Clinical trial NCT04347954
Conditions: COVID-19
Keywords: nasal spray PVP-I COVID-19
Sponsor: Stanford University
Start date: 2020-08-15; Completion date: 2020-12-13
Enrollment: 47 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study aims to determine the safety and efficacy of povidone-iodine (PVP-I) containing nasal sprays as compared to isotonic saline nasal sprays in COVID-19 positive patients. The primary outcome measure is SARS-CoV-2 viral titers in the nasal cavity and nasopharynx. In vitro studies have shown PVP-I to be highly virucidal against the viruses which cause SARS and MERS. Additionally, clinical studies have shown PVP-I saline sprays to be well tolerated in human subjects. PVP-I oral rinses and sprays have been trialed as methods to reduce the incidence and symptoms of viruses which cause the "common cold."

Detailed description:

Arms: arm 1: Participants will administer PVP-I 2% nasal spray for 5 days. Nasopharyngeal swabs will be taken on Day 1 at baseline, Day 1 at four hours post-first dose, and Day 5.

Participants will complete a daily symptom journal from Day 1 through Day 5. arm 2: Participants will administer PVP-I 0.5% nasal spray for 5 days. Nasopharyngeal swabs will be taken on Day 1 at baseline, Day 1 at four hours post-first dose, and Day 5.

Participants will complete a daily symptom journal from Day 1 through Day 5 arm 3: Participants will administer two sprays of isotonic saline nasal spray for 5 days. Nasopharyngeal swabs will be taken on Day 1 at baseline, Day 1 at four hours post-first dose, and Day 5.

Participants will complete a daily symptom journal from Day 1 through Day 5.
Interventions: intervention 1: Povidone-Iodine 2% intervention 2: Povidone-Iodine 0.5% intervention 3: Isotonic saline 0.9%
Intervention descriptions: intervention 1: Two sprays to each nare of PVP-I 2% via nasal spray bottle, four times a day intervention 2: Two sprays to each nare of PVP-I 0.5% via nasal spray bottle, four times a day intervention 3: Two sprays to each nare of isotonic saline (0.9% NaCl) via nasal spray bottle, four times a day

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
Effect of PVP-I Nasal Sprays vs Normal Saline Nasal Sprays on  
SARS-CoV-2 Nasopharyngeal Titers 
 
NCT04347954 
 
Document Date: July 10, 2020 
 
 
 


Background Summary 
Human transmission of SARS-CoV-2 (COVID-19) occurs primarily through droplet spread into the nose 
and mouth. Arresting COVID-19 replication after infection of the nasal tissues specifically would 
decrease the duration and severity of infection in COVID-19-exposed patients, and may significantly 
impact COVID human to human transmission. Povidone-iodine (PVP-I) solution is a widely available, 
inexpensive antiseptic medication, used in the surgical theater to reduce the incidence of surgical 
wounds and intranasally to reduce MRSA colonization. However, the role of PVP-I in the treatment of 
nasal infections is limited. Interestingly, prior in vitro studies have demonstrated dilute PVP-I solutions, 
in concentrations as low at 0.23%, produce a ≥ 4 log10 decrease (inactivation of ≥ 99.99%) in SARS and 
MERS virus titers within 15 seconds.1,2 Both viruses share high structural overlap with COVID-19. A study 
of 29 patients with recalcitrant sinusitis found reduced bacterial growth with good safety profile after 
use of 0.08% PVP-I nasal rinses.3 PVP-I nasal sprays of up to 4.4% concentration have also been used on 
healthy volunteers without adverse effects or nasal tissue damage.4 In Wuhan, China, PVP-I was recently 
used empirically by healthcare providers devoid of COVID-19 protection, given its ease of use, and 
potential for mitigating infection. Given this encouraging background, and current world events, we 
propose testing dilute PVP-I sprays as a topical treatment to directly ablate COVID infection within the 
nasal cavity. 
Specific aims 
1. To determine if PVP-I nasal sprays reduce viral shedding in the nasopharynx and nasal cavity 
a. Hypothesis 1: PVP-I nasal sprays will reduce viral shedding in the nasopharynx and nasal 
cavity as determined by PCR testing when compared to control groups 
2. To determine if PVP-I nasal sprays affect the severity and time to resolution of signs and 
symptoms of COVID-19 
a. Hypothesis 2a: PVP-I nasal sprays will not change the severity or time to resolution of 
systemic signs and symptoms (such as fever, fatigue) when compared to control groups 
b. Hypothesis 2b: PVP-I nasal sprays will reduce the duration of anosmia symptoms when 
compared to control groups 
3. To determine adverse effects of PVP-I nasal sprays 
a. Hypothesis 3: PVP-I nasal sprays will not be associated with a greater rate of adverse 
effects as compared to the control groups 
Methods 
Overview of study design 
This is a prospective, double-blind, placebo controlled, randomized control trial of COVID-19 positive 
patients that has three study arms. 
Arms:  
(1) 2% povidone iodine nasal spray – two sprays to each nare four times a day for 5 days 
(2) 0.5% povidone iodine nasal spray – two sprays to each nare four times a day for 5 days 
(3) Control – Dyed normal saline (0.9% NaCl) spray – two sprays to each nare four times a day for 5 days 


Study population: COVID-19 positive inpatients and outpatients 
Inclusion criteria: 
1. >/= 18 years ago 
2. Diagnosis of COVID-19 by lab test within 5 days of study participation 
Exclusion criteria: 
1. Allergy to "iodine," shellfish, or food dye  
2. Receiving intranasal steroids   
3. Sinus surgery within 30 days of beginning the study  
4. Intubated at the time of enrollment 
5. Pregnancy 
6. Participation in other COVID-19 studies - to be determined on a case by case basis 
Measurements/Outcomes 
The primary outcome measure is the viral load on nasopharyngeal swab determined by quantitative PCR 
testing. A baseline sample (Day 1) will be obtained prior to first administration of the sprays. Subsequent 
samples will be collected at 4 hours after first administration and on day 5 after initiating nasal sprays.  
Intake questionnaire – dates of symptom onset, comorbid conditions, specific questions regarding taste 
and smell disturbances 
Patient reported symptoms (completed on Day 3 and Day 5) – fever, fatigue, change or loss of sense of 
smell, change or loss of sense of taste, nasal congestion, sore throat, etc 
Adverse effects questionnaire (completed on Day 3 and 5) – Nasal burning/pain, headaches, ear pain, 
sneezing, nose bleeds, rash 
University of Pennsylvania Smell Identification Test (completed on day 1 and day 30) – to assess smell 
recovery in COVID-19 patients 
Statistics 
T-test or ANOVA to compare difference in mean viral load between groups. Chi-square to assess for 
differences in signs, symptoms, adverse effects. 
Sample size: 45 subjects (15 subjects per study arm) 
Study Procedures - Outpatient 
Recruitment strategy 
In terms of advertising to the general public, we will send out flyers for general distribution on social 
media (e.g., Facebook, Nextdoor, etc) that will allow interested persons in the general public to contact 
our team. Our social media advertising strategy is being developed in conjunction with StudyPages, a 
clinical trial recruitment company recommended by the Stanford Research Participation Program. 
Moderation of Facebook and other social media posts will be conducted as outlined in a separate 


