Directed Topical Drug Delivery for Treatment for PASC Hyposmia
Phase: PHASE2
Conditions: Post Acute Sequelae Covid-19 Hyposmia
Sponsor: Duke University

Study Title:  
Directed topical drug delivery for 
treatment for PASC hyposmia  
Study Product: 
Beclomethasone; Vectra F-microsponge ; PosiSep 
microsponge 
Protocol Number:  
TBD 
NCT ID:   
 
 
NCT05970731 
Principal Investigator:  
Bradley J. Goldstein, MD, PhD 
Sponsor:  
 
 
Investigator initiated study 
Funded by:   
 
Internal, Duke Head and Neck Surgery 
Version Number:   
v.1.2, 16October2023 
All versions should have a version number and a date. Use the international date format (day month 
year) and write out the month (e.g., 23 June 2015). 
 
 
 
 
______________________________  
 
______________________ 
Sponsor – Investigator 
 
 
 
 
Date 
 
Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
 
Study Timeline Extended  
Rationale – We prefer to perform the final 
smell test at a 3 month interval, as ongoing 
recovery for post-viral smell loss may take 
several months in many cases. 
 
 
 

DIRECTED TOPICAL DRUG DELIVERY FOR TREATMENT FOR PASC HYPOSMIA  
 
v.1.1, 13July 2023  
Confidential and Proprietary  
 
ii 
Table of Contents 
STATEMENT OF COMPLIANCE ......................................................................................................................... 1 
PROTOCOL SUMMARY....................................................................................................................................... 1 
1.1 
Synopsis ........................................................................................................................................... 1 
1.2 
Schema ............................................................................................................................................ 2 
1.3 
Schedule of Activities (SoA) ........................................................................................................... 3 
INTRODUCTION ................................................................................................................................................... 3 
1.4 
Study Rationale ............................................................................................................................... 3 
1.5 
Background ...................................................................................................................................... 3 
1.6 
Risk/Benefit Assessment ................................................................................................................ 4 
1.6.1 
Known Potential Risks ................................................................................................. 4 
1.6.2 
Known Potential Benefits............................................................................................. 5 
1.6.3 
Assessment of Potential Risks and Benefits ............................................................. 5 
OBJECTIVES AND ENDPOINTS ........................................................................................................................ 5 
STUDY DESIGN .................................................................................................................................................... 5 
1.7 
Overall Design ................................................................................................................................. 5 
1.8 
Scientific Rationale for Study Design ............................................................................................ 6 
1.9 
Justification for Dose ....................................................................................................................... 6 
1.10 
End of Study Definition ................................................................................................................... 6 
STUDY POPULATION .......................................................................................................................................... 6 
1.11 
Inclusion Criteria .............................................................................................................................. 6 
1.12 
Exclusion Criteria ............................................................................................................................ 6 
1.13 
Lifestyle Considerations ................................................................................................................. 7 
1.14 
Screen Failures ............................................................................................................................... 7 
1.15 
Strategies for Recruitment and Retention ..................................................................................... 7 
STUDY INTERVENTION ...................................................................................................................................... 8 
1.16 
Study Intervention(s) Administration ............................................................................................. 8 
1.16.1 
Study Intervention Description .................................................................................... 8 
1.16.2 
Dosing and Administration .......................................................................................... 8 
1.17 
Preparation/Handling/Storage/Accountability ............................................................................... 8 
1.17.1 
Acquisition and accountability ..................................................................................... 8 
1.17.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 8 
1.17.3 
Product Storage and Stability ..................................................................................... 8 
1.17.4 
Preparation ................................................................................................................... 8 
1.18 
Measures to Minimize Bias: Randomization and Blinding .......................................................... 9 
1.19 
Study Intervention Compliance ...................................................................................................... 9 
1.20 
Concomitant Therapy...................................................................................................................... 9 
1.20.1 
Rescue Medicine .......................................................................................................... 9 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL
 
9 
1.21 
Discontinuation of Study Intervention ............................................................................................ 9 
1.22 
Participant Discontinuation/Withdrawal from the Study............................................................. 10 
1.23 
Lost to Follow-Up .......................................................................................................................... 10 
SAFETY ASSESSMENTS .................................................................................................................................. 10 
1.24 
Efficacy Assessments ................................................................................................................... 10 
1.25 
Safety and Other Assessments ................................................................................................... 11 
1.26 
Adverse Events and Serious Adverse Events ............................................................................ 11 

