THESIS PROTOCOL

Efficacy of oral cryotherapy in the prevention of oral mucositis in

children with hematolymphoid malignancies receiving IV

Methotrexate-based chemotherapy:

A Randomized Controlled Trial

Dr. Aditya Gupta

DM Resident
Pediatric Oncology
Department of Pediatrics
All India Institute of Medical Sciences
New Delhi
 THESIS PROTOCOL
Efficacy of oral cryotherapy in the prevention of oral mucositis in children

with hematolymphoid malignancies receiving IV Methotrexate-based

chemotherapy: A Randomized Controlled Trial

Candidate

Dr. Aditya Gupta

DM Resident
Pediatric Oncology
Department of Pediatrics
AIIMS, New Delhi

Cheif Guide

Dr. Jagdish Prasad Meena

Associate Professor
Department of Pediatrics
(Oncology division)
AIIMS, New Delhi

Co Guides

Dr. Aditya Gupta

Associate Professor
Department of Pediatrics
(Oncology division)
AIIMS, New Delhi

Dr. Rachna Seth

Professor
Department of Pediatrics
(Oncology division)
AIIMS, New Delhi

Dr. MA Khan
Additional Professor
Department of Biostatistics
AIIMS, New Delhi
4. Objectives of the study Primary Objective
4.1 To determine the incidence of oral mucositis (O) following IV
methotrexate in Pediatric oncology patients (P) receiving oral
cryotherapy (I) compared to the standard of care (C).

Secondary Objectives
4.2 To determine the severity/ grading of oral mucositis in both
arms

4.3 To investigate the incidence of infectious complications in

both arms

4.4 To determine the risk factors predicting the development of

oral mucositis in both arms

4.5 To determine the incidence and spectrum of various

adverse effects following administration of IV
Methotrexate and risk factors for the same.
5. Why this study is required? • Oral mucositis (OM) is associated with significant
Please provide a brief justification. distress and morbidity.

• It has a significant impact in quality of life leading to

increased cost of treatment and duration of hospital
stay, predisposes to secondary infections, and
adversely affects the prognosis of the cancer.

• There are a limited number of proven safe and

effective preventive measures available for it.

• Meta-analysis in adult showed promising result of

Oral cryotherapy in the prevention of OM receiving
5FU based chemotherapy

• There are limited study for the efficacy of oral

cryotherapy for the prevention of OM in children
post IV methotrexate.

6. Methodology ❖ 6.1. Number of Chemotherapy Cycles: 330 cycles of IV

Methotrexate

❖ 6.2. Inclusion criteria

(a) Pediatric oncology patients aged 5-18 years receiving IV

Methotrexate

6.3. Exclusion criteria

1. Patients having received prior radiotherapy to head/neck
region
2. Patients having Diabetes Mellitus.
3. Patients receiving Methotrexate as a part of GVHD
prophylaxis for HSCT.
 4. Patients with a prior immunosuppressive disorder such as
HIV.

6.4. Study design: Open Labelled Stratified Randomized

Superiority Trial
6.5 Dosages of the drug:
Intervention Arm: Flavored ice cubes placed in mouth for 10
minutes every 8 hours
Control Arm: Betadine Gargles/Daily Tooth Brushing
6.6 Duration of treatment: 3 hours to 42 hours
6.7 Investigation specifically related to project: None
6.8 Permission to use copyrighted Questionnaire/Performa: Not
applicable
6.9. Brief Methodology
• Children, age 5-18 years, with cancer planned to receive
IV methotrexate, presenting to Department of
Pediatrics, AIIMS, New Delhi will be screened for
enrolment.
• After fulfilling inclusion and exclusion criteria, the
parent(s) will be approached for consent after
explaining the advantages and disadvantages of the
study, time duration needed for the trial.
• Oral mucositis will be assessed according to WHO oral
mucositis scale. Baseline information regarding type of
cancers, age/sex, anthropometry and the socio-
economic details will be collected at the time of
enrolment
• Computer generated stratified randomization with
variable block size will be done to ensure an equal
number of participants in each group. Four groups will
be made depending on type of chemotherapy. The
principal investigator shall administer the next serially
numbered therapy (Intervention or control)upon
enrolment of the patient after randomization to either of
the two groups: Intervention (I) group or control (C)
group.
• Allocation concealment will be ensured by using
randomization and identical opaque sealed envelope.
• Both the groups will be doing daily teeth bruising and
betadine mouth gargles (2%) (1:1) 3-4 times a day or
after every meal.
• The physical assessment for oral mucositis will be done
by the investigator on day 5 followed by day 10/14 days
and or whenever there is complain of oral ulcer or
mucositis. Primary and secondary outcomes of the
study will be evaluated, and data analysis will be done
accordingly.
7. Permission from Drug Controller 1. Required 2. Not required
General of India (DCGI) 3. Received 4. Applied when:
8. Permission from DGFT , if required 1. Required 2. N Not required
3. Received 4. A Applied when:

9.
a) Safety measures for proposed a) No safety concerns are expected from administration of
interventions flavored ice cubes. Patients vital would be monitored
regularly and patients would be monitored for any
b) Results of relevant laboratory possible aspiration while sucking on ice cubes
tests
b) No lab tests will be done specific to the study.

c) Result of studies in human

c) Previous studies in adults showed significant reduction in
incidence of oral mucositis in patient on cancer chemotherapy
receiving oral cryotherapy

10. Plans to withdraw standard Yes √ No

therapy
during conduct of research
11. Plan for provision of coverage Free treatment will be provided if any side effect is observed.
for
medical risk (s) during the study
period
12. How you will maintain Information obtained by the study will not be disclosed to any
confidentiality of subject? unauthorized person without their permission.
13 Cost Involved (Approx. in Rs.)
13.1 Cost of investigation 13.1 No investigations are done for the sole purpose of the
13.2 Disposables study
13.3 Implants 13.2 Free, from hospital supply
13.4 drugs / contrasts? 13.3 Not required
13.4 Approximately Rs 5000
Who will bear the costs of the 1. Patient 2. Project 3. Exempted
requirements? (mark √) 4. Other Agencies (Name) √ ICMR/ Self
14. Participant Information Sheet √Attached English version
(mark √ if yes) √ Attached Hindi version
√ Certified that Hindi version is a true translation of
English
15. Participant Informed Consent √Attached English version
Form √Attached Hindi version
(mark √ if yes) √ Certified that Hindi version is a true translation of
English version
16. Whether any work on this X (mark √ if yes, X if no)
project has
started or not?
17.Attached documents 17.1 Covering letter, through proper channel. Yes
(If any) 17.2 Copy of the detailed protocol is mandatory. Yes
17.3 Undertaking that the study shall be done in
accordance
with ICMR and GCP guidelines - Yes
17.4 In case of multicentric study, IEC clearance of
other
centers must be provided – Not applicable
17.5 Definite undertaking as to who will bear the
expenditure of injury related to the project- Yes
17.6 In case an insurance cover is intended, Insurance
certificate
must be provided (as per ICMR guidelines)- Not
applicable
17.7 Permission as mentioned in column 6.9- Not
applicable
17.8 Certificate/undertaking as mentioned in column
16-Yes
17.9: In case of Clinical trials, proof of registration of
Clinical trial with ICMR needs to be submitted –
Protocol
submitted for registration
17.10 Investigator should provide undertaking what
they
will do with the leftover sample tissue- No samples will
be
taken as part of the study.
17.11 Soft copy of all the documents in PDF in a two
separate
files (signed & unsigned) on a single
CD- Yes
17.12 Others: Assent form (English and Hindi version)-
attached
Introduction

Cancers occurring in the paediatric age group [Acute Lymphoblastic Leukaemia(ALL),

Acute Myeloid Leukaemia(AML), Central Nervous System(CNS) Tumours, Neuroblastoma,
Non-Hodgkin’s Lymphoma(NHL) etc] represent an important cause of morbidity and
mortality. In India, cancer is the 9th most common cause of mortality among children in the
5-14 years age group. (1)(2)

However, survival of children suffering from cancer has improved dramatically over the
years with overall survival rate approaching 80% in developed countries. (3)

Chemotherapy remains the mainstay for management of paediatric cancers and refinement of
chemotherapeutic regimens overs the years being an important reason for improvement of
survival.(4)

However , chemotherapy is known to cause many adverse effects including but not limited to
bone marrow suppression, oral mucositis, nausea and vomiting, secondary carcinogenicity,
cardiotoxicity etc.

Oral Mucositis

Oral mucositis is a common adverse effect of chemotherapy for cancers. It refers to

ulceration/inflammation of the oral cavity mucosa. (5)
It significantly impairs the quality of life of patients undergoing chemotherapy – it limits
their ability to tolerate solid/liquid foods leading to poor nutrition/weight loss and the oral
lesion also predisposes to secondary infections.

Pediatric population as compared to adults is more predisposed to development of oral

mucositis.(5) The reported incidence of oral mucositis post conventional chemotherapy is as
high as 50-70% as compared to 20-50% in adults and approaching 90-100% in children
undergoing Hematopoietic stem cell transplantation.(6)(7)

In addition, the predominant type of childhood cancer is haematological, which is proposed

to lead to higher rates of oral mucositis than in patients with solid tumours.(8)

Pathophysiology

Development of Oral mucositis is considered multifactorial and complex – apart from the
antiproliferative action of anti-cancer drugs other events including and not limited to
cell/nuclear damage/inflammatory activation/bacterial colonization are thought to be at
interplay along with various other host/genetic factors contributing to its development.

WHO outlines the natural history of oral mucositis into a total of 5 stages(9):

i. Inflammatory stage- Release of pro-inflammatory cytokines triggering the initial

inflammatory response beginning around 5 days after chemotherapy.
ii. Maximization stage- Enzyme induced apoptosis/cell death along with activation of
various growth factors
iii. Amplification and signalling stage- Further enhancement of cellular injury due to
enhanced pro inflammatory cytokine signalling
 iv. Ulceration stage- mucosal lining gets disrupted, ulceration occurs along with an
increased predisposition to secondary infection
v. Cure stage- Tissue repair at local site with formation of granulation tissue and control
of microflora.

Histologically, the lesions of oral mucositis show mucosal atrophy, with an inflammatory
exudates in the lamina propria which may progress to ulceration with necrotic reaction at the
ulcer base.

Grading of Oral Mucositis

The diagnosis of oral mucositis is clinical, with symptoms such as odynophagia,

stomatodynia, dysphagia being present along with erythema/ulcerations in oral
mucosa/cavity after exposure to antineoplastic drugs

Severity of the oral mucositis lesions is graded using two of the commonly used scales –
WHO or NCI-CTCAE – which are described as follows:

WHO Grading for Oral Mucositis

Grade Description
0 None
I (Mild) Oral soreness, erythema
II (Moderate) Oral erythema, ulcers, solid diet tolerated
III (Severe) Oral ulcers, liquid diet only
IV (Life threatening) Oral alimentation impossible

NCI-CTCAE Grading for Oral Mucositis

Grade Description
Grade 0 None
Grade 1 Painless ulcers, erythema, or mild soreness in the absence of lesions
Grade 2 Painful erythema, oedema, or ulcers but eating or swallowing
possible
Grade 3 Painful erythema, oedema, or ulcers requiring IV hydration
Grade 4 Severe ulceration or requiring parenteral or enteral nutritional
support or prophylactic intubation
Grade 5 Death related to toxicity
The consequences of oral mucositis
Natural history of oral mucositis is well researched and known. It typically begins 3-4 days
post chemotherapy reaching a peak over 7-14 days and then gradually resolves unless
complicated by an infection.

▪ Oral Mucositis significantly impairs the quality of life with patient complaining of pain,
anorexia, and difficulty in swallowing.
▪ Inadequate oral intake secondary to oral mucositis leads to weight loss and
anorexia.(10)
▪ Pain and discomfort associated with oral mucositis affects sleep and mental well-being
of patient.
▪ Oral mucositis in patients is known to increase the risk of bacteraemia and septicaemia
up to 4 times as compared to individuals who do not develop oral mucositis.(11)
▪ Oral mucositis and its associated complications lead to a delay in chemotherapy
affecting survival from the primary diagnosis.
▪ Management of oral mucositis and its associated complications significantly increase
the hospital cost, need for admission and cost of managing the disease. (12)

Management/Prevention of Oral Mucositis

Several modalities have been tried for prevention of oral mucositis post chemotherapy –
albeit with varying level of success and failure. These include and are not limited to are
palifermin, laser therapy, cryotherapy, benzydamine mouthwash, chlorhexidine mouthwash,
glutamine, growth factors like G-CSF/GM CSF mouth rinse, ketamine mouthwash

Oral hygiene protocols: Severe different oral hygiene measures have been used to improve
healing and decrease the antecedent risk of infections post oral mucositis. Though an obious
benefit is unproven, currently there are no recommendations for against their use.(13) A 38%
decrease in incidence of oral mucositis was reported in children using the oral care protocol
compared with children in the control group. (14)

Cytoprotective agents: Several potentially protective agents, including but not limited to
amifostine, sucralfate, and glutamine etc have been tried, but with no obvious efficacy.

Cryotherapy: Several studies have found cryotherapy to be extremely effective in

preventing oral mucositis post-chemotherapy, with the hypothesised mechanism to be
vasoconstriction of oral mucosa vessels that leads to a reduction in the inflow of
inflammatory mediators to the oral mucosa. Cryotherapy is usually carried out by placing ice-
chips/ cubes in the mouth before starting chemotherapy; and has been found to be useful only
for some chemotherapeutic agents, mainly those with a short plasma half-life (such as 5 FU).
(15)

Growth factors: Several growth factors, either as systemic agents or as mouth washes, have
been tried to prevent the development of oral mucositis. The most notable amongst all of
these is palifermin which is a recombinant keratinocyte growth factor, and has strong
evidence for its benefit. It is US FDA approved for the treatment of severe oral mucositis, but
its cost is prohibitive. Oral rinses with other growth factors namely G-CSF and GM-CSF
have been tried, but a benefit of such practise is yet to get established.(16)
Low level Laser Therapy (LLLT):
A meta-analysis has reported that therapeutic LLLT reduces the severity of oral mucositis
and oral pain in paediatric population.(17)

Analgesic mouthwash: These have been tried for the symptomatic benefit, with a few
showing promising results. A recent study suggested the role of Doxepin oral rinse in the
treatment of oral mucositis pain.(18)

Several other agents that have been tried, but have revealed no concrete use include oral 2%
morphine mouthwash, chlorhexidine mouth wash, allopurinol, and oral mucosal protectants
and all these modalities have shown a variable effect on mucositis among various studies.
(19). Definitive treatment is still not approved.

COG supportive care guidelines (2020)

Summary of Recommendations for the Prevention of Oral and Oropharyngeal Mucositis in

Children receiving Treatment for Cancer or undergoing Hematopoietic Stem Cell
Transplantation.(20)

Recommendations Strength of
recommendations
What prophylactic interventions are effective at preventing or reducing the severity of
oral and oropharyngeal mucositis in children (0-18 years) receiving treatment for
cancer or undergoing hematopoietic stem cell transplantation?
We suggest that cryotherapy may be offered to cooperative Weak recommendation,
children receiving chemotherapy or HSCT conditioning with Moderate quality
regimens associated with a high rate of mucositis. evidence
We suggest that low-level light therapy may be offered to Weak recommendation,
cooperative children receiving chemotherapy or HSCT High quality evidence
conditioning with regimens associated with a high rate of
mucositis.
We suggest that keratinocyte growth factor may be offered to Weak recommendation
children receiving HSCT conditioning with regimens associated High quality evidence
with a high rate of severe mucositis.
Methotrexate and Oral Mucositis

Intravenous Methotrexate either given as high dose methotrexate(>500mg/m2) infusion over

24-36 hours or in escalating doses (Capizzi Methotrexate) forms the backbone of therapy for
various pediatric malignancies namely ALL, Non-Hodgkin’s Lymphoma and Osteosarcoma.
However, one of the most commonly occurring toxicities following methotrexate
administration is development of oral mucositis.
The reported incidence of oral mucositis following high dose methotrexate is in the range of
40-60% with incidence of severe mucositis in the range of 15-25% following each
cycle/infusion of methotrexate. (21)(22)
This contributes to significant morbidity in the form of requirement of tube
feeding/parenteral nutrition/ development of secondary infection and antecedent use of
Antibiotics along with hospital admissions and sometimes death.

Role of Cryotherapy

Various agents have been tried to either prevent/decrease the overall incidence of oral
mucositis or decrease the severity of its symptoms.
These include but are not limited to amifostine /palifermin/chlorhexidine
mouthwash/ketamine etc.
Oral cryotherapy as an intervention/modality has been used for adult patients with the
postulated mechanism to be vasoconstriction leading to decreased influx of both
inflammatory mediators and antineoplastic drug to oral mucosa.
Oral cryotherapy involves placing ice chips/cubes in the mouth before/during/after
chemotherapy.
It has shown to be effective for adult patients receiving 5 Fluorouracil/Melphalan; decreasing
rates of oral mucositis by up to 50%.(23)

Oral Cryotherapy for Methotrexate

While chemotherapy has been used in adult patients receiving 5 FU/Melphalan there is a
paucity of data/clinical trials regarding its effectiveness for IV methotrexate or any clinical
trial in children evaluating its efficacy. (24)
Children as compared to adults are more prone to develop oral mucositis though lesions tend
to heal faster too as compared to adults. (5)

Review of Literature

Online medical databases Pubmed, Google Scholar and MEDLINE were searched With the
key words “Cryotherapy” +”Mucositis” + “Methotrexate” along with search for terms.
Search revealed 470 items out which 62 were randomised controlled trials and 14 meta-
analysis were found. There were only 3 trials in paediatric age group – two in the setting of
HSCT and a single one in Chemotherapy.
Study title Study Results Conclusion
Author/journal design

Cryotherapy in the Randomize The incidence of severe Cryotherapy during MTX

prevention of oral d (grade 3-4) oral administration does not
mucositis in Controlled mucositis, was reduce severe oral mucositis
patients receiving Trial comparable in patients in patients undergoing
low-dose 130 receiving or not myeloablative allogeneic
methotrexate patients cryotherapy HSCT.
following Blinding No difference was
myeloablative Unclear observed in the incidence
allogeneic stem cell of oral mucositis grade 2-
transplantation: a 4 and the duration of oral
prospective mucositis grade 3-4 or 2-
randomized study 4
of the Gruppo
Italiano Trapianto
di Midollo Osseo
nurses group
E Gori et al Bone
Marrow
Transplantation
(2007) 39, 347–352
(24)

Interventions for Adults receiving

preventing oral Meta - fluorouracil-based Oral cryotherapy leads to
mucositis in analysis (5FU) chemotherapy for large reductions in oral
patients with cancer solid cancers mucositis of all severities in
receiving treatment: Oral cryotherapy adults receiving 5FU for
oral cryotherapy. probably reduces oral solid cancers. We are less
Riley et al. mucositis of any severity confident in the ability of
Cochrane Database (RR 0.61, 95% CI 0.52 to oral cryotherapy to reduce
of Systematic 0.72, 5 studies, 444 oral mucositis in adults
Reviews 2015, Issue analysed, moderate receiving high-dose
12. Art. No.: quality evidence melphalan before HSCT
CD011552.(23) Adults receiving high-
dose melphalan-based
chemotherapy before .
haematopoietic stem cell
transplantation (HSCT)
Oral cryotherapy may
reduce oral mucositis of
any severity (RR 0.59,
95% CI 0.35 to 1.01, 5
studies, 270 analysed, low
quality evidence).
Efficacy of Oral Patients treated with oral
Cryotherapy in the cryotherapy were Oral cryotherapy is effective
Prevention of Oral Meta- associated with a in preventing oral mucositis
Mucositis analysis significantly lower risk of in patients undergoing
Associated with developing oral mucositis chemotherapy for the
Cancer of any grade (risk ratio management of solid
Chemotherapy: (RR), 0.67 (95% CI: malignancies. The use of
Systematic Review 0.56–0.81, p < 0.05)) oral cryotherapy in
with Meta-Analysis preventing oral mucositis in
and Trial Sequential bone marrow transplantation
Analysis settings showed promising
Gopinath et al Curr. efficacy, but the evidence is
Oncol. 2021, 28, not conclusive and requires
2852–2867. h more high-quality
randomized controlled trials
(25)
Prevention of oral Randomize Forty-nine children (mean The feasibility criteria were
mucositis with d age 10.5 years) were not met, and the RCT could
cryotherapy in Controlled included in analysis not show that
children undergoing Trial (OC = 26, control = 23). Oralcryotherapy reduces the
hematopoietic stem 49 patients The feasibility criteria incidence of severe oral
cell Blinding were not met. mucositis
transplantations—a Unclear Compliance was poor,
feasibility study and especially for the younger
randomized children, and only 15
controlled trial children (58%) used OC
Kamvsag et al as instructed.
Supportive Care in
Cancer (2020)
28:4869–4879(26)

Effect of flavoured Randomize There was highly Cryotherapy inhibits

ice chips in d significant decrease in the methotrexate induced
reduction of oral Controlled occurrence of oral stomatitis in a statistically
mucositis among Trial mucositis observed in significant manner. Though
children receiving 40 patients both the groups but more both plain ice cube as well
chemotherapy Blinding in the children receiving as flavoured ice cubes made
Mishra et al 2017 Unclear flavoured ice chips at up of honey and tulsi is
International p<0.001 on 5th day and effective in reduction oral
Journal of 15th day of assessment mucositis but study findings
Pharmaceutical than the plain ice chip reveals that the flavoured
Sciences Review ice cubes (honey and tulsi)
and Research is more effective than plain
March 2017 ice cubes in reduction of
(27) oral mucositis in the patient
receiving methotrexate
Rationale for Study

Oral mucositis contributes to significant morbidity amongst pediatric cancer patients

undergoing systemic chemotherapy.
Cryotherapy offers to be a simple yet cost effective modality for prevention of the same.
Its role in decreasing the incidence of oral mucositis has conclusively been proven for adult
patients receiving 5-FU/Melphalan.
However, no study has been done to evaluate efficacy of oral cryotherapy for either
methotrexate in reducing the incidence of oral mucositis or evaluating its efficacy/safety and
tolerability in children.

Research Question

Whether oral cryotherapy (I) is useful in the reduction of oral mucositis in children (5-18
years of age) on cancer chemotherapy receiving IV methotrexate (P) and causes reduction in
incidence of oral mucositis following the same (O) as compared to standard of care (C)

Research Hypothesis

Oral cryotherapy is useful in reduction of incidence of oral mucositis in children on cancer

chemotherapy following administration of IV Methotrexate

Objectives

Primary

To determine and compare the incidence of oral mucositis following IV methotrexate in

paediatric oncology patients receiving oral cryotherapy versus standard of care.

Secondary
1. To determine the severity/ grading of oral mucositis in both arms
2. To determine the incidence of Infectious complications in both arms
3. To determine the risk factors predicting the development of oral mucositis in both
arms
4. To determine the incidence and spectrum of various adverse effects following
administration of IV Methotrexate and risk factors for the same.

Study design: Two arm parallel Randomised controlled Trial

Study setting: Department of Pediatrics

Study duration: 1year 9 months , Jan 2021 – September 2022

Inclusion criteria

1. Paediatric oncology patients aged 5-18 years receiving IV Methotrexate

Exclusion criteria
1. Consent not given
2. Patients having received prior radiotherapy to head/neck region
3. Patients having Diabetes Mellitus.
4. Patients receiving Methotrexate as a part of GVHD prophylaxis for HSCT.
5. Patients with a prior immunosuppressive disorder such as HIV.

Definitions

Oral Mucositis
Ulceration/inflammation of the oral cavity mucosa.

Febrile Neutropenia
Fever >100.4°F (>38°C) for 1 hour or a single reading of 101°F (38.3°C ) with an absolute
neutrophil count (ANC) of ≤500 cells/microliter, or an ANC of ≤1000 cells/microliter with a
projected nadir of ≤500 cells/microliter.

Pneumonia - pathological chest X-ray and/or computed tomography scan accompanied signs
and symptoms of lower respiratory tract infection(fever, chest pain, cough)

Bacteraemia
Fever with a positive blood culture for bacteria isolated from peripheral blood or from the
central venous indwelling catheter.

Neutropenic Enterocolitis
Presence of neutropenia (ANC < 500 × 106 cells/L) , bowel wall thickening of >4 mm on
radiographic imaging, along with clinical features compatible with enterocolitis and the
exclusion of other diagnoses such as veno occlusive disease or other abdominal syndromes

Sepsis
The systemic inflammatory response syndrome in the presence of suspected or proven
infection constitutes sepsis.

Screening and enrolment

All children, 5-18 years of age, with cancer, who are scheduled to receive IV methotrexate
will be screened for enrolment.
The details of all patients eligible for planned intervention would be entered in the screening
form. After meeting the inclusion criteria, and applying the exclusion criteria, the parent(s)
would be approached for consent. At the time of getting consent, the parents will be
explained regarding the pros and cons of the study. After obtaining a written consent of either
of the parents, along with that of a witness, the patient will be enrolled in the study. The
consent will be taken as the signature of either of the parents, or the left thumb print
impression for the parent(s) who can’t read or write.
Baseline information regarding the age, sex, anthropometry, demographics, type of
malignancy, type of chemotherapy, date of last chemotherapy, socio-demographic details,
anthropometry , examination findings will be collected at the time of enrolment .

Randomisation and Blinding

The children going to receive a cycle of chemotherapy will be randomised into two arms after
enrolment into the study: Intervention (I) and control (C) arm.

Each cycle of IV methotrexate would be randomised, hence a patient can be enrolled multiple
times into different arms.

We shall use computer generated stratified block randomization with variable block size, to
ensure an equal number of cycles in each arm. The participants and the investigators will not
be blinded.

Allocation of the patients to receive the treatments would be done by sequentially numbered
opaque sealed envelope. The envelopes would be prepared by a person not associated with
the conduct of the study. The envelopes would be sequentially opened at the time of
randomisation and enrolment.

Intervention

Patients enrolled into the intervention arm would be asked to suck on flavoured ice cubes in
their mouth.

Patients receiving Capizzi methotrexate over 1 hour would be asked to hold flavoured ice
cubes 5 min prior to infusion, another ice cube during 1 hour infusion as long as its
possible/comfortable and then every 1 hour for a duration of 10 minutes for 3 hours

Patients receiving high dose Methotrexate over 24-36 hours would be asked to intermittently
suck on flavoured ice cubes in mouth during the initial bolus infusion over 30 min then every
8 hours for a minimum of 10 minutes to as long as comfortable till the end of infusion and till
patient starts with intravenous leucovorin rescue.

Patients enrolled into the control arm would be asked to follow the unit oral hygiene protocol
with regular brushing with soft tooth bristles and twice a day betadine gargles.

Patients would be followed up at the end of infusion, start of oral/IV leucovorin and on day 5
and day 10 along with any self-report for development of oral mucositis and till 14 days from
the randomization for secondary outcomes.

Each patient can be enrolled multiple times into the study after taking consent. The same
patient can be enrolled into either arm during further enrolment at time of randomisation.
 Assessment

Objective Outcome variable Method of measurement

Determination of rate of oral mucositis Development of oral mucositis Clinical Examination
in control arm and intervention arm

Determination of severity/ grading of Severity of oral mucositis WHO criteria for grading of
oral mucositis in both arms. oral Mucositis lesions.

Determination of rate of Febrile Development of febrile Complete Blood Counts

neutropenia/Infectious complications in neutropenia/Infectious with differential counts,
both arms complications Axillary Temperature,
Clinical Examination, Blood
Cultures, USG Abdomen
Determination of incidence of various Development of a known Clinical Examination , Liver
adverse effects following IV adverse effect such as Acute function tests, Renal
methotrexate Kidney Injury, Function tests, Complete
Thrombocytopenia, Anaemia blood counts.
requiring Blood transfusion

Sample Size Estimation

Reported incidence of any grade of oral mucositis following each cycle of IV methotrexate is
in the range of 40-50%. We propose that our intervention (oral cryotherapy) would result in
40 % reduction of incidence of oral mucositis from 40 % bringing it down to 25 %. To detect
the difference of 15% for 80 % power and 5 %level of significance with two sided test, the
required sample size for our study is approximately 165 cycles in each arm. So, total sample
size for our study is 330 cycles of IV methotrexate.
Statistical analysis

To describe patient’s characteristics (demographic and clinical), the data will be summarized
and analyzed using statistical package for social sciences (SPSS, version 24.0) or STATA
(version 14) software. Continuous data will be expressed as mean ± SD or Median (IQR) and
Qualitative data will be expressed as number and percentage as appropriate. Data will be
tested for normality using the Kolmogorov–Smirnov test. Student t-test will be used to
compare the normal variables between the groups, whereas the Mann–Whitney U-test test
will perform to compare the non-normal variables between the groups. For comparison of
categorical data, the Chi-square/Fisher’s exact test will be performed to see the association. A
value of p less than 0.05 will be considered to represent statistical significance of the study.

General

Analysis will be performed according to the CONSORT statement. Both intention to treat
and per protocol analysis will be performed. Continuous variables will be summarized with
standard descriptive statistics including means, standard deviations, median and ranges.
Categorical variables will be summarized using means, frequencies and percentage, 95%
confidence interval will be provided for descriptive statistics as warranted. The primary
objective of the study (difference in the incidence of oral mucositis ) between the two arms
will be compared by estimating effect size and determining its 95% CI. Differences among
comparison groups in continuous variable will be estimated using student t-test for normal
distribution variables and using Wilcoxon rank sum test for variables that do not follow
normal distribution. Differences in categorical variables will be assessed using Chi-Square
test or Fisher Exact test. A p-value of <0.05 will be considered significant.

Data management

Data will be recorded on the case record form/proforma (CRF) by the investigator. Results of
laboratory investigations and follow up visits will also be recorded on the CRF. The original
signed consent form for each participant will also be kept with the CRF. The data will be
transferred from the CRF to electronic format by the primary investigator and will be
checked by Co-investigators for its accuracy. The research records maintained by the
investigator will be considered as the source document for the purpose of auditing the study.
STUDY FLOW
REFERENCES

1. International Childhood Cancer Day: Much remains to be done to fight childhood cancer
[Internet]. Available from: https://www.iarc.who.int/wp-
content/uploads/2018/07/pr241_E.pdf

2. SUMMARY- REPORT on CAUSES of DEATH: 2001-03 in INDIA [Internet].

Available from:
https://www.censusindia.gov.in/vital_statistics/summary_report_death_01_03.pdf

3. Smith MA, Seibel NL, Altekruse SF, Ries LAG, Melbert DL, O’Leary M, et al.
Outcomes for Children and Adolescents With Cancer: Challenges for the Twenty-First
Century. J Clin Oncol. 2010 May 20;28(15):2625–34.

4. Adamson PC. Improving the outcome for children with cancer: Development of targeted
new agents. CA Cancer J Clin. 2015 Jun;65(3):212–20.

5. Nemes J, Jenei Á, Márton I. A gyermekkori malignus kórképek kemoterápiájának

leggyakoribb mellékhatása, az oralis mucositis. Irodalmi áttekintés. Orv Hetil. 2018
Apr;159(13):495–502.

6. Fayle SA, Curzon ME. Oral complications in pediatric oncology patients. Pediatr Dent.
1991 Oct;13(5):289–95.

7. Vokurka S, Steinerova K, Karas M, Koza V. Characteristics and risk factors of oral

mucositis after allogeneic stem cell transplantation with FLU/MEL conditioning regimen
in context with BU/CY2. Bone Marrow Transplant. 2009 Nov;44(9):601–5.

8. Childers NK, Stinnett EA, Wheeler P, Wright JT, Castleberry RP, Dasanayake AP. Oral
complications in children with cancer. Oral Surg Oral Med Oral Pathol. 1993
Jan;75(1):41–7.

9. Sonis ST. The pathobiology of mucositis. Nat Rev Cancer. 2004 Apr;4(4):277–84.

10. Bressan V, Stevanin S, Bianchi M, Aleo G, Bagnasco A, Sasso L. The effects of

swallowing disorders, dysgeusia, oral mucositis and xerostomia on nutritional status, oral
intake and weight loss in head and neck cancer patients: A systematic review. Cancer
Treat Rev. 2016 Apr;45:105–19.

11. González-Barca E, Fernández-Sevilla A, Carratalá J, Grañena A, Gudiol F. Prospective

study of 288 episodes of bacteremia in neutropenic cancer patients in a single institution.
Eur J Clin Microbiol Infect Dis. 1996 Apr;15(4):291–6.

12. Sonis ST. Oral Mucositis in Head and Neck Cancer: Risk, Biology, and Management.
Am Soc Clin Oncol Educ Book. 2013 May;(33):e236–40.

13. McGuire DB, Correa MEP, Johnson J, Wienandts P. The role of basic oral care and good
clinical practice principles in the management of oral mucositis. Support Care Cancer.
2006 Jun;14(6):541–7.
14. Cheng KKF, Molassiotis A, Chang AM, Wai WC, Cheung SS. Evaluation of an oral care
protocol intervention in the prevention of chemotherapy-induced oral mucositis in
paediatric cancer patients. Eur J Cancer. 2001 Nov;37(16):2056–63.

