Format A

I. Title of proposal:“ LINK BETWEEN GENOTYPE AND IRON DEPOSITION

IN HEART AND LIVER IN CHILDREN WITH TRANSFUSION DEPEND-
ENT THALASSEMIA

II. Details of investigators:

1. Dr Priya Marwah
Professor
Department of Paediatrics
Mahatma Gandhi Medical College &
Hospital, Jaipur-302022
Email: priyamarwah21@gmail.com
Contact no.: 9829460720

2. Dr Shweta Sharma
Associate Professor
Department of IHBT
Mahatma Gandhi Medical College &
Hospital, Jaipur-302022
E Mail: drshwetssharma@mgumst.org
Contact no. : 9829332844

III. Brief description of study

1) Introduction:

Beta –Thalassemia is a genetic blood disease with a high incidence in the Mediterranean
basin, Middle East, Indian subcontinent, Central Asia and far East. (1) Beta Thalassemia is
characterized by a wide spectrum of clinical manifestations and laboratory findings and the
disease phenotype largely depends on the underlying mutations of the Beta globin chain.
(2)More than 200 different mutations that affect the beta globin gene have been identified and
their frequency varies significantly among countries or even in different regions of a single
country. (3) The correlation between phenotype and genotype is complex because other sec-
ondary / tertiary modifiers and environmental factors interact with different allelic variants
(2) and modulate the complex pathophysiology of Beta Thalassemia. Transfusion dependent
thalassemia (TDT) is the most severe clinical form of beta thalassemia and its current treat-
ment consists of regular transfusions. Chronic transfusions are not risk free and iron overload
represents the main drawback. Iron overload is cytotoxic and induces organ damage and fail-
ure in liver, heart, pancreas, thyroid and the central nervous system. (4) The introduction of
the chelation therapy has led to a decrease of the iron burden, significantly prolonging the
survival of the patients [5]. Moreover, the deployment of the T2* magnetic resonance ima-
ging (MRI) technique for the noninvasive quantification of organ-specific iron overload has
offered the possibility to design tailor-made chelation therapies meeting the individual pa-
tient’s needs, further improving the prognosis [6]. However, hepatic, cardiovascular and en-
docrine complications still occur [6]. The underlying genetic defect in thalassemia is an im-

Page 1 of 8
portant factor in the development of these complications because the homozygous β0 geno-
type state demands more red cells consumption and a greater rate of iron overloading [7]

References: 1. Cao, A.; Galanello, R. Beta-thalassemia. Genet. Med. 2010, 12, 61–76.
[Google Scholar] [CrossRef] [PubMed]

2. Thein, S.L. Genetic modifiers of beta-thalassemia. Haematologica 2005, 90, 649–660.

[Google Scholar] [PubMed
3. Weatherall, D.J. The inherited diseases of hemoglobin are an emerging global health
burden. Blood 2010, 115, 4331–4336. [Google Scholar] [CrossRef] [PubMed]
4. Hentze, M.W.; Muckenthaler, M.U.; Andrews, N.C. Balancing acts: Molecular control of
mammalian iron metabolism. Cell 2004, 117, 285–297. [Google Scholar] [CrossRef]
5. Borgna-Pignatti, C.; Rugolotto, S.; De Stefano, P.; Zhao, H.; Cappellini, M.D.; Del
Vecchio, G.C.; Romeo, M.A.; Forni, G.L.; Gamberini, M.R.; Ghilardi, R.; et al. Survival and
complications in patients with thalassemia major treated with transfusion and deferoxamine.
Haematologica 2004, 89, 1187–1193. [Google Scholar] [PubMed]
5.Argyropoulou, M.I.; Kiortsis, D.N.; Astrakas, L.; Metafratzi, Z.; Chalissos, N.; Efremidis,
S.C. Liver, bone marrow, pancreas and pituitary gland iron overload in young and adult
thalassemic patients: A T2 relaxometry study. Eur. Radiol. 2007, 17, 3025–3030. [Google
Scholar] [CrossRef] [PubMed
6.Pepe, A.; Pistoia, L.; Gamberini, M.R.; Cuccia, L.; Lisi, R.; Cecinati, V.; Maggio, A.;
Sorrentino, F.; Filosa, A.; Rosso, R.; et al. National networking in rare diseases and reduction
of cardiac burden in thalassemia major. Eur. Heart J. 2021. [Google Scholar] [CrossRef]
[PubMed]
7. Pistoia, L.; Meloni, A.; Salvadori, S.; Spasiano, A.; Lisi, R.; Rosso, R.; Maggio, A.;
D’Ascola, D.G.; Cuccia, L.; Mangione, M.; et al. Cardiac involvement by CMR in different
genotypic groups of thalassemia major patients. Blood Cells Mol. Dis. 2019, 77, 1–7.
[Google Scholar] [CrossRef] [PubMed]

3) Aims and clear research objectives of the study:

1. The aim of the present study is to evaluate the impact of the genotype on hepatic, and
myocardial iron content, and on hepatic, and cardiac complications in children with
transfusion-dependent β-thalassemia.

Page 2 of 8
4) Rationale of why a human study is needed to answer the research question:NA

5) Detailed description of the methodology of the proposed research, including sample

size (with justification), type of study design (observational/experimental / pilot /
randomised/blinded/etc.), types of data collection, inclusion & exclusion criteria,
intended intervention, dosages of drugs, route of administration, duration of treatment
and details of invasive procedures (if any), course of study, potential risks and benefits:

i) Methodology:
This will be a prospective longitudinal cross-sectional study to gather information on children
with TDT. All biochemical investigations will be performed using commercially available
kits at our laboratory.

Genotyping will be done using DNA sequencing techniques. Genomic DNA will be extracted
from peripheral blood leucocytes and all coding and non-coding regions of the β-globin gene
will be amplified by polymerase chain reaction (PCR) in different fragments

MRI exams will be performed on conventional clinical 1.5 T scanners equipped with a
phased-array receiver surface coil.

For iron overload assessment, a mid-transverse hepatic slice five or more axial slices and
basal, medium and apical short-axis views of the left ventricle (LV) will be acquired by T2*
gradient-echo multi-echo sequences.

The data will be captured on an excel sheet for the above information. Descriptive statistical
analysis will be done using essential tools such as mean, median, standard deviation and per-
centages.

ii) Sample size: 50

iii) Type of Study Design: Prospective longitudinal cross-sectional study

iv) Intended Intervention: This study does not have any intervention component.

v) Dosage of drugs: No additional drug will be used specifically for the study.

vi) Route of administration: Not applicable

vii) Duration of treatment: Not applicable.

viii) Details of invasive procedures (if any): No invasive procedure will be followed.

x) Duration of study: 6 months

Page 3 of 8
xi)Potential Risks: There is no potential risk associated with participation in this study.

xii) Benefits: A superior understanding of organ damage can be achieved by a comprehens-

ive assessment of the children with TDT, representing the ideal population to study the initial
stage of iron loading and the onset of its complications

6) Plan for statistical analysis of the study: The data will be captured on an excel sheet for
the above information from each centre. Descriptive statistical analysis will be done using ba-
sic tools such as mean, median, standard deviation and percentages.

IV. Types of subjects (Tick the correct option)

1) Volunteer

2) Patients

3) Vulnerable / special group subjects which include:

a) Pregnant women b) children c) elderly

d) fetus e) illiterate f) handicapped

g) terminally ill h) seriously ill i) mentally challenged

j) economically & socially backward k) captives l) health care workers

m) students n) armed forces

V. Statement on conflict of interest: No conflict of interest declared

VI. Declaration: I hereby declare that relevant intervention (medical/surgical/other) will be

supervised by authorised competent faculty working in Mahatma Gandhi Medical College &
Hospital, Jaipur.

VII. Checklist for attached documents:

a) Cover letter to Member Secretary, IEC, MGMC&H, Jaipur

b) Format A - for submission of study proposal to IEC

c) Format B - participant/patient information sheet

d) Format C – informed consent form (in English & Hindi)

e) Kindly note: Separate informed consent forms should be prepared when children are study
participants; an assent form for the children (age 7-18 years) and an informed consent form
for the parents

Page 4 of 8
 Name of Signature of Investigator Date Place
S. No Investigators
1.

2.

3.

4.

5.

Format B
GUIDELINES FOR PARTICIPANT / PATIENT INFORMATION SHEET

Please provide an answer under these headings. Include or exclude information, as applicable

1. Title of the study (as mentioned in the protocol): . LINK BETWEEN GENOTYPE
AND IRON DEPOSITION IN HEART AND LIVER IN CHILDREN WITH TRANS-
FUSION DEPENDENT THALASSEMIA

2. What is the purpose of the study and procedure / method of the research in simple lan-
guage? The aim of the present study is to evaluate the impact of the genotype on hepatic,
and myocardial iron content, and on hepatic, and cardiac complications in children with
transfusion-dependent β-thalassemia.

2. What kind of study products/procedures/tests/examinations are to be conducted on

subjects under study. Specify the name of drugs, dosage and frequency and how to ad-
minister :NA

3. What is the approximate number of participants involved: Number enrolled in study

duration. : 50

4. What will happen if the patient decides to take part in the study:

i. Risk and discomforts

There is no potential risk associated with participation in the study except

minor discomfort in the forearm while drawing blood and dizziness on rare
occasions. However, these are very rare and do not have any long-term
implications.

ii. Benefits (eg. knowledge gained may be beneficial to society/improvement in

treatment strategy)

Page 5 of 8
 If the results of this study are encouraging, the future patients may be be-
nefited. The treating physician will be able identify and manage high risk pa-
tients and might be able to choose best possible treatment options that could
improve disease outcomes.

iii. Is there compensation for participation- yes/no? If yes, specify amount/

insurance cover

No compensation will be provided for the participation in this study.

iv. What is the compensation for study related injury

You do not have a chance of research related injury by your participation in

this study. If any undesirable event happens to you during blood collection, we
will ensure that appropriate medical care is provided by the hospital. You will
not face any inconvenience or expenditure for this.

5. Alternatives to participation- list alternative treatments available, if any : Not

applicable

6. Confidentiality of records- the information in the study records will be kept

confidential. Data will be stored securely and will be made available only to persons
conducting the study and to the regulatory authorities.

7. Participation – Your participation in this study is voluntary; you may decline to

participate at any time without penalty and without loss of benefits to which you are
otherwise entitled.

8. Results of study will be used for publication and will be presented in conference
related to scientific research.

9. Contact information- please contact the nodal principal investigator (name, mobile
number, email id), if there is any question or problem for research related matters and
in case of new events of research-related injury

Dr Priya Marwah
Professor
Department of Paediatrics
Mahatma Gandhi Medical College &
Hospital, Jaipur-302022
Email: priyamarwah21@gmail.com
Contact no.: 9829460720

Dr Shweta Sharma
Associate Professor
Department of IHBT
Mahatma Gandhi Medical College &
Hospital, Jaipur-302022
E Mail: drshwetssharma@mgumst.org
Contact no. : 9829332844
Page 6 of 8
Format C

Informed Consent Form (English)

Study Title: -

Subject’s Name: .......................................................................................

Date of Birth/ Age (Years): ............................... Sex: ..............................

Please √ the
box given here
(1) I confirm that I have been explained the purpose and the
methodology of the study and I have cleared every doubt about the [ ]
study.
(2) I understand that my participation in the study is voluntary and that I
am free to withdraw at any time, without giving any reason, without [ ]
my medical care or legal rights being affected.
(3) I have been informed that this study is purely a research study and
participation in the above study would not be of any direct benefit or [ ]
risk to me and results of this study may be of help in future for the
society.
(4) I understand that the investigator of this study and others working on
the investigator’s behalf, the Institutional Ethics Committee will not
need my permission to look at my health records both in respect to [ ]
current study and any future research study that may be conducted in
relation to it.
(5) I understand that my identity will not be revealed in any information
released to third parties or Published. [ ]
(6) I agree not to restrict the use of any data or result that arise from this
study provided such a use is only for scientific purpose(s). [ ]
(7) I agree to take part in the above study [ ]

Name of the subject: ................................................................................

Signature of the subject: ..................................... Date: ....../......./.........
Name of the Investigator: ........................................................................
Signature of the Investigator: .............................. Date: ....../....../..........
Name of the witness: ...............................................................................
Signature of the witness: ....................................... Date: ....../....../........

Page 7 of 8
Informed Consent Form (Hindi)

पररयोजनाकाशीर्षक :

lwpuklgefri=

v/;;u 'kh"kZd......................................................................................................................................................
izfrHkkxhuke ..................................................................................................................................
tUefrfFk@vk;q¼o"kZ½ .....................................................fyax.........................................................
d`i;k ;gk¡fn;sx;sdks"Bdesa djsa

1- eSaiqf"Vdjrk@djrhgwW dh eq>s v/;;u ds mns~'; ,oadk;Ziz.kkyh ds ckjsesacrk;kx;kgSA ,oa

v/;;u ds ckjsesagjlansgLi"VgSA
2- eSa le>rk@le>rh gwWfd] v/;;u esaesjhHkkxhnkjhLoSfPNdgSA ,oaeSafdlhHkh le;
viuhHkkxhnkjhokilysus ds fy;s Lora= gwWArFkkfcukdksbZdkj.kcrk;s ,oabllsesjhfpfdRlk
ns[kHkkyrFkkesjsdkuwuhvf/kdkjizHkkforughagksaxsA
3- eq>s lwfprfd;kx;kgSfd ;g v/;;u iwjhrjg ls 'kks/k gSA ,oaesjhHkkxhnkjhfdlhHkhizR;{k
ykHk ;k tksf[keughagSArFkk bl v/;;u ls lekt ds fy;sHkfo"; esaenn dh tkldrhgSA
4- eSa le>rk@le>rh gwWfd bl v/;;u ds vUos"kdvkSjvUos"kd dh vkSj ls
rFkklaLFkkxruSfrdrklfefrdksorZeku v/;;u vkSjfdlhHkhHkfo"; ds lacaf/krvuqla/kku v/;;u
esaesjsLokLF; vfHkys[k dks ns[kus ds fy;svuqefr dh t:jr ughagksxhA
5- eSa le>rk@le>rh gw¡fdesjhigpkufdlhHkhrhljsi{k dks ;k izdkf'krdjus ds fy;sizdVugha dh
tk;sxhA
6- eSa bl v/;;u ds ifj.kke ds fdlhHkhMkVkdksoSKkfudmns~'; ds fy;sizfrcfU/krugha j[kus ds
fy;slgergwWA
7- eSamijksDr v/;;u esaHkkxysus ds fy;slgergwWA

izfrHkkxh dk uke
------------------------------------------------------------------------------------------------------------------------------
izfrHkkxh ds gLrk{kj --------------------------------------------------------------------------fnukad
--------------------------------
vUos"kd dk uke
--------------------------------------------------------------------------------------------------------------------------------
vUos"kd ds gLrk{kj ------------------------------------------------------------------------- fnukad
--------------------------------
xokg dk uke
------------------------------------------------------------------------------------------------------------------------------------
xokg ds gLrk{kj ------------------------------------------------------------------------------ fnukad
-------------------------------

Page 8 of 8