attached document and includes daily monitoring of comments and hiding/deletion of protected health 
information. Prospective participants can opt to have their contact information sent to the team. 
Potential subjects who have expressed interest in being contacted about research studies will be 
contacted by phone by one of the investigators. The study will be described, patients will have the 
opportunity to ask questions, and if they wish to proceed, they will be given details on their first in 
person study visit.  
Prospective participants that have undergone telephone screening will come to the clinic parking lot at 
801 Welch Rd or the Galvez lot at the designated date and time. At this in person study visit, the study 
will be reviewed again and the consent form signed if the patient still wishes to proceed. Randomization 
will take place. This will count as Day 1 of the study. 
Active Phase 
Given the known COVID-19 positive status, we are putting in place the following procedure for in person 
study visits. For first study visits scheduled on a Saturday, subjects will drive to the 801 Welch Rd parking 
lot which is the parking lot associated with the Department of Otolaryngology’s clinics. We have 
approval from the department chair and clinic leadership to use the parking lot. Participants will remain 
in their vehicle with the window rolled down for necessary study procedures. Return visits on day 5 will 
be scheduled for times either before 8 am or after 5 pm. Privacy will be ensured in several ways. First, 
the parking lot is behind the building and thus not visible from the main road. Second, we will be using 
moveable plastic barriers during study procedures to protect privacy. Lastly by having subjects only 
come in outside normal clinic hours (Saturday or pre/post-clinic), this will minimize the presence of 
other persons. 
We have also received approval from Julie Morris who is the Operations Manager of the Galvez research 
lot to utilize the tent space or the parking lot space at this site for study procedures. Weekday study 
procedures will take place at this site (270 Galvez Street). 
Participants will complete the first questionnaire and take the University of Pennsylvania Smell 
Identification Test (UPSIT) on the day of enrollment. This is a multiple-choice scratch and sniff test that is 
self-administered. A baseline nasopharyngeal sample will be taken. Next the first dose of the nasal spray 
will be given. Subjects will have the option to stay or return for the four hour sample collection 
timepoint. Four hours later, a member of the research team will obtain the 4-hour post-administration 
nasal sample. Subjects will then return home. Participants will be given (physical or electronic) a gift 
card for $25 at the end of the day. 
Participants will continue to self-administer the spray as instructed while at home. They will also take 
daily symptom questionnaires administered through REDCap. Participants will return for a drive-through 
nasal swab at 801 Welch Rd or at the Galvez lot on Day 5. 
On day 30, participants will complete an UPSIT, self-administered smell test, which will be given to 
patients with a self-addressed, pre-paid envelope to return. 
Close Out 


The study medication will be discontinued on Day 5. The second gift card ($25) will be mailed either 
through the postal service or through email to participants approximately 30 days after the first study 
visit upon completion of the final UPSIT. 
Specimen Handling 
Each sample will be labelled with a subject's unique record ID number. These samples will be processed 
in the Stanford clinical virology lab (permission has been obtained from Dr. Benjamin Pinsky) and results 
associated with a given record ID number in REDCap. 
Payment/Reimbursement 
Participants will be given a total of $50 in gift cards if they complete the study. They will receive a $25 
gift card at the end of the first in person study visit. If they complete the remaining in person visits on 
Days 5, they will be mailed (either via postal service or email) the second $25 gift card along with the 
final smell test. 
Safety of proposed treatment arms 
A small quantity of food dye is commonly used on mucosa membranes in the head and neck in routine 
clinical practice for instance to assess for fistula or to assess swallow function.5 It has also been used in 
numerous prior research studies assessing the distribution of drug delivery methods in the nasal cavity.6 
There is no added risk to including this in the control group saline solution. 
PVP-I solutions are routinely used as mouth washes with minimal absorption through the mucus 
membranes.7 Additionally, iodine solutions are used in the nose for MRSA decolonization and have been 
used long term in nursing home residents.8 Furthermore, prior studies have used concentrations as high 
as 4.4% in nasal spray form for extended periods in healthy volunteers without adverse effects.4 In our 
clinical practice, 10% PVP-I is used in the mouth and nose as a surgical prep prior to procedures in the 
operating room. Additionally, some of our patients with chronic sinus disease have been instructed to 
use high volume (240 mL) nasal rinses of PVP-I for several months without observed adverse effects or 
objective changes on nasal endoscopy. 
With long term use of iodine containing compounds, there is a theoretical risk of excessive iodine 
absorption which could affect the thyroid gland. However, given the short duration of our study, the 
cumulative exposure will remain far lower than in many common medical procedures.  
0.5% PVP-I contains 5 mg/mL and 2% PVP-I contains 20 mg/mL. The estimated volume delivered by two 
nasal sprays to each nare in a single administration is 0.33 mL.9  
0.33 ml/dose x 4 doses/day x 7 days = 37.2 mL of solution administered. 
At a 0.5% PVP-I concentration, the total amount of iodine administered is 186 milligrams. At 2.0% PVP-I, 
the total amount of iodine administered is 744 milligrams or 0.744 grams. The most common medical 
procedure in which patients are exposed to iodine are computed tomography (CT) scans which use 
iodinated contrast. The average dose per scan is estimated to be 15-37 grams of iodine10 which is an 
order of magnitude greater exposure to iodine than what is proposed in this study. 
 


Participant study timeline 
Day 0 
Enrollment, intake questionnaire, baseline NP swab, first dose of sprays, 4-
hour post NP swab, UPSIT 
Day 1 
Continue sprays 
Day 2 
Continue sprays, symptom questionnaire, adverse symptoms and 
compliance questionnaire 
Day 3 
Continue sprays, daily questionnaire 
Day 4 
Final day of sprays, NP swab, daily questionnaire, adverse symptoms and 
compliance questionnaire 
Day 6-29 
No study procedures 
Day 30 
Repeat UPSIT 
 
References 
1.  
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 ). Infect Dis Ther. 2015;4(4):491-501. doi:10.1007/s40121-015-0091-9 
2.  
Eggers M, Markus TK. In Vitro Bactericidal and Virucidal Efficacy of Povidone-Iodine Gargle / 
Mouthwash Against Respiratory and Oral Tract Pathogens. Infect Dis Ther. 2018;7(2):249-259. 
doi:10.1007/s40121-018-0200-7 
3.  
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. Eur 
Arch Oto-Rhino-Laryngology. 2019. doi:10.1007/s00405-019-05628-w 
4.  
Gluck U, Martin U, Bosse B, Reimer K, Mueller S. A clinical study on the tolerability of a liposomal 
povidone-iodine nasal spray: Implications for further development. ORL. 2007. 
doi:10.1159/000097758 
5.  
Kiong KL, Tan NC, Skanthakumar T, et al. Salivary fistula: Blue dye testing as part of an algorithm 
for early diagnosis. Laryngoscope Investig Otolaryngol. 2017. doi:10.1002/lio2.112 
6.  
Scheibe M, Bethge C, Witt M, Hummel T. Intranasal administration of drugs. Arch Otolaryngol - 
Head Neck Surg. 2008. doi:10.1001/archotol.134.6.643 
7.  
Kanagalingam J, Feliciano R, Hah JH, Labib H, Le TA, Lin JC. Practical use of povidone-iodine 
antiseptic in the maintenance of oral health and in the prevention and treatment of common 
oropharyngeal infections. Int J Clin Pract. 2015;69(11):1247-1256. doi:10.1111/ijcp.12707 
8.  
Miller L, Mckinnell J, Sing R, Kleinman K, Gombosev A, Dutciuc T. Reduction of MDRO 
Colonization in Nursing Home Residents with Routine Use of Chlorhexidine Bathing and Nasal 
Iodophor (Project PROTECT). Open Forum Infect Dis. 2016. 
9.  
Kirk-Bayley J, Challacombe S, Sunkaraneni V, Combes J. The Use of Povidone Iodine Nasal Spray 
and Mouthwash During the Current COVID-19 Pandemic May Protect Healthcare Workers and 
Reduce Cross Infection. SSRN Electron J. 2020. doi:10.2139/ssrn.3563092 
10.  
Lee SY, Rhee CM, Leung AM, Braverman LE, Brent GA, Pearce EN. A Review: Radiographic 
Iodinated Contrast Media-Induced Thyroid Dysfunction. J Clin Endocrinol Metab. 


2015;100(2):376-383. doi:10.1210/jc.2014-3292