A Pilot, Open-Labelled, Randomised Controlled Trial Of Povidone-Iodine Vs Essential Oil And Tap Water Gargling For COVID-19 Patients
Phase: PHASE2
Conditions: COVID-19
Sponsor: Universiti Sains Islam Malaysia

16th  July 2020 
 
 
 
Dear Sir/Madam, 
 
Official Title: Povidone-Iodine vs Essential Oils vs Tap Water Gargling for COVID-19 
Patients 
NCT No: NCT04410159 
Date of document: 1st May 2020 
 
 
I am writing to provide the study protocol, information sheet and consent form of the 
abovesaid study. The documents have been approved by the Ethical Review Board. 
 
 
 
 
Thank you 
 
NA Mohamed 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

STUDY PROTOCOL 
 
An Open Labelled, Randomised Controlled Trial Of Povidone-Iodine Vs 
Essential Oils Vs Tap Water Gargle For Covid-19 Patients: A Pilot Study 
 
Executive summary 
 
SARS-CoV-2 is transmitted via respiratory droplets from infected person and via 
contaminated surfaces. Hand hygiene, wearing mask, social distancing and 
environmental disinfection are important to prevent the virus spread. Gargling had 
been reported to have significant roles in the prevention and treatment of respiratory 
tract infection. However, the evidences are not strong enough to support its role in 
treatment and prevention of COVID-19. Therefore, the purpose of this study is to 
assess the ability of regular gargling to eliminate SARS-CoV-2 in the oropharynx and 
nasopharynx. This 4-arms interventional study compares the effect of gargling with  
i) 
povidone-iodine   
ii) 
essential oil  
iii) 
tap water 
iv) 
**control (no intervention)  
Findings from this study will provide new insight on the importance of gargling in the 
prevention of COVID-19 and other respiratory tract infections.  
 
 
 
 
 
 
 
 
 
 
 
 
 

Material and Methods 
 
Study design 
This 4-arms open labelled, randomized, parallel, pilot, interventional study compares 
the effect of gargling with povidone-iodine, and essential oils among COVID-19 
patients.  
 
Sample size and population 
 
Sample size: at least 5 per arm  
 
Patients will be randomly assigned to one of the groups as below: 
 
1. Gargle with povidone-iodine (Group A) 
2. Gargle with essential oil (Group B) 
4. Gargle with tap water (Group C) 
3. No intervention (Group D) 
 
Inclusion criteria 
1) adult aged 18 years and above 
2) able to understand instructions  
3) Stage 1 COVID-19   
4) < 5 days of illness (DOI) 
  
Exclusion criteria 
1. 
Less than 18 years old 
2. 
Unable to understand instructions 
3. 
Unable to gargle due to any possible reason (physical/psychological) 
4. 
Stage 2,3 COVID-19 
5. 
Respiratory symptoms or fever on admission 
6. 
Abnormal chest radiograph or computed tomography (CT) findings on 
admission 
7. 
those started on treatment for COVID-19 or COVID-19 complication  
8. 
Significant comorbidities 

9. 
Those reinfected with SARS-CoV-2 
10. 
Abnormal thyroid function test (for Group A) 
11. 
Allergy to any of the active ingredients. 
 
 
Experimental plan 
 
After written consent taken, all groups will be briefed regarding the study protocol 
separately.  
 
• Group A will be briefed on the correct procedures of gargling with Betadine®.  
The participants will be instructed to take 10ml of PVP-I, tilt their heads 
backward and gargle for 30 seconds, three times per day for 7 days 
 
• Group B will be briefed on the correct technique of gargling with Listerine®. The 
participants will be instructed to take 20ml of essential oils, tilt their heads 
backward and gargle for 30 seconds, three times per day for 7 days 
 
• Group C will be briefed on the correct technique of gargling with tap water. The 
participants will be instructed to take 100ml tap water, tilt their heads backward 
and gargle for 30 seconds, three times per day for 7 days 
 
• Group D will be briefed about the involvement in this study. They will be 
managed according to standard protocol of the hospital with no additional 
intervention. 
 
 
 
 
 
 
Primary Endpoint 
- 
RT PCR result of naso & oropharyngeal swab at day 6 
Secondary endpoints 

- 
RT PCR result of naso & oropharyngeal swab at day 12  
- 
Disease progression (signs and symptoms) 
- 
Laboratory and radiological progression 
 
 
Monitoring 
 
1. Oropharygeal and nasopharyngeal swabs will be taken at day 4 and 6 post 
intervention. The swabs will be subjected for detection of SARS-CoV-2 by real time 
RT-PCR.  
2. Patients will be given a chart for them to record their gargling practice and symptoms 
(if any) during the intervention period (7 days) 
3. Clinical data collection sheet will be provided to attending clinicians. The required 
information includes demographic data, daily vital signs, serial absolute lymphocytic 
count, CRP, chest radiograph and symptoms. Clinical monitoring will be done for 12 
days 
 
Data Analysis 
Statistical analysis will be performed using the IBM SPSS Statistics (v24.0) for 
descriptive and inferential statistics, such as the Fisher-Freeman-Halton exact test to 
determine associations between gargling groups and COVID-19 swab results. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Potential Risks 
Povidone iodine: 
Although measurable systemic absorption may occur with the long-term use of 
PVP-I, its clinical manifestation as thyroid dysfunction is not very common. 
Previous studies reported PVP-I mouthwash used four times daily for a short 

period (2 weeks) or once-daily for a prolonged period (24 weeks) did not affect 
thyroid function1.  
**Only those with normal thyroid function test will be enrolled in this study. 
 
Essential oils: 
Concerns have been raised about long term safety of ethanol in the 
formulation.The solution comprises of 4 essential oils (eucalyptol, menthol, 
thymol and methyl salicylate) 
 
Benefits 
 
Povidone iodine (Betadine) had been proven effective against viruses eg 
coronavirus (MERS, SARS, human CoV), influenza and bacteria. It has also 
proven effective against novel coronavirus (SARS-CoV2) in a recent in vitro 
study. 
 
Listerine had also been proven effective against influenza and herpes virus. It 
is widely available in the market with fair price.  
 
 
.  
Justification for the route of administration, dosage, dosage regimen, and 
treatment period 
 
Route of administration, dosage and regimen are according to manufacturers’ 
recommendations. 
 
This trial will be conducted in compliance with study protocol and 
manufacturers’ recommendation. 
 
 
Stopping and Discontinuation Criteria 
  
 
 
Respondents are allowed to stop or discontinue due to: 
- 
Own decision 
- 
Development of adverse effect 
- 
Progression of disease to Stage 3 
 
 
 
 
 
 
 
 
 
 
 

INFORMATION SHEET FOR SUBJECT/PATIENT 
 
STUDY TITLE: 
 An Open Labelled, Randomised Controlled Trial Of Povidone-Iodine Vs      
Essential Oils Vs Tap Water Gargle For Covid-19 Patients: A Pilot Study 
 
INTRODUCTION 
We are conducting a research regarding effect of gargling among COVID-19 patients. 
Gargling had been reported to have significant roles in the prevention and treatment 
of respiratory tract infection. However, the evidences are not strong enough to 
support its role in treatment and prevention of COVID-19. Therefore, the purpose of 
this study is to assess the ability of regular gargling to eliminate the virus. 
 
WHAT WOULD THIS INVOLVE? 
You will be asked to gargle frequently during your hospital stay (see INSTRUCTION). 
Additional nasopharyageal  swab will be taken at day 5 and 7 of intervention. You 
also need to fill in a form regarding frequency of gargling and symptoms of COVID-
19 (if any). 
 
THE BENEFITS 
Research conducted will contribute to the development of science and medicine.  Findings 
from this study will provide information on the effectiveness of gargling among COVID-19 
patients. If the result is favourable, gargling will be recommended as part of management 
strategies for COVID-19. 
 
RISKS AND DISCOMFORTS 
It is possible that you may develop an allergic reaction to the gargle solution. If you 
experience any symptoms you may choose either to continue or terminate your  
participation in this study. 
 
