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

This study has been terminated.
(In interim analysis, this study met the primary hypothesis.)
Sponsor:
Collaborator:
Janssen, LP
Information provided by:
Samsung Medical Center
ClinicalTrials.gov Identifier:
NCT01282879
First received: January 23, 2011
Last updated: January 24, 2011
Last verified: January 2011
  Purpose

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 Intervention Phase
Graft vs Host Disease
Drug: Itraconazole
Phase 4

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Samsung Medical Center:

Primary Outcome Measures:
  • incidence of proven or probable invasive fungal infections [ Time Frame: at day 100 after starting graft-versus-host disease (GVHD) treatment with corticosteroids based regimen in adjunction to itraconazole oral solution antifungal prophylaxis. ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • safety profiles of itraconazole oral solution [ Time Frame: during GVHD treatment with corticosteroids containing regimen ] [ Designated as safety issue: Yes ]
  • GVHD-specific survival (GSS) of patients receiving corticosteroids based GVHD treatment together with antifungal prophylaxis with itraconazole oral solution [ Time Frame: from the onset of acute or chronic GVHD to death due to GVHD itself or GVHD-related complications ] [ Designated as safety issue: No ]

Enrollment: 36
Study Start Date: December 2009
Study Completion Date: December 2010
Primary Completion Date: December 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: Sporanox oral solution

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.

  Eligibility

Ages Eligible for Study:   19 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01282879

Locations
Korea, Republic of
Chonnam National University Hwasun Hospital
Hwasun, Jeollanam-do, Korea, Republic of
Soonchunhyang University Bucheon Hospital
Bucheon, Kyounggi-do, Korea, Republic of
Gachon University Gil Hospital
Incheon, Korea, Republic of
Inha University Hospital
Incheon, Korea, Republic of
Inje University Pusan Paik Hospital
Pusan, Korea, Republic of
Samsung Medical Center
Seoul, Korea, Republic of, 135-710
Seoul National University Hospital
Seoul, Korea, Republic of
Soonchunhyang University Seoul Hospital
Seoul, Korea, Republic of
Chung-ang University Hospital
Seoul, Korea, Republic of
Sponsors and Collaborators
Samsung Medical Center
Janssen, LP
Investigators
Principal Investigator: Dong Hwan Kim, M.D./Ph.D. Division of Hematology/Oncology, Department of Medicine
  More Information

Publications:
Responsible Party: DongWhan Kim/assistant professor, Division of Hematology/Oncology, Department of Medicine,Samsung Medical Center, Sungkyunkwan University School of Medicine
ClinicalTrials.gov Identifier: NCT01282879     History of Changes
Other Study ID Numbers: 2009-08-099
Study First Received: January 23, 2011
Last Updated: January 24, 2011
Health Authority: Korea: Food and Drug Administration

Keywords provided by Samsung Medical Center:
Itraconazole oral solution
invasive fungal infections
prophylaxis
Graft vs Host Disease
transplantation

Additional relevant MeSH terms:
Graft vs Host Disease
Immune System Diseases
Pharmaceutical Solutions
Itraconazole
Hydroxyitraconazole
Therapeutic Uses
Pharmacologic Actions
Antifungal Agents
Anti-Infective Agents
14-alpha Demethylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on October 01, 2014