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Posaconazole Prophylaxis During ATG Treatment for hMDS/AA Patients

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ClinicalTrials.gov Identifier: NCT03318159
Recruitment Status : Not yet recruiting
First Posted : October 23, 2017
Last Update Posted : October 23, 2017
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Youngil Koh, Seoul National University Hospital

Brief Summary:
To investigate the efficacy of posaconazole as prophylaxis antifungal agent in aplastic anemia / hypoplastic myelodysplastic syndrome (AA/hMDS) patients undergoing antithymocyte globulin (ATG) treatment

Condition or disease Intervention/treatment Phase
Aplastic Anemia Myelodysplastic Syndromes Fungal Infection Drug: Posaconazole Phase 2

Detailed Description:

With compromised bone marrow function, patients with aplastic anemia (AA) and/and hypoplastic myelodysplastic syndrome (hMDS) are at an increased risk of invasive fungal infection. Moreover, the use of antithyocyte globulin (ATG), a part of standard first line treatment for AA/hMDS, increases the risk of fungal infection due to its antilymophocytic effects. It has been reported that fungal infection occurs most often in the first few weeks after initiation of ATG treatment, and the reported incidence of fungal infection overall varies from 9~80% for AA/hMDS patients. Among them invasive fungal infection accounts for 6-20% depending on reports. Such being the case, antifungal prophylaxis is recommended for AA/hMDS patients undergoing ATG treatment. More specifically, the British Committee for Standards in Haematology (BCSH) recognized the threat of increased invasive fungal infections in AA patients, and stipulated the use of mould (aspergillus) active azole, "preferably itraconazole or posaconazole" as prophylaxis. Unfortunately however, though many centers have adopted their own practice schemes, and antifungals have been routinely administered in the context of investigational regimens, there is no consensus as to which antifungal agent should be used.

Considering Aspergillus sp has remained the most common fungal isolate in AA patients for the past 20 years, it is only rational that an antifungal agent with broad spectrum, covering both yeast and fungi, be used in this context. Posaconazole, a triazole antifungal agent, not only has a broad coverage spectrum but also associated with predictable and reliable systemic bioavailability. Also for patients, once daily dosage is both pragmatic and convenient. According to meta-analyses of prophylactic antifungal agents use (published in 2007), fluconazole diminished the risk of fungal related mortality compared to placebo (RR 0.49, 95% CI: 0.32-0.75, P=0.0009). More importantly, when compared to fluconazole, posaconazole prophylaxis yielded even lesser fungal related mortality and significantly decreased invasive fungal infection rate. Considering the fact that posaconazole is already being used for acute myeloid leukemia (AML) and myelodysplastic syndromes patients undergoing induction treatment, it is only natural that posaconazole be used for AA/hMDS patients, who are at higher risk of developing invasive fungal infection compared to AML.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Intervention Model: Single Group Assignment
Intervention Model Description:

open label, single arm, phase 2, multicenter

*historical control will be used for comparison: historical control patients are defined as those diagnosed with AA/hMDS and underwent ATG treatment with either fluconazole or itraconazole prophylaxis.

Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Open Label, Phase II Study Investigating the Efficacy of Posaconazole as Prophylaxis Antifungal Agent in Aplastic Anemia / Hypoplastic Myelodysplastic Syndrome Patients Undergoing Antithymocyte Globulin Treatment
Anticipated Study Start Date : December 1, 2017
Estimated Primary Completion Date : June 30, 2019
Estimated Study Completion Date : December 31, 2019


Arm Intervention/treatment
posaconazole prophylaxis group
aplastic anemia / hypoplastic myelodysplastic syndrome patients undergoing antithymocyte globulin treatment and receiving posaconazole as prophylaxis antifungal agent
Drug: Posaconazole

Dosing of posaconazole Posaconazole tablet 300 mg twice daily on day 1; Maintenance dose: 300 mg once daily on day 2 and thereafter. Treatment period: 4 weeks

*if posaconazole tablet intolerance: posaconazole suspension 200mg tid




Primary Outcome Measures :
  1. the incidence of proven/probable/possible fungal infection [ Time Frame: during 4 weeks of posaconazole prophylaxis (i.e. upto 4 weeks) ]
    Define Invasive fungal infections according to guidelines of the Invasive Fungal Infections Cooperative Group of the European Organization for Research and Treatment of Cancer and Mycoses Study Group of the National Institute of Allergy and Infectious Diseases (Ascioglu S, Rex JH, de Pauw B, et al. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis. 2008;46:1813-1821.


Secondary Outcome Measures :
  1. overall survival [ Time Frame: through study completion, an average of 18 months ]
    The overall survival (OS) curves will be estimated using the Kaplan-Meier method

  2. any incidence of proven/probable/possible fungal infection [ Time Frame: through study completion, an average of 18 months ]
    Define Invasive fungal infections according to guidelines of the Invasive Fungal Infections Cooperative Group of the European Organization for Research and Treatment of Cancer and Mycoses Study Group of the National Institute of Allergy and Infectious Diseases (Ascioglu S, Rex JH, de Pauw B, et al. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis. 2008;46:1813-1821.



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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. willing and able to provide written informed consent for voluntary participation in the trial
  2. adult patients (≥18 years, <75 years old)
  3. no QTc prolongation on initial ECG
  4. Adequate organ function for treatment as follows:

A. Absolute neutrophil count > 1.5 x 109/L B. Platelets >100 x 109/L C. Serum creatinine ≤ 2.0 x ULN (upper limit of normal) D. Serum bilirubin ≤ 1.5 x ULN E. AST and ALT ≤ 2.0 x ULN

Exclusion Criteria:

  1. those suspected of fungal infection within 30 days of ATG treatment
  2. those allergic to -triazoles
  3. those with history of malignancies within 5 years and/or concomitant malignancy other than AA/hMDS
  4. those with history of chemotherapy, radiotherapy and/or other immunosuppressants
  5. female patients who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control
  6. active HBV, HCV patients
  7. HIV positive patients
  8. those with history of receiving organ transplantation

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03318159


Contacts
Contact: Youngil Koh, MD +82-10-9117-5012 go01@snu.ac.kr
Contact: Yeri Seo +82-2-331-2221 Ye-ri.seo@merck.com

Sponsors and Collaborators
Seoul National University Hospital
Merck Sharp & Dohme Corp.

Responsible Party: Youngil Koh, assistant professor, Seoul National University Hospital
ClinicalTrials.gov Identifier: NCT03318159     History of Changes
Other Study ID Numbers: H-1706-207-866
First Posted: October 23, 2017    Key Record Dates
Last Update Posted: October 23, 2017
Last Verified: October 2017

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Mycoses
Syndrome
Anemia
Myelodysplastic Syndromes
Preleukemia
Anemia, Aplastic
Disease
Pathologic Processes
Hematologic Diseases
Bone Marrow Diseases
Precancerous Conditions
Neoplasms
Antilymphocyte Serum
Posaconazole
Antifungal Agents
Immunologic Factors
Physiological Effects of Drugs
Immunosuppressive Agents
Anti-Infective Agents
Trypanocidal Agents
Antiprotozoal Agents
Antiparasitic Agents
14-alpha Demethylase Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Steroid Synthesis Inhibitors
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists