Clinical trial NCT03318159
Conditions: Aplastic Anemia Myelodysplastic Syndromes Fungal Infection
Sponsor: Seoul National University Hospital
Start date: 2018-04-20; Completion date: 2023-07-15
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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

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.

Arms: arm 1: aplastic anemia / hypoplastic myelodysplastic syndrome patients undergoing antithymocyte globulin treatment and receiving posaconazole as prophylaxis antifungal agent
Interventions: intervention 1: Posaconazole
Intervention descriptions: intervention 1: 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

Protocol documents:
Prot_SAP_ICF_000.pdf: 
Posaconazole prophylaxis during anti-thymocyte globulin treatment for hypoplastic 
myelodysplastic syndrome(HMDS)/ aplastic anemia(AA) patients 
 
Trial Registration: Clinicaltrials.gov NCT03318159, registered Jul 23, 2017 
Document Date: November 4, 2024 
 
Methods 
Study Design 
In this prospective, open label, single arm study(Clinicaltrials.gov no. NCT03318159), we enrolled 
patients with diagnosed hypoplastic myelodysplastic syndrome(HMDS) and aplastic anemia(AA) 
patients who received anti-thymocyte globulin(ATG) treatment at Seoul National University 
Hospital(SNUH) and Seoul National University Bundang Hospital from Aug 2018 through Jun 2023. 
All patients enrolled in the study provided written informed consent. Inclusion criteria were as 
follows : 1) ≥18 years and <75 years old, 2) hypoplastic myelodysplastic syndrome(HMDS) or aplastic 
anemia(AA) diagnosed, 3) anti-thymocyte globulin(ATG) treatment, 4) no QTc prolongation on initial 
ECG, 5) Serum creatinine and AST/ALT levels ≤ 2 times the upper limit of the reference range for 
laboratory and 6) Serum bilirubin levels ≤ 1.5 times the upper limit of the reference range for 
laboratory. Exclusion criteria were as follows : 1) Suspected fungal infection within 30 days of ATG 
treatment, 2) history of allergic to –triazoles, 3) diagnosis of other malignancy in the previous 5 
years, 4) previous chemotherapy, radiation, or immunosuppressive treatment, 5) pregnant or 
breastfeeding, male or female patients of reproductive potential who are not employing an effective 
method of birth control, 6) active HBV and HCV patiens and HIV positive patients, 7) history of 
receiving organ transplantation, 8) QTc prolongation is identified on baseline ECG of who have 
Torasdes de pointes syndrome and 9) on ergotamine alkaloids, CYP3A4(terfenadine, astemizole, 
cisapride, pimozide, halofantrine, quinidine) or HMG-CoA reductase inhibitors. 
Patients received 300mg Posaconazole orally twice daily on day 1 and 300mg once daily for 4weeks 
from day 2. Posaconazole should start on the same day as ATG, but if it’s not possible to start on 
the same day, it’s allowed to start within +/- 3 days. 
The primary end point was the incidence of proven/probable/possible fungal infection through 4-
week post-treatment period, and the secondary end points were overall survival, any fungal infection. 
Patients were followed up for 6 months from the end of prophylactic treatment for the occurrence 
of additional fungal infection and survival, respectively. 


The determination of sample size 
The incidence rate of invasive fungal infection is estimated to be 80% in childhood aplastic anemia 
patients undergoing ATG treatment (Pediatric Hematology and Oncology, 31:1, 20-28, 2014). 
Allowing for up to a rate of 30%, based upon a sample size of n=20 patients per group, this study 
will ensure that a two-sided test with α = 0.05 has 80% to detect the difference. We aim to recruit 
double the minimally required sample size. 
Statistical Analysis 
Categorical variables were compared using Student t-test or Pearson’s chi-square test as appropriate. 
P < 0.05 are considered statistically significant. Overall survival were evaluated by Kaplan-Meier 
analysis. 
Ethical Considerations 
This study was approved by the institutional review board at Seoul National University Hospital(IRB; 
1706-207-866) and was conducted in accordance with the guidelines of the Declatation of Helsinki 
for biomedical research. Informed consent was obtained from all participants. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Informed consent 
The information is prepared to explain the contents of this research. If you have any questions, 
please ask the principal investigator or other investigator. 
1. Clinical Trial Title 
Posaconazole prophylaxis during anti-thymocyte globulin treatment for hypoplastic myelodysplastic 
syndrome(HMDS)/ aplastic anemia(AA) patients 
2. Principal Investigator 
Professor Youngil Koh, Department of Hematology and Oncology 
3. Background 
In the case of aplastic anemia and dysplasia syndrome, which are continuously pancytopenia due 
to bone marrow dysfunction, there is a high risk of invasive fungal infection by themselves. 
Furthermore, the risk of fungal infection can be higher due to the anti-thymocyte globulin effect 
when treated. In particular, these fungal infections occur immediately after treatment, and the risk 
is reported to exceed about 15-20%. Therefore, it is clinically recommended to prevent antifungal 
drugs, but it has not been established yet, and for that reason, the best agent have not been known. 
Therefore, in this study we want to check whether the preventive use of posaconazole, a broad-
spectrum antimicrobial agent that is already widely used, can reduce the probability of fungal 
infection and increase the successful treatment rate. 
4. Investigational drugs 
Posaconazole 
- 
Efficacy/Effect : 
1) Treatment of patients with invasive aspergillosis who are refractory to amphotericin B or 
itraconazole or intolerant to these treatments 
2) Prevention of invasive fungal infections 
5. Precautions for use 
Major advedse event associated with the most frequently reported treatment in relation to 
medication include nausea, vomiting, diarrhea, fever, and elevated bilirubin. 
6. Clinical trial period 
Subjects will receive this drug from the day start of anti-thymocyte globulin treatment to 4weeks 


of drug. The research team will follow up for 6months the time of completion of the 4weeks 
medication. 
7. Clinical trial method 
If you participate in this study, you will receive a free supply of posaconazole. Patients received 
prescribed dose posaconazole twice a day on the first day of anti-thymocyte globulin treatment 
and once a day on the second day for a total of 4 weeks. If necessary, culture test for body fluids 
such as sputum and blood may be performed. The sample process will be performed in the 
treatment and examination process for regenerative anemia and dysplasia of the bone marrow, 
which will not be conducted in this study except for posaconazole administration.  
8. Benefits for study subjects 
By reducing the frequency of fungal infections, you can benefit from hospital stay and cost of 
treatment. 
9. Expenses and Compensation 
Participation in this clinical trial may provide you with a free supply of antifungal drugs, but may 
not have any other benefit. For the evaluation of fungal infection, chest imaging tests, blood tests, 
and culture tests for body fluids are needed. These tests are performed depending on the patient's 
condition. 
10. Requirements for study subjects 
There are no special requirements for study subjects. If you are discharged from the hospital after 
treatment, you must visit the hospital for evaluation of fungal infection at the 6th and 12th weeks 
from the date of induction chemotherapy. 
11. Voluntary participation/discontinuation of study 
Participation in clinical trials is entirely up to you. If you do not agree to participate in the clinical 
trial, it does not matter at all. In addition, even after consenting to participate in the trial, you can 
withdraw your consent to participate in the clinical trial at any time if you wish, and there will be 
no disadvantage or damage. 
12. Continous provision of new research-related information 
If the investigator becomes aware of any new facts during the study, the investigator will inform 
you or your representative of the facts at any time. 
13. Damage and compensation 


Although this drug is currently marketed and used, unexpected side effects may occur. 
Compensation will be determined in accordance with regulations related to Seoul National 
University Hospital and separate compensation agreements with insurance companies. Damage 
compensation can be compensated up to a maximum of 500 million per accident and 100 million 
per person. 
14. Confidentiality 
All records of your identity obtained in this research will be kept confidential, and even when the 
results are published, your personally identifiable information will be kept confidential. 
15. Contact person 
If additional information is needed regarding the clinical trial and the rights and interests of the 
subject, or in case of damage related to the clinical trial, contact: 02-743-7617 (research nurse), 
other emergency contact information, if you have any questions about the research, etc.) IRB 
(Institutional Review Board, Medical Research Ethics Review Board): 02-2072-0694 Clinical Research 
Ethics Center Contact: 02-2072-3509