Nasal Irrigation to Reduce COVID-19 Morbidity
Phase: NA
Conditions: Covid19
Sponsor: Augusta University

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eAppendix. Supplemental Methods 9.24.2021 IRB Approval 1.14.2021 
 
This supplement contains the following items: 
1. Final statistical analysis plan, summary of protocol changes and approvals. 
2. Recruitment detail 
3. Final Protocol 
 
 

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Rapid Initiation of Nasal Saline Irrigation to Reduce COVID-19 Severity:  
A single center randomized controlled non-blinded clinical efficacy study  
evaluating 0.1% Povidone-Iodine compared to alkalinized nasal irrigation BID 
 for the reduction of COVID-19 severity in COVID+ outpatients. 
 
Principal Investigators: Amy L. Baxter  
Co-Investigators:  Kyle Schwartz, Matthew Lyon, Richard Schwartz  
Department of Emergency Medicine Medical College of Georgia at Augusta University 
 
 
CONTENTS 
1. Administrative ..................................................................................................................................... 3 
2.    Introduction ......................................................................................................................................... 3 
 
1.1 Background and Rationale ............................................................................................................ 3 
 
1.2 Objectives ...................................................................................................................................... 3 
2. Study Methods .................................................................................................................................... 4 
 
2.1    Trial Design ................................................................................................................................. 4 
 
2.2    Randomization ............................................................................................................................ 4 
 
2.3    Sample Size ................................................................................................................................. 4 
 
2.4    Statistical Framework ................................................................................................................. 5 
 
2.5   Statistical Interim Analyses and Stopping Guidance ................................................................... 5 
 
2.6    Timing of the Final Analysis ........................................................................................................ 5 
3. Statistical Principles ............................................................................................................................. 5 
 
3.1    Confidence Intervals and P-Values ............................................................................................. 5 
       3.2    Protocol Deviations ..................................................................................................................... 5 
4. Trial Population ...................................................................................................................................... 5 
 
4.1  Screening Data ............................................................................................................................ 5 
 
4.2  Eligibility ...................................................................................................................................... 5 
 
4.3 Recruitment ................................................................................................................................. 6 
 
4.4 Withdrawal/Follow-up ................................................................................................................ 6 
 
4.5   Baseline Patient Characteristics .................................................................................................. 6 
5.  Analysis ................................................................................................................................................ 6  
 
5.1  Outcome Definitions .................................................................................................................. 6 
5.2    Analysis Methods ........................................................................................................................ 7 
       5.3    Missing Data ................................................................................................................................ 7 
5.4    Additional Analyses ..................................................................................................................... 7 
 
5.5    Harms .......................................................................................................................................... 8 
5.6     Statistical Software .................................................................................................................... 8 
11. Appendix 1 Full Recruitment Demographics and Protocol ................................................................. 9 
12. Appendix 2 Final Protocol.................................................................................................................... 11 
 

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Rapid Initiation of Nasal Saline Irrigation to reduce COVID-19 morbidity and mortality (RINSI) – 
Statistical Analysis Plan 
1. Administrative Information 
a. Trial Registration Clinical Trials.gov NCT04559035 
b. Funding: Investigator initiated 
c. Statistical Analysis version 9.7.21-2 Protocol Version 1.14.21-3 
d. SAP Revision history 
Protocol Version 7-27-20 – Prospective randomized controlled trial of alkalinization 
compared to povidone-iodine twice daily nasal irrigation initiated on the same day of 
notification of positive COVID-19 Test to reduce morbidity and mortality. 
Protocol Version 10-16-2020 – Change to allow healthcare workers to participate. Due 
to disproportionate difficulty enrolling Black population, protocol changes allowing 
enrollers to leave a message and re-call, revising study flyer to emphasize benefit and 
moving “clinical research” language lower on the page. 
Interim Review of Primary Outcomes 12-6-2020 – Due to introduction of monoclonal 
antibodies, anticipated vaccination, and staffing, decision to do interim analysis early. 
Discovery that zero patients had been hospitalized, compared to an expected 25% and a 
rate of 16.4% in the state. Recalcluation of power analysis grouping all nasal irrigation 
patients compared to matched controls. 
Protocol version 1-11-2021 – Change to case-control analysis of primary outcome 
comparison of hospitalization and death to matched unenrolled controls using 5-
hospital EHR data. IRB approved 1.14.2021. 
Analysis change 8-7-2021 – Change to primary outcome analysis of prospective 
participants from randomized clinical trial. After contractual barriers to accessing EHR, 
decision to use national CDC dataset as an observational arm for binomial analysis of 
probabilities between original group and laboratory confirmed cases. Final analysis 
based on dataset accessed 8-20-2021 
Analysis update 11-28-2021 – Dr. Swartout re-ran statistical analysis using updated 
information in CDC dataset accessed 11-4-2021. 
e. Contributors 
i. Statistician responsible: Kevin M. Swartout Department of Psychology, Georgia 
State University, Atlanta GA 
ii. Principal Investigator and SAP author: Amy Baxter, Department of Emergency 
Medicine, Augusta University, Augusta GA USA 
 
2. Introduction 
a. Background and rationale Research suggests that acidic pH and nasal viral load 
contribute to replication and disease severity of COVID-19. We plan to test saline nasal 
irrigation of 240cc with either alkalinized nasal saline or 0.1% virucidal povidone-iodine 
twice daily in participants recently testing positive for SARS-CoV-2. We hypothesize that 
nasal irrigation debridement with either the basic or virucidal intervention will be 
correlated with reduced COVID-19 progression to hospitalization, and reduction in 
symptom severity, supportive oxygen, and death in COVID-19 positive patients 55 years 
of age and older. 

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b. Objectives- To determine if twice-daily saline nasal irrigations with either 0.1% povidone-
iodine or 2.5 mL of baking soda in one of two over-the-counter irrigation devices in 
patients tested positive for COVID-19 improves clinical outcomes: 
i. Primary Outcome: To assess reduction in COVID-19-related hospitalizations and 
death compared to a national dataset. 
ii. Secondary Outcomes:  
1. Assess reduction in hospital visits, symptoms, admission, supplemental 
oxygen use, ICU admission, and death in patients with alkalinization or 
virucidal additives to nasal irrigation.  
2. Evaluate impact of nasal irrigation compared to published historical 
reports and meta-analyses of outcomes in similar patient groups 
including household spread. 
3. Evaluate impact of race, days of symptoms, and pre-existing conditions 
on utility of nasal irrigation to reduce adverse outcomes of any kind. 
3. Study Methods 
a. Trial design - a consecutive prospective, randomized parallel group trial to evaluate the 
efficacy of either alkalinization or povidone-iodine twice daily nasal irrigation initiated on 
the day of positive test notification for reduction of COVID-19 symptoms and disease 
progression to hospitalization or death. The enrolled participants were also compared to 
a national dataset as a nested case-cohort. 
b. Randomization - Block randomization to the twice daily irrigation with alkalinization or 
povidone-iodine was done by random number generator (random.org) stratified by sex. 
With odd numbers signifying alkaline and even povidone-iodine, numbered opaque 
envelopes were prepared in separate sequences for male or female participants to be 
opened after consent, indicating the appropriate additive to be given to the patient. The 
list of positives for the day from the lab were called in sequential order to obtain a 
consecutive sample that met all inclusion criteria and did not meet any exclusion criteria. 
On days with potential participant volume exceeding 10, the call order was randomized 
by random number generator. 
c. Sample Size - We assumed a baseline admission rate of 25%, with a small to moderate 
impact of the additive to the irrigant (Cohen’s d=3). To reduce hospitalizations to 10%, 
100 patients per group would be required for 80% power. Initial assumptions by the 
statistician were that irrigation additive as well as mechanical unit would be variables, 
thus the IRB approved protocol was for 400 patients. Published support that any 
pressurized unit was sufficient reduced the target enrollment to 200.  
After determining a zero hospitalization rate in early December, the trial’s revised target 
enrollment was 79 irrigation participants with 158 matched controls. Assuming that 25% 
of the matched control participants and 10% of the treatment participants would visit the 
hospital (60% reduction), 79 participants in the nasal irrigation condition would have .80 
(80%) power to detect that proportional difference. Power was calculated two ways, by 
running a simulation comparing the likelihood of hospitalization, and using a z-test 
comparing independent proportions. Both analyses assumed reduced variation in 
proportions due to accounting for the correlates of testing time, age, sex, and race, and 

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resulted in similar calculations. The inability to evaluate and match underlying conditions 
in the control group could increase variability, thus a 1:2 matching schema was chosen. 
d. Framework - The RINSI trial was completed using a probability of proportions framework, 
using an exact binomial test to assess the probability of observing the proportion of 
patients with morbidity or mortality in this study compared to a national rate. Initial 
comparisons between groups were conducted to evaluate superiority of either irrigation 
regimen. 
e. Statistical Interim Analyses and Stopping Guidance - An interim analysis was anticipated 
when half of enrollment had been achieved. The availability of monoclonal antibodies 
changing risk catetories, vaccinations, and end of year staffing concerns led to a decision 
to do an early interim analysis. With the discovery that none of the patients had been 
hospitalized, rather than conduct a full analysis a new power analysis was conducted, 
leading to the decision to enroll up to a target of 79 patients with 1:2 matched controls 
to speed publishing results. 
f. Timing of Final Analysis - The final analysis began after the 28-day outcome was 
completed for all participants January 18th. During the blinded collection of outcome 
data from the five hospitals in the catchment area, the discovery of blocked access due to 
legal agreements was made. Several months of discussion and meetings were not able to 
resolve access to the matched control data. In May and June, discussions with the 
Georgia Department of Public Health were undertaken to get access to case and 
hospitalization data without results. August 7th a CDC correspondence directed the team 
to the national database as a comparison cohort stratified by age, allowing the final 
analysis comparing the outcomes in enrolled patients compared to the CDC dataset last 
accessed 8/20/2021. 
g. Time points at which outcomes were measured: Primary outcomes were measured 28 
days after enrollment. Secondary outcomes of symptoms were collected daily via online 
survey for the first 14 days. Subjects were called on Day 2, 7, 14, and 28 to check on 
current symptoms and outcomes. 
4. Statistical Principles 
a. Confidence Intervals and P Values: alpha will be 0.05 and 95% confidence intervals will 
be reported for relative risk. Standard Error will be reported for exact binomial tests. 
b. Adherence and protocol deviations: Symptom outcomes will be reported for patients 
completing the daily symptom diary. Adherence to irrigation was recorded in daily online 
surveys, and confirmed with uploaded photographs of used saline packets or pods, or 
phone calls for patients unable to upload photographs.  
c. Analysis populations: The primary outcomes of hospitalization and death were by 
intention to treat. Adherence, symptom, and household spread will be reported for 
patients filling out a minimum of two daily surveys, and all completing initial survey. 
5. Trial Population 
a. Screening Data: We will report the number of patients with positive tests, the number 
reached, the number screened and reasons for non-enrollment. 
b. Eligibility:  
i. Inclusion Criteria - Capable of understanding and providing informed consent 
using remote consent; Willingness and physical capacity to initiate nasal 

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irrigation and to adhere to the protocol; Willing to give additional contact phone 
number of another person who will know the health status of the participant 
and agree to be contacted if needed for follow-up; 55 years of age or older; Has 
access to and the willingness and ability to adhere to the technological 
requirement of the study i.e. able to use a smartphone for voice and text and 
email and access to the internet at home; English speaking; Positive rapid 
COVID-19 test performed the day of or the day before enrollment 
ii. Exclusion Criteria - Currently doing daily nasal irrigation; Current supplemental 
oxygen therapy; Unwillingness to try nasal irrigation or use nasal irrigation twice 
a day; Nasal surgery within the past year or chronic sinusitis; Prior COVID-19 
infection or positive test >1 day before present; Symptoms longer than 7 days 
prior to testing as reported to researchers; Allergy to iodine or shellfish; 
Participation in another prospective COVID related research project (clinical 
trial). 
c. Recruitment: Information to be included in the CONSORT flow diagram: See Figure 1. 
Recruitment procedures are in Appendix 1. Reasons for refusal are in Appendix 2. 
d. Withdrawal and follow-up: Those discontinuing nasal irrigation will be reported with 
reasons.  
e. Baseline Characteristics: characteristics of all irrigation patients compared to CDC 
database characteristics will be reported, including sex, age, race, pre-existing conditions 
with mean and standard deviation where possible. 
6. Analysis 
a. Outcome Definitions –  
i. Primary Outcome: hospitalization or death from COVID-19 within 28 days of 
enrollment – Obtained by self-report, report of family member, and confirmed 
by chart review. For the purposes of the study, COVID-19 related chief 
complaints will include any of the top five symptoms associated with emergency 
department presentation: Cough, Fever (subjective or >100.4°F/38°C), Myalgia, 
Headache, or Dyspnea. Other ED presentations resulting in discharge without 
subsequent admission will not meet the criteria of morbidity severity related to 
this study. In cases where patients are admitted, discharge diagnosis or cause or 
contributing cause of death will be considered for categorization of COVID-
related or not-COVID related. In cases where potential for COVID-19 related 
admission or death is ambiguous, a member of the research team (MD) blinded 
to group will be asked to assess the information gathered from the chart and 
make a determination of COVID or non-COVID related. 
ii. Secondary Outcomes – Obtained by online surveys, in addition to confirmatory 
phone call information collected day 2,7,14, and 28.  
1. Duration of COVID-19 symptoms (loss of smell, fatigue, presence or 
absence of fever >100.4, subjective fever, chills, muscle aches, runny 
nose, cough (new onset or worsening of chronic cough), shortness of 
breath, nausea or vomiting, headache, loss of smell, abdominal pain, 
diarrhea (>3 loose/looser than normal stools/24 hours) 

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2. Confirmed or symptomatic household members with new cases after 
initiation of daily surveys 
3. COVID-19 related ED visits, supplemental oxygen use, ICU admission 
4. Dose-response of daily irrigation related to symptoms 
5. Adverse events related to irrigation, including discomfort not leading to 
or leading to discontinuation and reason 
b. Analysis methods –  
i. Primary Outcome -To compare observed hospital admission rates among 
participants compared with national rates of severe disease (admission or 
death) published by CDC, the binomial test was used. As it is an exact test, 
Clopper-Pearson confidence intervals were used giving a SE and P value. 
Relative risks were calculated for bad outcomes compared to the total number 
of cases, and hospitalization only when status was reported to give lower and 
upper ranges of impact given our concerns of reporting bias in the dataset. Chi 
squares were calculated for differences between demographics in the enrolled 
group and the national dataset. Deaths in patients for whom hospitalization 
were not reported were included in the numerator as an indicator of severity. 
ii. Differences by irrigant method. Prior to combining the randomized groups to 
compare with the national dataset, the plan was as follows: to examine sex and 
racial differences on the dependent variables, t-tests will be used unless non-
normal distribution is noted, in which case Mann Whitney U will be used. 
Baseline measures of duration, pre-existing conditions, and symptoms will be 
compared across the conditions to ensure that the randomization process was 
effective. Analyses of compliance by device and the previously mentioned 
dependent variables will be conducted to determine whether the brand of 
device impacted outcomes. If any of these analyses result in significant findings, 
they will be considered as covariates in subsequent analyses. To test the effect 
of treatment group in disease severity, Kaplan-Meier survival plots will be 
calculated. Pearson’s correlation coefficient will assess if an inverse linear 
relationship exists between number of irrigation uses and illness severity 
outcomes. 
c. Missing Data – Only laboratory confirmed cases were used. Hospitalization status yes or 
no was reported for 43% of laboratory-confirmed CDC case records in correlating age 
ranges and the same enrollment time period. To avoid overestimating by reporting bias, 
we calculated the admission rate retaining all laboratory-confirmed cases in the 
denominator, including when hospitalization status was missing or unreported.  
(Hospitalizations reported yes)  
______________________________________________________ 
(Hospitalization Yes + No + Unknown + Missing) 
 
Because there were no deaths in our sample, we could not calculate a comparative rate 
with the national database. To capture the burden of mortality which likely was or 
should have been preceded by hospitalization, we included deaths as an additional 
measure of severity only when hospitalization was unknown or missing. Thus, the rate 
of deaths is under-estimated. 

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Deaths reported 
___________________________________ 
 (Hospitalization Unknown + Hospitalization Missing) 
 
We did not include deaths in cases where hospitalizations are reported in our analysis to 
avoid counting outcomes with increased severity twice. Thus the comparison rate used 
for binomial testing was: 
 
Hospitalizations + Death when hospitalization unknown or missing 
(Hospitalizations Yes + No + Unknown + Missing) 
d. Harms – Adverse events are summarized in Table 3. 
e. Statistical Software - IBM SPSS Statistics for Windows, Version 27.0. 
Armonk, NY: IBM Corp; (MedCalc Software Ltd. 
https://www.medcalc.org/calc/relative_risk.php (Version 20.009))   
 
 

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Appendix 1: Final Full Recruitment Methods and Demographics 
Recruitment 
 
There will be two groups of participants: an active (exposed to intervention) group and a 
passive control group. The passive “nonexposed” control group (not interested in enrolling 
or not able to be contacted ) will be people 55 years of age and older who tested positive 
for COVID-19 during the time period of the study that were not enrolled in the study. The 
names and birthdays of these individuals will be collected so that approximately 4 weeks 
later the EMR can be searched to see if they sought care at an Emergency Department or 
were hospitalized for COVID-19 related symptoms. The other group of participants will be 
the active group.  
Active participants will be community outpatients who have tested positive for COVID-19. 
Participants will be recruited by obtaining a list of outpatient positive results from the AU 
testing center of patients age 55 years or older. Persons on this list will be called by a 
member of the research team and asked if they are interested in participating in the study. 
If they do not pick up the phone a voice mail will be left (see script) and they will be called 
back up to two additional times (unless the participant calls us back first). 
At the AU local testing site potential participants will be given an informational flyer about 
the study.  The flyer will also be made into posters that will be posted at the testing site. 
The flyer will explain that if they test positive they may be eligible to participate in a 
research study evaluating the effects of nasal irrigation on symptoms associated with 
COVID-19, and instructing them to call the number on the flyer for more information when 
their positive test result returns. The flyer will also provide information about the on-line 
health care portal which can be used to obtain test results more quickly. In addition to the 
flyer a banner will be added to the health care portal informing users about the study and 
providing contact information where they can learn more. A minimum of once a day a 
member of the research team will obtain the list of positive results from the on-site testing 
facility.  Those individuals who tested positive and who meet study inclusion criteria will 
be called and asked if they are interested in participating in the study (see phone script). If 
patient is interested in hearing more the study will be explained and remote consent will 
be obtained. Participants will be asked to enter the phone number of the research team 
into their cell phone in order easily identify future calls. 
4.1.1. Eligible participants will be consented remotely and their study materials (consisting of a 
nasal irrigation device (Neilmed sinus irrigation bottle or Navage unit) with 28+ 
accompanying saline pods/packets, two gallon jugs of distilled water, a physical copy of 
the consent form, an instructional sheet, and the randomly allocated additive (baking soda 
or betadine) with a ½ tsp scoop), will be delivered to their residence by a member of the 
research team using COVID-19 precautions (masks, maintaining 6 ft. or more physical 
distance, door drop off) later that day.  

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The Neilmed and Navage irrigation devices will be distributed on alternating days with the 
goal of distributing them evenly among participants to avoid conflicts of interest. Neilmed 
will be distributed on Monday, Wednesday, Friday, and Sunday, while Navage will be 
Tuesday, Thursday, and Saturday.   
After having the study procedures explained to them and consenting to the research, the 
Active participants will be provided with an instructional sheet along with their research 
materials. This sheet will contain detailed instructions on how to mix ½ tsp of their 
allocated additive into the saline solution and perform a nasal irrigation, and include 
instructions on how to view a Youtube video demonstrating how to conduct a nasal 
irrigation with the provided device. The Active participants will be instructed to perform 
nasal irrigation twice a day for the next 14 days, ideally with a window of at least six hours 
between irrigations. The participants will be provided with instructions on how to access 
the online surveys, which are distributed to them each day through their email.  
Irrigation data will be collected over Qualtrics surveys, which will be delivered on a daily 
basis to the participants email address for a period of 14 days following enrollment. In 
addition to the number of irrigations performed each day, the Qualtrics surveys collect 
background information related to demographic, medical history, current medications, 
current symptoms, and daily adherence by way of a photograph of the used saline 
containers. The participants will be called for follow-up on days 2, 7, 14, & 28. Participants 
who have not filled out a survey for two consecutive days will be called at any time during 
the first 14 days, and the total number of irrigations performed will also collected verbally 
over the phone on the 14th day of participation if the patients are unable to upload 
pictures to the database. On the 28th day, the participants or their designated follow-up 
person will be asked about hospitalizion or medical care related to COVID-19 within the 
study period. A chart review of the EHR containing data from the five community hospitals 
will also be conducted to determine the same. 
 
 
 
 

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Appendix B – Final Protocol 
Nasal Irrigation to Reduce COVID-19 Morbidity 
 
NCT04559035 
 
Revision: 1/11/2021 
 
 
 

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Protocol Title: [COVID-19] Saline Nasal Irrigation to Reduce COVID-19 Severity   
Principal Investigators: Amy Baxter, MD; Matt Lyon, MD 
1. Objectives 
Describe the purpose, specific aims, and hypothesis:  
Research suggests that acidic pH and nasal viral load contribute to replication and disease severity 
of COVID19. We plan to test saline nasal irrigation with either Alkalinized nasal saline or ½ tsp of 
the virucidal povidone-iodine twice daily in patients recently testing positive for SARS-CoV-2. We 
hypothesize that nasal irrigation debridement with either the basic or virucidal intervention will be 
correlated with reduced COVID-19 progression to hospitalization, and reduction in symptom 
severity, supportive oxygen, and death in COVID-19 positive patients 55 years of age and older 
Specific Aims: 
Evaluate the number of twice-daily saline nasal irrigations with either povidone-iodine or ½ tsp of baking soda in one 
of two over-the-counter irrigation devices in patients tested positive for COVID-19 with regards to clinical outcomes. 
 
      Technical Objective 1: To assess reduction in COVID19-related hospital visits, symptoms,  admission, supplemental 
oxygen use, ICU admission, and death in patients with differing nasal irrigation frequency. 
 
Technical Objective 2: Assess reduction in hospital visits, symptoms, admission, 
supplemental oxygen use, ICU admission, and death in patients with alkalinization or 
virucidal additives to nasal irrigation.  
 
• 
Evaluate impact of nasal irrigation compared to published historical reports and meta-analyses of outcomes in 
similar patient groups including household spread. 
• 
Evaluate impact of nasal irrigation on COVID-19 related hospitalization compared to hospitalization data in 
matched control group.  
• 
Evaluate dose-response of irrigation to clinical outcomes as noted above. 
• 
Evaluate impact of race, days of symptoms, and pre-existing conditions on utility of nasal irrigation to reduce 
adverse outcomes of any kind. 
Click here to enter text. 
 
 

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Describe the background and rationale for the study: 
 
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogen is a single stranded positive sense RNA virus, 
with a similar spike receptor binding mechanism as SARS-CoV and MERS-CoV. Clinical coronavirus disease 2019 (COVID-
19) caused by the pathogen differs in several notable ways from previous viral coronaviridae: younger patients are dramatically 
less impacted than the elderly; obesity, diabetes, race and hypertension are independent risk factors; male patients fare more 
poorly than females; the duration from infection to mild symptoms to severe symptoms averages 14-17 days; anosmia is present 
in up to 80% of patients; and asymptomatic transmission is common. 
 
Recent work demonstrates that the attack entry overwhelmingly occurs via respiratory or aerosolized droplets entering in the 
nasal mucosa at the ACE2 receptors in ciliated epithelial cells,(1) explaining many of the clinical pathogenic differences. Nasal 
ACE2 receptors are upregulated in obesity, diabetes and hypertension. Children have minimally developed sinuses, lower 
expression of ACE2 and TMPSSR genes, and much smaller nasal cavities compared to adults, with males over 70 having 
significantly larger cavities and mucosa than women.(2) Furthermore, viremia is infrequent, supporting the hypothesis of local 
mechanical spread of the virus toward the lungs as a predominant means of infectivity. Alternately, genetic expression of the 
ciliated nasal ACE2 and TPMSSR genes has been shown to activate expression in the lungs. 
 
The preponderance of nasal entry and the slow time frame for sufficient viral replication suggest that a topical debridement may 
reduce the viral load and ability of the virus to replicate sufficiently, allowing time for immune response without inciting an 
overwhelming cytokine storm. While drug treatment tests are ongoing, the nasal entry point and previous work in reduction of 
viral load and symptoms with other pathogens suggest topical antiviral and pH changing interventions could be uniquely 
effective at reducing attachment, viral fusion, and viral load, thus reducing morbidity and mortality. 
 
Significance 
If this study yields positive results and shows nasal irrigation to be a safe, inexpensive and accepted 
method for reducing COVID19 severity in a racially diverse and economically challenged population at 
higher risk for morbidity and mortality, it will potentially save hundreds of thousands of lives. 
 
Research & Development by others 
1) Nasal viral load is highly proportional to infectivity.(4) Mechanically flushing out SARS-CoV-2 would be expected 
to reduce the viral load.  
2) The nasal mucosa is specifically the site of SARS-CoV-2 entry; ACE2 receptors are highly expressed in nasal 
epithelial cells.(1) Indeed, an intranasal inhibitor of spike fusion eliminated disease in mice exposed to SARS-
CoV-2. “Intranasal application of EK1C4 before or after challenge with HCoV-OC43 protected mice from 
infection, suggesting that EK1C4 could be used for prevention and treatment of infection by the currently 
circulating SARS-CoV-2 and other emerging SARSr-CoVs.”(3) 
3) Mechanical reduction of cellular infection: The viral lipid layers of SARS-CoV-2 need to fuse after the spike 
attaches to ACE2 receptors, so physical flow of nasal irrigation may reduce likelihood of intracellular fusion 
and thus infection. Per the Nature article, “Our data highlight the possibility that viral transmissibility is 
dependent on the spatial distribution of receptor accessibility along the respiratory tract.” 

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4) Buying immunologic time: given the apparent mechanical rather than blood-borne slow advance of COVID-2 
illness from nasopharnyx to oropharynx to trachea to lung, the possibility exists that reducing viral load through 
debriding could aid effective immune response in the same way that debriding burns reduces time of healing. 
People with obstructive illnesses and patients over 80 have dramatically increased lung connections, the 
collateral ventilation through channels of Lambert and Pores of Kohn. Again, children under 5 do not have this 
system, lending credence to the surface area/mechanical model of viral severity. The respiratory spread of 
SARS-COV also spread mechanically, but more efficiently in lungs,(5) supporting interventions prior to 
respiratory progression. 
5) Irrigation works for colds: Nasal lavage (rinsing) seems better than spray. Multiple RCTs show statistically 
significant results, and the mechanical concepts of COVID lend greater rationale than upper respiratory 
infections with shorter incubation periods. In addition, nasal irrigation significantly reduce not only load but 
duration and severity of other viral illnesses even when symptoms had been established as much as 48 hours.(6, 
7) Given the slow progression of COVID-19, earlier initiation of irrigation in positive patients not yet requiring 
hospitalization could have a more marked impact on reducing morbidity. 
6) Nasal antimicrobial reduces viral infections in bovine animals: from 28% in those pre-treated with one intranasal 
NO dose compared to 78% of animals treated with saline placebo.(8) For humans, dilute povidone-iodine is 
widely used for chronic sinus infections and decolonizing before surgery.(9-12) 
7) SARS-CoV-2 may have difficulty fusing with alkaline pH. Previous coronaviridae have needed acidic or neutral 
pH for the lipid layer between virus and cell to fuse. Alkalinizing the nares may help. The fact that African 
Americans have more acidic nasal mucosa (6.4 compared to 6.8 in whites) could contribute to the differential 
infection rate,(13) rendering this intervention helpful in a population with higher attack rates and severity. In 
addition, drug targets such as zinc, quercetin, and ivermectin act by prohibiting the acidification of the 
endosomes where viral replication takes place. Providing weak base through mild alkalinization to 7.3 could 
directly reduce the ability of viral replication. 
8) SARS-CoV-2 is sensitive to povidone-iodine solution,(14) as are other viral pathogens,(15) and it  is safe for the 
nasal passages.(9) 
9) Mortality in countries where nasal irrigation is widespread is dramatically lower than in countries where irrigation 
is not standard. Thailand, Vietnam, Laos and Cambodia have populations in which up to 80% of the population 
commonly use nasal irrigation.(6, 16, 17) Death rates there are fractional compared to other countries which 
only wear masks or bow in greeting but do not have a cultural habit of irrigation. 
 
         FDA regulations.  The components of the device – an intranasal irrigation device hand-powered- is rated Class I 
510(K) Exempt 874.5550 Product Code KMA. Povidone-Iodine (Betadine) is an FDA approved over the 
counter drug at strengths of 10% and above and is labeled and indicated for nasal use NDA 019476. 
 
References 
 
1 Sungnak W, Huang N, Becavin C, et al. SARS-CoV-2 entry factors are highly expressed in nasal 
epithelial cells together with innate immune genes. Nature medicine. 2020 Apr 23. 
 
2 Loftus PA, Wise SK, Nieto D, Panella N, Aiken A, DelGaudio JM. Intranasal volume increases with age: 
Computed tomography volumetric analysis in adults. The Laryngoscope. 2016 Oct;126(10):2212-5. 

15 
 
 
3 Xia S, Liu M, Wang C, et al. Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly 
potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate 
membrane fusion. Cell research. 2020 Apr;30(4):343-55. 
 
4 Stilianakis NI, Drossinos Y. Dynamics of infectious disease transmission by inhalable respiratory 
droplets. Journal of the Royal Society, Interface. 2010 Sep 6;7(50):1355-66. 
 
5 Sims AC, Burkett SE, Yount B, Pickles RJ. SARS-CoV replication and pathogenesis in an in vitro model 
of the human conducting airway epithelium. Virus research. 2008 Apr;133(1):33-44. 
 
6 Kanjanawasee D, Seresirikachorn K, Chitsuthipakorn W, Snidvongs K. Hypertonic Saline Versus 
Isotonic Saline Nasal Irrigation: Systematic Review and Meta-analysis. American journal of rhinology & 
allergy. 2018 Jul;32(4):269-79. 
 
7 Ramalingam S, Graham C, Dove J, Morrice L, Sheikh A. A pilot, open labelled, randomised controlled 
trial of hypertonic saline nasal irrigation and gargling for the common cold. Scientific reports. 2019 Jan 
31;9(1):1015. 
 
8 Regev-Shoshani G, Church JS, Cook NJ, Schaefer AL, Miller C. Prophylactic nitric oxide treatment 
reduces incidence of bovine respiratory disease complex in beef cattle arriving at a feedlot. Research in 
veterinary science. 2013 Oct;95(2):606-11. 
 
9 Bruyere F, Laine P, Saint-Jalmes G, Malavaud S, Pradere B. Mucosal impact of alcoholic povidone-
iodine indicated in preoperative disinfection. The Journal of hospital infection. 2020 Mar;104(3):302-4. 
 
10 Eggers M, Eickmann M, Zorn J. Rapid and Effective Virucidal Activity of Povidone-Iodine Products 
Against Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and Modified Vaccinia Virus 
Ankara (MVA). Infectious diseases and therapy. 2015 Dec;4(4):491-501. 
 
11 Kariwa H, Fujii N, Takashima I. Inactivation of SARS coronavirus by means of povidone-iodine, 
physical conditions, and chemical reagents. The Japanese journal of veterinary research. 2004 
Nov;52(3):105-12. 
 
12 Rieser GR, Moskal JT. Cost Efficacy of Methicillin-Resistant Staphylococcus aureus Decolonization 
With Intranasal Povidone-Iodine. The Journal of arthroplasty. 2018 Jun;33(6):1652-5. 
 
13 Ireson NJ, Tait JS, MacGregor GA, Baker EH. Comparison of nasal pH values in black and white 
individuals with normal and high blood pressure. Clinical science (London, England : 1979). 2001 
Mar;100(3):327-33. 
 
14 Eggers M, Koburger-Janssen T, Eickmann M, Zorn J. In Vitro Bactericidal and Virucidal Efficacy of 
Povidone-Iodine Gargle/Mouthwash Against Respiratory and Oral Tract Pathogens. Infectious diseases 
and therapy. 2018 Jun;7(2):249-59. 
 

16 
 
2. Background 
 
15 Panchmatia R, Payandeh J, Al-Salman R, et al. The efficacy of diluted topical povidone-iodine rinses in 
the management of recalcitrant chronic rhinosinusitis: a prospective cohort study. European archives of 
oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies 
(EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery. 2019 
Dec;276(12):3373-81. 
 
16 Piromchai P, Puvatanond C, Kirtsreesakul V, Chaiyasate S, Thanaviratananich S. Effectiveness of nasal 
irrigation devices: a Thai multicentre survey. PeerJ. 2019;7:e7000. 
 
17 Nimsakul S, Ruxrungtham S, Chusakul S, Kanjanaumporn J, Aeumjaturapat S, Snidvongs K. Does 
Heating up Saline for Nasal Irrigation Improve Mucociliary Function in Chronic Rhinosinusitis? American 
journal of rhinology & allergy. 2018 Mar;32(2):106-11. 
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17 
 
3. Inclusion and Exclusion Criteria 
List the inclusion/exclusion criteria: 
 
Inclusion Criteria 
• 
Capable of understanding and providing informed consent using remote consent 
• 
Willingness and physical capacity to initiate nasal irrigation and to adhere to the protocol 
• 
Willing to give additional contact phone number of another person who will know the health status of the participant and 
agree to be contacted if needed for follow-up 
• 
55 years of age or older 
• 
Has access to and the willingness and ability to adhere to the technological requirement of the study i.e. able to use a 
smartphone for voice and text and email and access to the internet at home 
• 
English speaking  
• 
Positive rapid COVID-19 test performed the day of or the day before enrollment 
 
Exclusion Criteria 
• 
Currently doing daily nasal irrigation 
• 
Current supplemental oxygen therapy 
• 
Unwillingness to try nasal irrigation or use nasal irrigation twice a day 
• 
Nasal surgery within the past year or chronic sinusitis 
• 
Prior COVID-19 infection or positive test >1 day before present 
• 
Symptoms longer than 7 days prior to testing as reported to researchers 
• 
Allergy to iodine or shellfish 
• 
Participation in another prospective COVID related research project (clinical trial). 
 
 
Click here to enter text. 
 
4. Number of Subjects/Records/Samples Collected 
Indicate the total number of subjects to be accrued/records reviewed/samples collected across all sites: 
400 
 
5. Recruitment Methods 
Describe when, where, and how potential subjects will be recruited: 
There will be two groups of participants: an active (exposed to intervention) group and a passive control group. The passive 
“nonexposed” control group (not interested in enrolling or not able to be contacted ) will be people 55 years of age and older 
who tested positive for COVID-19 during the time period of the study that were not enrolled in the study. The names and 
birthdays of these individuals will be collected so that approximately 4 weeks later the EMR can be searched to see if they 
sought care at an Emergency Department or were hospitalized for COVID-19 related symptoms. The other group of 
participants will be the active group.  

18 
 
Post Procedure Measures (n = 200): Treatment diary; clinical outcomes called weekly 
 
Active participants will be community outpatients who have tested positive for COVID-19. Participants will be recruited by 
obtaining a list of outpatient positive results from the AU testing center of patients age 55 years or older (See data collection 
form.) Persons on this list will be called by a member of the research team and asked if they are interested in participating in 
the study. If they do not pick up the phone a voice mail will be left (see script) and they will be called back up to two 
additional times (unless the participant calls us back first). 
 
At the AU local testing site potential participants will be given an informational flyer about the study (see recruitment flyer).  
The flyer will also be made into posters that will be posted at the testing site. The flyer will explain that if they test positive 
they may be eligible to participate in a research study evaluating the effects of nasal irrigation on symptoms associated with 
COVID-19, and instructing them to call the number on the flyer for more information when their positive test result returns. 
The flyer will also provide information about the on-line health care portal which can be used to obtain test results more 
quickly. In addition to the flyer a banner will be added to the health care portal informing users about the study and 
providing contact information where they can learn more. A minimum of once a day a member of the research team will 
obtain the list of positive results from the on-site testing facility.  Those individuals who tested positive and who meet study 
inclusion criteria will be called and asked if they are interested in participating in the study (see phone script). If patient is 
interested in hearing more the study will be explained and remote consent will be obtained. Participants will be asked to 
enter the phone number of the research team into their cell phone in order easily identify future calls.  
 
Flow Chart of Study Recruitment and randomization 
 
 
 
 
 
 
 
 
 
 
Testing Patient Pool (n = 600/day) 
Block Randomized by sex and race to 
intervention  
Study Sample positive/day 10%+ n=60 
Study Sample positive over 55 years (n=24/day) 
 Measures: Demographic, symptoms, treatments 

19 
 
6.   Multiple Site                                                                    ☐ X  N/A                                                   
A site is defined as an institution/organization/university that is collaborating with Augusta University 
 
If this research involves multiple sites, specify which is the lead site and describe the roles of each site in the study. 
 
If Augusta University will serve as the lead site, indicate that all required approvals are already obtained or will be obtained at 
each site prior to project implementation. In addition: 
 
Describe the processes you have in place to ensure successful coordination of activities among sites. For example, do all sites 
have the most current version of the protocol, consent document, and HIPAA authorization? How will modifications be 
communicated to sites and approved prior to implementation? How will participating sites be kept abreast of any problems, 
interim results, or the eventual closure of the study? 
 
Describe the mechanisms you have in place to ensure that all local site investigators conduct the study appropriately and that 
engaged participating sites safeguard data as required by local information security policies. Please confirm that all non-
compliance  and /or unanticipated problems associated with the study protocol or applicable requirements will be reported in 
accordance with local policy. 
 
Click here to enter text. 
7. Reliance Agreements/Single IRB                                ☐ X  N/A                                                       
Reliance agreements (i.e. IRB Authorization Agreement (IAA), Individual Investigator Agreement (IIA), etc.) are formal 
arrangements between institutions allowing the IRB of one institution to rely on the IRB of another institution for review of 
human subjects research. Investigators working at multiple institutions, each having an IRB, may choose to have one IRB 
become the IRB of record over some or all participating sites. This means that the AU IRB is either the reviewing IRB (IRB of 
Record) or is relying on another IRB for IRB oversight of the research activity.  
 
If the study will utilize a reliance agreement or a single IRB, please describe which institution(s) will be relying on another IRB 
for review and which institution will be responsible for the IRB oversight of the relying IRB(s). 
 
Note: Requests for Reliance Agreements should be submitted by the Augusta University study team. All request for Reliance 
Agreements should be submitted through IRB Net following the procedures outlined in Forms and Templates 
 
Click here to enter text. 
 
 
8. Procedures Involved 
 
a. Describe the procedures involved to include those procedures that are standard evaluation 
and/or care and those that are solely for research purposes: 
For research purposes: 
Following consent– Block randomization to the twice daily irrigation with alkalinization or betadine will be done by 
random number generator. Out of the list of positives for the day (from both the lab and any call ins) we will call in 
sequential order to obtain a consecutive sample that meets all inclusion criteria and do not meet any exclusion criteria.  
 
For the other patients on the list from the lab who tested positive for COVID-19 and meet 
screening criteria (age 55 or older, etc.) their information will be kept on a password protected 
spreadsheet and stored on the _HUMAN folder in box (also referred to as a research box) so that 
approximately one month later we can go back and determine hospitalization rates to be 

20 
 
compared to the hospitalization rate of the study group.  
 
 
Following consent participants will have a box of study supplies delivered to their residence by a member of the research 
team using COVID-19 precautions (masks, maintaining 6 ft. or more physical distance, door drop off). At this time the 
research team member will ask the participant to confirm receipt of the materials via text. 
 
Either NeilMed nasal irrigation unit or Navage will be available on different days, with a goal of 50% of each device used 
in order to avoid concerns about conflict of interest.  
  
Participants will be called (Day 2 call) after they receive their materials to answer any questions. Directions for nasal lavage 
will be included with the materials and via email. Participants will be instructed to watch a 1 minute video 
https://www.youtube.com/watch?v=DYZDeiOVJx0  on days with NeilMed supplies, or  
https://www.youtube.com/watch?v=qIfgNNLX1L8 if they received a Navage. 
 
Intervention – twice-a-day nasal lavage 
Twice-a-day virucidal group: Participants randomized to betadine will receive 2 gallon jugs of distilled water, two NeilMed 
Sinus Irrigation bottles and 28 salination packets (with some extras), OR one Navage unit with 28 SaltPods (and some 
extras), and a cardboard receptacle labeled “used saline containers” to keep track of adherence.  
 
Those randomized to receive betadine will also receive one bottle of povidone-iodine, a one-sheet instruction with 
photographs demonstrating how to add ½ tsp betadine in addition to the salination packet to the sinus irrigation bottle or 
Navage unit reservoir prior to SaltPod, along with a ½ tsp measuring spoon.  
 
Twice-a-day alkalinized group: Participants randomized to alkalinization will receive 2 gallon jugs of distilled water, two 
Neilmed bottles with 28 saline packets, OR one Navage unit with 28 SaltPods, and a cardboard receptacle labeled “used 
saline containers” to keep track of adherence. Those randomized to alkalinization will also receive a box of baking soda, ½ 
tsp measuring spoon and instructions on how to add the baking soda. 
 
When study materials are procured the identifying information for the products (lot number, etc.) 
will be recorded so that we can track what materials were given to the participants. We will use 
the accountability log and the device accountability log (see attached).  
 
As part of the materials box an instruction sheet will be included (see attached) that will detail the 
process for nasal irrigation and equipment cleaning. The websites for on-line resources will be 
included as well as study team contact information. Participants will be reminded on the 
instruction sheet that they should be the only one using the equipment for their safety and the 
safety of other household members. Information on this sheet will also include procedures for 
tracking material use via Qualtrics (see data collection sheet) and remind participants that at the 
end of the study they will keep or discard of all used and unused materials but that none are to 
be returned to researchers nor transferred to another person.  
 
Prompts to complete study materials (see attached) will be sent to participants (text and/or email) 
via Qualtrics twice a day for the duration of the study period. 

21 
 
 
• 
Measures 6.1, 6.2, 6.3 (below) will be collected one time on enrollment. 
• 
Measures 6.4, 6.5 will be collected in daily log on paper or online survey  
Measure 6.6 will be collected at study conclusion after study day 28. If hospitalization occurred we 
will gather this information from The Georgia Regional Academic Community Health Information 
Exchange (GRAChIE) which serves healthcare providers across Georgia bringing health information 
from one healthcare professional to another, seamlessly connecting health information. GRAChIE 
health information exchange allows healthcare professionals to appropriately access and securely share 
a patient’s health information electronically through a member’s EMR system. 
6.1 Background information. Patients will complete a demographic questionnaire that includes age, date of birth, residence type 
(homeless, single family, apartment living or group living), county of residence, sex (male, female, unknown, other), race, 
and ethnicity. (See data collection instrument.) 
 
6.2 Patient medical history. Patient will be asked preexisting medical history as found on the CDC person of interest form, 
including Chronic Lung disease (Emphysema, COPD), Asthma, Type 1 Diabetes Mellitus, Type 2 Diabetes Mellitus, 
Cardiovascular Disease, Hypertension, Chronic Renal Disease, Weight and height to calculate obesity with BMI>30, 
Immunocompromised condition (if YES specify medications they are taking), Current cancer, Current Smoker, treatment if 
any, and symptoms.  (See data collection instrument.) 
 
6.3 Interventions: Patients will be asked if they have used any interventions against COVID, including acetaminophen, 
ibuprofen, DOAN’s Packets, aspirin, Melatonin, Vitamin C, Vitamin D, Quercetin, Zinc, Chinese Traditional Medicines, or 
other. (See data collection instrument.) 
 
6.4 Current Symptoms. Patient will be asked for number of days since first subjectively sick, loss of smell, loss of taste, fatigue, 
presence or absence of fever >100.4 (if yes how many days), subjective fever, chills, muscle aches, runny nose, cough (new 
onset or worsening of chronic cough), shortness of breath, nausea or vomiting, headache, abdominal pain, diarrhea (>3 
loose/looser than normal stools/24 hours). (See data collection instrument.) 
 
6.5 Daily Adherence: Participants will receive two daily reminders to do nasal irrigation and subsequent verification, and 
asked to keep a daily study diary using Qualtrics. The additive packages for nasal irrigation will be attached to a one page 
card with numbers and days to help patients visually assess whether they have done it yet that day. During the daily 
verification participants will be asked to report from their diary the presence or absence of the following symptoms: loss of 
smell, fatigue, cough, muscle aches, harder to breathe, AND to report any other medications taken, AND to provide a 
photograph of this card as well as the number of used packets in the box. (See data collection instrument.) 
 
An investigator will call the patient or their designated contact at Day 2, 7, 14, and 28. 
 
6.6 Outcomes: The following outcomes will be collected via GRAChIE as described above (see data collection spreadsheet): 
visit to an emergency department Y/N; chief complaint was the patient hospitalized y/n (if yes admission date/discharge 
date); was the patient administered supplemental oxygen y/n was the patient admitted to an intensive care unit y/n was 

22 
 
patient mechanically intubated Y/N was patient given assisted ventilation with CPAP/HighFlow/BIPAP Y/N did the patient 
die as a result of this illness Y/N (date of death). 
 
For the purposes of the study, COVID-19 related chief complaints will include any of the top 
five symptoms associated with emergency department presentation: Cough, Fever 
(subjective or >100.4°F/38°C), Myalgia, Headache, or Dyspnea.18 Other ED presentations 
resulting in discharge without subsequent admission will not meet the criteria of morbidity 
severity related to this study. In cases where patients are admitted, discharge diagnosis or 
cause or contributing cause of death will be considered for categorization of COVID-related or 
not-COVID related. In cases where potential for COVID19 related admission or death is 
ambiguous, a member of the research team (MD) will be asked to assess the information 
gathered from the chart and make a determination of COVID or non-COVID related. 
 
18. MMWR Morb Mortal Wkly Rep. 2020;69(24):759   
 
8.1. Participants will receive two prompts a day to complete the nasal lavage and complete the data collection diary. 
8.2. Participants who opt for the online data collection tool will be provided with a phone call to follow up on data 
collection when they don’t complete online data collection for two days. In the case of a patient reporting a summary 
number of irrigation events or a range of irrigation events, the estimate or median number of irrigation events range 
will be used for analysis. If no data is obtained after confirmation of the initial irrigation, the patient’s data will be 
excluded from the continuous variable irrigation analyses, but will be included in analysis of betadine/alkaliniaztion 
and Navage/Neilmed by intention to treat. 
8.3. Sources of Research Material – See “measures”. Background information will be obtained from the patient at the time 
of enrollment. (see Measures). Outcomes will be assessed by records stored in GRAChIE and from the participant and 
designated contact person.  
8.4. Instrument - For the study, an irrigation diary will be created, and packets of nasal irrigation will be attached to a one 
page card with numbers and days to help patients visually assess whether they have done it yet that day. A photograph 
of this card will be requested as part of the patient diary. 
8.5. Follow-up – An investigator blinded to allocation will call the patient on Day2, Day 7, Day 14 and Day 28 to check on 
their current symptoms (if the participant is unable to be contacted after three attempts on any of these designated days 
the secondary contact will be called up to three times to check on the participant's current symptoms. 
 