CONFIDENTIALITY 
The results of the data obtained will be reported in a collected manner with no 
reference to specific individual. Hence, the data from each individual will remain 
confidential. As a subject/patient/parent, you have the right to know the results for 
you only. 
 
DID I HAVE TO TAKE PART? 
The participation in this study is voluntary. If you prefer not to take part, you do not 
have to give a reason and your doctor will not be upset and your decision will not 
affect the treatment given. You may also withdraw at any point in time during the 
study. 
 
PAYMENT AND COMPENSATION 
You do not have to pay for participating in this study and no payment available for 
participating in this study. 
 For futher enquiries, please do not hesitate to contact me, Dr Nurul Azmawati binti 
Mohamed at drnurul@usim.edu.my or 012-9646276. We will answer your questions 
appropriately. 

 
INFORMATION SHEET FOR CONTROL GROUP 
STUDY TITLE: 
An Open Labelled, Randomised Controlled Trial Of Povidone-Iodine Vs 
Essential Oils Vs Tap Water Gargle For Covid-19 Patients: A Pilot Study 
 
INTRODUCTION 
We are conducting a research regarding effect of gargling among COVID-19 patients. 
Gargling had been reported to have significant roles in the prevention and treatment 
of respiratory tract infection. However, the evidences are not strong enough to 
support its role in treatment and prevention of COVID-19. Therefore, the purpose of 
this study is to assess the ability of regular gargling to eliminate the virus. 
 
WHAT WOULD THIS INVOLVE? 
As you are in the control group, you do not have to do anything. We would like to 
compare your viral load and clinical progression with those in the intervention group. 
Therefore, additional nasopharyageal  swab will be taken at day 5 and 7 of 
intervention. You also need to fill in a daily chart regarding symptoms of COVID-19 
(if any). 
THE BENEFITS 
Research conducted will contribute to the development of science and medicine.  Findings 
from this study will provide information on the effectiveness of gargling among COVID-19 
patients. If the result is favourable, gargling will be recommended as part of management 
strategies for COVID-19. 
 RISKS AND DISCOMFORTS 
As you are in the control group, there is no risk on gargling, but there is risk of pain 
during nasopharyngeal swab. The procedure is similar to that you have gone 
through before.  
CONFIDENTIALITY 
The results of the data obtained will be reported in a collected manner with no 
reference to specific individual. Hence, the data from each individual will remain 
confidential. As a subject/patient/parent, you have the right to know the results for 
you only. 
 
DID I HAVE TO TAKE PART? 
The participation in this study is voluntary. If you prefer not to take part, you do not 
have to give a reason and your doctor will not be upset and your decision will not 
affect the treatment given. You may also withdraw at any point in time during the 
study. 
 
PAYMENT AND COMPENSATION 
You do not have to pay for participating in this study and no payment available for 
participating in this study. 
For futher enquiries, please do not hesitate to contact me, Dr Nurul Azmawati binti 
Mohamed at drnurul@usim.edu.my or 012-9646276. We will answer your questions 
appropriately. 
 
 

CONSENT FORM 
 
TITLE OF THE PROJECT 
AN OPEN LABELLED, RANDOMIZED, CLINICAL TRIAL OF POVIDONE-IODINE 
VS ESSENTIAL OILS VS TAP WATER FOR COVID19 PATIENTS 
 
 
 
 
I,…………………………………………………………………………………………………………… 
(IC number)…………………………………………………………….. 
address…………………………………………………………………………………………………………………………………
……………………………………………………………………………… 
…………………………………………………………………………………………………… 
have read the information on the research project stated above and have also been given 
explanation by the person in charge about the purpose of this document. I have been 
adequately informed about the purpose, set-up, course and risk of the study.  At any time 
during and after my participation to the study, I am aware that the investigator is responsible 
for providing me any additional information about the study. I also have the right to know 
about the results of the research. 
I AGREE/DISAGREE to participate in this research project.   
 
 
 
 
 
 
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Signature  
Date: 
Phone number: 
 
 
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Name of researcher/representative:  
 
Signature 
 
 
Date 
NRIC: 
 
 
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Name of witness: 
 
 
 
 
Signature 
 
 
Date 
NRIC: