Efficacy of Eltrombopag & Prednisolone Versus Prednisolone Monotherapy in Newly Diagnosed Immune Thrombocytopenia- A Randomized Control Trial
Phase: PHASE1
Conditions: Primary Immune Thrombocytopenia
Sponsor: Renata PLC

 
 Protocol Title (Scientific Title) -  
“Efficacy of Eltrombopag & Prednisolone Versus Prednisolone Monotherapy in Newly 
Diagnosed Immune Thrombocytopenia- A Randomized Control Trial”  
 
 
Brief Title-  
Role of Eltrombopag as First Line Therapy in Primary Immune Thrombocytopenia.  
 
 
Last Update- - 22.01.2024 
Approval Date- 22.01.24  
 
Principle Investigator: 
Name: Dr Mohammad Manirul Islam 
Qualification: MBBS, FCPS (Hematology) 
Detail Address: Associate Professor, Department of Hematology& BMT Unit, 
Dhaka Medical College and Hospital, Dhaka. 
 
Mobile: 01715049573                          
e-mail: manirk54@yahoo.com 
 
 
 
 
 
 
 
 

1 
 
1. 
Title of Study: 
Efficacy of Eltrombopag & Prednisolone Versus Prednisolone Monotherapy in 
Newly Diagnosed Immune Thrombocytopenia- A Randomized Control Trial 
 
2.     Brief Title- Role of Eltrombopag as First Line Therapy in Primary Immune 
Thrombocytopenia.  
 
3. 
Principal Investigator(s):  
Name: Dr Mohammad Manirul Islam 
Qualification: MBBS, FCPS (Hematology) 
Detail Address: Associate Professor, Department of Hematology& BMT Unit, 
Dhaka Medical College and Hospital, Dhaka. 
 
Mobile: +8801715049573                                    
e-mail: manirk54@yahoo.com 
4. 
Co-Investigator(s): 
Name: Dr Gazi Yeasinul Islam  
Qualification: MBBS, FCPS (Hematology) 
Detail Address: Medical Officer, Department of Hematology& BMT Unit, 
Dhaka Medical College and Hospital, Dhaka. 
 
Mobile: +8801716715995                                         
e-mail: yeasin100heam@gmail.com 
5. 
Place of the Study/Institution(s): 
Department of hematology and BMT Unit, Dhaka Medical college hospital, Dhaka 
 
 
6. 
Type of Study: A double blind, placebo control, Randomized Clinical Trial.  
7. 
Duration of Study: One year 
 
 
 

2 
 
 
 
 
Put Tick sign (√) appropriate answers against each of the following statement 
 (If not Applicable, Please write NA) 
 
 
1. Source of Population:  
4. Are subjects clearly informed about: 
  (a) Ill Subject 
√Yes 
No 
(a) Nature and purpose of    
Study 
√Yes 
No 
 (b) Non-ill Subject 
Yes 
√No 
(b) Procedures to be followed    
   including alternatives used 
√Yes 
No 
  (c) Minors or persons under        
guardianship 
Yes 
√No 
  (c) Physical risks 
√Yes 
No 
2. Does the study Involve:  
 
 
 (d) Private questions 
√Yes 
No 
 (a) Physical risks to subjects 
√Yes 
No 
 (e) Invasion of the Body 
√Yes 
No 
 (b) Social Risks 
Yes 
√No 
 (f) Benefits to be derived  
√Yes 
No 
  (c) Psychological risks to         
subjects 
Yes 
√No 
 (g) Rights to refuse to participate or 
to withdraw from study 
√Yes 
No 
 (d) Discomfort to subjects 
√Yes 
No 
 (h) Confidential handling of data 
√Yes 
No 
 (e) Invasion of the body 
√Yes 
No 
 (i) Compensation where there are 
risks or loss of working time or 
privacy is involved in any particular 
procedure  
√Yes 
No 
 (f) Invasion of Privacy 
Yes 
√No 
5. Will signed consent form/verbal consent be 
required:  
 (g) Disclosure of information 
damaging to subject or others 
Yes 
√No 
 (a) From Subjects 
√Yes 
No 
3. Does the study involve:  
 
 
 (b) From parent or guardian(if 
subjects are minors)  
Yes 
√No 
 (a) Use of records(hospital, 
medical, death, birth or other) 
Yes 
√No 
6. Will precautions be taken to protect 
anonymity of subjects 
√Yes 
No 
 (b) Use of fetal tissue or        
abortus 
Yes 
√No 
 
 
 
  (c) Use of organs or body        
fluids 
√Yes 
No 
 
 
 

3 
 
PREPARATION OF AN ABSTRACT 
FOR 
NATIONAL RESEARCH ETHICS COMMITTEE (NREC) 
 
This will be a double blind, placebo control, randomized control trial, conducted in Department 
of Hematology, DMCH for one year. Newly diagnosed ITP patients will be enrolled in the study 
after being selected by inclusion and exclusion criteria. Total sample size would be 100 (50 in 
each group). Enrolled patients would be divided into two groups (1:1) by block randomization. 
One group will get Eltrombopag& Prednisolone and other group will get Eltrombopag& 
Placebo. Researchers or any one related to the study in DMCH, patients & their attendants, no 
one will know which patient will get placebo or eltrombopag. Patient would be followed up on 
1st, 2nd and 4th week of starting therapy. This clinical trial intends to find out role of eltrombopag 
as first line therapy when used with prednisolone in newly diagnosed patient. According to the 
requirement of Ethical Review Committee following topic has been answered. 
1.  
Describe the requirements in respect of the population and explain the rationale for 
using population of special groups such as children, Incompetent person or groups whose ability 
to give voluntary informed consent is questionable. 
 Study population of this study are adult male & female (≥18 years), patient with newly 
diagnosed ITP attending OPD or IPD of department of hematology DMCH. Children shall be 
excluded from the study.  There will be no inclusion of children, incompetent person or whose 
ability to give voluntary informed consent is questionable.   
2.  
Describe and assess any potential risks - physical, psychological, social, legal or other 
and assess the likelihood and seriousness of such risks. If methods of research create potential 
risks, describe other methods, if any, that were considered and why they cannot be used. 

4 
 
 Physical risk is minimum. Only physical risk is to any hazard during sample taking. There is no 
psychological risk. The study does not include any questions or procedure that can produce 
psychological trauma.  There is no social harm. Diseases status and personal information of 
patients will be secret as per doctor-patient confidentiality. Costs of drugs and investigations will 
be provided from research fund. Patients will get compensation money (500 tk each) if there are 
any risks or loss of working time or privacy is involved in any particular procedure. So there will 
be no economic burden. There is no legal entanglement if they participate in the study.     
3.  
Describe procedures for protecting against or minimizing potential risks and assessment 
of their likely effectiveness. 
        Newly diagnosed ITP patients with severe bleeding at presentation will not be included in 
the study as they need emergency rescue treatment. A Data and Safety Monitoring Board 
(DSMB) will be formed which will include two members of NREC, one biostatistician, one 
hematologist and one medicine specialist. Any adverse event (Drugs side effects- headache, 
weight gain, changes in liver enzymes, high blood sugar) or serious adverse event (grade 3 or 
grade 4 bleeding [26], hospitalization, thrombosis) will be delt with proper medical care.  
4.  
Include a description of the methods for safeguarding confidentiality or protecting 
anonymity. 
Every participant will be given an individual number. The participant will be known by that 
number throughout the study. In case record form participants will be identified by the number. 
Actual identity (name, address) of participants will be kept in a secret locker and only accessible 
by principal investigator. Anonymity of the participants will be maintained even after 
publication.  

5 
 
5.  
When there are potential risks to the subject, or the privacy of the individual may be 
involved, the investigator is required to obtain a signed informed consent from the participant. 
For minors, informed consent must be obtained from the authorized legal guardian or parent of 
the subject. Describe consent procedures to be followed including how and where informed 
consent will be obtained. 
Informed written consent will be taken from patients. No minor person will be included in the 
study. So permission from legal guardian will not be necessary. Patient will be briefed 
extendedly by principal or co-investigator. Then they will be provided written consent form. 
After reading their questions will be answered and inquires will be addressed. If they agreed to 
participate in the study their sign will be taken in written form.  
(a)  
If signed consent will not be obtained, explain why this requirement should be waived 
and provide an alternative procedure such as a verbal consent. 
 Signed consent will be obtained 
(b) If information is to be withheld from a subject, justify this course of action. 
No information will be withheld from subjects. Their chance of getting placebo will also be 
explained. They will be assure that they are getting treatment even in placebo group as 1st line 
drug prednisolone will be in both group.  
(c)  
If there is a potential risk to the subject or privacy of the individual or loss of work time 
is involved in any particular procedure, include a statement in the consent form stating whether 
any compensation will be available. 

6 
 
    There will be no potential risk except some side effects of drugs, which will be monitored. 
There will be an Institutional protocol safety board- A team of two doctors and one nurse will be 
assigned for supportive care of the study. Their contact number will be provided to the 
participants. So they can contact in any inquiry, confusion or emergency. Their anonymity will 
be maintained. We will not any extra time from them as they have to come in follow up even 
they were not in the study.  
6.  
If the study involves an interview, describe where and in what context the interview will 
take place. State approximate length of time required for the interview. 
          Patient’s history, examination and reports will be evaluated. It may take 10-15 minutes. 
We will do the interview and physical examination in OPD of department of hematology, 
DMCH.  
7.  
Assess the potential benefit to be gained by the individual subject as well as the benefits 
which may accrue to society in general as a result of the work. Indicate how the benefits may 
outweigh the risks. 
         Patients can be benefited from free drugs (eltrombopag and prednisolone), free 
investigations (related to ITP), good supportive care and regular follow up. The study result may 
help to select suitable drug combination for future ITP patients. There are some risks like loss of 
time during follow up, weight gain, raised blood sugar. But it is more beneficial to treat ITP and 
reduce unnecessary risks of bleeding.  
 8.  
In case of an experimental drugs, provide information about its status of registration for 
open sale in Bangladesh and in other developed countries. 
         Prednisolone is a well-known drug and in use for a long time in Bangladesh. Eltrombopag 
is licensed to use in Bangladesh. Safety and efficacy of prednisolone and eltrombopag in ITP is 

7 
 
already established. Eltrombopag is approved in 80 counties for use in ITP. 
9.  
For experimental 'new' drugs* which are not registered in Bangladesh provide full 
information about the toxicity studies carried out in animals or human volunteers. Published 
papers on this regard shall be annexed. 
Prednisolone and eltrombopag both are registered in Bangladesh for use.  
10.  
If placebo is to be used justify its uses and why the study cannot be done without its use. 
       Placebo is used to avoid dissatisfaction of the patients. If placebo is it used, one group will 
get prednisolone only and patient of that group can think one drug may not be enough for 
treatment. If we give placebo and patients, researchers both are blinded they have nothing to 
worry about.  
11.  
If an experimental 'new' drug is to be used give a statement regarding its sponsorship 
and the conditions for such sponsorship. 
Prednisolone and eltrombopag both are registered in Bangladesh for use. However, both drug for 
the study will be provided by Renata limited Bangladesh. There are no terms with the 
pharmaceutical in exchange of drugs and financial support. MOU with Renata limited is attached 
in appendix.  
12.  
State if the activity requires the use of records (hospital, medical, birth, death or other), 
organs, tissues, body fluids, the fetus or the abortus. 
        There will be no use of hospital, medical, birth, death or other records. No organs, tissues, 
the fetus or the abortus will be used in the study. Only blood will be taken for investigations.  

8 
 
RESEARCH PROPOSAL  
 
 
Title: Efficacy of Eltrombopag & Prednisolone Versus Prednisolone Monotherapy in 
Newly Diagnosed Immune Thrombocytopenia- A Randomized Control Trial. 
Summary: This will be a double blind, placebo control, randomized control trial, and conducted 
in Department of Hematology, DMCH for one year. Newly diagnosed ITP patients will be 
selected after meeting inclusion and exclusion criteria, they will be thoroughly informed about 
the study, used drugs, randomization, risk and benefits, follow up. If they agree to participate in 
the study, their consent will be taken and they will be enrolled in the study. Detail history and 
clinical exam will be done. Key points are- History of spontaneous bleeding in last month, 
History of vaccination, History of recent viral infection, fever, Presence of organomegaly. 
Primary investigation will be- CBC PBF, RBS, ANA, TSH, Anti H. pyloriIgG, Anti-HCV, 
APTT, BMS (if indicated). Main outcome variable will be platelet count and number of 
spontaneous bleeding. Total sample size would be 100 (50 in each group). Enrolled patients 
would be divided into two groups (1:1) by block randomization. One group will get 
Eltrombopag& Prednisolone and other group will get Eltrombopag& Placebo. Researchers or 
any one related to the study in DMCH, patients & their attendants, no one will know which 
patient will get placebo or eltrombopag. Only respectable third party will know the information.  
Patient would be followed up on 1st, 2nd and 4th week of starting therapy. Patient would be 
evaluated in every follow up by history, physical examination and investigation. History of any 
spontaneous bleeding event, any discomfort or new symptoms science last follow up will be 
noted. General examination will be performed in every follow up. CBC and RBS will be done in 
every follow up. Institutional protocol safety board will be responsible for monitoring and 
management of any adverse event. Data will be collected on predesigned case record form and 

9 
 
will be collected by face-to-face interview, physical examination and collecting laboratory 
reports.  After data collection data will be edited, cleaned and prepared for analysis at the end of 
the study. The statistical analysis will be conducted using SPSS (statistical package for the social 
science) version 25 statistical software. The result of the study may help to increase treatment 
response rate in newly diagnosed ITP. This could increase durability of first line treatment and 
decrease relapse. The result of the study will be published in national and international journals.  
 
 
Introduction 
Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by immunologic 
destruction of otherwise normal platelets and suppression of platelet production. The diagnosis 
of ITP remains one of exclusion; no robust clinical or laboratory parameters are currently 
available to establish its diagnosis with accuracy. A platelet count (Plt) less than 30 x 109/L 
generally indicates severe disease.  ITP is said to be ‘‘newly diagnosed’’ if time of presentation 
from the diagnosis is within 3 months, “persistent” if within 3-12 months and chronic if lasting 
for more than 12 months. 
The mechanisms behind ITP are complex and poorly understood, although it is well known that 
antiplatelet autoantibodies play a central role. An altered response by splenic T follicular helper 
cells induce proliferation and differentiation of auto reactive B-cells.These produce antiplatelet 
autoantibodies, predominantly of the immunoglobulin (Ig)G isotype, which are able to react with 
a series of platelet receptors, mainly glycoprotein (GP) Iib/IIIa and GPIb/IX, but also GPV, 
GPIa/Iia, or GPIV. These antigen-antibody complex induce cell destruction. The course of the 
disease may vary in each individual case according to the specific autoantibodies, and targeted 

10 
 
surface glycoproteins, which determine the nature of the prevailing pathogenic mechanism (i.e. 
accelerated clearance, inhibited megakaryopoiesis or platelet apoptosis). The covered platelets 
experience splenic sequestration and subsequent phagocytosis by mononuclear macrophages. 
Macrophages still play an additional harmful role in ITP since they behave as the main antigen-
presenting cell. On the other hand, CD8+ T-cells also contribute to thrombocytopenia by 
increasing platelet apoptosis. Recently, the Ashwell–Morell receptor (AMR), which is an 
asialoglycoprotein counter receptor predominantly expressed in hepatocytes, has also been 
shown to play an important role in anti-GPIbα-antibody-mediated platelet clearance. As a 
consequence, the circulating half-life of platelets is markedly reduced. Furthermore, bone 
marrow megakaryocytes are unable to produce platelets normally, which exacerbates 
thrombocytopenia: 
on 
the 
one 
hand, 
there 
is 
an 
autoimmune 
response 
against 
megakaryocytes;[3] on the other hand, the circulating thrombopoietin (TPO), which is the main 
growth factor of megakaryocytes, does not increase to a level high enough to stimulate the 
production of these at the required rate. 
First-line treatment options for ITP usually include corticosteroids (dexamethasone, prednisone) 
and immunoglobulins [intravenous immunoglobulin (IVIG), Rho(D) immune globulin (anti-D)], 
which produce fast but transient responses. Corticosteroids show an initial response in 60–70% 
of patients within 2–14 days, but the response often lasts <6 months.[11] IVIG will produce a 
response in 1–3 days in 90% of patients, but the response typically lasts only 2–4 weeks. 
For patient’s refractory to first-line treatments, common therapeutic options include TPO-Ras 
(thrombopoietin receptor agonist), the anti-CD20 antibody rituximab, splenectomy, and 
immunosuppressive agents (azathioprine, cyclosporine A (CSA), cyclophosphamide, danazol, 
dapsone, mycophenolatemofetil, and vincristine). 

11 
 
TPO-Ras are the only therapeutic option for ITP that increases platelet production. In addition to 
promoting platelet production from existing megakaryocytes, TPO-Ras may also enhance 
proliferation of megakaryocytes in bone marrow, as suggested by in vitro studies and clinical 
trials in patients with aplastic anemia. Importantly, TPO-Ras may reduce platelet destruction by 
restoring Treg (regulatory T cell) and regulatory B-cell activity, thereby attenuating the 
autoimmune response to platelets. In patients treated with TPO-Ras for >3 months, Treg activity 
was significantly improved compared with the pretreatment group (p = 0.001) and was similar to 
the Treg activity in healthy subjects (p = 0.9).[14] Moreover, preliminary evidence suggests that 
autoantibody levels in patients with ITP may progressively decrease with TPO-RA treatment, 
which may contribute to restoration of immune tolerance to platelets. 
Eltrombopag is an oral Thrombopoietin Receptor Agonist (TPO-RA) which is  approved for use 
in more than 80 countries, including the United States and European Union countries. In 
randomized, controlled trials, eltrombopag has been shown to safely and durably increase 
platelet count in both adults and children with refractory ITP. Clinical evidence from patients 
who received eltrombopag for up to 8.8 years supports that eltrombopag retains its safety and 
efficacy with long-term continuous use, even though it would be necessary to evaluate further 
related events associated with eltrombopag for a longer term. 
Improving the efficacy and durability of first-line treatments would reduce the number of 
patients who fail therapy and, therefore, help spare them from the burdensome ‘trial and error’ 
period. Several clinical trials studied role of eltrombopag as first line treatment in combination 
with other agents eg- dexamethasone, rituximab. Gómez- Almaguer et al. studied role of 
eltrombopag and high-dose dexamethasone as frontline treatment of newly diagnosed ITP in 
adults. [1] Another studied role of eltrombopag, low dose rituximab, and dexamethasone 

12 
 
combination as frontline treatment of newly diagnosed ITP. [2] Margo et al studied role of 
eltrombopag and High-dose dexamethasone in chronic ITP. [3] 
This study intends to find out role of eltrombopag as first line therapy. In this study we shall 
compare response of prednisolone and eltrombopag against prednisolone as first line treatment in 
newly diagnosed ITP.  
 