For the control group, after enrollment is stopped, eligible patients with a positive test who 
were not enrolled will be separated into two groups: those who refused enrollment and 
those who were not able to be reached or responded too late to be enrolled on the day of 
contact. One control will be chosen from each group by the following criteria: sex, race, 
age +/- 2 years, date of test +/- 1 week. If there are no matches following this schema, 
date of test will be expanded to +/- two weeks. If race is listed as “unspecified”, initial 
experience with enrolled patients supports that commonly this is chosen by Black patients. 
Thus, when matching with a Black patient, two “unspecified” matches will be chosen and 
searched in order in GRAChIE. The first patient with matching race will be the Control 
included. If the criteria for matching cannot be met with 1 from each of the “refused” and 
“uncontacted” pools, two matches will be found in the other pool. The EMR will then be 
searched for the following information from the Control group within 28 days of the day 

23 
 
they could have been enrolled (see data collection spreadsheet) : visit to an emergency 
department Y/N, chief complaint; was the patient hospitalized y/n (if yes admission 
date/discharge date); was the patient administered supplemental oxygen y/n); was the 
patient admitted to an intensive care unit y/n was patient mechanically intubated Y/N); was 
patient given assisted ventilation with CPAP/HighFlow/BIPAP Y/N did the patient die as a 
result of this illness Y/N (date of death). 
 
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b. Describe and explain the study design: 
If the study involves multiple conditions where each condition involves different procedures, 
please provide a table that breaks down the procedures by condition and in chronological 
order. Include when and where they are performed. 
This is a single center randomized controlled non-blinded clinical efficacy study evaluating nasal 
irrigation with either alkalinized saline or dilute Povidone-Iodine twice a day for 14 days for the 
reduction of COVID-19 severity in COVID+ outpatients. 
Click here to enter text. 
c. Data Types and Source Records: 
          Briefly describe the actual source records or measures that will be used to collect data about                    
participants. (All surveys, interview scripts, and data collection forms will be attached elsewhere in the application. 
Do not add other documents to the protocol.)  Describe what data will be collected and how it will be collected at all 
measurement/data collection time-points. 
 
d. Describe the procedures performed to lessen the probability or magnitude of risks: 
Data will be collected via Qualtrics, phone calls, and GRAChIE. Information will be stored and 
collected in a coded manner. Data will be stored in the _HUMAN folder in Box (also 
referred to as a research box) for secure storage. A master code list will be used to assign a 
study number to each participant.  
In addition, we will be following all CDC guidelines and Augusta University research policies 
in the collection of this data. We have designed the study to use existing infrastructure 
possible to recruit for the study and will use masks and social distancing for no-contact 
study material delivery by a member of the research team. 
Clk hereto enter text. 
e. Describe the duration of an individual subject’s participation in the study and the time 
involved also include the overall duration of the project: 
A participant’s involvement in the study will last 28 days from the time of enrollment. For the 
first 14 days approximately 15-30 minutes will be involved in order to complete both nasal 

24 
 
lavages as well as to provide information in the daily diary, and respond to prompts or 
phone calls.  
Click here to enter text. 
 

25 
 
 
9. Data and Specimen Management 
 

26 
 
a. Describe the data analysis plan, including any statistical procedures: 
Interim analysis planned at 200 patients. In the event that the patients enrolled show 
an overwhelming trend toward less or greater severity or lack of efficacy with 
povidone-iodine versus alkalination for safety or for preponderance of efficacy of 
irrigation itself, study will be halted to analyze the case: control outcomes for 
disease severity: ED visit, admission, ICU, death, and historic outcomes for 
household transmission. The povidone-iodine/alkalinization and frequency of 
irrigation endpoints will be evaluated separately as power permits.  
 
8.6. Endpoints 
8.6.1. 
Primary – Primary outcome will be a statistical difference between need for hospitalization 
visit by number of nasal irrigations completed and by group. The case:control analysis will 
be conducted by intention to treat. 
8.6.2. 
Secondary - Secondary outcomes include differences between symptoms, supplemental 
oxygen use, ICU admission, mortality.  
   
Statistical Analysis -  Initial analyses will be conducted to determine whether demographic variables are 
related to the following dependent variables: hospital visit; oxygen use; admission; ICU admission; mortality. 
To examine sex and racial differences on the dependent variables, t-tests will be used unless non-normal 
distribution is noted, in which case Mann Whitney U will be used. Baseline measures of duration, pre-
existing conditions, and symptoms will be compared across the conditions to ensure that the randomization 
process was effective. Analyses of compliance by device and the previously mentioned dependent variables 
will be conducted to determine whether the brand of device impacted outcomes. If any of these analyses 
result in significant findings, they will be considered as covariates in subsequent analyses. To test the effect 
of treatment change in disease severity, either t-tests for normally distributed data or the Mann-Whitney will 
be used. Pearson’s correlation coefficient will assess if an inverse linear relationship exists between number 
of irrigation uses and illness severity outcomes. 
9.2.1 
Based on histogram plotting of the main outcome variable, hospital use, it will be 
determined whether t-tests for normally distributed data or the Mann Whitney will be used 
to test for differences between BID and once daily conditions. Separate analyses will be 
conducted examining preexisting conditions, self-administered interventions, and duration 
of symptoms. Paired t-tests will evaluate the effect of BID alkalinized rinses on hospital 
use, oxygen, ICU, and death.  Given previously established correlation between the 
preexisting conditions and disease severity, Tukey’s procedure will be used to control for 
Type I error rather than the more conservative Bonferroni correction. 
 
Click here to enter text. 
☐  N/A       
 
b. When applicable, provide a power analysis: 
9.3 Analysis  
☐  N/A       
 
 

27 
 
Power Analysis: The analysis will include treatment compliance with doses as a continuous variable 
correlated with clinical outcome), and full compliance (two rinses daily until resolution of symptoms or 
hospitalization).  A 2-sided Fisher’s exact test for binary outcomes will be used, with an alpha of 0.05 and 
beta of 0.80 requiring 100 patients in each group, anticipating an a priori severity of 20% needing oxygen or 
hospitalization and a 50% reduction to 10% being significant. Subanalyses will evaluate the prevalence of 
relevant pre-existing conditions and severity of symptoms at initiation of treatment. 
 
9.3.1 
Below is a table of different effect sizes and the associated sample size  assuming a 
statistical power of 80%. 
 
Effect size 
n per group 
Total N  
.3 
 
 
 
 
.5 
 
 
.7 
 
 
 
 
Different effect sizes have been noted for different nasal irrigation studies, 
with most starting within 48 hours of influenza or rhinoviridae with shorter 
incubation periods. 
9.3.2 Case Control matching: Power was calculated two ways, by running a 
simulation comparing the likelihood of hospitalization, and using a z-test 
comparing independent proportions. Both analyses assumed reduced 
variation in proportions due to accounting for the correlates of age, sex, and 
race, and resulted in similar calculations. Assuming that 25% of the 
matched control participants and 10% of the treatment participants would 
visit the hospital (60% reduction), 79 participants in the nasal irrigation 
condition would have .80 (80%) power to detect that proportional 
difference. The inability to evaluate and match underlying conditions in the 
control group can increase variability, thus a 1:2 matching schema was 
chosen recommended over 1:1.   
Click here to enter text. 
c. 
Describe how data and specimens will be handled: 
☐  N/A       
 
 
i. 
What information will be included in that data or associated with the specimens? 
A Master code list will be used to assign a study identification number to each 
participant. The participant number will be associated with any data that are 
collected so the data will be stored with no directly linked identifiers. An additional 
code list will be used to connect the subject ID with the ID assigned for the chart 
review portion of the study. 
ii. 
Where and how data and/or specimens will be stored? 
_HUMAN folder in box (also referred to as a research box) 
iii. 
How long will the data and/or specimens be stored? 
3 years after end of study 

28 
 
iv. 
Who will have access to the data or specimens? 
Research Team 
v. 
Who is responsible for receipt or transmission of the data and/or specimens? 
Research Team 
vi. 
How will data and/or specimens be transported? 
Electronically 
 
10. Provisions to Monitor the Data to Ensure the Safety of Subjects ☐ X N/A 
 
The plan might include establishing a data monitoring committee and a plan for reporting data 
monitoring committee findings to the IRB and the sponsor. 
a. Describe the plan to periodically evaluate the data collected regarding both harms and 
benefits to determine whether subjects remain safe. 
Click here to enter text. 
b. Describe what data are reviewed, including safety data, untoward events, and efficacy data. 
Click here to enter text. 
c. Describe how the safety information will be collected (e.g., with case report forms, at study 
visits, by telephone calls with participants). 
Click here to enter text. 
d. Describe the frequency of data collection, including when safety data collection starts. 
Click here to enter text. 
e. Describe who will review the data. 
Click here to enter text. 
f. Describe the frequency or periodicity of review of cumulative data. 
Click here to enter text. 
g. Describe any conditions that trigger an immediate suspension of the research. 
Click here to enter text. 
 

29 
 
11. Withdrawal of Subjects                                                                     ☐ N/A       
a. If applicable, describe anticipated circumstances under which subjects will be 
withdrawn from the research without their consent. 
Withdraw from study: Participants can end participation in the study at any time. A subject’s participation in 
the study will be discontinued for any of the following complications, but will still be included in the final 
analysis: 
• 
inability to tolerate irrigation 
• 
inability to perform irrigation 
• 
The sponsor or study doctor decides to stop the study. 
• 
The study doctor stops your taking part in the study for your safety. 
• 
You are not eligible to take part in the study. 
• 
Your condition changes and you need treatment that is not allowed while you are taking part in 
the study. 
• 
You do not follow the instructions from the study staff. 
 
 
 
Click here to enter text. 
 
☐  N/A       
b. If applicable, describe any procedures for orderly termination. 
Stopping Rules. The study will be temporarily suspended, if a single patient has evidence of any adverse 
effects of irrigation. 
Click here to enter text. 
☐  N/A       
c. If applicable, describe procedures that will be followed when subjects 
withdraw from the research, including partial withdrawal from procedures 
with continued data collection. 
If a participant withdraws or is withdrawn any data collected up to that 
point will be kept and used in the analysis as possible. 
Click here to enter text. 
☐  N/A       
 

30 
 
12. Risks to Subjects 
a. List the reasonably foreseeable risks.  
8.7. Potential Risks -  The possibility exists that inability to complete nasal irrigation could cause coughing or that the 
splashing of the nasal irrigant itself could increasing exposure in households. There is a possible risk of infection due 
to improper cleaning of the irrigation devices. It is known that mild itching/stinging with the rinse is a possible side 
effect of the treatments. This will be included in the ICD and explained to participants during the consent process. 
There is the possibility of a loss of confidentiality but procedures have been put in place to prevent this.   
Click here to enter text. 
 
b. If applicable, describe any costs that subjects may be responsible for 
because of participation in the research. 
Click here to enter text. 
X ☐  N/A       
c. If applicable, describe risks to others who are not subjects. 
Click here to enter text. 
X ☐  N/A       
 
 
 
13.  Potential Benefits to Subjects 
Describe the potential benefits that individual subjects may experience from taking part in the research.  
There is the potential for a direct and even life-saving benefit to the subjects who volunteer to participate. 
 
 
14.  Confidentiality 
Describe the procedures for maintenance of confidentiality. 
Any information that is obtained in connection with research that can be identified with a subject will remain confidential. 
Patients will be assigned a study number which will match their informed consent, and all information will be recorded and 
stored in a coded manner. Statisticians involved in the project will have access to de-identified data for the purposes of analysis.  
Copies of the informed consents will be kept by the AU Department of Emergency Medicine.  Patient samples will not be 
obtained.  Augusta University and The Institutional Review Board reserve the right to audit any research files to assure the 
quality of any data used in this research.  
 
 
Click here to enter text. 
 
15. Incomplete Disclosure, Authorized Deception, or Deception                                         
☐ X  N/A                                 
See the Deception Policy on Augusta University Website. 
 
If the study will use incomplete disclosure or deception, describe the incomplete disclosure or deception, and provide a 
rationale explaining why it is necessary to the research.  
 

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Describe the debriefing process that will be used to make participants aware of the incomplete disclosure or deception, 
including their right to withdraw any record of their participation. 
 
Click here to enter text. 
 
 
16.  Consent Process 
If you are obtaining consent of subjects describe the consenting process. Be sure to include the process to 
be used if enrolling illiterate, non-English speakers, individuals with impaired decision making capacity to 
consent, as applicable. 
Eligible patients who are obtained from the list of positives provided by the testing lab will be 
contacted by phone. The study will be explained to them and any questions they have will be 
answered. If they choose to participate remote consent will be obtained and documented by a 
member of the research team. 
 
Remote consent will be obtained using the Remote Informed Consent Process that is included in 
the Phone Script for Active Participant Group 1 and the Phone Script for Active Participant Group 
2 (see attached documents). For those with access to email or fax the consent document will be 
provided that way and the rest of the steps followed. 
 
Because of the time sensitive nature of the study any participant who does not have access to email 
for fax will be provided a copy of the entire consent document as the first step in the door drop off. 
After dropping off the document the researcher will return to their car and call the participant as 
well as adding a 3rd party witness to the process and follow the remote consent procedures process 
as described for those participants who do not have access to a fax or email.  
 
  
 
17.  Compensation for Research-Related Injury                      
This section is not required when research involves no more than Minimal Risk to subjects.☐ X N/A 
a. 
Describe the available compensation in the event of research related injury. 
Click here to enter text. 
 
18. Qualifications to Conduct Research and Resources Available                                                        
Describe the qualifications of you and your staff to conduct this research. The IRB is looking for information such as area(s) of 
expertise, past research experience, relevant certifications, etc. 
 
For international research or research with vulnerable populations, describe the qualifications (e.g., training, experience, 
oversight) of you and your staff as required to conduct the research. When applicable describe the knowledge of the local study 
sites, culture, and society. Provide enough information so the IRB knows that you have qualified staff for the proposed research. 
 
Note: If you specify a person by name, a change to that person will require prior approval by the IRB. If you specify people by 
role (e.g., coordinator, research assistant, Sub-Investigator, or pharmacist), a change to that person will not require prior 
approval by the IRB, provided that person meets the qualifications described above to fulfill their roles. 

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Matt Lyon, MD is a professor of Emergency Medicine, Vice Chairman for Academic Programs & Research for the Department 
of Emergency Medicine and also the Director of the Center for Ultrasound Education for Augusta University. Recently Dr. 
Lyon has been helping to lead AU's efforts in combating COVID-19 via telemedicine. Dr. Lyon has more than 20 years of 
research experience and has been the PI on more than 30 approved studies. Dr. Lyon will be supported by the Department of 
Emergency Medicine research team which includes Dr. Gibson who has years of research experience and currently serves as a 
Vice Chair for the IRB, Dr. Kuchinski who has been managing research for more than 3 years as well as Houlton Boomer who 
will be assisting with the regulatory. Any other study members will be trained in the protocol by the PI and research staff.  
 
a. Describe the availability of medical or psychological resources that subjects might need 
as a result of an anticipated consequences of the human research. 
N/A 
 
b.   Describe your process to ensure that all persons assisting with the research are 
adequately informed about the protocol, the research procedures, and their duties and 
functions. 
The PI and members of the research staff will ensure that all member of the study team are trained in the protocol.  
 
.