A Prospective Study on the Therapeutic Outcomes of Mebo and Tantum Verde in Patients With Oral Mucositis
Phase: PHASE3
Conditions: Oral Mucositis (Ulcerative) Due to Radiation
Sponsor: Cairo University

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I. Administrative information: 
1. Title:  
Evaluation of the Chemo-preventive effect of Combined Topical and Systemic Metformin on 
Oral Leukoplakia: A Randomized Clinical Trial 
 
2.Date of Submission to clinical trials: 
12/9/2025 
3.Date of Ethical Approval:  
April 2021 
4. Protocol Registration:  
The protocol is being registered on clinicaltrial.gov  
5. Protocol version:  
This protocol has only one version (the one submitted) 
6. Funding:  
Self-Funded 
 
7. Author contributions and responsibilities: 
• G.A.Z: Conceptualization, Investigation, Resources, Writing - Original Draft, Writing - 
Review & Editing 
• M.G.A: Methodology, Investigation, Visualization , Resources, Writing - Original Draft, 
Writing - Review & Editing 
• A.H.H: Methodology, Investigation, Visualization , Writing - Original Draft, Writing - 
Review & Editing 
• T.H.S: Methodology, Investigation, Supervision ,Writing - Original Draft, Writing - 
Review & Editing 
• N.A.A: Conceptualization, Formal analysis, Supervision, Writing - Original Draft, 
Writing - Review & Editing 
 
 
 
 
 

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I. Introduction 
1. Background and rationale: 
Research question:  
In patients with oral mucositis, will MEBO result in clinical improvement as compared to 
Benzydamine Hydrochloride spray?   
PICO: 
Population [P]: patients with oral mucostis attending the National Cancer Institute clinic 
Intervention [I]: MEBO 
Comparison [C]: Benzydamine Hydrochloride spray 
 Outcome [o]: clinical improvement and quality of life 
 
Statement of the problem: 
Oral mucositis (OM) refers to mucosal damage secondary to cancer therapy occurring in the oral 
cavity. Mucositis can be caused by chemotherapy and/or radiation therapy. It occurs in approximately 
20% to 40% of patients receiving conventional chemotherapy, 80% of patients receiving high dose 
chemotherapy as conditioning for hematopoietic stem cell transplantation, and nearly all patients 
receiving head and neck radiation therapy. OM can disturb speaking and eating, resulting in 
nutritional deficiency.(4)  
The management of oral mucositis is a challenge, due to its complex biological nature. Over the last 
10 years, different strategies have been developed for the management of oral mucositis.(5)  
 
Rationale for conducting the research: 
Outcome measure 
Method of measurement 
Unit of measurement 
1ry  Outcome 
Clinical improvement 
World Health Organization 
(WHO)scale.(1) 
Oral Mucositis Assessment 
Scale (OMAS).(2) 
Ordinal   
2ry 
Outcome 
quality of life 
Patient-Reported Oral 
Mucositis( PROMS scale).(3) 
Continuous outcome (Score 
codes). 

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Oral  mucositis  consequences can range from pain, decreased oral intake, impaired speech and 
swallowing to adverse events as severe as septicemia, increased hospitalization, and G-tube 
feeding (6)  
A wide variety of agents have been tested to prevent OM or reduce its severity.(7)This trial will 
assess the usefulness of MEBO versus Benzydamine Hydrochloride mouth wash  in management 
of oral mucositis in patients receiving radiotherapy and/or chemotherapy. 
Background:  
The term “mucositis” was introduced to describe inflammation of the oral mucosa induced 
by radiotherapy, chemotherapy and bone marrow transplantation. At present, oral mucositis is 
considered to be the most serious non-hematological complication of cancer treatment.(8) 
 Numerous predisposing factors have been blamed for oral mucositis, including: the type 
of tumor involved, age of the patient, dental health, the nutritional condition of the patient, the 
maintenance of kidney and liver function and the type of cytostatic agent used.(9) 
Clinically, oral Mucositis may appear as erythema, edema or ulceration that can be 
accompanied by alterations ranging from mild burning sensation to large and painful ulcers that 
worsen patient's quality of life and limit basic oral functions such as speech, swallowing of saliva 
or eating.(10)  
  According to  Multinational Association for Supportive Care in cancer and the  
International Society of Oral Oncology (MASCC/ISOO) guidelines for the management of 
mucositis, Management of oral mucositis is divided into the following sections: nutritional 
support, pain control, oral decontamination, palliation of dry mouth, management of oral bleeding 
and therapeutic interventions for oral mucositis.(11) 
 
              Since the primary symptom of oral mucositis is pain which significantly affects 
nutritional intake, mouth care and quality of life, thus, management of mucositis pain is a primary 
component of any mucositis management strategy.  Use of  saline mouth rinses, ice chips and 
topical mouth rinses containing an anesthetic such as 2% viscous lidocaine can help in reducing 
pain (12) 
              
Based on the pathogenesis of mucositis with complex biological inflammatory pathways, 
various therapeutic approach have been proposed to improve oral mucositis.(13) 
The current guidelines recommend the use of non-medicated oral rinses such as 
Benzydamine hydrochloride mouthwash and the use of short-term pain killers. Benzydamine 
hydrochloride - which is a non-steroidal anti-inflammatory drug - can be used in the form of 
mouth rinse to reduce the severity of oral mucositis. Other management strategies include 
cryotherapy before the start of chemotheraputic agent administration and application of low-level 

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laser therapy. Palifermin (Keratinocyte growth factor) is the only recommended preventive 
measure recommended by the ESMO Clinical Practice Guidelines.(14) 
 
7. Objectives 
Aim of the study: 
To assess the effect of MEBO versus Benzydamine Hydrochloride spray regarding clinical 
improvement of oral mucositis and quality of life of patients receiving readiotherapy and/or 
chemotherapy 
 
8.Study design: 
Phase III Randomized clinical trial (parallel arms) 
 
 
 
 
 
 
 
 
 
 
 
 
 

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II. Materials and Methods 
Participants: 
9.Study settings: 
The patients will be selected from the pool of the Out-Patient Clinic of National Cancer Institute  
Population: A random sample of adult patients receiving radiotherapy and having sign and 
symptoms of oral mucositis  
 
10.Eligibility criteria: 
A- Inclusion criteria: 
1) Patients having clinical signs of chemotherapy-induced or radiotherapy-induced OM 
(WHO oral mucositis grading scale: Grade II, III and IV) 
2) Patients over the age of 18 years 
3) Patients having no history of allergy, allergic rhinitis and asthma 
B- Exclusion criteria: 
1) Patients allergic to the used treatment 
2) Patient receiving systemic steroids  
3) Patients who don't approve to participating in the clinical trial. 
 
11.Interventions: 
Enrolment: Enrolment is expected to be done within a one-year period. The enrolled patients 
will be divided randomly into two groups, each consisting of 33 patients. 
 Intervention group: Patients will receive mixture of MEBO three times daily for 14 days 
Control Group: Patients will receive Benzydamine Hydrochloride spray three times daily for 
14 days.   
Follow up: The patients will be recalled at one week interval for 14 days.  
 
 
 

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Criteria for discontinuing intervention: 
Occurrence of any harmful side effects from either of the treatment modalities. 
Strategies to improve adherence to intervention: 
The patients will be recalled at one week interval and asked to bring the drug package. 
12.Outcomes: 
 
Clinical parameters: 
Clinical improvement of the lesion:      
The clinical data will be scored according to The World Health Organization (WHO)scale(1).  It is 
graded from 0 to 4. If the patient has no signs and symptoms, it is graded as 0. If the patient has 
painless ulcers, edema, or mild soreness, it is graded as 1. If there is painful erythema, edema, or 
ulcers but able to eat, it is graded as 2. If there is painful erythema, edema, or ulcers but unable eat, it 
is graded as 3. If there a requirement for parenteral or enteral support, it is graded as 4  
Adverse Events 
Any adverse events and safety issues related to the administered drugs will be reported. 
Quality of life 
The secondary outcomes will be quality of life assessed by PROMS scale.(2) 
The PROMS scale consists of 10, 100-mm horizontal visual analogue scales addressing oral 
functions affected by oral mucositis. Participants will be asked to mark a point on the line that 
best represents their present intra-oral condition. During the baseline examination and prior to 
their completion of the actual PROMS scale questionnaire, participants were subjected to a few  
training test-visual analogue scale questions focused on simple everyday topics to familiarize 
them with the concept of visual analogue scale assisted measurements(19). The participants will 
Outcome measure 
Method of measurement 
Unit of measurement 
1ry  Outcome 
Clinical improvement 
World Health Organization 
(WHO)scale.(1)  
Oral Mucositis Assessment 
Scale (OMAS).(2) 
Numerical rating score 
2ry 
Outcome 
Quality of life 
Patient-Reported Oral 
Mucositis (PROMS 
questionnaire).(3) 
Continuous outcome (Score 
codes). 

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complete the PROMS questionnaire thrice; baseline, after the first week, and at the end of the 
study after the second week.  
 
 
 
 
 
13. Participant timeline 
Enrolled patients will be divided randomly into two groups, each consists of 33patients. 
 Intervention group: Patients will receive mixture of Mebo and pumpkin seed oil spray three 
times daily  
Control Group: Patients will receive Benzydamine Hydrochloride spray three times daily   
Follow up: The patients will be recalled at one week interval for 14 days.  

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14. Sample size: 
According to the study by Ahmed et al. [7] , the effect size reported for the mean mucositis score 
was 1.011. We used a power of 80%, alpha of 5% and an allocation ratio of 1:1 to calculate a 
sample size of 17 subjects per group.  
 
15. Recruitment: 
A random selection of adult patients complaining from signs and symptoms of oral mucositis 
attending at the clinic of National Cancer Institute will be enrolled by the investigator in the 
study in a consecutive order starting from January 2022 without any financial incentives. 
16. Allocation: 
16a. Randomization: 
Method of random sequence generation: computerized random number generator 
Type of randomization: Simple  
Allocation ratio: 1:1. 
 
16b. Allocation concealment mechanism: 
All randomization numbers will be concealed in separate, sealed, opaque, serially numbered 
envelopes.  
 
16c. Implementation: 
NAA will generate the random sequence and perform the allocation concealment while the 
investigator will enroll and assign participants to interventions. 
 
17. Masking/blinding: 
This will not be possible as treatments are given in different forms 
 
C) Data collection, management, and analysis: 
18. Data collection methods 
 
Outcome data will be collected as printed questionnaires, clinical pictures, and written grading. 
Outcome data will be entered into excel sheets and clinical photos will be downloaded as a soft 
copy. Data will be backed up with the supervisors. 
19. Data management: 

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Patient data will be stored on safe computers with antivirus software accessed only by the 
investigators.  
20. Statistical methods: 
Data will be analyzed using IBM SPSS advanced statistics (Statistical Package for Social 
Sciences), version 21 (SPSS Inc., Chicago, IL). Descriptive statistics in case of normal 
distribution will be presented as mean and standard deviation, while if non-normal; median 
and 25th and 75th percentile will be used. Intergroup comparison will be done using t-test or 
Mann-Whitney test while Intra-group comparison will be done using student's t- test. 
 
 

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D) Data monitoring: 
21. Monitoring 
The collected data will be monitored by the main supervisor and co-supervisor. The entire study 
will be monitored by the Faculty of Dentistry's Ethical committee.  
 
22. Harms 
 Any adverse effect from the treatment will be recorded and documented in details. 
23. Audit 
Auditing will be done by the Faculty of Dentistry's Ethical committee.  
 
 
 

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III. Ethics and dissemination 
21. Research ethics approval 
After proper study design revision, the study protocol will be presented to the ethical committee 
for approval. 
22. Protocol amendments 
The protocol will be registered on clinicaltrials.gov in its current form, further amendments will 
be updated on the system. 
23. Informed consent 
informed consent will be obtained by the investigator from all study participants. 
24. Confidentiality 
The candidate will be responsible for data collection and storage. Patient's personal information 
will be available to the candidate and the research team only.  
25. Declaration of interest 
If there will be any conflict of interest it will be declared by the investigators. 
26. Access to data 
The Data (Demographic, Clinical and Analytical) will be available only to the supervisors 
 
30. post-trial care 
Any harm from the study, the participants will be managed completely. 
 
 
 
 
V. Appendices: 
32. Informed consent 
Informed consent form is as follows in Arabic and English 
 
 

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VII.References: 
1.  
Assessment P, Assessment S. Symptom Management Guidelines : ORAL MUCOSITIS 
* Step-Up Approach to Symptom Management : Interventions Should Be Based On 

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Current Grade Level and Include Lower Level Grade. :1–11.  
2. Patil, K. et al. (2015) ‘Use of curcumin mouthrinse in radio-chemotherapy induced oral mucositis 
patients: A pilot study’, Journal of Clinical and Diagnostic Research, 9(8), pp. ZC59–ZC62. doi: 
10.7860/JCDR/2015/13034.6345. 
3.  
Kushner JA, Lawrence HP, Shoval I, Kiss TL, Devins GM, Lee L, et al. Development 
and validation of a patient-reported oral mucositis symptom (PROMS) scale. J Can Dent 
Assoc (Tor). 2008;74(1).  
4.  
Shankar A, Roy S, Bhandari M, Rath GK, Biswas AS, Kanodia R, et al. Current trends 
in management of oral mucositis in cancer treatment. Asian Pacific J Cancer Prev. 
2017;18(8):2019–26.  
5.  
Seiler S, Kosse J, Loibl S, Jackisch C. Adverse event management of oral mucositis in 
patients with breast cancer. Breast Care. 2014;9(4):232–7.  
6.  
Dodd MJ, Dibble S, Miaskowski C, Paul S, Cho M, MacPhail L, et al. A comparison of 
the affective state and quality of life of chemotherapy patients who do and do not 
develop chemotherapy-induced oral mucositis. J Pain Symptom Manage. 
2001;21(6):498–505.  
7.  
Joanna Briggs Institute. Prevention and treatment of oral mucositis in cancer patients. 
Best Pract. 1998;2(3):1–6.  
8.  
Kostler WJ, Hejna M, Wenzel C, Zielinski CC. Oral Mucositis Complicating 
Chemotherapy and/or Radiotherapy: Options for Prevention and Treatment. CA Cancer 
J Clin. 2001;51(5):290–315.  
9.  
Naidu MUR, Ramana GV, Rani PU, Mohan IK, Suman A, Roy P. Chemotherapy-
induced and/or radiation therapy-induced oral mucositis - Complicating the treatment of 
cancer. Neoplasia. 2004;6(5):423–31.  
10.  
CAMPOS MIDC, CAMPOS CN, AARESTRUP FM, AARESTRUP BJV. Oral 
mucositis in cancer treatment: Natural history, prevention and treatment. Mol Clin 
Oncol. 2014;2(3):337–40.  
11.  
Lalla R V., Sonis ST, Peterson DE. Management of Oral Mucositis in Patients Who 
Have Cancer. Dent Clin North Am. 2008;52(1):61–77.  
12.  
Al-Ansari S, Zecha JAEM, Barasch A, de Lange J, Rozema FR, Raber-Durlacher JE. 
Oral Mucositis Induced By Anticancer Therapies. Curr Oral Heal Reports. 
2015;2(4):202–11.  
13.  
Bowen J, Al-Dasooqi N, Bossi P, Wardill H, Van Sebille Y, Al-Azri A, et al. The 
pathogenesis of mucositis: updated perspectives and emerging targets. Support Care 
Cancer. 2019;27(10):4023–33.  
14.  
Peterson DE, Boers-Doets CB, Bensadoun RJ, Herrstedt J. Management of oral and 
gastrointestinal mucosal injury: ESMO Clinical Practice Guidelines for diagnosis, 
treatment, and follow-up. Ann Oncol [Internet]. 2015;26(July):v139–51. Available 
from: http://dx.doi.org/10.1093/annonc/mdv202 
15.  
Stelmakh A, Abrahamovych O, Cherkas A. Highly purified calf hemodialysate 
(Actovegin®) may improve endothelial function by activation of proteasomes: A 
hypothesis explaining the possible mechanisms of action. Med Hypotheses [Internet]. 
2016;95:77–81. Available from: http://dx.doi.org/10.1016/j.mehy.2016.09.008 
16.  Sharquie KE, Noaimi AA, Latif TM. Treatment of Recurrent Aphthous Stomatitis by 
100% Topical Pumpkin Seed Oil. J Cosmet Dermatological Sci Appl. 2017;07(04):324–

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35.  
17.  
Shaban A, Sahu RP. Pumpkin Seed Oil: An Alternative Medicine. Int J Pharmacogn 
Phytochem Res. 2017;9(2):223–7.  
18.  
Gussgard AM, Hope AJ, Jokstad A, Tenenbaum H, Wood R. Assessment of cancer 
therapy-induced oral mucositis using a patient-reported oral mucositis experience 
questionnaire. PLoS One. 2014;9(3).  
19.  
Raeessi MA, Raeessi N, Panahi Y, Gharaie H, Davoudi SM, Saadat A, et al. “ Coffee 
plus Honey” versus “ topical steroid” in the treatment of Chemotherapy-induced Oral 
Mucositis: A randomised controlled trial. BMC Complement Altern Med. 
2014;14(1):1–7.