Safety and Efficacy of Steroids in the Management of Fulminant Hepatic Failure Due to Hepatitis A Virus in the Pediatric Age Group
Phase: PHASE4
Conditions: Fulminant Hepatic Failure
Sponsor: National Liver Institute, Egypt

COVER PAGE 
 
Title: Steroids in Fulminant Hepatitis A in the Pediatric Age Group  
 
Clinical trial number: NCT02375867  
 
Contents: - Study Protocol - Statistical analysis plan – Results 
 
Date: 11 December 2018 
 
 

STUDY PROTOCOL 
 
Background  
Fulminant hepatic failure (FHF) (alternatively, acute liver failure [ALF]) is a rare but life-
threatening critical illness that occurs most often in patients who do not have a preexisting liver 
disease. It is the clinical manifestation of liver cell death of a critical degree with insufficient 
hepatocellular regeneration and is characterized by hepatic encephalopathy and/or 
coagulopathy1. The mortality rate without liver transplantation (LT) is over 40% in patients with 
acetaminophen-induced FHF and 80% in those with nonacetaminophen-related FHF 2. This 80% 
decreases to 30% when LT and artificial liver support system are available 3. Hepatitis A virus 
(HAV) is considered to be the commonest cause of acute viral hepatitis worldwide. In acute 
infection with HAV, a cellular immune response attacking virus-infected cells is responsible for 
the clinical manifestations and the recovery mediated by CD8+ T cells and CD4+ T cells, in 
addition to B cell response producing immunoglobulin [Ig]M and IgG according to the time-
course of the disease. HAV infection can cause FHF and death in about 0.2% of clinical cases 4. 
Extensive destruction of infected hepatocytes by T cell-mediated lysis was supposed to be the 
cause of FHF 5. Hepatitis A virus (HAV) is the most common cause of acute viral hepatitis 
worldwide. In acute HAV infection, a cellular immune response attacking virus-infected cells is 
responsible for the clinical manifestations and the recovery mediated by CD8+ T cells and CD4+ 
T cells, in addition to B cell response producing immunoglobulin [Ig]M and IgG according to the 
time-course of the disease. Although rare, HAV infection can cause FHF and death in 
approximately 0.2% of clinical cases 4. Overwhelming elimination of infected hepatocytes by T 
cell-mediated lysis was supposed to be the cause of FHF 5.   

Material and methods 
 Study population:  
This study included 26 children with fulminant hepatitis A. They were recruited over a 
period of 4 years duration and divided into two groups. Group one is comprised of 18 children 
with fulminant HAV infection who received steroid therapy beside standard supportive measures 
(steroid group). The second group is comprised of 15 children with fulminant HAV infection 
who did not receive steroid therapy, but only standard supportive measures (non steroid group). 
All cases were recruited from the department of Pediatric Hepatology, Gastroenterology and 
Nutrition, National Liver Institute, Menofiya University. Those patients whose parents accepted 
to receive steroids were allocated in the steroids group; others were allocated in the control 
group. From each group a random sample was chosen using SPSS. An informed consent was 
signed by the parents of the steroid-treated patients before recruitment in the study which was 
approved by the Research Ethics Committee of National Liver Institute.  
Etiological diagnosis and group allocation  
Fulminant hepatitis A is defined by an acute onset of liver disease, due to HAV infection, 
with no known evidence of chronic liver disease, together with hepatic based coagulopathy 
(prothrombin time [PT] ≥20 seconds or international normalized ratio [INR] ≥2.0) that is not 
corrected by parenteral vitamin K and/or hepatic encephalopathy (must be present if the PT is 
15–19.9 seconds or the INR is 1.5– 1.9, but not if PT is ≥20 seconds or INR is ≥2.0) 5. After full 
investigations for possible etiologies, patients with proved etiology other than HAV or those with 
indeterminate FHF were not included.  
 

Serum viral markers  
Anti-HAV IgM was detected by enzyme linked immunosorbent assay (ELISA) (Dia Pro, 
Italy). Anti-hepatitis E virus IgM was tested by ELISA (Dia Pro, Italy). Hepatitis B surface 
antigen (HBsAg), anti-hepatitis B core IgM and IgG types, were tested for by ELISA kits (Sorin 
Biomedica Co, Spain). HBV-DNA was tested by COBAS AMPLICOR monitor test, version 2.0, 
Roche Molecular Systems, Inc., Branchburg, NJ, 08876 USA. Hepatitis C virus (HCV) antibody 
was tested by 4th generation ELISA (Innogenetics, Ghent-Belgium). Real-time polymerase chain 
reaction for HCV-RNA was performed using COBAS® Ampliprep/COBAS® TaqMan®, Roche 
Molecular Systems, Inc., Branchburg, NJ, 08876 USA.  
Treatment regimen and modifications  
Patients were initially assigned to receive prednisolone at a dose of 1 mg/kg/d or its 
equivalent dose of methylprednisolone (0.8 mg/kg/d) for those who cannot take oral 
prednisolone (as patients with encephalopathy or vomiting). In those with improved PT (while 
on steroid therapy) below 20 seconds in conscious patients or below 15 seconds in 
encephalopathic patients, the steroid dose was maintained for further two weeks then withdrawal 
started. In those who had deterioration of liver functions upon withdrawal, treatment was 
continued for a longer duration till satisfactory biochemical improvement was achieved. The 
treatment was scheduled to be discontinued if uncontrollable hyperglycemia, gastrointestinal 
bleeding, or brain edema develops.  
Outcome assessment  
The parameters of the primary response were improvement of PT followed by 
improvement of alanine transaminase and aspartate transaminase together with decreasing 
bilirubin during the period of observation. The overall clinical outcome (recovery or death) was 

considered secondary response parameter. Treatment tolerability and side effects were also 
monitored.   
 
 

Statistical analysis plan (SAP)  
Quantitative data were presented as mean ± standard deviation (SD) while qualitative 
data were presented as number and percentage. For both homogenously distributed and non 
homogenously distributed quantitative data, significance was tested by either independent 
samples t-test or by Mann-Whitney U test, respectively. Chi-square test or Fisher's exact test was 
used for the measurement of the qualitative data significance. Significance was set at P value < 
0.05. A stepwise regression analysis was performed to examine independent factors associated 
with the outcome. Standardized regression coefficient (β), 95% confidence interval (CI) and P 
values of each independent factor are presented. Statistical analysis was performed using SPSS, 
version 13 (SPSS Inc, Chicago, IL, USA).   
 
 

Sponsor/Collaborators 
Sponsor: National Liver Institute, Egypt   
Investigator: Mostafa M. Sira [msira] 
Official Title: Associate Professor of Pediatric Hepatology 
Affiliation: National Liver Institute, Egypt 
Collaborators: 
Quesna Central Hospital, Ministry Of Health, Egypt 
 
Human Subjects Review: 
Board Status: Approved     Approval Number: 00104/2015  
Board Name: NLI IRB 00003413 FWA0000227  
Board Affiliation: National Liver Institute, Menoufiya University IRB ,Shebin El-koum, EGYPT 
 
Study Officials:  
 
     Contact: Hanaa A El-Araby, M.D.    +2-048-222-2740    helaraby@liver-eg.org 
     Contact: Haidy M Zakaria, M.Sc.    +20100-5768-306    drhaydi2000@gmail.com 
     Principal Investigator: Hanaa A El-Araby, M.D. 
     Sub-Investigator: Mostafa M Sira, M.D. 
     Sub-Investigator: Haidy M Zakaria, M.Sc. 
     Sub-Investigator: Tahany A Salem, M.Sc. 
     Sub-Investigator: Ahmad M Sira, M.D. 
     Sub-Investigator: Doaa Y Elbadry, M.B; B.Ch. 
     Sub-Investigator: Mohamed A Ali, M.Sc. 
     Sub-Investigator: Rawan M Salama, M.B; B.Ch. 
     Sub-Investigator: Menan E Salem, M.D. 
     Sub-Investigator: Shaimaa S Goda, M.Sc. 
     Sub-Investigator: Sara M Eltaras, M.Sc. 
     Sub-Investigator: Basma M Abd-Alaaty, M.Sc. 
     Sub-Investigator: Fatma O Khalil, M.D. 
     Sub-Investigator: Sahar S Abou-Zeinah, M.Sc. 

Results 
 
Table 1: Outcome of steroid therapy  
Characteristics 
Steroid 
(n = 18)  
Non-Steroid 
(n = 15)  
P-value 
Type of steroids 
        Methylprednisolone 
10 (55.6)
--
        Prednisolone 
8 (44.4) 
--
Duration of steroids (days)
       Minimum-Maximum (median)
5 – 50 (22)
--
Outcome 
       Living 
15 (83.3) 
4 (26.7) 
0.001 
       Dead 
3 (16.7) 
11 (73.3) 
Number of living patients were significantly higher in the steroid group compared to non-steroid 
group 
 
 
Table 2: Stepwise regression analysis for parameters with significance between living and dead 
patients 
Characteristics 

P-value 
95% CI
 
Lower
Upper
Steroid therapy 
0.571 
0.001 
0.268 
0.865 
Prothrombin time (seconds) 
NI 
--
--
--
: regression coefficient; CI: confidence interval; NI: not included 
Steroid therapy was the only independent parameter associated with survival of patients 

 
Figure 1. Serial changes of prothrombin time (A) and total bilirubin (B) in the steroid group.  
PT: prothrombin time 
 
 

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