 

13 
 
Research objectives 
General objective 
To determine efficacy of eltrombopag & prednisolone over prednisolone monotherapy in 
newly diagnosed patients with immune thrombocytopenia by accessing change in platelet 
count and number of spontaneous bleedings.  
Specific objectives 
• To determine response of eltrombopag and prednisolone in increasing platelet count and 
reducing incidence of spontaneous bleeding in newly diagnose ITP patients.  
• To determine response of prednisolone alone in increasing platelet count and reducing 
incidence of spontaneous bleeding in newly diagnose ITP patients. 
• To compare response of eltrombopag &prednisolone group and prednisone alone group. 
 
 

14 
 
 
Hypothesis 
Eltrombopag and prednisolone combination is more efficacious than prednisolone alone as a first 
line treatment in newly diagnosed patients with ITP. 
 
 

15 
 
Rationale of the study 
ITP is not uncommon in our country. Prednisolone is the most used drug in first line therapy and 
it shows initial response of 70-80%. [4] We want to improve the response rate of first-line 
treatment by adding eltrombopag with prednisolone. Though eltrombopag is recommended for 
second line therapy, some studies use eltrombopag as first line therapy. A single-arm study of 
dexamethasone in combination with 4 weeks of eltrombopag used upfront in adult patients with 
newly diagnosed ITP produced 90-100% response at completion of therapy and 66.7% relapse-
free survival at 1 year. [1] A phase 3 randomized trial of eltrombopag versus standard first line 
pharmacological management for newly diagnosed ITP in children is currently going on. [5] Our 
main objective is to find out the efficacy of eltrombopag and prednisolone against prednisolone 
alone as first line treatment in newly diagnosed ITP 
 

16 
 
Methodology 
Study design: A double blind, placebo control, Randomized Clinical Trial 
Study period: One year  
Place of study: Department of Hematology and Bone Marrow Transplant Unit, Dhaka Medical 
College Hospital (DMCH), Dhaka, Bangladesh. 
Study population:  Newly diagnosed ITP patients attending OPD and IPD of Department of 
Hematology and Bone Marrow Transplant Unit, Dhaka Medical College and Hospital (DMCH), 
Dhaka. 
Selection criteria 
Inclusion criteria: 
1. Patients with newly diagnosed ITP 
2. Platelet Count ≤ 30x109/L 
3. Age between 18 to 70 years.  
Exclusion criteria: 
1. Persistent or chronic  ITP 
2. Pregnant women 
3. Secondary ITP- ITP due to SLE, Anti-phospholipid syndrome, Evans syndrome, HCV or 
H Pylori associated ITP. 
4. History of vaccination, recent viral infection, fever 
5. Evan’s Syndrome 
6. Known case of chronic renal failure or liver diseases  
7. Grade 3 or 4 bleeding at presentation.   

17 
 
Sampling technique: Block Randomization 
Sample Size 
The sample size was determined by using the following formula             
𝑛 = 𝑃1(100 −𝑃1) + 𝑃2(100 −𝑃2)
(𝑃1 −𝑃2)2
 × (𝑍∝+ 𝑍𝛽)2 
P1= Experimental Group (Eltrombopag and Prednisolone) Response – There is no such study 
found but Eltrombopag and dexamethasone in first line therapy showed 90-100% response. [1] 
We want to consider P1 as 90% for sample size calculation.  
P2= Control Group (Prednisolone only) Response- Prednisolone as first line therapy shows 70-
80% response. [4] We want to consider P2 as 70% for sample size calculation.  
𝑍∝ = level of significance. For this study we want 5% level of significance. The value would be 
1.96 
𝑍𝛽 = given power. For this study we want 80% power. The value would be 0.842 
𝑛 = 90 × 10 + 70 × 30
(95 −75)2
 × (1.64 + 0.84)2 
𝑛= 3000
400  × 6.15 
𝑛= 46.12 
46 participants in each group. We want to consider attrition 10%. So, sample of one group will 
be 46+4 = 50 and total sample would be 50+50=100. 
 

18 
 
Variables  
1. Independent Variable 
o Age 
o Occupation 
o Sex 
o Home District 
2. Dependent Variables- 
Main Outcome variables 
Other associated variables 
o Changes in Platelet count  
o Changes in hemoglobin 
o Spontaneous bleedings 
o Changes in Total WBC count 
3. Confounding variables 
o DM 
o Thyroid diseases 
o Ischemic heart diseases 
o any other auto-immune diseases e.g. 
vitiligo.  
Study procedure 
 
After meeting inclusion and exclusion criteria patients will be thoroughly informed about the 
study, used drugs, randomization, risk and benefits, follow up. If they agree to participate in the 
study, their consent for this study will be taken and they will be enrolled in the study. 
Detail history and clinical exam will be done. Key points are- History of spontaneous bleeding in 
last month, History of vaccination, History of recent viral infection, fever, Presence of 
organomegaly.  
Primary investigation will be- CBC PBF, RBS, ANA, TSH, Anti H. pyloriIgG, Anti-HCV, 
APTT, BMS (if indicated) 
 

19 
 
NB: 
1. If APTT is more than 10 sec of control, patient would be evaluated for Anti-Phospholipid 
Syndrome by anti-cardiolipin Antibody and Anti-beta2 glycoprotein1 Antibody 
2. If Hemoglobin in less than 11.5gm/dL patient would be evaluated for Anemia by Iron 
Profile or Coomb’s Test based on CBC parameter and PBF findings]  
Randomization: Enrolled patients would be divided into two groups (1:1) by block 
randomization. Block Randomization would be done by computer generated pattern. One such 
plan has attached in appendix III, page 49 as a sample. Actual randomization plan will be 
provided by Renata limited team who know about eltrombopag and placebo. Randomization 
allocation delivered only to the enrolling site study staff. A voluntary nurse will be in charge of 
enrolling the patients according to randomization plan.  
Blinding and placebo control: It will be a double-blind study. Researchers nor participants will 
know who is getting placebo/eltromopag.  One group will get Prednisolone & Eltrombopag and 
another group will get Prednisolone & Placebo. Eltrombopag, Prednisolone and Placebo will be 
provided by Renata Limited Bangladesh and patient will get at free of costs. Placebo will have 
same size, shape, color, markings, taste, smell and packaging like Eltrombopag. Eltrombopag 
and placebo will be provided in separate color-coded box marked-A (red) or B (green). Group A 
and Group B participants will be given colored cards (red and green) for identification. They will 
receive tablets from marked box. Researchers or any one related to the study in DMCH, patients 
& their attendants no will know which box contain placebo or eltrombopag. Only respectable 
person of Renata limited will know the information. The team who knows the information will 
be head by their CEO. At the end point all data will be submitted to the team who know about 
placebo.  

20 
 
Experimental Group - Eltrombopag& Prednisolone    Control Group - Prednisolone and Placebo 
Dose- Prednisolone 1mg/kg/day for 28 days     Eltrombopag/Placebo 25mg/day for 28 days 
Follow Up- 
Follow up at the end of 1st week, 2nd week and 4th week 
Patient would be evaluated in every follow up by history, physical examination and 
investigation. History of any spontaneous bleeding event, any discomfort or new symptoms 
science last follow up. General examination will be performed in every follow up. CBC, RBS, 
ALT, AST and creatinine will be done in every follow up. 
Primary End Point-28 days after starting therapy. Complete Response is expected after 28 days 
of therapy. 
 Patient would continue therapy and follow up in OPD but would not be included in the study. 
Supportive care and rescue-  
A Data and Safety Monitoring Board (DSMB) will be formed which will include two members 
of NREC, one biostatistician, one hematologist and one medicine specialist. Any adverse event 
(Drugs side effects- headache, weight gain, changes in liver enzymes, high blood sugar) or 
serious adverse event (grade 3 or grade 4 bleeding, hospitalization, thrombosis) will be delt with 
proper medical care.  
If any patient shows no response within 14 days and has grade 3 or 4 bleeding, rescue with 
methyl prednisolone or IV Ig would be given and discontinued from study. If group A patient 
reaches platelet count >400x109\L, eltrombopag will be stopped.  
 

21 
 
Pharmacodynamics and pharmacokinetics of Eltrombopag and Prednisolone 
Pharmacodynamics and pharmacokinetics of Eltrombopag and Prednisolone is attached in 
appendix  
Data Collection-  
Data will be collected on predesigned case record form and will be collected by face-to-face 
interview, physical examination and collecting laboratory reports.  
Operational Definition-  
ITP- Widely accepted abbreviation, ITP, has variably been defined as “immune 
thrombocytopenic Purpura,” “idiopathic thrombocytopenic Purpura,” and, most recently, 
“immune thrombocytopenia.” It is an autoimmune disorder characterized by immunologic 
destruction of otherwise normal platelets most commonly occurring in response to an unknown 
stimulus. ITP may occur in isolation (primary) or in association with other disorders 
(secondary). Secondary causes include- Systemic lupus erythematosus, Antiphospholipid 
syndrome, 
Autoimmune 
thrombocytopenia 
(eg, 
Evans 
syndrome), 
Infection 
with 
cytomegalovirus, H. pylori, hepatitis C, HIV, varicella zoster, Lymphoproliferative disorders, 
Vaccination side effect. 
Newly diagnosed, Persistent and Chronic ITP-Newly diagnosed ITP is considered as lasting 
up to 3 months, followed by persistent (3-12 months) and chronic disease (12 months). 
Complete response (CR) – A platelet count ≥ 100x109/L and the absence of bleeding.  
Partial Response–A platelet count ≥ 30x109/L and a greater than 2-fold increase in platelet 
count from baseline and the absence of bleeding.  

22 
 
No response (NR) –A platelet count <30x109/L or a less than 2-fold increase in platelet count 
from baseline or the presence of bleeding.  
Indication of BMS in ITP- No response or relapse following first-line therapy, presence of 
atypical clinical or laboratory features, Age >60 years, before splenectomy  
Grade 3 bleeding- Bleeding requiring blood transfusion &\or associated with moderate 
hemodynamic instability.  
Grade 4 bleeding- Bleeding with severe hemodynamic instability, internal organ bleeding, CNS 
bleeding.  
 
 
Utilization of Results: The result of the study may help to increase treatment response rate in 
newly diagnosed ITP. It can help to establish Eltrombopag as first line therapy. This could 
increase durability of first line treatment and decrease relapse. The result of the study will be 
published in national and international journals.  
 
Facility: The study will be conducted in department of hematology and BMT unit, DMCH. 
Study population are newly diagnosed ITP patients attending our OPD and IPD. Their sample for 
investigation will be collected by technologist of our department. CBC will be done in our 
department with Sysmex XN-2000 auto analyzer. Team of volunteer doctor and nurse will be 
responsible for managing any clinical emergency of the patients. The drugs and placebo will be 
stored in our department. Some investigation facility is not available in our department. These 
investigations will be carried out in BSSMU.  

23 
 
Statistical Analysis Plan 
After data collection data will be edited, cleaned and prepared for analysis at the end of the 
study. At the end of the study, all data will be submitted to the team who know about 
placebo/eltrombopag. The statistical analysis will be conducted using SPSS (statistical package 
for the social science) version 25 statistical software.  The findings of the study will be presented 
by frequency and percentage in tables. Means and standard deviations for continuous variables 
and proportion for categorical variables will be used to describe the characteristics of the total 
sample. Association between two qualitative variables will be assessed by Chi-square test, where 
p<0.05 with 95% confidence level will be considered as significant. Appropriate statistical tests 
will be done to interpret the findings of the study. 
 
 

24 
 
 
Flowchart 
Patient with platelet count < 30x109/L 
 
Investigation for thrombocytopenia 
 
Primary ITP and Enrolled in the Study after meeting  
Inclusion and exclusion criteria 
 
Blocked Randomization and Blinding 
 
Experimental Group 
Eltrombopag and Prednisolone group 
 
 
1st  and 2nd and 4th week follow up 
Control Group 
Prednisolone and Placebo group 
 
 
1st  and 2ndand 4thweek follow up 
 
 
Data tabulation, cleaning, editing 
 
Data analysis 
 
Result expressed and prepare for publication 
 
 
Secondary ITP 
If 
Patient 
develop 
grade 3 or 4 bleeding 
rescue would be done 
and 
excluded 
from 
study 

25 
 
 
Work schedule 
 
 
Activity ↓    (months → ) 
1st 
2nd 3rd 4th 
5th 
6th 
7th 8th 9tth 
10th 11th 12th 
Literature review 
 
 
 
 
 
 
 
 
 
 
 
 
Study design and protocol 
writing 
 
 
 
 
 
 
 
 
 
 
 
 
IRB/BMRC clearance 
 
 
 
 
 
 
 
 
 
 
 
 
Patient selection and 
enrollment 
 
 
 
 
 
 
 
 
 
 
 
 
Collection of data 
 
 
 
 
 
 
 
 
 
 
 
 
Data cleaning, editing,  
 
 
 
 
 
 
 
 
 
 
 
 
Data analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 Preparing result and 
writing for publication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

26 
 
 
Ethical consideration 
• Before starting this study, the research protocol will be submitted and approved by the 
Institutional Review Board of DMCH, Dhaka and national research ethics committee, 
BMRC.  
• Eltrombopag is an oral TPO-RA approved for use in more than 80 countries, including 
the United States and European Union countries.[16] Prednisolone is widely used drug. 
We are not exposing patient to any new drugs which safety and efficacy is not well 
established.  
• All participants will be informed about the objectives, methodology and purpose of the 
study in an easily understandable way.  
• All information regarding benefits and hazards regarding the study will be delivered to 
the all participants & only those who agree to participate will be included in the study.  
• Verbal and written consents will be obtained from all participants without any influences 
prior to data collection.  
• Data obtained from the study will be used only for research purposes. The confidentiality 
of all study information will be maintained strictly.  
• Participants can withdraw themselves from the study at any time even after giving 
consent.  
 
 

27 
 
 
Reference 
1. Gómez-Almaguer D, Herrera-Rojas MA, Jaime- Pérez JC, et al. Eltrombopag and high-
dose 
dexamethasone 
as 
frontline 
treatment 
of 
newly 
diagnosed 
immune 
thrombocytopenia in adults. Blood 2014; 123: 3906–3908. 
2. Gomez-Almaguer D, Cantu-Rodriguez O, Gutierrez-Aguirre CH, et al. Eltrombopag, low 
dose rituximab, and high-dose dexamethasone combination for patients with newly 
diagnosed immune thrombocytopenia: a pilot ‘total therapy’ study. Blood 2016; 128: 
1369–1369. 
3. Magro D, Levato L, Eugenio P, et al. Highdose dexamethasone and eltrombopag in 
chronic immune thrombocytopenia: a single institution experience. Haematologica 2017; 
102: 1–217. 
4. Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation 
and management of primary immune thrombocytopenia. Blood 2010;115:168–86. 
5. Kristin A. Shimano, Rachael F. Grace, Carolyn M. Bennett, Robert J Klaassen, Cindy 
Neunert, et al; A Phase 3 Study of Eltrombopag Vs. Standard First-Line Management for 
Newly Diagnosed Immune Thrombocytopenia in Children. Blood 2019; 134 
(Supplement_1): 2369. Doi: https://doi.org/10.1182/blood-2019-125487 
 

28 
 
 
INFORMED CONSENT FORM 
 
 
This consent form informed the participants about the necessary information, pro and con 
of the research and help the participants to make decision. 
 
 
Name of the study: “Efficacy of Eltrombopag & Prednisolone versus Prednisolone 
Monotherapy in Newly Diagnosed Immune Thrombocytopenia- A Randomized Control 
Trial.” 
Chief Researcher: Dr. Md. Manirul Islam, Associate Professor, Hematology Department & 
BMT Unit, DMCH. 
Associate Researcher: Dr Gazi Yeasinul Islam, Medical Officer, Hematology Department & 
BMT Unit, DMCH. 
Purpose of the study: To determine efficacy of eltrombopag & prednisolone over 
prednisolone monotherapy in newly diagnosed patients with immune thrombocytopenia. 
Data Provider: Patient himself/herself. 
Role of Participants: At first Patient will be evaluated for the eligibility criteria with some 
questions & some investigations. Participants will be divided into two groups. Patient or 
researcher cannot choose groups. It will be done randomly. One group will get prednisolone 
& eltrombopag and other group will get prednisolone and placebo (it has no pharmacological 
effect). Neither researcher nor participants will know which group will get placebo. Even if 

29 
 
you get placebo, only prednisolone is enough for your treatment, you will not be 
untreated.Patient has to take the drugs orally. He/She has to come for follow up at 1th, 2th& 
4th week after starting drug. In every follow up he/she will be evaluated by physical 
examination & investigation. Patient has to follow some rules when he/she is taking drug. 
Violation of some rules will disqualify him/her for the study. All investigations and drugs 
will be provided from researchers.  
Eltrombopag and Prednisolone as a drug: These drugs is to take orally daily. These drugs 
has used in different trials all over the world. Both drug has approval to use in different 
countries including ours. 
Benefit of the participant in the research: only prednisolone as first line therapy has 
success rate of 70-80%. We want to add eltrombopag to achieve success rate of 90-100% 
Risks & discomforts: Risks of participating in this study is almost zero. Eltrombopag is safe 
in humans, is proven by many studies. Even after that we will investigate any adverse effect 
in every follow up. Nothing will be done that can is harmful for your health. There will be a 
team of doctors and nurse to monitor their health, any adverse reaction and answering any 
inquiries. Team members contact number will be provided to you.    
Alternate Treatment: If you are not interested in the study, alternate treatment options will 
be offered. You will never be treated differently.  
Incentives & cost of drugs: All investigations and drugs will be provided from researchers 
during the research period. 

30 
 
Confidentiality: Your personal, disease, treatment & outcome related all information will be 
confidential during & after the study. Information related to research will be published 
anonymously. 
Voluntary Participation: Participation in this research is fully voluntary. You can with 
draw yourself at any stage of research. Your rights of treatment will always be preserved.  
Related question: Please let us know if you have any question. If you feel like throwing any 
question in future, then please contact researcher.  
 
Dr Mohammad Manirul Islam 
MBBS, FCPS (Hematology) 
Associate Professor  
Department of Hematology & BMT Unit, 
Dhaka Medical College and Hospital, Dhaka 
 
 
 
 
 
 
 
 
 
 

31 
 
 
 
 Informed consent 
 
 
I, the below signing person, read / listen to the information of consent form. I have 
understood the process of the study in sound mind. I have clarified other queries by asking 
questions. I am willing to participate in this study voluntarily, in sound mind.  
 
 
I clearly understand that participation is voluntary, harmless, helpful for me & other 
patients in the future.   
 
 
 
 
Participant Sign 
or Thumb impression 
Witness sign 
or Thumb impression 
Signature of Researcher 
 
 
 
 
 
 
 

32 
 
 
 
Case Record Form 
Efficacy of Eltrombopag & Prednisolone versus Prednisolone Monotherapy in 
Newly Diagnosed Immune Thrombocytopenia- A Randomized Control Trial. 
Data Number-                   Randomization number-               
[Please mark with a marker]  
Group-A 
Group- B 
Co- Morbidity- IHD, HTN, DM, Thyroid diseases, any other autoimmune diseases-  
 
No Yes 
Specify 
History of spontaneous bleeding in last 
month 
 
 
How many episode- 
Bleeding sites-  
 
History of vaccination 
 
 
 
History of recent viral infection, fever 
(within one month) 
 
 
Mention if infectious agent is known 
Presence of Organomegaly- (Liver, 
spleen or other)  
 
 
 
 
 
 
 
 
Primary Investigations-  
CBC- Hb-           MCV-         TC-        ANC-          -  
PBF 
RBS- 
ANA- 
TSH- 
Anti H. pyloriIgG-  
Anti-HCV- 
APTT- 
BMS- 
 

33 
 
 
 
Primary 
1st follow up 
2nd follow up 
3rd follow up 
Platelet 
Count 
 
 
 
 
MPV 
 
 
 
 
PWD 
 
 
 
 
Weight 
 
 
 
 
RBS 
 
 
 
 
TC 
ANC 
 
 
 
 
Hemoglobin 
 
 
 
 
ALT 
AST 
 
 
 
 
S. Creatinine 
 
 
 
 
Spontaneous 
Bleeding 
 
 
 
 
 
 
 
Note: 
 
 
 
Data Collected By- 
Name- 
Designation- 
Address-  
 
 
 

34 
 
 
Procedure of maintaining confidentiality 
• Patient’s name, address, phone number other information will be kept in different master 
record book.  
• Patients shall be provided a small card containing their code number, group, follow up 
date, emergency contact number.  
• Case record form will contain a code number. During data collection and analysis 
patients will be recognized by that number only.  
• Access to master record book would be limited  
• Maser record book will be stored in a separate cabinet.  
• Electronic data are stored in password-protected computers or files 
• No identity of participants will be exposed to any outside person. 
• Diseases and treatment history of the patient will be confidential.  
• Data will be stored as per advice of data monitoring and safety board.   
• Proper consent will be taken in the presence of a witness in a closed room.  
• Privacy of the patient will be maintained. 
 
 
 

35 
 
A Sample of Randomization Plan From 
 
1. Group B 
 
2. Group A 
 
3. Group B 
 
4. Group A 
 
5. Group B 
 
6. Group B 
 
7. Group A 
 
8. Group A 
 
9. Group B 
 
10. Group A 
 
11. Group B 
 
12. Group A 
 
13. Group A 
 
14. Group B 
 
15. Group A 
 
16. Group B 
 
17. Group B 
 
18. Group A 
 
19. Group B 
 
20. Group A 
 
21. Group A 
 
22. Group B 
 
23. Group B 
 
24. Group A 
 
25. Group B 
 
26. Group B 
 
27. Group A 
 
28. Group A 
 
29. Group A 
 
30. Group B 
 
31. Group B 
 
32. Group B 
 
33. Group A 
 
34. Group A 
 
35. Group B 
 
36. Group A 
 
37. Group B 
 
38. Group A 
 
39. Group A 
 
40. Group B 
 
41. Group B 
 
42. Group A 
 
43. Group B 
 
44. Group A 
 
45. Group A 
 
46. Group B 
 
47. Group A 
 
48. Group B 
 
49. Group A 
 
50. Group B 
 
51. Group B 
 
52. Group B 
 
53. Group A 
 

36 
 
54. Group A 
 
55. Group A 
 
56. Group B 
 
57. Group A 
 
58. Group A 
 
59. Group B 
 
60. Group B 
 
61. Group A 
 
62. Group A 
 
63. Group B 
 
64. Group B 
 
65. Group A 
 
66. Group B 
 
67. Group B 
 
68. Group B 
 
69. Group A 
 
70. Group B 
 
71. Group A 
 
72. Group A 
 
73. Group B 
 
74. Group A 
 
75. Group A 
 
76. Group B 
 
77. Group B 
 
78. Group A 
 
79. Group A 
 
80. Group A 
 
81. Group B 
 
82. Group A 
 
83. Group B 
 
84. Group B 
 
85. Group B 
 
86. Group A 
 
87. Group A 
 
88. Group B 
 
89. Group A 
 
90. Group B 
 
91. Group A 
 
92. Group B 
 
93. Group B 
 
94. Group A 
 
95. Group B 
 
96. Group A 
 
97. Group A 
 
98. Group B 
 
99. Group A 
 
100. Group B 
 
100 subjects randomized into blocks of102242281042 28448 2 284 10 
2 
 
 

37 
 
Appendix 
 
Pharmacokinetics and Pharmacodynamics of Eltrombopag and Prednisolone 
Eltrombopag 
Eltrombopag is a thrombopoietin receptor agonist used to treat thrombocytopenia or aplastic 
anemia associated with various etiologies. 
Mechanism of Action- Eltrombopag is an orally bioavailable, small-molecule TPO-receptor 
agonist that interacts with the transmembrane domain of the human TPO-receptor. Eltrombopag 
is a stimulator of STAT and JAK phosphorylation. Unlike recombinant TPO or romiplostim, 
Eltrombopag does not activate the AKT pathway in any way. It should be noted that when given 
to patients with aplastic anemia, other lineages besides platelet count were increased, suggesting 
that either eltrombopag enhanced the effect of TPO in vivo; or there is a yet uncovered 
mechanism of action at work 
Absorption- Peak absorption of Eltrombopag occurs around 2-6 hours following oral 
administration, and the total oral absorption of drug-related material following a 75 mg dose was 
estimated to be at least 52%. 
Volume of distribution- Based on a radiolabel study, the concentration of eltrombopag in blood 
cells is approximately 50% to 79% of plasma concentrations. Eltrombopag is highly protein 
bound (>99%). 
Metabolism- Eltrombopag is predominantly through pathways including cleavage, oxidation, and 
conjugation with glucuronic acid, glutathione, or cysteine. In vitro studies suggest that CYP1A2 

38 
 
and CYP2C8 are responsible for the oxidative metabolism of eltrombopag. UGT1A1 and 
UGT1A3 are responsible for the glucuronidation of eltrombopag 
Elimination-Eltrombopag is eliminated primarily via the feces (59%), along with 31% being 
renally excreted. 
Side effects 
Hepatotoxicity – may increase liver enzymes 
Thromboembolic complication- portal vein thrombosis has been reported in some cases of CLD. 
Most common adverse side effects are nausea, diarrhoea, upper respiratory tract infection, 
vomiting, myalgia, UTI, anaemia, fatigue, headache. 
 
Pharmacokinetics and Pharmacodynamics of Prednisolone 
Prednisolone is a glucocorticoid used to treat adrenocortical insufficiency, inflammatory 
conditions, and some cancers. 
Pharmacodynamics- Corticosteroids bind to the glucocorticoid receptor, inhibiting pro-
inflammatory signals, and promoting anti-inflammatory signals. Prednisolone has a short 
duration of action as the half life is 2.1-3.5 hours. Corticosteroids have a wide therapeutic 
window as patients make require doses that are multiples of what the body naturally produces. 
Patients taking corticosteroids should be counselled regarding the risk of hypothalamic-pituitary-
adrenal axis suppression and increased susceptibility to infections. 
Mechanism of action- The short term effects of corticosteroids are decreased vasodilation and 
permeability of capillaries, as well as decreased leukocyte migration to sites of 

39 
 
inflammation. Corticosteroids binding to the glucocorticoid receptor mediates changes in gene 
expression that lead to multiple downstream effects over hours to days. 
Glucocorticoids inhibit neutrophil apoptosis and demargination; they inhibit phospholipase A2, 
which decreases the formation of arachidonic acid derivatives; they inhibit NF-Kappa B and 
other inflammatory transcription factors; they promote anti-inflammatory genes like interleukin-
10. 
 Lower doses of corticosteroids provide an anti-inflammatory effect, while higher doses are 
immunosuppressive. High doses of glucocorticoids for an extended period bind to the 
mineralocorticoid receptor, raising sodium levels and decreasing potassium levels.  
Absorption - Oral prednisolone reaches a Cmax of 113-1343ng/mL with a Tmax of 1.0-2.6 
hours.1 Oral prednisolone is approximately 70% bioavailable. 
Volume of distribution- A 0.15mg/kg dose of prednisolone has a volume of distribution of 
29.3L, while a 0.30mg/kg dose has a volume of distribution of 44.2L 
Protein Bound- Prednisolone's protein binding is highly variable, ranging from 65-91% in healthy 
patients. 
Mechanism- Prednisolone can be reversibly metabolized to prednisone which is then metabolized 
to 17α,21-dihydroxy-pregnan-1,4,6-trien-3,11,30-trione (M-XVII), 20α-dihydro-prednisone (M-
V), 6βhydroxy-prednisone (M-XII), 6α-hydroxy-prednisone (M-XIII), or 20β-dihydro-
prednisone (M-IV).  20β-dihydro-prednisone is metabolized to 17α,20ξ,21-trihydroxy-5ξ-pregn-
1-en-3,11-dione(M-XVIII).  Prednisolone is metabolized to Δ6-prednisolone (M-XI), 20α-

40 
 
dihydro-prednisolone (M-III), 20β-dihydro-prednisolone (M-II), 6αhydroxy-prednisolone (M-
VII), 
or 
6βhydroxy-prednisolone(M-VI). 
 6αhydroxy-prednisolone 
is 
metabolized 
to 
6α,11β,17α,20β,21-pentahydroxypregnan-1,4-diene-3-one (M-X).  6βhydroxy-prednisolone is 
metabolized 
to 
6β,11β,17α,20β,21-pentahydroxypregnan-1,4-diene-3-one 
(M-VIII), 
6β,11β,17α,20α,21-pentahydroxypregnan-1,4-diene-3-one 
(M-IX), 
and 
6β,11β,17α,21-
tetrahydroxy-5ξ-pregn-1-en-3,20-dione (M-XIV).  MVIII is metabolized to 6β,11β,17α,20β,21-
pentahydroxy-5ξ-pregn-1-en-3-one (M-XV) and then to MXIV, while MIX is metabolized to 
6β,11β,17α,20α,21-pentahydroxy-5ξ-pregn-1-en-3-one (M-XVI) and then to MXIV.  These 
metabolites and their glucuronide conjugates are excreted predominantly in the urine 
Route of excretion: Prednisolone is over 98% eliminated in urine 
Plasma half Life: Prednisolone has a plasma half life of 2.1-3.5 hours. This half life is shorter in 
children and longer in those with liver disease