15. For the Mucositis Study Group of the Multinational Association of Supportive Care in
Cancer/International Society of Oral Oncology (MASCC/ISOO), Peterson DE, Öhrn K,
Bowen J, Fliedner M, Lees J, et al. Systematic review of oral cryotherapy for
management of oral mucositis caused by cancer therapy. Support Care Cancer. 2013
Jan;21(1):327–32.

16. For the Mucositis Study Group of the Multinational Association of Supportive Care in
Cancer/International Society of Oral Oncology (MASCC/ISOO), Raber-Durlacher JE,
von Bültzingslöwen I, Logan RM, Bowen J, Al-Azri AR, et al. Systematic review of
cytokines and growth factors for the management of oral mucositis in cancer patients.
Support Care Cancer. 2013 Jan;21(1):343–55.

17. He M, Zhang B, Shen N, Wu N, Sun J. A systematic review and meta-analysis of the

effect of low-level laser therapy (LLLT) on chemotherapy-induced oral mucositis in
pediatric and young patients. Eur J Pediatr. 2018 Jan;177(1):7–17.

18. Leenstra JL, Miller RC, Qin R, Martenson JA, Dornfeld KJ, Bearden JD, et al. Doxepin
rinse versus placebo in the treatment of acute oral mucositis pain in patients receiving
head and neck radiotherapy with or without chemotherapy: a phase III, randomized,
double-blind trial (NCCTG-N09C6 [Alliance]). J Clin Oncol Off J Am Soc Clin Oncol.
2014 May 20;32(15):1571–7.

19. Dodd MJ, Dibble SL, Miaskowski C, MacPhail L, Greenspan D, Paul SM, et al.
Randomized clinical trial of the effectiveness of 3 commonly used mouthwashes to treat
chemotherapy-induced mucositis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod.
2000 Jul;90(1):39–47.

20. Available from:

https://childrensoncologygroup.org/downloads/COG_SC_Guideline_Document.pdf

21. Maiguma T, Hayashi Y, Ueshima S, Kaji H, Egawa T, Chayama K, et al. Relationship

between oral mucositis and high-dose methotrexate therapy in pediatric acute
lymphoblastic leukemia. Int J Clin Pharmacol Ther. 2008 Nov 1;46(11):584–90.

22. Mandal P, Samaddar S, Chandra J, Parakh N, Goel M. Adverse effects with intravenous
methotrexate in children with acute lymphoblastic leukemia/lymphoma: a retrospective
study. Indian J Hematol Blood Transfus Off J Indian Soc Hematol Blood Transfus. 2020
Jul;36(3):498–504.

23. Riley P, Glenny A-M, Worthington HV, Littlewood A, Clarkson JE, McCabe MG.
Interventions for preventing oral mucositis in patients with cancer receiving treatment:
oral cryotherapy. Cochrane Database Syst Rev. 2015 Dec 23;(12):CD011552.

24. Gori E, Arpinati M, Bonifazi F, Errico A, Mega A, Alberani F, et al. Cryotherapy in the
prevention of oral mucositis in patients receiving low-dose methotrexate following
myeloablative allogeneic stem cell transplantation: a prospective randomized study of the
 Gruppo Italiano Trapianto di Midollo Osseo nurses group. Bone Marrow Transplant.
2007 Mar;39(6):347–52.

25. Al-Rudayni AHM, Gopinath D, Maharajan MK, Veettil SK, Menon RK. Efficacy of Oral
Cryotherapy in the Prevention of Oral Mucositis Associated with Cancer Chemotherapy:
Systematic Review with Meta-Analysis and Trial Sequential Analysis. Curr Oncol. 2021
Jul 29;28(4):2852–67.

26. Kamsvåg T, Svanberg A, Legert KG, Arvidson J, von Essen L, Mellgren K, et al.
Prevention of oral mucositis with cryotherapy in children undergoing hematopoietic stem
cell transplantations-a feasibility study and randomized controlled trial. Support Care
Cancer Off J Multinatl Assoc Support Care Cancer. 2020 Oct;28(10):4869–79.

27. Effect of Flavored (Honey and Tulsi) Ice Chips on Reduction of Oral Mucositis among
Children Receiving Chemo Therapy [Internet]. Available from:
https://globalresearchonline.net/journalcontents/v43-1/07.pdf
 Study Proforma

S. No. I C

Date of enrollment………………………

Name.........................................Age..............Sex.............Weight........Height........

UHID NO...............................................POC NO.............................

Address:…………………….

Parent’s /guardian occupation: Education:

Contact no

Socioeconomic status Upper (I) Upper Middle/lower Lower/ upper Lower

(Modified Kuppuswami middle (II) middle (III) Lower (IV) (V)
scale)

Residence Urban Rural Approximate distance Approx. time to reach to AIIMS

from AIIMS

Primary Hematological Solid Other

Diagnosis

Chemotherapy Name of Protocol Cycle/course of protocol

Details

First chemotherapy cycle Yes No

Last chemotherapy received on <7 days >7days

 H/o Yes/ no Before from onset of OM Site Doses
radiation
< 7 days >7 days

Name of last chemotherapy drugs 1.

2.
3.
4.
5.

Details of current IV Methotrexate

S. Name of agents Doses Date of Date of Duration
N start finish
1.

Stratified randomization

A B C D
B-ALL & B-LBL T-ALL & T- ALL Relapse NHL (BFM
LBL protocol-
getting block
therapy)
MTX: @ 3 gm/m2 MTX: @ 5 Mtx @1g/m2 MTX: @ 5
gm/m2 gm/m2

I C I C I C I C

Mucositis Yes/No Date of D- of Date Duration

Reported report therapy OM
being
passive
WHO-OM 0 Grade-1 Grade-2 Grade 3 Grade 4
grading None Oral Oral erythema, Oral ulcers, Oral
soreness, ulcers, solid diet liquid diet only alimentation
erythema tolerated impossible

Standard therapy:
Oral hygiene Yes/No Frequency
1. Betadine gargle
(2%)
2. Daily brushing

Febrile neutropenia Yes/no Date of report

Need for Yes/ no Indication Outcome

hospitalization

Delays in administration of Yes No How many days

chemotherapy

Day 5 CBC
Day 5
LFT/RFT

Anemia/thrombocytopenia Requiring Transfusion

AKI(Cr>!.5X)

ALT/AST Elevation >10X

Follow up at D- Alive Death Cause of death

10/14
 Patient Information Sheet (PIS) (for Legally Appointed Representative (LAR)]

1. Title of the Study/Project: Efficacy of oral cryotherapy in the prevention of oral mucositis in
children with hematolymphoid malignancies receiving IV Methotrexate-based chemotherapy: A
Randomized Controlled Trial
2. Name of Principal Investigator: Dr. Aditya Gupta Phone No: 9990350017
3. Name of Chief Guide: Dr. Jagdish Prasad Meena, Phone No: 011-2659 3619
4. Aim of the research: To determine whether placing ice cubes in mouth(oral cryotherapy) while
receiving the drug Methotrexate as a part of cancer chemotherapy for children would result in
decrease in incidence of oral mucositis(mouth pain and mouth ulcers) as compared to doing
betadine gargles and daily brushing.
5. Methods: Your child would be randomised to receive either ice cubes or do betadine gargles
along with daily tooth brushing. The randomisation would be based on chance and your child has
equal chance of going into either. Your child will be asked to suck on ice cubes intermittently
every 6 hour for 1 day or every hour for 10 minutes for 3 hours or would be asked to follow the
routine betadine gargles and daily tooth brushing. Your child will be evaluated by calling to OPD
5 days after receiving methotrexate and after 10 or 14 days after receiving methotrexate. He/she
would be evaluated for development of oral mucositis i.e. mouth ulcers/mouth pain.
6. Expected duration of the subject participation: Your child would be followed up daily
telephonically along with scheduled OPD visits 5 days after receiving Methotrexate and 10/14
days after receiving Methotrexate.
7. The benefits to be expected from the research to the subject or to others: The study will help
to determine the effect of using ice cube (oral cryotherapy) on decreasing the incidence of oral
mucositis(mouth ulcers/pain) in children with cancer receiving IV methotrexate. This will also
help to find a better and safer alternative for the prevention of mucositis(Mouth ulcers/pain),
which will be cost effective and having lesser side effects. Your child will be provided the ice
cubes free of cost during the study. The cost of your child’s usual treatment will be borne by you
as before.
8. Any risk to the child associated with the study: This is a 14 days study that usually causes no
harm to your child. Your child will be asked to suck on ice cubes intermittently every 6 hour for 1
day or every hour for 10 minutes for 3 hours. Vital parameters of your child will be recorded. No
blood sample will be drawn for this study.
9. Maintenance of confidentiality of records: Confidentiality of records will be maintained.
10. Provision of free treatment for research-related injury: Free treatment will be provided if any
side effect is observed.
11. Compensation of subjects for disability or death resulting from such injury: It will not be
provided. However, the child would be treated free of cost if any side effect is observed during
treatment.
12. Your freedom to participate and to withdraw from the research at any time without penalty
or loss of benefits to which you would otherwise be entitled. In case you refuse to participate
or withdraw consent at a later date, it will not jeopardize your child’s care, there will be no
prejudice against your child and he/she will continue to receive the best available facilities at
AIIMS, New Delhi.
13. Costs and sources of investigations, disposables, implants, and drugs/contrast media: You
will not pay any fee for study. Ice cubes under the study will be provided free of cost.
 भागीदारी जानकारी शीट (कानन
ू ी रूप से ननयक्
ु त प्रनतननधि के लिए)

1. अनस
ु न्धान शीर्षक: मेथोट्रे क्सेट-आिारित कीमोथेिेपी प्राप्त किने वािे कैं सि बच्चों में
मौखिक म्यक
ू ोसाइटटस की िोकथाम में मौखिक क्रायोथेिेपी की प्रभावकारिता: एक
यादृच्च्िक ननयंत्रित पिीक्षण
2. मख्
ु य अन्वेर्क का नाम: डॉ आटित्य गप्ु ता, फोन नंबि: 9990350017
3. मख्
ु य मागष दशषक का नाम: डॉ जगिीश प्रसाि मीना, फोन नंबि: 011-2659-3619
4. अनुसंधान का उद्दे श्य: यह ननिाारित किने के लिए कक बच्चों के लिए कैं सि कीमोथेिेपी
के एक भाग के रूप में मेथोट्रे क्सेट िवा प्राप्त किते समय बीटाडाइन गिािे किने औि
िै ननक ब्रश किने की तुिना में मुंह में बफा के टुकडे (मौखिक क्रायोथेिेपी) ििने से
मौखिक म्यूकोसाइटटस (मुंह ििा औि मुंह के िािे) की घटनाओं में कमी आएगी की नहीं.
5. ववधधयााँ: आपके बच्चे को या तो बफा के टुकडे प्राप्त किने के लिए यादृच्च्िक ककया
जाएगा या िै ननक टूथ ब्रलशंग के साथ बीटाडीन गिािे किना होगा। िैंडमाइजेशन मौके पि
आिारित होगा औि आपके बच्चे के पास इनमें से ककसी एक में जाने की समान
संभावना है। आपके बच्चे को 1 टिन के लिए हि 6 घंटे में रुक-रुक कि या हि घंटे 10
लमनट के लिए 3 घंटे के लिए बफा के टुकडे चूसने के लिए कहा जाएगा या ननयलमत
बीटाडाइन गागाल्स औि िै ननक टूथ ब्रलशंग का पािन किने के लिए कहा जाएगा।
मेथोट्रे क्सेट प्राप्त किने के 5 टिन बाि औि मेथोट्रे क्सेट प्राप्त किने के 10 या 14 टिनों
के बाि ओपीडी में कॉि किके आपके बच्चे का मूल्यांकन ककया जाएगा। मौखिक
म्यूकोसाइटटस यानी मुंह के िािे/मुंह में ििा के ववकास के लिए उसका मूल्यांकन ककया
जाएगा
6. भाग लेने वाले की भागीदारी की अपेक्षित अवधध: मेथोट्रे क्सेट प्राप्त किने के 5 टिन बाि
औि मेथोट्रे क्सेट प्राप्त किने के 10/14 टिनों के बाि अनुसूधचत ओपीडी यािाओं के साथ
आप बच्चे का िै ननक टे िीफोन पि पािन ककया जाएगा।
7. शोध से भाग लेने वाले या दस
ू रों के ललए अपेक्षित लाभ: इस अध्ययन से यह पता
िगाने में मिि लमिेगी कक मेथोट्रे क्सेट प्राप्त किने वािे कैं सि से पीडडत बच्चों में ओिि
म्यक
ू ोसाइटटस (मंह
ु के िािे/ििा) की घटनाओं को कम किने पि बफा के टुकडे (मौखिक
क्रायोथेिेपी) का उपयोग किने के प्रभाव को कैसे कम ककया जाए। यह म्यक
ू ोसाइटटस (मंह
ु
के िािों/ििा) की िोकथाम के लिए एक बेहति औि सिु क्षक्षत ववकल्प िोजने में भी मिि
किे गा, जो कक िागत प्रभावी औि कम िष्प्ु प्रभाव वािा होगा। अध्ययन के िौिान आपको
बफा के टुकडे नन:शल्
ु क प्रिान ककए जाएंगे। आपके सामान्य इिाज का िचा पहिे की
तिह आप वहन किें गे।
8. अध्ययन से जुडे बच्चे को कोई खतरा: यह 14 टिनों का अध्ययन है जो आमतौि पि
आपके बच्चे को कोई नुकसान नहीं पहुंचाता है। आपके बच्चे को 1 टिन के लिए हि 6
 घंटे में रुक-रुक कि बफा के टुकडे चस
ू ने के लिए या हि घंटे 10 लमनट के लिए 3 घंटे
तक चस
ू ने के लिए कहा जाएगा। आपके बच्चे के महत्वपण
ू ा मापिं डों को िजा ककया
जाएगा। इस अध्ययन के लिए ककसी िक्त का नमन
ू ा नहीं लिया जाएगा।
9. मरीज़ के अलभलेखों की गोपनीयता का रखरखाव: मिीज़ के अलभिेिों की गोपनीयता
बनाए ििी जाएगी।
10. अनस
ु ंधान से संबंधधत चोट के ललए मफ्
ु त उपचार का प्रावधान: यटि कोई साइड इफेक्ट
िे िा जाता है तो मफ्
ु त उपचाि प्रिान ककया जाएगा।
11. ऐसी चोट के पररणामस्वरूप ववकलांगता या मत्ृ यु के ललए ववर्यों का मुआवजा: यह इस
अध्ययन के लिए िागू नहीं है औि इसे प्रिान नहीं ककया जाएगा। यटि कोई साइड
इफेक्ट िे िा जाता है तो मुफ्त उपचाि प्रिान ककया जाएगा।
12. आप स्वतंत्र हैं ककसी भी समय दं ड या लाभ के नक
ु सान के बबना अनुसंधान से हटना
और वापस लेना जो आप अन्यथा हकदार होंगे। यटि आप बाि की तािीि में सहमनत में
भाग िेने या वापस िेने से इनकाि किते हैं, तो यह आपके िोगी की िे िभाि में कोई
ितिे नहीं होगा, आपके िोगी के खििाफ कोई पव
ू ााग्रह नहीं होगा औि वह एम्स, नई
टिल्िी में सवोत्तम उपिब्ि सुवविाएं प्राप्त होती िहें गी।
13. लागत और जांच के स्रोत, डडस्पोजेबल, प्रत्यारोपण, और ड्रग्स / कोंट्रास्ट मीडडया: आप
अध्ययन के लिए कोई शुल्क नहीं िें गे। अध्ययन के तहत बफा के टुकडे को मुफ्त में प्रिान
ककया जाएगा।
PARTICIPANT INFORMED CONSENT FORM (PICF) (for Legally Appointed
Representative (LAR)]

Protocol / Study number: ______________________

Participant identification number for this trial: _______________________
Title of project: Efficacy of oral cryotherapy in the prevention of oral mucositis in
children with hematolymphoid malignancies receiving IV Methotrexate-based chemotherapy:
A Randomized Controlled Trial

Name of Principal Investigator: Dr Aditya Gupta, Phone No: 9990350017

Name of Chief Guide: Dr Jagdish Prasad Meena, Phone No: 011-2659 3619

The contents of the information sheet dated………… that was provided, have been read
carefully by me / explained in detail to me, in a language that I comprehend, and I have fully
understood the contents. I confirm that I have had the opportunity to ask questions.
The nature and purpose of the study and its potential risks / benefits and expected duration of
the study, and other relevant details of the study have been explained to me in detail. I
understand that my child’s participation is voluntary and that I am free to withdraw my child
at any time, without giving any reason, without my child’s medical care or legal right being
affected.
I understand that the information collected about my child from his/her participation in this
research and sections of any of my child’s medical notes may be looked at by responsible
individuals from AIIMS. I give permission for these individuals to have access to my child’s
records.
Please initial box
(Subject)
(i) I confirm that I have read and understood the information sheet dated [ ]
__________for the above study and have had the opportunity to ask questions.
(ii) I understand that my child’s participation in the study is voluntary and that I [ ]
am free to withdraw my child at any time, without giving any reason, without my
medical care or legal rights being affected.
(iii) I understand that the Sponsor of the clinical trial, others working on the [ ]
Sponsor’s behalf, the Ethics Committee and the regulatory authorities will not
need my permission to look at my child’s health records both in respect of the
current study and any further research that may be conducted in relation to it,
even if I withdraw my child from the trial. I agree to this access. However, I
understand that my child’s identity will not be revealed in any information
released to third parties or published.
(iv) I agree not to restrict the use of any data or results that arise from this study [ ]
provided such a use is only for scientific purpose(s).
(v) I agree to take part of my child in the above study. [ ]

---------------------------------------------
(Signatures / Left Thumb Impression of L.A.R.) Date: Place:
Name of person giving consent: ________________________________
Relation with participant: ____________________________________
Name of the Participant: ____________________________________
Son / Daughter / Spouse of:__________________________________
Date of Birth / Age: ____________________________________
Complete postal address: _____________________________________
Qualification: _____________________________________
Occupation: Student/Self-employed/Service/Housewife/Others (tick as appropriate).
Annual Income of the subject: _____________________________________
Annual Income of the father: _____________________________________
Name and address of the nominee(s) and his relation to the subject (for the purpose of
compensation in case of trial related death):……………………… ………………………
………………………………………………………………………………..

This is to certify that the above consent has been obtained in my presence.

------------------------------
Signatures of the Principal Investigator Date:
Place:

1) Witness – 1 2) Witness – 2
------------------------------ --------------------------------
Signatures Signatures

Name: Name:

Address: Address:
 भागीदारी सूधचत सहमतत प्रपत्र (कानूनी रूप से ननयुक्त प्रनतननधि के लिए)
प्रोटोकॉि/ अध्यन संख्या: ______________________
इस जाचं के लिए भागीिािी की पहचान संख्या_______________
अनुसन्धान शीर्षक: मेथोट्रे क्सेट-आिारित कीमोथेिेपी प्राप्त किने वािे कैं सि बच्चों में मौखिक
म्यक
ू ोसाइटटस की िोकथाम में मौखिक क्रायोथेिेपी की प्रभावकारिता: एक यादृच्च्िक ननयंत्रित पिीक्षण
मुख्य अन्वेर्क का नाम: डॉ आटित्य गुप्ता, फोन नंबि: 9990350017
मुख्य मागष दशषक का नाम: डॉ जगिीश प्रसाि मीना फोन नंबि: 011-2659-3619
मैंने टिनांक_______________ के सूचना पि में टिये गए सभी तथ्यो को पढ लिया हैं| मुझे मेिी समझ में
आने वािीं भाषा में ववस्तािपूवाक बत्ता टिया है औि मैनें तथ्यो को भिी भांनत समझ लिया है| मैं पुच्ष्प्ट किता हूूँ
कक मुझे प्रश्न पूिने का अवसि टिया गया है|
मुझे अध्ययन की प्रकृनत, उद्िे श्य औि इसके सम्भाववत िाभ/जोखिमों औि अध्ययन की सम्भाववत अवधि
एवं अन्य प्रासंधगक जानकािी के बािे में ववस्ताि पूवाक समझा टिया गया है | मैं समझाता हूूँ कक इस अध्ययन
में मेिे बच्चे की भागीिािी स्वैनिक है औि इस अध्ययन से ककसी भी समय त्रबना कोई कािण बताए, त्रबना मेिे
बच्चे की धचककत्सा िे िभाि या कानूनी अधिकािों को प्रभाववत ककये मैं अपने बच्चे का नाम वावपस िे
सकता/सकती हूूँ |
मैं समझता हूूँ कक इस अनुसन्िान में मेिे बच्चे की भागीिािी से मेिे बच्चे के बािे में एकि जानकािी औि
धचककत्सीय टटप्पणीयों को एम्स अस्पताि के च्जम्मेिाि िोगो द्वािा िे िा जायेगा I मैं इन व्यच्क्तयों को
अपने बच्चे की रिकोडा िे िने कक अनम
ु नत प्रिान किता/किती हूूँ |
कृपया बॉक्स में
हस्ताक्षि किे (कताा)
(i) मैं पुच्ष्प्ट किता / किती हूूँ कक मैंने टिनांक ..........को िी गयी अध्ययन से [ ]
सम्बंधित सूचना शीट पढ़ औि समझ िी है औि मुझे सवाि पूिने का मौका टिया
गया है I
(ii) मैं समझता / समझती हूूँ कक अध्ययन में मेिे बच्चे की भागीिारिता स्वैनिक है [ ]
औि मैं कभी भी स्टडी से त्रबना कोई कािण टिए अपने बच्चे को हटा सकता / सकती
हूूँ च्जसका मेिे बच्चे की िे िभाि पि कोई असि नहीं पडेगा I
(iii) मुझे पता है कक अध्ययन के स्पोंसि, अनुसंिानकताा, एधथक्स सलमनत औि [ ]
ननयंिक अधिकािी मेिी आज्ञा के त्रबना, मेिे बच्चे के स्टडी से हटने के बाि भी मेिे
रिकार्डास इस अध्ययन औि इससे सम्बंधित अध्ययन के लिए िे ि सकते हैI में
इसके लिए तैयाि हूूँ ककन्तु कोई भी जानकािी िपने में मेिे बच्चे की पहचान नहीं
होगी I
(iv) मुझे इस अध्ययन से उत्पन्न आंकडे या परिणाम के उपयोग में कोई आपवत्त नहीं [ ]
है बशते यह वैज्ञाननक उद्येश लिए प्रयोग हो I
(v) मैं उपयुाक्त अध्ययन में मेिे बच्चे को भाग िेने के लिए अपनी सहमनत प्रिान [ ]
किता /किती हूूँ |
---------------------------------------------

(एल.ए.आर. के हस्तािर / बाएं अंगूठे का तनशान) टिनांक: स्थान:

सहमनत िे ने वािे का नाम: ________________________________

भागीिािी से रिश्ता: ________________________________

भागीिािी का नाम: ________________________________

वपता/पनत का नाम: ________________________________

जन्म की टिनांक/आयु: ________________________________

पूिा पता: ________________________________ ________________________________

________________________________ ________________________________

योग्यता: ________________________________

व्यवसाय: ववद्याथी / िि
ु की नौकिी/सिकािी नौकिी/हाउस वाइफ/ अन्य (टटक किे ) |

कताा की वावषाक आय: ________________________________

वपता की वावषाक आय: ________________________________

सहभागी के उतिाधिकािी का नाम, पता, व रिश्ता (स्टडी सम्बंधित मत्ृ यु होने पि मुवावजा हे तु):

________________________________ ________________________________

________________________________ ________________________________

यह प्रमाखणत ककया जाता हे कक उपयुक्ता सहमनत मेिी उपस्थनत में िी गईं हैं |

मुख्य अन्वेषक के हस्ताक्षि टिनाक: स्थान:

१) गवाह के हस्ताक्षि २) गवाह के हस्ताक्षि

नाम नाम
पता पत

ASSENT FORM - INFORMATION TO PARTICIPATE IN A RESEARCH STUDY

(Participant aged 8 - 12 and 13 -18 Years)

Study Title: Efficacy of oral cryotherapy in the prevention of oral mucositis in

children with hematolymphoid malignancies receiving IV Methotrexate-based chemotherapy

Name of Principal Investigator: Dr Aditya Gupta Tel. No: 9990350017

Name of Chief Guide: Dr. Jagdish Prasad Meena, Phone No: 011-2659 3619

Dear Participant,
This sheet informs you about the research study that we are conducting. By doing research
we understand the disease and its treatment better. This sheet informs you about the type,
aim, and any risks associated in the research study that we are conducting. Through research,
we understand the disease and its treatment better. This will benefit not only you, but also
hundreds of children like you
You are receiving methotrexate as a part of chemotherapy. Methotrexate causes oral
mucositis(Mouth pain/ulcers). As a part of the study, you will be asked to put ice cubes in
your mouth and suck on them intermittently every 8 hourly for 1 day or you would be asked
to do betadine gargles along with daily brushing of teeth. You will be followed up
telephonically for development of oral mucositis and asked to visit in OPD 5 day after
receiving Methotrexate and 10/14 days after receiving methotrexate.
We will look at your medical records for the purpose of the study, and the confidentiality of
these records will be maintained. No one other than ones conducting the study will have
access to this data. All complications occurring as a part of the disease or due to drugs will be
managed in our institute free-of-cost. Admission if needed, for complications like febrile
neutropenia will be done on a priority basis. Once you give the consent to the study, it is not
necessary that you are obliged to complete the study. You can withdraw your consent
anytime. Your treatment with us will not be hindered as a result.
We hope to learn a lot from you
Thank you.

Problems or questions:
If you have any questions about the study you may contact us at any time point in the
following address:
Dr Aditya Gupta, Senior Resident (DM Pediatric oncology)
Department of Paediatrics, AIIMS, New Delhi
Phone No: 9990350017
Parent/LAR (when participant is between 8-12 years)
I certify that the study described above has been explained to ___________________, in
terms
he/she could understand and that were appropriate to his/her age and ability to comprehend,
and
that he/she freely assented to Participate in the study.
Participant (Aged 13-18 years)
I certify that the study has been explained to me in presence of my guardians, in terms we
(me and
my guardians) could understand and that were appropriate to my age and ability to
comprehend, and
that subsequently | freely assented to Participate in the study.
I agree for the participation in the above study.
____________________
_______________________________
Signature / Left Thumb Impression of Participant Signature /Thumb Impression
of Parent /LAR

Name:___________________________ Name________________
Participant's Initials Relationship with Participant
Date (__/__/______) Date (__/__/______)
Participant’s Date of Birth (DD/MMM/Yyyy)
Age (in Completed years)
Address:

Signature / Left Thumb Impression of witness

Name of Witness
Parent/guardian/ LAR Assent
I certify as a guardian that the study has been explained to my child in presence of me, in
terms we (me and my child) could understand and that were appropriate to my child’s age
and ability to comprehend, and that subsequently he/she freely assented to Participate in the
study.
_______________________________
Signature /Thumb Impression of Parent/LAR
Name:___________________________
Relationship with Participant
 सहमतत प्रपत्र - एक शोध अध्ययन में भाग लेने के ललए सच
ू ना
(प्रततभागी आयु 8-12 और 13-18 वर्ष)

अध्ययन शीर्षक: बाि धचककत्सा ििु ाक-गहन कीमोथेिेपी के बाि िंबे समय से अलभनय पेग-
कफल्ग्राच्स्टम बनाम पािं परिक कफल्ग्राच्स्टम: एक यादृच्च्िक श्रेष्प्ठता पिीक्षण
प्रधान अन्वेर्क का नाम: डॉ आटित्य गुप्ता ििू भाष: 9990350017
मुख्य मागषदशषक का नाम: डॉ. जगिीश प्रसाि मीना, फोन नंबि: 011-2659 3619

वप्रय प्रनतभागी,
यह शीट आपको हमािे द्वािा ककए जा िहे शोि अध्ययन के बािे में सूधचत किती है। शोि किने से हम
बीमािी औि उसके इिाज को बेहति ढं ग से समझते हैं। यह शीट आपको हमािे द्वािा ककए जा िहे शोि
अध्ययन के प्रकाि, उद्िेश्य औि उससे जुडे ककसी भी जोखिम के बािे में सूधचत किती है। शोि के
माध्यम से हम बीमािी औि उसके इिाज को बेहति ढं ग से समझते हैं। इससे आपको ही नहीं, आप जैसे
सैकडों बच्चों को भी फायिा होगा।

आप कीमोथेिेपी के एक भाग के रूप में मेथोट्रे क्सेट प्राप्त कि िहे हैं। मेथोट्रे क्सेट मौखिक
श्िेष्प्मा (मुंह ििा/शािे) का कािण बनता है। अध्ययन के एक भाग के रूप में , आपको अपने
मुंह में बफा के टुकडे डािने औि 1 टिन के लिए हि 8 घंटे में रुक-रुक कि चूसने के लिए
कहा जाएगा या आपको िांतों की िै ननक ब्रलशंग के साथ-साथ बीटाडीन गिािे किने के लिए
कहा जाएगा। मौखिक म्यूकोसाइटटस के ववकास के लिए आपका टे िीफोन पि पािन ककया
जाएगा औि मेथोट्रे क्सेट प्राप्त किने के 5 टिन बाि औि मेथोट्रे क्सेट प्राप्त किने के 10/14
टिनों के बाि ओपीडी में जाने के लिए कहा जाएगा।

हम अध्ययन के उद्िेश्य के लिए आपके मेडडकि रिकॉर्डास को िे िेंगे औि इन रिकॉर्डास की गोपनीयता

को बनाए ििा जाएगा। अध्ययन किने वािे के अिावा ककसी औि के पास इस डेटा तक पहुंच नहीं
होगी। िोग के एक भाग के रूप में या िवाओं के कािण होने वािी सभी जटटिताओं का प्रबंिन हमािे
संस्थान में ननिःशुल्क ककया जाएगा। यटि आवश्यक हो तो फेब्राइि न्यट्र
ू ोपेननया जैसी जटटिताओं के
लिए प्रवेश प्राथलमकता के आिाि पि ककया जाएगा। एक बाि जब आप अध्ययन के लिए सहमनत िे
िे ते हैं, तो यह आवश्यक नहीं है कक आप अध्ययन को पूिा किने के लिए बाध्य हों। आप अपनी सहमनत
कभी भी वापस िे सकते हैं। परिणामस्वरूप हमािे साथ आपके उपचाि में कोई बािा नहीं आएगी।
हमें आपसे बहुत कुि सीिने की उम्मीि है
िन्यवाि।
समस्याएं या प्रश्न:
यटि अध्ययन के बािे में आपके कोई प्रश्न हैं, तो आप ककसी भी समय ननम्नलिखित पते पि हमसे
संपका कि सकते हैं:
डॉ आटित्य गप्ु ता, सीननयि िे च्जडेंट (डीएम पीडडयाटट्रक ऑन्कोिॉजी)
बाि िोग ववभाग, एम्स, नई टिल्िी
फोन नंबि: 9990350017

माता-वपता/एलएआर (जब प्रततभागी 8-12 वर्ष के बीच का हो)

मैं प्रमाखणत किता/किती हूं कक ऊपि वखणात अध्ययन को ___________ के संिभा में समझाया गया है
वह समझ सकता/सकती है औि जो उसकी उम्र औि समझने की क्षमता के लिए उपयुक्त है, औि
कक उन्होंने अध्ययन में भाग िेने के लिए स्वतंि रूप से सहमनत िी है।

प्रततभागी (आयु 13-18 वर्ष)

मैं प्रमाखणत किता/किती हूं कक अध्ययन मुझे मेिे अलभभावकों की उपच्स्थनत में समझाया गया है, हम
(मैं औि ) के संिभा में
मेिे अलभभावक) समझ सकते थे औि जो मेिी उम्र औि समझने की क्षमता के लिए उपयुक्त थे, औि
कक बाि में | अध्ययन में भाग िेने के लिए स्वतंि रूप से अनुमनत िी गई।
मैं उपिोक्त अध्ययन में भाग िेने के लिए सहमत हूं।

____________________ _______________________
प्रततभागी के हस्तािर/बाएं अंगूठे का तनशान माता-वपता/कानन
ू ी रूप से तनयुक्त प्रतततनधध
के हस्तािर/अंगूठे का तनशान

नाम ________________
प्रनतभागी का प्रथमाक्षि प्रनतभागी के साथ संबंि
टिनांक (__/__/________) टिनांक (__/__/________)
प्रनतभागी की जन्म नतधथ (डीडी/एमएमएम/वषा)
आयु (पूणा वषों में)
पता:

गवाह के हस्तािर/बाएं अंगूठे का तनशान

गवाह का नाम
माता-वपता/अलभभावक/ कानूनी रूप से तनयुक्त प्रतततनधध सहमतत
मैं एक अलभभावक के रूप में प्रमाखणत किता हूं कक मेिे बच्चे को मेिी उपच्स्थनत में अध्ययन के बािे में
समझाया गया है, इस संिभा में कक हम (मैं औि मेिा बच्चा) समझ सकते थे औि जो मेिे बच्चे की उम्र
औि समझने की क्षमता के लिए उपयुक्त थे, औि बाि में वह स्वतंि रूप से अध्ययन में भाग िेने की
स्वीकृनत प्रिान की।

_______________________________
माता-वपता/ कानन
ू ी रूप से तनयुक्त प्रतततनधध के हस्तािर/अंगूठे का तनशान
नाम:___________________________. प्रनतभागी के साथ संबंि: