Clinical trial NCT04428359
Conditions: Verruca Viral
Keywords: Warts Intralesional MMR Vitamin D Immunotherapy
Sponsor: B.P. Koirala Institute of Health Sciences
Start date: 2020-06-01; Completion date: 2021-01-30
Enrollment: 66 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Common warts are papulonodular epidermal lesions caused by human papillomavirus (HPV) usually by the strains 1, 2, 4, 27 or 57. Cutaneous warts occur in 7% to 10% of the general population, with a maximum incidence between 12 and 16 years. There are multiple destructive treatment modalities of wart but they have many adverse effects. Hence immunotherapy is becoming popular in treatment of warts. It is believed that the injection to the HPV-infected tissue induces a strong nonspecific pro-inflammatory signal and attracts the antigen-presenting cells. Which then promotes a Th1 cytokine response and leads to delayed-type hypersensitivity reaction leading to the eradication of the HPV-infected cells.

We are undertaking a study to evaluate and compare the safety and efficacy of 2 such immunotherapeutic agents namely, IL measles, mumps and rubella (MMR) vaccine versus IL vitamin D3 for the treatment of warts.

RESEARCH HYPOTHESIS Null Hypotheses: IL MMR vaccine is not better than IL Vitamin D in the treatment of wart Alternative hypothesis: IL MMR vaccine is better than IL Vitamin D in the treatment of wart

Method: A total of 60 patients will be included in the study, 30 in each group. Group A and Group B patients will be injected with 0.5 ml of IL MMR and 0.5 ml of IL vitamin D3 respectively into a single or a maximum of 5 warts at a time in case of multiple warts. The IL injection will be given every 3 weeks for a maximum of 5 doses. Clinical assessment will be done by taking photographs and measurements at baseline, before each treatment session, and 3 months after the completion of treatment. The response will be evaluated by a decrease in the size and number of the wart(s) and photographic comparison. The response will be considered complete if there is a complete clearance of the wart(s), good if the wart(s) will regress in size by 75-99%, moderate if they regress by 50-74% and no or mild if there will be a 0-49% decrease in wart(s). Immediate and late side effects of MMR and Vitamin D will be evaluated after each session. Follow up will be made monthly for 3 months to detect any recurrence. Quality of life (QoL) will be measured in wart patients, using the Nepali version of the dermatology life quality index (DLQI) questionnaire before initiation of treatment and at the end of follow up.

Statistical analysis will be done using Statistical Package for the Social Sciences 10.5 version.

Detailed description:
INTRODUCTION Warts are common skin conditions resulting from infection of keratinocytes by human papillomavirus (HPV). After infection of the basal layer, there is clonal proliferation leading to epidermal thickening and hyperkeratinization and eventually results in a visible wart. HPVs are ubiquitous, epitheliotropic non-enveloped small double-stranded DNA viruses. Over 150 types of HPVs have been identified. Among them verruca vulgaris are usually caused by HPV types 1, 2, 4, 27 or 57, and plane warts by HPV types 3 or 10.

Cutaneous warts occur in 7% to 10% of the general population, with a maximum incidence between the ages of 12 and 16 years. In children, clearance can occur after only a few months, with 50% at 1 year and about 65%-78% by 2 years. The rate of clearance is influenced by factors like virus strain, host immune status, extent and duration of warts. The transmission of warts occurs from direct contact or indirectly via fomites.

There are multiple destructive, antiproliferative and antiviral agents in treatment of warts. Other modalities include hypnotherapy, acupuncture, local hyperthermia, therapeutic vaccination and combinations of the previous agents. Destructive therapies usually come with many adverse effects hence immunotherapy is becoming more popular, especially in the treatment of refractory cutaneous and genital warts. These include various topical, intralesional (IL) and systemic agents. IL Measles, Mumps, rubella (MMR) and IL vitamin D3 are examples of immunotherapeutic agents.

Immunotherapy is defined as a type of biological therapy that uses substances to stimulate or suppress the immune system to help the body fight cancer, infection, and other diseases. Immunotherapy can affect the immune system in general or can be cell-specific.

Immunotherapy is believed to induce a strong nonspecific pro-inflammatory signal and attract the antigen-presenting cells. This is associated with the release of cytokines such as IL-2, IL-8, IL-12, IL-I8, tumor necrosis factor-α, and interferon-γ. This then promotes a Th1 cytokine response which leads to the activation of delayed-type hypersensitivity reaction leading to the eradication of the HPV-infected cells. Furthermore, the trauma of the injection may also cause a resolution in previously sensitized individuals. Vitamin D3 is also claimed to regulate epidermal cell differentiation and proliferation and may modulate cytokine production through its action upon vitamin D receptors (VDRs). Since IL antigen immunotherapy enhances recognition of the virus by the immune system it causes clearance of both treated and untreated lesions and helps to prevent future clinical infection through induction of long-term acquired immunity to HPV.

MMR vaccine is included in immunization schedule of Nepal so pre-sensitization skin test is not needed as all patients are expected to be immune. The presence of 3 different antigens in MMR increases the sensitivity to the injected antigen and decreases the likelihood of anergy. Side effects of MMR include pain during injection, flu-like symptoms, pruritus and burning sensation.

IL vitamin D is a novel addition to therapies in warts as it is a simple, effective, well-tolerable, and inexpensive method with negligible local and systemic side effects. Side effects of Vitamin D3 include transient mild to moderate pain, edema at the site of injection and mild erythema. Additionally, it would be safer to monitor serum vitamin D and calcium levels before and after intralesional vitamin D treatment to prevent possible hypervitaminosis D.

RATIONALE Intralesional Immunotherapy is an emerging method of treatment of wart in which injection in a single wart causes the resolution of distant warts as well. Compared to other destructive modalities, it is more effective and comfortable for the patient as it obviates the need for individual treatment of each wart. In addition it has a lower rate of recurrence, avoids adverse effects such as scarring, is more cost-effective in multiple warts and decreases the time a physician has to spend on each patient. Further both injection MMR and Vitamin D3 are readily available as compared to other immunotherapeutic agents like purified protein derivative and candida antigen.

IL MMR vaccine has been used for a longer time than IL vitamin D and there are more comparative studies showing efficacy of MMR vaccine with rates of clearance ranging from 70.4% to 82.4%. The clearance rates for IL vitamin D ranges from 40% to 90%.

The advantages of vitamin D over MMR vaccine are cost-effectiveness, non-requirement of maintenance of cold chain, easy availability, and feasibility of use in immunosuppressed patients.

As per Institute of Medicine (IOM), the tolerable upper intake of vitamin D is 4000 IU/day for anyone older than 9 years such that annual maximum dose will be 1,460,000 IU. The total amount of vitamin D that we will be administering will be 1,500,000 IU. Furthermore, since we are giving it intralesionally systemic absorption is likely to be low although data on exact amount of IL vitamin D that gets absorbed systemically is not available. In other studies, patients have been evaluated clinically for signs and symptoms of hypervitaminosis D however, no signs of toxicity were observed.

As per our literature search,

1. No previous studies on immunotherapy in wart have been conducted in our country
2. No comparative studies have been done to compare IL MMR and IL vitamin D3 in treatment of wart hence we aim to establish efficacy of each and compare the two.

OBJECTIVES

Primary Objectives:

1. To determine the efficacy of IL MMR vaccine in the treatment of Wart
2. To determine the efficacy of IL vitamin D in the treatment of wart
3. To compare the efficacy of IL MMR vaccine and IL Vitamin D

Secondary Objective:

1. To determine the clinical and demographic profile of patients with different types of warts visiting Dermatology outpatient department(OPD) of BP Koirala Institute of Health Sciences (BPKIHS)
2. To determine the side effects of IL MMR vaccine and IL Vitamin D in treatment of wart
3. To determine Dermatology life quality index (DLQI) in wart patients.

Operational definition Wart - clinical diagnosis made by a dermatologist Complete response (100%)- Complete disappearance of warts including distant ones and skin texture at the site is restored to normal Excellent response (75-99%)-Reduction in size and number including distant ones and few residual warts still visible Good response (50-74%)-Some reduction in size only including that of distant ones but no decrease in number of warts Poor or no response (0-49%)-No significant change in size and number of warts Recurrence- Recurrence during the study period

MATERIALS AND METHODOLOGY Materials: Study population will be all patients clinically diagnosed with warts visiting the Dermatology OPD of BPKIHS, Dharan.

Study design: Prospective comparative longitudinal study Study Period: Probable duration of the study will be 1 year after approval from the Institutional Review Committee (IRC) and Nepal Health Research Council (NHRC) Ethical Clearance: Taken from IRC, BPKIHS and NHRC Conflict of interest: None Sampling Technique: Census method with all consecutive patients meeting inclusion criteria for initial 6 months Sample size The study considers a 95% confidence interval, 80% power to estimate sample size. According to the literature review, it was found that there was 84.6% and 40% improvement in MMR and Vitamin D respectively.

Now using the sample size estimation formula for 2 proportion {(Zα√2p(1-p)+ Z1-β√((p1(1-p1) p2(1-p2)}2))/(p1-p2)2 Where n= sample size for each group p1 = 0.846 p2 = 0.40 p= (p1 +p2)/2 Zα=1.96 Z1-β = 1.28 Using above formula, n= 12.3 The formula for actual sample size is n/4{1+√(1+4/n\|p1-p2\|)}2 na = 16.48 Adding 10% in calculated value to reduce bias sampling technique, the minimum sample size in each group is 18.13 =19 Considering loss of follow up, sample size in each group= 30 Total sample size= 60

Methodology Based on the computer generated random number table, patients satisfying inclusion criteria will be assigned to either Group A or Group B once they come to OPD. Informed consent will be taken and detailed information including personal data, past history, medical history, drug history, clinical data like site, size, number and distribution of lesions will be recorded in preset pro forma. Photographs of the lesions will be taken before the first treatment session, in every treatment session and 3 months after last session.

Group A Freeze-dried MMR vaccine single-use vials stored at 2°C-8°C will be reconstituted with 0.5 mL of distilled water immediately before IL use. If reconstituted vaccine is not used within 8 hours it must be discarded. All Group A patients will receive IL injection of upto 0.5 mL of reconstituted MMR vaccine into a single or a maximum of 5 warts at a time in case of multiple warts with 31 G insulin syringe with beveled edge facing upward. Amount of injection on each wart will depend on the size of each wart. The injection will be given every three weeks for a maximum of 5 doses.

Group B All Group B patients will receive a maximum of 0.5 mL Inj. Vitamin D3 (600,000 IU; 15mg/ml) in each session after injection of IL lignocaine with 31 G insulin syringe. In cases of multiple warts, a maximum of 5 warts will be injected at a time. Amount of injection on each wart will depend on the size of each wart. The session will be done at 3 weekly intervals for a maximum of 5 sessions or until complete resolution of warts, whichever is earlier. In patients of group B serum vitamin D level will be measured after 20 days of 3rd dose and 1 month after the last dose to ensure safe monitoring.

Patient and physician global assessment using 'Visual Analog Scale score' and photographic comparison will be used to assess the response to treatment as mentioned in operational definition. Immediate and late adverse effects in both groups will be evaluated after each treatment session. Necessary investigations and intervention will be done if needed. Follow up will be made monthly for 3 months to detect any recurrence.

Quality of Life(QoL) QoL will be measured in wart patients, using the Nepali version of the dermatology life quality index (DLQI) questionnaire before initiation of treatment and at the end of follow up. DLQI contains 10 questions that involves 6 sections: symptoms and feelings, daily activities, leisure, work and school, personal relationships and treatment. Questions 1 and 2 assess symptoms and feelings; 3 and 4, daily activities; 5 and 6, leisure; 7, work and school; 8 and 9, personal relationships and 10, treatment. The clinically meaningful change or reduction in the DLQI score is measured as the change in score from one band to the other.

Statistical analysis

1. Data handling: Data will be entered in Microsoft Excel 2010 and statistical analysis will be done using Statistical Package for the Social Sciences 10.5 version
2. Coding: Alpha numerical code will be used
3. Monitoring: Data will be entered after every day of work and supervised by guide.
4. Statistical Analysis:

   1. Chi square test to compare the categorical data between the groups.
   2. Paired t test for comparing normally distributed continuous variables at different time point within the group
   3. Independent 't' test for comparing normally distributed continuous variables at different time point between the groups
   4. Wilcoxon signed rank test to compare the not normally distributed variables, ordinal data
   5. Mann- Whitney U test to compare the not normally distributed variables, ordinal data.
   6. Kaplan-Meier curves to compare the response rate on each follow up visit between the groups.

Test of significance will be considered when value of p ≤ 0.05.

Arms: arm 1: All Group A patients will receive intralesional MMR. arm 2: All Group B patients will receive intralesional Vitamin D3
Interventions: intervention 1: Measles-Mumps-Rubella Vaccine intervention 2: Vit D
Intervention descriptions: intervention 1: Group A patients will receive intralesional injection of upto 0.5 mL of reconstituted MMR vaccine into a single or a maximum of 5 warts at a time in case of multiple warts. Intralesional injection will be given every three weeks for a maximum of 5 doses or until complete resolution, whichever is earlier. intervention 2: Group B patients will receive a maximum of 0.5 mL Inj. Vitamin D3 (600,000 IU; 15mg/ml) in each session after injection of IL lignocaine with 31 G insulin syringe. In cases of multiple warts, a maximum of 5 warts will be injected at a time. The session will be done at 3 weekly intervals for a maximum of 5 sessions or until complete resolution of warts, whichever is earlier

Protocol documents:
Prot_SAP_ICF_000.pdf: 
 
Title: A COMPARATIVE STUDY TO ASSESS EFFICACY OF INTRALESIONAL 
MMR (MEASLES, MUMPS, RUBELLA) VACCINE AND INTRALESIONAL 
VITAMIN D3 IN TREATMENT OF WARTS 
NCT number: NCT04428359 
Date: 18/05/2020 
Authors:  
 
Dr. Bibisha Baaniya 
Dr. Nidhi Shah 
Dr. Suchana Marahatta 
 
 
 
 
Address for Correspondence 
Dr. Bibisha Baaniya 
Junior Resident, 2018 Batch 
Department of Dermatology and Venereology 
BPKIHS, Dharan 
Email. cul.bibisha@gmail.com 
Institutional email: office.academics@bpkihs.edu 
 
 
 


SUMMARY OF POST GRADUATE THESIS PROTOCOL 
1. Study title                         
 : A comparative study to assess efficacy of 
Intralesional MMR (Measles, Mumps, Rubella) 
vaccine and Intralesional Vitamin D3 in treatment 
of Warts 
2. Name of the author            : Dr. Bibisha Baaniya 
3. Department 
 
       : Department of Dermatology and Venereology 
4. Name of co- author 
  : Dr. Nidhi Shah 
 
 
    Associate Professor 
 
 
 
         Department of Dermatology and Venereology 
5. Name of Co-author 
 
 
: Dr. Suchana Marahatta, 
 
 
 
 Associate Professor 
 
 
 
 
Department of Dermatology and Venereology 
6. Email ID of the author and co-authors: cul.bibisha@gmail.com & 
 
 
 
 
 
 
       nidhishah.md@gmail.com 
 
 
 
 
 
 
       suchanamarahatta@yahoo.com 
7. Rationale of the research  : As per my literature search, 
1. No previous studies on immunotherapy in wart 
have  been conducted in our country 
2. No comparative studies have been done to 
compare IL MMR and IL vitamin D3 in treatment 
of wart hence we aim to establish efficacy of 
each and compare the two in our country 
8. Objectives 
      
     : Primary Objectives:  


1. To determine the efficacy of IL MMR vaccine in 
the treatment of Wart 
2. To determine the efficacy of IL vitamin D in the 
treatment of wart 
3. To compare the efficacy of IL MMR vaccine and 
IL Vitamin D 
 
 
 
 
 
Secondary Objectives:  
1. To determine the frequency of patients with 
different types of warts visiting Dermatology 
outpatient department of BPKIHS 
2. To determine the side effects of IL MMR 
vaccine  and IL Vitamin D in treatment of wart 
3. To determine Dermatology life quality index 
(DLQI) in wart patients. 
9. Research Hypothesis      : Null Hypotheses (H0): 
IL MMR vaccine is not better than IL Vitamin D in 
the      treatment of wart 
Alternative hypothesis: 
IL MMR vaccine is better than IL Vitamin D in the 
treatment of wart 
10. Material & Methods:  
(a) Whether study involves Human/animals or both : Human only 
(b) Population/ participants : Patients with warts visiting Dermatology outpatient  
                                                 department 
(c) Type of study design      :     Prospective comparative longitudinal Study 


(d) Setting                          
: Outpatient Department of Dermatology and 
Venereology, BPKIHS 
(e) Sample Selection criteria:  
(i) Inclusion Criteria               : 
1. Clinically diagnosed patients who have more than    
three warts or single wart in difficult to treat sites 
(periungual, palms and soles) 
2. Age > 12 years  
(ii) Exclusion Criteria :  
1. Patients not under any systemic or topical treatment of warts for the last 
four weeks 
2. Patients with a past history of an allergic response to MMR or any other 
vaccine or Vitamin D 
3. Patients with current acute febrile illness or any bacterial infection 
4. Immunosuppressed patients 
5. Pregnant or lactating women 
6. Patients having a past history of asthma, allergic skin disorders or 
convulsions 
7. Patients with keloidal tendency 
8. Patient refusal for consent 
9. Treating physician’s decision to give other treatment modality 
10. Patients with hypervitaminosis D, muscle weakness, bone pain, altered 
sensorium 
(f) Expected sample size  
: 60 (30 in each group) 
(g) Control groups  
 
: not applicable 


(h) Probable duration of study : one year 
(i) Parameter/Variables to be measured: Age, sex, race, occupation, number of 
warts, site of warts, response rate, 
DLQI 
(j) Outcome measures 
 : Response rate of warts to IL MMR and IL 
Vitamin D3 
(k) Statistical methods to be employed :  
a. Data handling: Data were entered in Microsoft Excel 2010 (Microsoft 
Corporation, Redmond, Washington, USA) and statistical analysis was done 
using Statistical Package for the Social Sciences 10.5 version (Chicago, Inc) 
b. Coding: Alpha numerical code was used 
c. Monitoring: Data was entered after every day of work and supervised by 
guide. 
d. Statistical analysis: will be conducted as per both per-protocol and intention-
to treat population (defined as all enrolled patients to whom study drug will be 
given; with the last observation carried forward) basis using two sided tests. 
For descriptive statistics, percentage, mean, S.D., median, and minimum, 
maximum will be calculated along with graphical and tabular presentation. 
For inferential statistics, statistical methods that will be used are as follow 
1. Chi square test and Fisher’s exact test to compare the categorical data 
between the groups. 
2. Paired t test for comparing normally distributed continuous variables 
(pretreatment and post treatment DLQI) at different time point within the 
groups. 
3. Mann- Whitney U test to compare the not normally distributed variables (age, 


duration of illness, size, number) 
4. Kaplan–Meier curves to compare the response rate (complete, excellent, good 
or poor response) on each follow up visit (week 3, 6, 9, 12) between the 
groups. 
 
Test of significance will be considered when value of p ≤ 0.05. 
 (l) Ethical clearance  
: Will be obtained from the Institutional Review 
Committee (IRC), BPKIHS and Nepal Health 
Research Council (NHRC) 
(m) Permission to use copyright questionnaire/Proforma : N/A 
11. For Intervention trial  
a. Permission from Drug Controller of Nepal: not required 
b. Safety measure   
 
:will be applied 
c. Plan to withdraw 
           :As per the decision of treating physician 
12. Maintain the confidentiality of subject : Yes 
13. References 
 
 
: attached 
14. Whether available resources are adequate: adequate 
15. Other resources needed 
: not needed 
16. Cost involved (Approx in NRS)  
a. Investigations 
 
 
 :60,000 (approximate) 
b. Surgery   
 
 
:NA 
c. Drugs  
 
 
 
:64,500 (approximate) 
Group A- MMR cost × number of participants × number of sessions per patient 
 
=350×30×5 
 
=52,500 


Group B- Vitamin D cost × number of participants × number of sessions per 
patient 
 
=80×30×5 
 
=12,000 
Total cost = 64,500 
Both MMR and Vitamin D are easily available in local pharmacy. 
17. Who will bear the cost of the requirements? Patient 
18. ANNEXURE:  
a. Participants record form (clinical data sheet): Attached 
b. Participant Information sheet  
i.  Attached English  
c. Participant Informed consent form  
i.  Attached English  
 
 
 


ABBREVIATIONS 
ANOVA -  Analysis of Variance 
BCG 
-  Bacillus Calmette Guerin 
BPKIHS -  BP Koirala Institute of Health Sciences 
DLQI 
-  Dermatology Life Quality Index 
DNA 
-  Deoxyribonucleic Acid 
DNCB 
-  Dinitrochlorobenzene 
DPCP 
-  Diphenylcyclopropenone 
G 
-  Gauze 
HPV 
-  Human Papilloma Virus 
IOE 
- 
Institute of Medicine 
IFN 
-  Interferon 
IL 
-  Intralesional, Interleukin 
IRC 
-  Institutional Review Committee 
MD 
-  Doctor of Medicine 
MMR 
-  Measles, Mumps, Rubella 
NA 
-  Not applicable 
NHRC 
-  Nepal Health Research Council 
NK 
-  Natural Killer 
OPD 
-  Outpatient Department 
QoL 
-  Quality of Life 
RCT 
-  Random Control Trial 
SADBE 
-  Squaric acid dibutyl ester 
TEIB 
-  Triethyleneiminobenoquinone 
Th 
-  T- helper 
TLR 
- 
 Toll like receptor 
VAS 
- 
Visual Analogue scale 
VDR 
- 
 Vitamin D receptor 
VDRA 
- 
 Vitamin D receptor activator 
 
 
 


TABLE OF CONTENTS 
 
INTRODUCTION ................................................................................................... 1 
RATIONALE OF THE STUDY ............................................................................... 6 
REVIEW OF LITERATURE .................................................................................... 8 
OBJECTIVES ....................................................................................................... 19 
RESEARCH HYPOTHESIS ................................................................................. 20 
MATERIALS AND METHODOLOGY ................................................................... 21 
REFERENCES .................................................................................................... 26 
ANNEXURES ....................................................................................................... 33 
Proforma for Wart patients ............................................................................ 33 
Patient Information Sheet (English/Nepali) .................................................... 36 
Informed consent (English/Nepal) ................................................................. 40 
 
 
  
 
 


 
1 
 
INTRODUCTION 
Warts are papulonodular epidermal lesions with a horny or papillomatous surface 
caused due to infection by human papillomavirus (HPV). 1  
 
Cutaneous warts occur in 7% to 10% of the general population, with a maximum 
incidence between the ages of 12 and 16 years.2 Warts can persist as it is for 
years and then spontaneously clear at any time from a few months to a few years. 
In children, clearance can occur even after only a few months, with 50% at 1 year 
and about 65%–78% by 2 years. 2,3 The rate of clearance is influenced by factors 
like virus strain, host immune status, extent, and duration of warts 4 
 
HPVs are ubiquitous, epitheliotropic non-enveloped small double-stranded DNA 
viruses.5 Over 150 types of papillomavirus have been identified based on DNA 
studies and serological detection of type-specific antibodies against HPV capsid 
antigens.1,6 Among them verruca vulgaris or common warts are usually caused by 
Human Papilloma Virus (HPV) types 1, 2, 4, 27 or 57, and plane warts by HPV 
types 3 or 10.2  
 
The transmission of warts occurs from direct contact or indirectly via fomites. 
Usually, warts spread in swimming pools and bathrooms as the skin is macerated 
and is more prone to minor abrasions and infections thus serving as conduits for 
HPV to the basal keratinocytes, the primary targets for HPV infection. 2,6 There 
they undergo a latent phase of slow replication and then induce epidermal 
hyperplasia and hyperkeratosis as the epidermis grows superficially. 7 


 
2 
 
The destructive therapies in treatment of wart include salicylic acid, trichloroacetic 
acid, cryotherapy, silver nitrate, phenol, cantharidin, surgical interventions and 
lasers; antiproliferative agents include bleomycin, vitamin D analogs, podophyllin, 
podophyllotoxin, and 5-fluorouracil; antiviral agents include cidofovir and 
retinoids.2 
Other 
modalities 
include 
hypnotherapy, 
acupuncture, 
local 
hyperthermia, therapeutic vaccination, and combinations of the previous agents.8 
 
Destructive therapies are usually uncomfortable, require multiple sessions and 
individual treatment of each wart, and are often associated with variable efficacy, 
high recurrence, and significant adverse effects such as scarring.9 Hence 
immunotherapy is becoming more and more popular, especially in the treatment 
of refractory cutaneous and genital warts. These include various topical, 
intralesional (IL), and systemic agents.10 
 
Immunotherapy is defined as a type of biological therapy that uses substances to 
stimulate or suppress the immune system to help the body fight cancer, infection, 
and other diseases. Immunotherapy can affect the immune system in general or 
can be cell-specific. 10 
Immunotherapeutic agents include: 
1. Prophylactic vaccination using viral antigens 
2. Therapeutic vaccination using viral antigens 
3.  Pro-inflammatory cytokines and tumor destroyers (interferon)  
4. Immune enhancement  
a. Topical (imiquimod)  
b. Systemic (cimetidine, levamisole, zinc sulfate)  


 
3 
 
5. Induction of delayed (cellular) hypersensitivity  
a. Intradermal (tuberculin, candidin, trichophyton, mumps antigen, BCG, 
Vitamin D) 
b. Topical (DNCB, DPCP, SADBE, TEIB)  
6. Combination treatment 11,12 
 
The exact mechanism of immunotherapy is not yet known but it is believed that 
the injection to the HPV-infected tissue induces a strong nonspecific pro-
inflammatory signal and attracts the antigen-presenting cells. This is associated 
with the release of cytokines such as IL-2, IL-8, IL-12, IL-I8, tumor necrosis factor–
α, and interferon-γ.13,14 This then promotes a Th1 cytokine response which leads 
to the activation of cytotoxic T cells and natural killer cells i.e. delayed-type 
hypersensitivity reaction leading to the eradication of the HPV-infected cells.15,16 
Furthermore, the trauma of the injection may also cause a resolution in previously 
sensitized individuals.17 Since intralesional antigen immunotherapy enhances 
recognition of the virus by the immune system it causes clearance of both treated 
and untreated lesions and helps to prevent future clinical infection through 
induction of long-term acquired immunity to HPV.13 
 
Measles, Mumps Rubella (MMR) vaccine is included in immunization schedule so 
pre-sensitization skin test is not needed as all patients are expected to be 
immune.5 In 1989, monovalent measles vaccine was introduced in Nepal for 
vaccination of infants at age nine months. In 2013, measles-rubella (MR) vaccine 
was introduced into the national routine immunization schedule and replaced 
monovalent measles vaccine.18 The presence of three different antigens in MMR 


 
4 
 
increases the sensitivity to the injected antigen and decreases the likelihood of 
anergy.8 Side effects of MMR include pain during injection, flu-like symptoms, 
pruritus and burning sensation.19,20 
 
Intralesional (IL) vitamin D is a novel addition to therapies in warts as it is a 
simple, effective, well-tolerable, and inexpensive method with negligible local and 
systemic side effects21,22 
 
Side effects of Vitamin D3 include transient mild to moderate pain, edema at the 
site of injection, resolving within 1 week mild erythema.22 Further it would be safer 
to measure serum vitamin D and calcium levels before and after intralesional 
vitamin D treatment to prevent possible hypervitaminosis D.23 
 
Vitamin D3 acts on the principle of immunotherapy by stimulating cell-mediated 
immunity21 In addition, it is also claimed to regulate epidermal cell differentiation 
and proliferation and may modulate cytokine production through its action upon 
vitamin D receptors(VDRs).22 VDRs are present in the keratinocytes, 
melanocytes, fibroblasts, and immune system cells of the skin. Activation of Toll-
like receptor (TLR) of human macrophages up-regulates the expression of vitamin 
D receptor and vitamin D1- hydroxylase genes, leading to induction of the 
antimicrobial peptide like thymic stromal, lymphopoietin and cathelecidin. 24,12 It 
also reduces the synthesis of IL1a and IL6 resulting in decreased inflammation. 
VDR activators (VDRAs) have been shown to inhibit cell replication and have 
immunomodulatory properties.25 
 


 
5 
 
It is supposed that combining intralesional immunotherapy with a destructive 
treatment method might enhance the efficacy, shorten the treatment duration, and 
reduce the possible side effects.7 
 
 
 


 
6 
 
RATIONALE OF THE STUDY 
 
Intralesional Immunotherapy is a emerging method of treatment of wart in which 
injection in a single wart causes the resolution of distant warts as well. Compared 
to other destructive modalities, it is more effective and comfortable for the patient 
as it obviates the need for individual treatment of each wart. In addition it has a 
lower rate of recurrence, avoids adverse effects such as scarring, is more cost-
effective in multiple warts and decreases the time a physician has to spend on 
each patient. Further both injection MMR and Vitamin D3 are readily available as 
compared to other immunotherapeutic agents like PPD and candida antigen.      
 
 
        IL MMR vaccine has been used for a longer time than IL vitamin D and there are 
more comparative studies showing efficacy of MMR vaccine with rates of 
clearance ranging from 70.4%  to 82.4%.26,27 The clearance rates for IL vitamin D 
ranges from 40%  to 90%.22,28 As per Committee to Review Adverse Effects of 
Vaccines; Institute of Medicine (IOE), there is evidence of causal relationship 
between MMR vaccine and measles inclusion body encephalitis in individuals with 
demonstrated immunodeficiencies.29 Hence immunodeficiency is one the 
exclusion criterias for MMR administration. 
 
 
 
The advantages of vitamin D over MMR vaccine are cost-effectiveness, non-
requirement of maintenance of cold chain, easy availability, and feasibility of use 
in immunosuppressed patients. 
As per Institute of Medicine (IOM), the tolerable upper intake of vitamin D is 4000 
IU/day for anyone older than 9 years such that annual maximum dose will be 
1,460,000 IU.30 The total amount of vitamin D that we will be administering will be 


 
7 
 
1,500,000 IU. Furthermore, since we are giving it intralesionally systemic 
absorption is likely to be low although data on exact amount of IL vitamin D that 
gets absorbed systemically is not available. In other studies, patients have been 
evaluated clinically for signs and symptoms of hypervitaminosis D however, no 
signs of toxicity were observed. 12,21,22,23,28,31 
 
As per my literature search, 
1. No previous studies on immunotherapy in wart have  been conducted in our 
country 
2. No comparative studies have been done to compare IL MMR and IL vitamin 
D3 in treatment of wart hence we aim to establish efficacy of each and 
compare the two. 
 
 


 
8 
 
REVIEW OF LITERATURE 
Warts are common skin conditions resulting from infection of keratinocytes by 
human papillomavirus (HPV)1. The development of epidermal thickening and 
hyperkeratinization occurs following infection at the basal layer and clonal 
proliferation, which eventually results in a visible wart, weeks or even months 
later.2 
 
Many studies have documented the prevalence of cutaneous warts in children 9–
13, ranging widely from 3.3% in the USA to 33% in the Netherlands.32 In a study 
conducted by. Liu et al it was found that 1.4% of college students were affected 
with warts on their hands and/or feet. 33 This frequency is estimated to be 7 to 
10% of the population in Europe and in the United States.34 According to age 
group, the prevalence of warts is highest in school-aged children, followed by 
adults then preschool-aged children. 1 In Great Britain, 6.5% of the school children 
had plantar warts, and 9.5% had warts at other sites.34 
 
Most large studies have found no evidence of a sex difference in wart prevalence. 
However, a female preponderance is seen in the frequency of plantar warts.34  In 
the East Anglia survey, 8.4% of females had plantar warts compared to 4.9% of 
males.1  
 
The use of swimming pools, sports clubs, gymnasiums, or public baths increases 
the risk of contracting plantar warts. School children and young adults constitute a 
high epidemiologic risk population and an important source of the dissemination of 
cutaneous warts since their families are more often infected up to 50% of cases. 


 
9 
 
Among butchers and workers in the meat-handling industry, the prevalence of 
warts on the hands is much higher than in the general population as their hands 
are subjected to many traumatisms. Other factors thought to be responsible are 
cold, permanently humid conditions, in which workers often use the same tools 
and working tables.34 
 
Classification of warts35 
Cutaneous warts can be classified in relation to the clinical morphology and the 
type of infecting HPV as follows: 
1. Common wart (Verruca Vulgaris) 
a. typical or exophytic 
b.  mosaic 
c. endophytic,  
d. papillomatous or filiform 
 
2. Plane and intermediate warts 
3. Myrmecia 
4. Pigmented plaques 
. 
1. Typical common warts are exophytic, i.e. elevated. Their surface is rough 
irregular, hyperkeratotic, with minute papillary projections. 
2. Mosaic warts appear usually in plantar locations. They are superficial, only 
slightly raised above the skin level, hyperkeratotic, multiple, confluent with 
polygonal outlines, and painless. 


 
10 
 
3. Endophytic common warts appear characteristically in palmar and plantar 
localizations. Deep plantar common warts are most often multiple, painless, 
with a slightly raised, hyperkeratotic surface. Even for experienced 
dermatologists, the differentiation between myrmecias and deep common 
warts is difficult. 
4. Papillomatous common warts are usually less typical, resembling 
papillomas, localized most often on the face, head, neck, in the folds. 
5. Plane warts are slightly raised above the skin level, smaller than common 
warts, with flatter, smoother surfaces and irregular outline. Intermediate 
warts, a term applied to lesions that cannot be classified as common or 
plane warts, combine clinical features of both. 
6. Myrmecia warts, if in plantar location, are often referred to as deep plantar 
warts. They may also be palmar and the warts are endophytic, deep, and 
more often single. Characteristic findings include small bleeding points and 
punctate dots appearing after trimming off the hard horny covering. 
         
        A few atypical warts, example, pigmented plaques in immunosuppressed 
patients, remain unclassified until more is known about the incidence and 
natural history.35 
 
Intralesional MMR vaccine 
The mechanism of action of intralesional MMR immunotherapy is still an enigma. 
Some authors hypothesize that it acts through the induction of a strong 
nonspecific inflammatory response against the HPV-infected cells.19,20 It has also 
been suggested that the trauma itself may cause wart clearance in previously 


 
11 
 
sensitized individuals.15 The cytokines produced by immune system such as 
interleukin (IL)-2, IL-4, IL-5, IL-8, interferon (IFN)-γ and tumor necrosis factor 
(TNF)-α stimulate a strong immune response against HPV may be another 
possible mechanism of action.21 Another author reports that the response to 
antigen injection was associated with the proliferation of peripheral blood 
mononuclear cells that promotes Th1 cytokines including IFN-γ and IL 2, which 
further activate cytotoxic T cells and natural killer (NK) cells that eradicate HPV-
infected cells.17,26 
 
Subjects can be tested for existing immunity by intrademal injection of 0.1 mL of 
MMR vaccine into the skin of the forearm. Determination of a positive reaction 
requires erythema and induration of at least 5 mm in diameter within 48–72 hours. 
Patients reactive to the skin test are labelled responders and IL MMR is more 
effective in them.20 
 
Nofal A et al conducted a randomized controlled trial (RCT) with 135 patients of 
which 85 patients received the MMR vaccine and 50 received Normal saline as 
control. Both treatment groups were injected in single largest wart at 2 weekly 
intervals until complete clearance for a maximum of 5 treatment and were 
followed up bimonthly for 6 months. In the MMR group, complete response was 
achieved in 80% and 84.6% of patients presenting with recalcitrant and multiple 
warts respectively. No recurrence was observed in the MMR group and side 
effects included pain during injection and flu-like symptoms. 20 
 
 


 
12 
 
 
Author 
Setting 
Type of 
Study 
Sample 
size 
Type of 
wart 
Percentage of 
complete clearance 
Nofal A and 
Nofal 
E, 
201020 
 
Zagazig University, 
Egypt 
Randomize
d controlled 
trial 
135 
Common 
warts 
Recalcitrant 
wart- 
80% 
Multiple Wart-84.6% 
Nofal A et al. 
20158 
Zagazig University, 
Egypt 
Prospective 
65 
recalcitran
t wart 
63% 
Naseem 
R 
and Aamir S, 
201336 
Federal 
postgraduate 
medical Institute & 
Sheikh 
Zayed 
Hospital, 
Lahore, 
Pakistan 
Prospective 
170 
Common 
warts 
81.3% 
Mohamad 
NS 
et 
al, 
201337 
 
Alexandria 
Main 
University Hospital, 
Egypt 
Quasi 
experimenta
l trial 
100 
Plantar 
wart 
82% 
Shah A et al, 
201638 
NHL 
Municipal 
Medical 
College, 
Ahmedabad, 
Gujarat, India 
Prospective 
study 
50 
Common 
warts 
72% 
Raju J et al, 
201639 
Mysore 
Medical 
College 
& 
Research Institute, 
Mysore, India 
Prospective 
study 
27 
Common 
warts 
70.4% 
Rohit V et al, 
201740 
Chalmeda 
Anand 
Rao 
Institute 
of 
Medical Sciences, 
Telangana, India. 
Case-
control 
study 
50 
Common 
warts 
72% 
Chauhan PS 
et al, 201727 
 
Dr.R.P. 
Govt. 
Medical 
College, 
Kangra 
(Tanda), 
Himachal Pradesh, 
India 
Prospective 
study 
51 
Common 
warts 
82.4% 
Table 1: Comparison of different studies on IL MMR in warts 
 


 
13 
 
Again in 2015, Nofal et al conducted a similar study in recalcitrant wart where 
they included sixty-five patients. Recalcitrant warts were defined as warts 
persistent for more than two years despite treatment with at least two different 
modalities. Distant warts were defined as warts at different anatomic sites away 
from the treated wart. Complete clearance of the lesions was observed in 41 
patients (63%), partial response in 15 patients (23%), and no response in nine 
patients (14%). Complete response was demonstrated in 74.5% of those 
presenting with distant warts. Side effects were mild and insignificant in the form 
of pain during injection, itching, erythema, and edema at the site of injection and 
flu-like symptoms. Recurrence was detected in two patients only8 
 
Similarly in a study conducted by Naseem, Aamir in 2013 there were total 170 
patients and final efficacy came as 81.3% which shows that a large number (122) 
of patients show complete response to the MMR vaccination.36 
 
 
Nagat Sobhy Mohamad, et al observed that the response of the target wart, 
MMR- treated group showed a significantly higher rate of complete clearance 
compared with the control group (82% versus 0% respectively). The rate of partial 
response was 6% versus 30%, and the rate of no response was 12% versus 70%, 
respectively. Regarding the response of untreated distant warts, the MMR-treated 
group showed 86.9% complete and 13.1% partial clearance of the warts whereas 
the control group showed 100% no response.37 
 
In a prospective study conducted in the Dermatology outpatient department of V.S 
Hospital, Ahmedabad by Shah A et al over a period of one year patients received 


 
14 
 
intralesional MMR vaccine 0.5ml into a single wart or the largest wart in case of 
multiple lesions at an interval of two weeks for three treatments. The response 
was evaluated as 0-49% as no response, 50-99% as partial response and 100% 
as complete response. Follow up was made every 02 weeks for 06 weeks and 
then monthly for 06 months to detect any recurrence. They found complete 
response was seen in 36 (72%), partial response in 08 (16%) and no response in 
06 (12%) patients. No recurrence was observed. Pain at the site of injection in 18 
(36%) and the flu like symptoms in 02 (04%) patients were observed. 38 
 
In 2016 J Raju et al injected MMR vaccine into the largest single wart 
intralesionally and gave subsequent injections every 2 weeks apart for about 3 to 
5 times and obtained complete remission of warts in 70.4% of patients, partial 
remission in 22.2% and no response in 7.4% of patients. 39 
 
Vontela R et al observed complete clearance in 72% patients and partial 
clearance in 16% of patients receiving the MMR vaccine. No response is seen in 
12% of patients. The recurrence rate during the 6 months follow up period is 12%. 
Pain during injection was noted in 60% of patients without any other adverse 
effects in the treated patients. The mean duration taken to show the complete 
clearance of the lesions is 9 weeks40 
 
In 2017 Chauhan et al injected 0.25 mL MMR vaccine intralesionally in the 
largest wart and repeated at 2-week interval until complete clearance or a 
maximum of five doses. They evaluated outcome as complete clearance, 
excellent, good, or unsatisfactory response on a visual analog scale at every visit 


 
15 
 
and at 4 and 8 weeks, thereafter by comparing baseline clinical photographs. 
They used a Likert scale for patient satisfaction level assessment similarly. Out of 
51 patients who completed the study 42 (82.4%) of them showed complete 
clearance of warts and 9 (17.6%) patients showed good or unsatisfactory 
response. In 4 (7.8%) patients, warts subsided completely after one dose itself. 
The four patients showing an excellent response after five doses initially also 
continued to improve during a follow‑up period of 8 weeks. Except for injection site 
pain, no adverse effects were noted. There was no recurrence of warts among 
them.27  
 
Intralesional Vitamin D3 
Vitamin D3 acts on the principle of immunotherapy by stimulating cell-mediated 
immunity21 Vitamin D is also claimed to regulate epidermal cell differentiation and 
proliferation and may modulate cytokine production through its action upon 
vitamin D receptors.22 The vitamin D receptors are present in the keratinocytes, 
melanocytes, fibroblasts, and immune system cells of the skin. Activation of Toll-
like receptor (TLR) of human macrophages up-regulates the expression of vitamin 
D receptor and vitamin D1- hydroxylase genes, leading to induction of the 
antimicrobial peptide 24 like thymic stromal, lymphopoietin and cathelecidin. It also 
reduces the synthesis of IL 1a and IL6 resulting in decreased inflammation. VDR 
activators (VDRAs) have been shown to inhibit cell replication and have 
immunomodulatory properties. 25 
 
 
 


 
16 
 
Author 
Setting 
Type of 
study 
Sample 
size 
Type of 
wart 
Percentage of 
complete 
clearance 
Recurre
nce 
Aktaş et al. 
201623 
Different 
hospitals 
of 
Turkey 
Prospective 
study 
20 
Common 
warts 
80% 
No 
Jakhar, 
Kaur, 
and 
Misri 201821 
NDMC 
Medical 
College 
and 
Hindu 
Rao 
Hospital, 
Delhi 
case report 
1 
Periungal 
wart 
- 
Not 
mentione
d 
Raghukumar 
et al. 201722 
Hassan 
Institute 
of 
Medical 
Sciences, 
Hassan, 
Karnataka 
state, India 
Prospective 
study 
64 
recalcitrant 
warts 
90% 
2(3.7%) 
Kareem 
et 
al. 201912 
Al-Azhar 
University, 
Cairo, Egypt 
RCT 
50 
Common 
warts 
40% 
Not 
mentione
d 
El-Taweel, 
Salem, 
and 
Allam 201928 
Benha 
University, 
Egypt 
Prospective 
study 
20 
Common 
warts 
40% 
No 
Manjunath K 
et al. 201931 
Mandya 
Institute 
of 
Medical 
Sciences, 
Mandya, 
Karnataka, 
India 
Prospective 
study 
42 
Multiple 
warts 
78.57% 
1(5.26%) 
Table no. 2: Comparison of studies on IL Vitamin D3 in Warts 
 


 
17 
 
Aktas et al conducted study with 20 patients with single or multiple plantar warts. 
Vitamin D3 (0.2 mL, 7.5 mg/mL) was injected into the base of the warts after 
prilocaine (0.1 mL, 20 mg/mL) injection. A maximum of 5 warts were treated in 1 
session, with a maximum 2 injections performed at 4-week intervals. In total, 16 of 
20 patients (80%) showed complete resolution of warts, and 1 patient showed 
partial resolution. Three patients failed to show any response. No recurrence or 
serious adverse effects were observed. 23 
 
In a case report done by Jakhar, Kaur, and Misri in 2018, the injection was given 
at a dose of 0.1 mL/cm2 just beneath the wart. A maximum of 0.4 mL was used in 
a single session in cases of multiple warts. The session was repeated at 2-week 
intervals for a maximum of 4 sessions or complete resolution of warts, whichever 
is earlier. The resolution of warts typically started in 7 to 10 days, and warts are 
shed spontaneously within 4 to 6 weeks. The only side effect was pain during 
injection, which was minimized with a dose of lidocaine before injection with 
vitamin D3. Two to 4 sessions are usually required on average for complete cure. 
21 
 
Raghukumar et al. conducted a study in 2017 in 64 patients with recalcitrant 
warts. Complete response with IL vitamin D was seen in 54 of 60 (90%), partial 
response in 4 of 60 (6.66%), and no response in 2 of 60 (3.33%). The average 
number of injections required to achieve a complete resolution was 3.66. 
Complete resolution of distant warts was noticed in all patients.22 
 


 
18 
 
Kareem et al. conducted RCT in 50 patients who were divided into two groups: 
thirty patients as cases group who received an intralesional injection of 0.2 ml of 
vitamin D3 (300.000 IU) and another twenty patients as a control group who were 
injected with normal saline solution. Standardized photographs were taken before, 
one month and three months after the procedure. The degree of the response was 
classified into complete, partial and no response. Complete clearance of the target 
injected warts was seen in 40% of patients in the cases group and 5% of patients 
in the control group (P≤0.001) that was statistically significant.12 
 
Similarly, in a study conducted by El-Taweel et al. 20 patients with verruca 
vulgaris and deep palmoplantar warts were included. Forty percent of the lesions 
treated with IL vitamin D3 showed complete clearance and the rate of distant wart 
response was 17.65%. Among different demographic and clinical variables in the 
studied patients, smoking and older age seemed to decrease the therapeutic 
response 28 
 
In a prospective study conducted by Shilpa et al on 2019, 33 of 42 patients 
(78.57%) showed a complete response, 6 patients (14.28%) showed moderate 
response and three patients (7.14%) showed mild response with IL vitamin D3. 
Recurrence was observed in one patient with the palmoplantar wart. No serious 
adverse effects were reported.31  
 
 
 


 
19 
 
OBJECTIVES 
Primary Objectives:  
1. To determine the efficacy of IL MMR vaccine in the treatment of Wart 
2. To determine the efficacy of IL vitamin D in the treatment of wart 
3. To compare the efficacy of IL MMR vaccine and IL Vitamin D 
 
Secondary Objective:  
1. To determine the clinical and demographic profile of patients with different 
types of warts visiting Dermatology outpatient department of BPKIHS 
2. To determine the side effects of IL MMR vaccine  and IL Vitamin D in 
treatment of wart 
3. To determine Dermatology life quality index (DLQI) in wart patients. 
 
 
 
 
 


 
20 
 
RESEARCH HYPOTHESIS 
Null Hypotheses (H0): 
IL MMR vaccine is not better than IL Vitamin D in the treatment of wart 
Alternative hypothesis: 
IL MMR vaccine is better than IL Vitamin D in the treatment of wart 
 
Operational definition 
Wart – clinical diagnosis made by a dermatologist 
Grades 
of 
clinical 
improvement 
Definition 
VAS 
score 
Complete response 
Complete disappearance of warts including 
distant ones and skin texture at the site is 
restored to normal 
100% 
Excellent response 
Reduction in size and number including distant 
ones and few residual warts still visible 
75–99% 
Good response 
Some reduction in size only including that of 
distant ones but no decrease in number of 
warts 
50-74% 
Poor or no response 
No significant change in size and number of 
warts 
0–49% 
 
Recurrence 
Recurrence during the study period 
 
Table no. 3 : Patient and physician global assessment using visual analog scale 
score27 
 
 


 
21 
 
MATERIALS AND METHODOLOGY 
Materials: 
The study population will be all patients clinically diagnosed with warts visiting the 
Dermatology outpatient department of BPKIHS, Dharan.  
 
Study design: 
 A Prospective comparative longitudinal study 
 
Study Period:  
The probable duration of the study will be one year after approval from the 
Institutional Review Committee and Nepal Health Research Council (NHRC) 
 
Ethical Clearance 
Ethical clearance will be taken from Institutional Review Committee (IRC), 
BPKIHS and Nepal Health Research Council (NHRC). 
 
Conflict of interest: None 
 
Sampling Technique: Census method with all consecutive patients meeting 
inclusion criteria for initial 6 months 
 
Inclusion criteria 
1. Clinically diagnosed patients who have more than three warts or single wart in 
difficult to treat sites (periungual, palms and soles) 
2. Age >/= 12 years 


 
22 
 
 
Exclusion criteria 
1. Patients under any systemic or topical treatment of warts for the last 4 weeks 
2. Patients with a past history of an allergic response to MMR or any other 
vaccine or Vitamin D 
3. Patients with current acute febrile illness or any bacterial infection 
4. Immunosuppressed patients 
5. Pregnant or lactating women 
6. Patients having a past history of asthma, allergic skin disorders or convulsions 
7. Patients with keloidal tendency 
8. Patient refusal for consent 
9. Treating physician’s decision to give other modality of treatment 
10. Patients with hypervitaminosis D, muscle weakness, bone pain, altered 
sensorium 
 
Sample size 
The study considers a 95% confidence interval, 80% power to estimate sample 
size. According to the literature review, it was found that 84.6% and 40% 
improvement were seen with IL MMR and IL Vitamin D respectively.20,12 
Now using the sample size estimation formula for 2 proportion 
Now 
using 
the 
sample 
size 
estimation 
formula 
for 
2 
proportion 
 n = 2p(1-p) (Zβ + Zα/2)2  
           (p1-p2) 
2 
n= sample size for each group 
p1 = 0.846 
 
 
 


 
23 
 
p2 = 0.40 
 
 
 
p= (p1 +p2)/2 
Zα/2=1.96 at 95% CI 
Zβ = 0.842 at 80% power 
Using above formula, n= 18.54 
Considering loss of follow up, sample size in each group= 30 
Total sample size= 60 
 
Methodology 
Based on the computer generated random number table, patients will be assigned 
to either Group A or Group B once they come to OPD. Informed consent will be 
taken. After that detailed information of all the patients satisfying inclusion criteria 
will be recorded in preset pro forma. This will include personal data, past history, 
medical history, drug history, clinical data like site, size, number, distribution of 
lesions. History of muscle weakness, bone pain, altered sensorium, anaphylaxis 
and immunosuppression will also be taken. In patients of group B serum vitamin D 
level will be measured after 20 days of 3rd dose and 1 month after the last dose to 
ensure safe monitoring. Photographs of the lesions will be taken before the first 
treatment session, in every treatment session and 3 months after last session. 
 
Group A 
Freeze‑dried MMR vaccine single-use vials stored at 2°C–8°C will be 
reconstituted with 0.5 mL of provided diluent (distilled water) as per 
manufacturer’s instruction immediately before intralesional use. If reconstituted 
vaccine is not used within 8 hours it must be discarded.37 All Group A patients will 


 
24 
 
receive intralesional injection of upto 0.5 mL of reconstituted MMR vaccine into a 
single or a maximum of 5 warts at a time in case of multiple warts with 31 G 
insulin syringe with beveled edge facing upward. Amount of injection on each wart 
will depend on the size of each wart. The intralesional injection will be given every 
three weeks for a maximum of 5 doses or until complete resolution, whichever is 
earlier.5 
 
Group B 
All Group B patients will receive a maximum of 0.5 mL Inj. Vitamin D3 (600,000 
IU; 15mg/ml) in each session after injection of IL lignocaine with 31 G insulin 
syringe. In cases of multiple warts, a maximum of 5 warts will be injected at a 
time. Amount of injection on each wart will depend on the size of each wart. The 
session will be done at 3 weekly intervals for a maximum of 5 sessions or until 
complete resolution of warts, whichever is earlier. 22 
 
Patient and physician global assessment using ‘Visual Analog Scale score’ and 
photographic comparison will be used to assess decrease in size and number of 
warts and thus the response to treatment. The clinical improvement will rated as 
complete response, excellent response, good response, poor or no response by 
the patient and physician global assessment using visual analog scale score at 
each visit taking baseline clinical photograph as controls. Immediate and late 
adverse effects of MMR vaccine and Vitamin D will be evaluated after each 
treatment session. Necessary investigations and intervention will be done if 
needed. Follow up will be made monthly for three months to detect any 
recurrence. 


 
25 
 
 
Quality of Life 
Quality of life (QoL) will be measured in wart patients, using the Nepali version of 
the dermatology life quality index (DLQI) questionnaire before initiation of 
treatment and at the end of follow up. DLQI contains 10 questions that involves 6 
sections: symptoms and feelings, daily activities, leisure, work and school, 
personal relationships and treatment. Questions 1 and 2 assess symptoms and 
feelings; 3 and 4, daily activities; 5 and 6, leisure; 7, work and school; 8 and 9, 
personal relationships and 10, treatment.  
 
The DLQI consists of 10 questions. Each question is given 4 options from not at 
all effect (score 0) to very much effect (score 3). The minimum and maximum 
possible score, thus, is 0 and 30 respectively. The interpretation of the patients’ 
score is done as follows:  
 
Meaning of DLQI Scores 
0-1 = no effect at all on patient’s life 
2-5 = small effect on patient’s life 
6-10 = moderate effect on patient’s life 
11-20 = very large effect on patient’s life 
21-30 = extremely large effect on patient’s life 
The clinically meaningful change or reduction in the DLQI score is measured as 
the change in score from one band to the other in the above-mentioned 
interpretation chart. 
 


 
26 
 
Statistical analysis 
1. Data handling: Data will be entered in Microsoft Excel 2010 (Microsoft 
Corporation, Redmond, Washington, USA) and statistical analysis will be 
done using Statistical Package for the Social Sciences 10.5 version 
(Chicago, Inc) 
2. Coding: Alpha numerical code will be used 
3. Monitoring: Data will be entered after every day of work and supervised by 
guide. 
4. Statistical analysis will be conducted as per both per-protocol and 
intention-to treat population (defined as all enrolled patients to whom study 
drug will be given; with the last observation carried forward) basis using two 
sided tests. 
For descriptive statistics, percentage, mean, S.D., median, and minimum, 
maximum will be calculated along with graphical and tabular presentation. 
For inferential statistics, statistical methods that will be used are as follow 
a. Chi square test and Fisher’s exact test to compare the categorical data 
between the groups. 
b. Paired t test for comparing normally distributed continuous variables 
(pretreatment and post treatment DLQI) at different time point within the 
groups. 
c. Mann- Whitney U test to compare the not normally distributed variables 
(age, duration of illness, size, number) 
d. Kaplan–Meier curves to compare the response rate (complete, excellent, 
good or poor response) on each follow up visit (week 3, 6, 9, 12) between 
the groups. 


 
27 
 
 
Test of significance will be considered when value of p ≤ 0.05. 
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17.  Kus S, Ergun T, Gun D, Akin O. Intralesional tuberculin for treatment of 
refractory warts. J Eur Acad Dermatol Venereol. 2005 Jul;19(4):515-6. 
doi:10.1111/j.1468-3083.2004.01175.x 
18.  Khanal S, Sedai TR, Choudary GR, Giri JN, Bohara R, Pant R, Gautam M, 
Sharapov UM, Goodson JL, Alexander J, Dabbagh A, Strebel P, Perry RT, 
Bah S, Abeysinghe N, Thapa A. Progress Toward Measles Elimination - 
Nepal, 2007-2014. MMWR Morb Mortal Wkly Rep. 20. 
19.  Na CH, Choi H, Song SH, Kim MS, Shin BS. Two-year experience of using 
the measles, mumps and rubella vaccine as intralesional immunotherapy for 
warts. Clin Exp Dermatol. 2014 Jul;39(5):583-9. doi: 10.1111/ced.12369. 
doi:10.1111/ced.12369 
20.  Nofal A, Nofal E. Intralesional immunotherapy of common warts: Successful 
treatment with mumps, measles and rubella vaccine. J Eur Acad 
Dermatology Venereol. 2010;24(10):1166-1170. doi:10.1111/j.1468-
3083.2010.03611.x 
21.  Jakhar D, Kaur I, Misri R. Intralesional vitamin D3 in periungual warts. J Am 
Dermatology. 2018;80(5):e111-e112. doi:10.1016/j.jaad.2018.11.007 
22.  Raghukumar S, Ravikumar BC, Vinay KN, Suresh MR, Aggarwal A, 
Yashovardhana DP. Intralesional Vitamin D3 injection in the treatment of 
recalcitrant warts: A novel proposition. J Cutan Med Surg. 2017;21(4):320-
324. doi:10.1177/1203475417704180 
23.  Aktaş H, Ergin C, Demir B, Ekiz Ö. Intralesional Vitamin D injection may be 
an effective treatment option for warts. J Cutan Med Surg. 2016;20(2):118-


 
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122. doi:10.1177/1203475415602841 
24.  Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, 
Schauber J, Wu K, Meinken C, Kamen DL, Wagner M, Bals R, Steinmeyer 
A, Zügel U, Gallo RL, Eisenberg D, Hewison M, Hollis BW, Adams JS, 
Bloom BR, Modlin RL. Toll-like receptor triggering of a. 
25.  Moscarelli L, Annunziata F, Mjeshtri A, et al. Successful Treatment of 
Refractory Wart with a Topical Activated Vitamin D in a Renal Transplant 
Recipient. Case Rep Transplant. 2012;2011:1-3. doi:10.1155/2011/368623 
26.  Raju J, Swamy A V, Swamy BLN, Raghavendra KR. INTRALESIONAL 
MEASLES , MUMPS AND RUBELLA ( MMR ) VACCINE-AN EFFECTIVE 
THERAPEUTIC TOOL IN THE TREATMENT OF WART . 
doi:10.18410/jebmh/2015/1176 
27.  Chauhan PS, Mahajan VK, Mehta KS, Rawat R, Sharma V. The Efficacy 
and Safety of Intralesional Immunotherapy with Measles, Mumps, Rubella 
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Dermatol Online J. 2019 Jan-Feb;10(1):19-26. doi: 10. 
doi:10.4103/idoj.IDOJ 
28.  El-Taweel AEA, Salem RM, Allam AH. Cigarette smoking reduces the 
efficacy of intralesional vitamin D in the treatment of warts. Dermatol Ther. 
2019;32(2). doi:10.1111/dth.12816 
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Evidence and Causality. Washington (DC): National Academies Press (US); 
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from:https://www.ncbi.nlm.nih.gov/books/NBK190025/ 


 
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30.  Institute of Medicine Committee to Review Dietary Reference Intakes for 
Vitamin D. Calcium. The National Academies Collection: reports funded by 
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31.  Kavya M, Shashikumar BM, Harish MR, Shweta BP. Safety and Efficacy of 
Intralesional Vitamin D3 in Cutaneous Warts: An Open Uncontrolled Trial. J 
Cutan Aesthet Surg. 2017 Apr-Jun;10(2):90-94. doi: 
10.4103/JCAS.JCAS_82_16. doi:10.4103/JCAS.JCAS 
32.  Silverberg JI, Silverberg NB. The US Prevalence of Common Warts in 
Childhood: A Population-Based Study. J Invest Dermatol. 
2013;133(12):2788-2790. doi:10.1038/jid.2013.226 
33.  Liu J, Li H, Yang F, Ren Y, Xia T, Zhao Z, Cao X, Wang Z, Yin M, Lu S. 
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18;8(1):15450. doi: 10.1038/s41598-018-33511-. doi:10.1038/s41598-018-
33511-x 
34.  Laurent R, Kienzier JL. Epidemiology of HPV infections. Clin Dermatol. 
1985;3(4):64-70. doi:10.1016/0738-081X(85)90050-1 
35.  Jablonska S, Orth G, Obalek S, Croissant O. Cutaneous warts clinical, 
histologic, and virologic correlations. Clin Dermatol. 1985;3(4):71-82. 
doi:10.1016/0738-081X(85)90051-3 
36.  Naseem R, Aamir S. The efficacy of intralesional measles, mumps, rubella 
(MMR) antigen in treatment of common warts. Pakistan J Med Heal Sci. 


 
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2013;7(4):1130-1133. 
37.  Sobhy Mohamad N, Badran F, Yakout E. Evaluation of the efficacy of a 
combination – measles, mumps and rubella vaccine in the treatment of 
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doi:10.7241/ourd.20134.118 
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an intralesional immunotherapy in treatment of warts. Int J Res Med Sci. 
2016;4(2):472-476. doi:10.18203/2320-6012.ijrms20160298 
39.  Raju J, Swamy A V, Swamy BLN, Raghavendra KR. INTRALESIONAL 
MEASLES , MUMPS AND RUBELLA ( MMR ) VACCINE-AN EFFECTIVE 
THERAPEUTIC TOOL IN THE TREATMENT OF WART . 
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Cutaneous Warts : A Case Control Study. 2017;(December):57-60. 
 
 
 
 
 
 
 
 
 
 


 
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ANNEXURES 
Department of Dermatology and Venereology 
BPKIHS, Dharan 
Proforma for Wart patients 
SN:                         Group:                        OPD/Inpatient no:                                Date: 
Name  
 
 
         
Age (years): 
 
 
 
 
  Sex:   
 
 
 
Race/ethnicity: 
Education:                                      
  
  Occupation: 
Address: 
 
 
 
 
    Phone no.  
History: 
1) Duration of wart:      
 
 
2) Type of wart:                                     
3) 
Site 
of 
lesions: 
Scalp/Face/Neck/Trunk/Upper 
extremities/Lower 
Extremities/Palms/soles/finger/toes 
4) Number of Lesions at presentation: 
5) Size of lesion: 
6) Progression of lesion: Gradual/Rapid/Stable/ Regressing 
7) Any associated Symptoms:  
Pruritus: none/ mild/ moderate/ severe 
Pain: none/ mild/ moderate/ severe 
Burning sensation: none/ mild/ moderate/ severe 
8) Associated personal Systemic illness: Yes/No 
If yes: HIV/ Diabetes/ Asthma/ Allergic skin disorders/ Convulsion/ bone pain/ muscle weakness 
9) Pregnant/ lactating mother: Yes/No/ NA 
10) Taking any other drugs: Yes/No 
If yes: Corticosteroids/ Immunosuppressive/ Others 
11) Past treatment taken: Yes/ No                                                                                                              
    If yes:  Self-care (Herbs/ Drugs/ Bought from pharmacy) 
Traditional (Traditional healer/ Herbalist/ Other) 
Seek medical help or treatment (Topical/ Systemic/ Both/ Surgical) 
Improvement: Worse/ No/ Mild/ Moderate/ Good 
Time since last treatment: 
Reason for treatment: 


 
34 
 
Treatment given: IL MMR/ IL Vitamin D  
 
 
Response to treatment 
Number 
of visits 
Date 
Percentage 
decrease 
from 
baseline 
Percentage 
decrease 
from last visit 
Side effects 
(pain ,redness, edema, Infection, scarring, 
ulcer, 
pigmentary 
changes, 
flu 
like 
symptoms, 
anaphylaxis, 
confusion, 
polyuria, polydipsia, anorexia, nausea, 
vomiting, muscle weakness, bone pain, 
altered sensorium) 
Remarks 
(Vitamin 
D 
level 
20 
days 
after 3rd 
visit, 
1 
month 
after last 
dose) 
1st  
 
 
 
 
 
2nd  
 
 
 
 
 
3rd  
 
 
 
 
 
4th  
 
 
 
 
 
5th  
 
 
 
 
 
 
Follow Up 
Number of visits 
Date 
Percentage decrease from 
baseline 
Recurrence (Yes/No) 
Remarks 
6th  
 
 
 
 
7th  
 
 
 
 
8th  
 
 
 
 


 
35 
 
 
 


 
36 
 
Department of Dermatology and Venerology 
                                            BPKIHS, Dharan, Nepal 
Patient Information Sheet 
I Dr. Bibisha Baaniya, Junior Resident of Department of Dermatology and 
Venereology at B.P. Koirala Institute of Health sciences, am doing a research 
under supervision Of Chief Guide Dr. Nidhi Shah. The title of research is “A 
comparative study to assess efficacy of Intralesional MMR (Measles, 
Mumps, Rubella) vaccine and Intralesional Vitamin D3 in treatment of 
Warts”. I am going to give you information and invite you to be the part of this 
research. Before you decide, you can talk to anyone you feel comfortable with 
about the research. 
There may be some words that you do not understand. Please ask me to stop as 
we go through the information and I will take time to explain. If you have questions 
later, you can ask me, the study doctor or the staff. 
 
Importance of the research 
Intralesional immunotherapy is a newly emerged but more comfortable, 
efficacious and cost effective method of treatment of warts. 
 
Purpose of the research 
1. To determine the efficacy of IL MMR vaccine in the treatment of Wart 
2. To determine the efficacy of IL Vitamin D in the treatment of wart 
3. To compare the efficacy of IL MMR vaccine and IL Vitamin D 
 
Participant selection: We are inviting all the patients attending dermatology OPD 
diagnosed as Warts. 
 
 


 
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Voluntary Participation 
Your participation in this research is entirely voluntary. It is your choice whether to 
participate or not. Whether you choose to participate or not, all the services you 
receive at this clinic will continue and nothing will change. If you choose not to 
participate in this research project, you will be offered the treatment that is 
routinely offered in this hospital for treatment of your condition. 
 
Procedures and Protocol 
 A preset proforma will be filled up for every patient which includes personal data, 
past history, medical history, drug history, clinical data like site, size, number, 
distribution. A thorough clinical examination of the patients will be recorded.  
 
The session of injection will be done at 3 weekly intervals for a maximum of 5 
sessions or until complete resolution of warts, whichever is earlier and thereafter 
monitoring will be done monthly for 3 months. Photograph of the lesions will be 
taken before the first treatment session, in every treatment session and 3 months 
after last session. In patients of group B who need 3 or more sessions, serum 
vitamin D level will be measured after 20 days of 3rd dose and 1 month after the 
last dose to ensure safe monitoring. 
 
Direct or indirect benefits to participant, community or others 
Compared to other destructive modalities, immunotherapy is more effective and 
comfortable for the patient as it obviates the need for individual treatment of each 
wart. In addition it has a lower rate of recurrence, avoids adverse effects such as 
scarring, is more cost-effective in multiple warts and decreases the time a 
physician has to spend on each patient. Further it can be easily made available in 


 
38 
 
periphery, hence the impact that it is going have becomes multifold especially in 
context of Nepal. 
 
Foreseeable Risks, discomfort or inconvenience to patient 
Side effects include pain during injection, flu-like symptoms, pruritus, burning 
sensation, edema, mild erythema, hyperpigmentation. 
 
Cost and source of investigations, drugs, and surgery 
Patient must bear the cost of drugs. However, the cost of measuring serum 
vitamin D level and injecting procedure will be free of charge and we investigator 
ourselves will be liable for this. If any adverse effects occur then the consultation 
charge will be free but patient must bear the drug charges if needed. Insurance 
coverage will be provided as per Social Health Insurance scheme of Nepal 
government.  
 
Confidentiality 
The information that we collect from this research project will be kept confidential. 
Information about you that will be collected during the research will be put away 
and no-one but the researchers will be able to see it. Any information about you 
will have a number on it instead of your name. Only the researchers will know 
what your number is and we will lock that information up with a lock and key. It will 
not be shared with or given to anyone except those working in the Department of 
Dermatology. 
 
Sharing the Results 
The knowledge that we get from doing this research will be published in a thesis 
paper and later may be published in a scientific research journal. 


 
39 
 
 
Right to Refuse or Withdraw 
You do not have to take part in this research if you do not wish to do so and 
refusing to participate will not affect your treatment at this clinic in any way. You 
will still have all the benefits that you would otherwise have at this clinic. You may 
stop participating in the research at any time that you wish without losing any of 
your rights as a patient here. Your treatment at this clinic will not be affected in 
any way. 
 
Whom to Contact 
If you have any questions you may ask me now or later, even after the study has 
started. If you wish to ask questions later, you may contact: 
Dr. Bibisha Baaniya 
BPKIHS, Dharan 
Email Address: cul.bibisha@gmail.com 
Phone no: 9841744777 
 
 
 


 
40 
 
Department of Dermatology and venereology 
BPKIHS, Dharan, Nepal 
Informed consent 
Name of the Candidate:  
Age:  
 
 Gender:  
Address:  
Telephone no.  
 
 
 
Email:  
The content 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 
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 participation is voluntary and that I am free to 
withdraw at any time, without giving any reason, without my medical care or illegal 
right being affected.  
I understand that the information collected about me from my participation in this 
research and sections of any of my medical notes may be looked at by 
responsible individuals from BPKIHS. I give permission for these individuals to 
have access to my record.  
I hereby give consent to take part in the above study and allow to perform the 
procedure and any other medical service that may become necessary during the 
procedure.  
I also consent for medical photographs/video and I have been informed that these 
photographs/video will be used without revealing the identity. I understand that 


 
41 
 
these along with the information I provide may be used in medical record, for 
purpose of publication in textbook or medical journal and dissertation purpose, or 
for medical education.  
The consent form has been signed by me when I was not under the influence of 
any drugs.  
Patient’s Signature……………………………. 
Researcher/ doctor’s signature………………..  
Guardian’s signature………………….. 
Date: 
Witness Signature:  
 
If Illiterate  
I have witnessed the accurate reading of the consent form to the potential 
participant, and the individual has had the opportunity to ask questions and to 
understand the nature of the study. I confirm that the individual has given the 
consent freely.  
Researcher/Doctor’s Signature……………………..  
Date:  
Witness signature………………………  
Thumb print of participant  
Right       Left