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

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

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.

Study Overview

• Status: Terminated
• Conditions: Graft vs Host Disease
• Intervention / Treatment: Drug: Itraconazole

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 Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 4

Contacts and Locations

Study Locations

• Korea, Republic of
  • Incheon, Korea, Republic of
    • Inha University Hospital
  • Incheon, Korea, Republic of
    • Gachon University Gil Hospital
  • Pusan, Korea, Republic of
    • Inje University Pusan Paik Hospital
  • Seoul, Korea, Republic of
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 135-710
    • Samsung Medical Center
  • Seoul, Korea, Republic of
    • Chung-ang University Hospital
  • Seoul, Korea, Republic of
    • SoonChunHyang University Seoul Hospital
  • Jeollanam-do
    • Hwasun, Jeollanam-do, Korea, Republic of
      • Chonnam National University Hwasun Hospital
  • Kyounggi-do
    • Bucheon, Kyounggi-do, Korea, Republic of
      • SoonChunHyang University Bucheon Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

  1. acute GVHD, grade 2-4
  2. 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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

Outcome Measure	Time Frame
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

Collaborators and Investigators

• Sponsor: Samsung Medical Center
• Collaborators: Janssen, LP
• Investigators: Principal Investigator: Dong Hwan Kim, M.D./Ph.D., Division of Hematology/Oncology, Department of Medicine

Publications and helpful links

General Publications

• Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr KA, Morrison VA, Segal BH, Steinbach WJ, Stevens DA, van Burik JA, Wingard JR, Patterson TF; Infectious Diseases Society of America. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008 Feb 1;46(3):327-60. doi: 10.1086/525258. No abstract available.
• Goodman JL, Winston DJ, Greenfield RA, Chandrasekar PH, Fox B, Kaizer H, Shadduck RK, Shea TC, Stiff P, Friedman DJ, et al. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med. 1992 Mar 26;326(13):845-51. doi: 10.1056/NEJM199203263261301.
• 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.

Study record dates

Study Major Dates

• Study Start: December 1, 2009
• Primary Completion (Actual): December 1, 2010
• Study Completion (Actual): December 1, 2010

Study Registration Dates

• First Submitted: January 23, 2011
• First Submitted That Met QC Criteria: January 24, 2011
• First Posted (Estimate): January 25, 2011

Study Record Updates

• Last Update Posted (Estimate): January 25, 2011
• Last Update Submitted That Met QC Criteria: January 24, 2011
• Last Verified: January 1, 2011

More Information

Terms related to this study

• Keywords: prophylaxis; transplantation; Itraconazole oral solution; invasive fungal infections; Graft vs Host Disease
• Additional Relevant MeSH Terms: Infections; Immune System Diseases; Bacterial Infections and Mycoses; Mycoses; Invasive Fungal Infections; Graft vs Host Disease; 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: 2009-08-099

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No