Posaconazole Prophylaxis During ATG Treatment for hMDS/AA Patients

Sponsor

Seoul National University Hospital (Other)

Overall Status

Unknown status

CT.gov ID

NCT03318159

Collaborator

Merck Sharp & Dohme LLC (Industry)

Enrollment

Location

Arm

26.3

Anticipated Duration (Months)

1.5

Patients Per Site Per Month

Study Details

Study Description

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 Design

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Allocation:

N/A

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.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

Actual Study Start Date :

Apr 20, 2018

Anticipated Primary Completion Date :

Jun 30, 2019

Anticipated Study Completion Date :

Jun 30, 2020

Arms and Interventions

Arm	Intervention/Treatment
Other: 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

Arm

Intervention/Treatment

Other: 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

Outcome Measures

Primary Outcome Measures

the incidence of proven/probable/possible fungal infection [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

overall survival [through study completion, an average of 18 months]
The overall survival (OS) curves will be estimated using the Kaplan-Meier method
any incidence of proven/probable/possible fungal infection [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

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:

those suspected of fungal infection within 30 days of ATG treatment
those allergic to -triazoles
those with history of malignancies within 5 years and/or concomitant malignancy other than AA/hMDS
those with history of chemotherapy, radiotherapy and/or other immunosuppressants
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
active HBV, HCV patients
HIV positive patients
those with history of receiving organ transplantation