graft-versus-host Disease Following Allogeneic Hematopoietic Stem Cell Transplantation

Study Start Date :

Dec 1, 2009

Actual Primary Completion Date :

Dec 1, 2010

Actual Study Completion Date :

Dec 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: itraconazole, prophylaxis, Oral solution For GVHD patients who are required systemic glucocorticoids therapy, itraconazole oral solution will be administered at a dose of 200mg every 12 hours.	Drug: Itraconazole 200mg bid, oral solution, until a dose of prednisone was tapered to 10mg/day in case of prednisone alone therapy group, or until prednisone was stopped in case of CNIs plus prednisone, CNIs plus prednisone plus mycophenolate mofetil, or mycophenolate mofetil plus prednisone group, etc. Other Names: Sporanox oral solution

Arm

Intervention/Treatment

Experimental: itraconazole, prophylaxis, Oral solution

For GVHD patients who are required systemic glucocorticoids therapy, itraconazole oral solution will be administered at a dose of 200mg every 12 hours.

Drug: Itraconazole

200mg bid, oral solution, until a dose of prednisone was tapered to 10mg/day in case of prednisone alone therapy group, or until prednisone was stopped in case of CNIs plus prednisone, CNIs plus prednisone plus mycophenolate mofetil, or mycophenolate mofetil plus prednisone group, etc.

Other Names:

Sporanox oral solution

Outcome Measures

Primary Outcome Measures

incidence of proven or probable invasive fungal infections [at day 100 after starting graft-versus-host disease (GVHD) treatment with corticosteroids based regimen in adjunction to itraconazole oral solution antifungal prophylaxis.]

Secondary Outcome Measures

safety profiles of itraconazole oral solution [during GVHD treatment with corticosteroids containing regimen]
GVHD-specific survival (GSS) of patients receiving corticosteroids based GVHD treatment together with antifungal prophylaxis with itraconazole oral solution [from the onset of acute or chronic GVHD to death due to GVHD itself or GVHD-related complications]

Eligibility Criteria

Criteria

Ages Eligible for Study:

19 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients developing or developed acute or chronic GVHD within the last 10 days which require systemic immunosuppressive therapy of corticosteroids with- or-without other immunosuppressive agents including calcineurin inhibitors.

acute GVHD, grade 2-4
chronic GVHD, mild grade with high risk or moderate to severe grade

Written informed consent form

Exclusion Criteria:

Aspartate transaminase or alanine transaminase level > 10 times UNL or Bilirubin or alkaline phosphatase level > 5 times UNL
Active or chronic hepatitis virus B or C infection requiring antiviral therapy
Estimated life expectancy < 30 days
History of allergy, sensitivity, or any serious reaction to itraconazole oral solution
Previous history of Zygomycosis
Evidence of active fungal disease including high galactomannan titer above 0.5, within 2 weeks.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Chonnam National University Hwasun Hospital	Hwasun	Jeollanam-do	Korea, Republic of
2	Soonchunhyang University Bucheon Hospital	Bucheon	Kyounggi-do	Korea, Republic of
3	Gachon University Gil Hospital	Incheon		Korea, Republic of
4	Inha University Hospital	Incheon		Korea, Republic of
5	Inje University Pusan Paik Hospital	Pusan		Korea, Republic of
6	Samsung Medical Center	Seoul		Korea, Republic of	135-710
7	Chung-ang University Hospital	Seoul		Korea, Republic of
8	Seoul National University Hospital	Seoul		Korea, Republic of
9	Soonchunhyang University Seoul Hospital	Seoul		Korea, Republic of