DIRECTED TOPICAL DRUG DELIVERY FOR TREATMENT FOR PASC HYPOSMIA  
 
v.1.1, 13July 2023  
Confidential and Proprietary  
 
iii 
1.26.1 
Definition of Adverse Events (AE) ............................................................................ 11 
1.26.2 
Definition of Serious Adverse Events (SAE)............................................................ 11 
1.26.3 
Classification of an Adverse Event ........................................................................... 11 
1.26.4 
Time Period and Frequency for Event Assessment and Follow-Up...................... 12 
1.26.5 
Adverse Event Reporting........................................................................................... 13 
1.26.6 
Serious Adverse Event Reporting ............................................................................ 13 
1.26.7 
Reporting Events to Participants .............................................................................. 13 
1.26.8 
Events of Special Interest .......................................................................................... 13 
1.26.9 
Reporting of Pregnancy ............................................................................................. 13 
1.27 
Unanticipated Problems ............................................................................................................... 14 
1.27.1 
Definition of Unanticipated Problems (UP) .............................................................. 14 
1.27.2 
Unanticipated Problem Reporting ............................................................................. 14 
1.27.3 
Reporting Unanticipated Problems to Participants ................................................. 14 
STATISTICAL CONSIDERATIONS ................................................................................................................... 15 
1.28 
Statistical Hypotheses .................................................................................................................. 15 
1.29 
Sample Size Determination .......................................................................................................... 15 
1.30 
Populations for Analyses .............................................................................................................. 16 
1.31 
Statistical Analyses ....................................................................................................................... 16 
1.31.1 
Data 
16 
1.31.2 
Analysis of the Primary Efficacy Endpoint(s) ........................................................... 16 
1.31.3 
Analysis of the Secondary Endpoint(s) .................................................................... 16 
1.31.4 
Safety Analyses .......................................................................................................... 17 
1.31.5 
Baseline Descriptive Statistics .................................................................................. 17 
1.31.6 
Planned Interim Analyses .......................................................................................... 17 
1.31.7 
Sub-Group Analyses .................................................................................................. 17 
1.31.8 
Tabulation of Individual participant Data .................................................................. 17 
1.31.9 
Exploratory Analyses ................................................................................................. 17 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ......................................... 17 
1.32 
Regulatory, Ethical, and Study Oversight Considerations ........................................................ 17 
1.32.1 
Informed Consent Process ........................................................................................ 17 
1.32.2 
Study Discontinuation and Closure .......................................................................... 18 
1.32.3 
Confidentiality and Privacy ........................................................................................ 19 
1.32.4 
Future Use of Stored Specimens and Data ............................................................. 19 
1.32.5 
Key Roles and Study Governance ........................................................................... 19 
1.32.6 
Clinical Monitoring ...................................................................................................... 19 
1.32.7 
Quality Assurance and Quality Control .................................................................... 20 
1.32.8 
Data Handling and Record Keeping ......................................................................... 20 
1.32.9 
Protocol Deviations .................................................................................................... 21 
1.32.10 
Publication and Data Sharing Policy ........................................................................ 21 
1.32.11 
Conflict of Interest Policy ........................................................................................... 21 
1.33 
Additional Considerations ............................................................................................................. 22 
1.34 
Abbreviations ................................................................................................................................. 23 
1.35 
Protocol Amendment History ....................................................................................................... 24 
 

DIRECTED TOPICAL DRUG DELIVERY FOR TREATMENT FOR PASC HYPOSMIA  
 
v.1.0, 1 March 2023  
 
Confidential and Proprietary 
 
Page 1 
STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with International Conference on Harmonization Good Clinical 
Practice (ICH GCP) and the following:  
 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 
CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled.  Any amendment to 
the protocol will require review and approval by the IRB before the changes are implemented to the 
study.  In addition, all changes to the consent form will be IRB-approved; a determination will be made 
regarding whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form. 
 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Study Title: 
DIRECTED TOPICAL DRUG DELIVERY FOR TREATMENT FOR PASC 
HYPOSMIA 
Study Product: 
 
Beclomethasone; Vectra F-microsponge ; PosiSep microsponge 
Study Description: 
This study will compare topical intranasal directed administration of a 
Vectra F or PosiSepmicrosponge with Beclomethasone versus placebo for 
the treatment of persistent olfactory loss due to COVID-19. We 
hypothesize that treatment with drug will result in improved olfactory 
function.  
Objectives: 
 
Primary Objective:  To determine if directed topical drug treatment results 
in improved olfactory function, compared to placebo. 
 
Endpoints: 
Primary Endpoint: Olfactory function at 6 and 18 weeks post-enrollment. 
Secondary Endpoints: Olfactory-specific quality of life questionnaire. 
Study Population: 
Adult patients of either gender presenting to Duke Rhinology Clinic with 
hyposmia following COVID19 lasting > 3 months, documented by abnormal 
score on objective olfactory testing. 
Phase: 
2  
Description of 
Sites/Facilities Enrolling 
Participants: 
Duke University School of Medicine Head and Neck Surgery clinic. 
Description of Study 
Intervention: 
Subjects will be randomized to receive either Beclomethasone or placebo. 
Drug will be administered topically on an intranasal microsponge, placed 
in the olfactory cleft using a nasal endoscope, on Day 1 and repeated on 
day 14. 
Study Duration: 
12 months 
Participant Duration: 
4.5 Months  
 
 

DIRECTED TOPICAL DRUG DELIVERY FOR TREATMENT FOR PASC HYPOSMIA  
 
v.1.0, 1 March 2023  
 
Confidential and Proprietary 
 
Page 2 
1.2 
SCHEMA 
 
 
Prior to  
Enrollment 
 
 
 
 
 
 
 
 
 
 
Visit 1 
Day 0 
 
 
Visit 2 
2 weeks 
± 5 days  
 
 
Visit 3 
6 weeks 
(± 1 week) 
 
Visit 4 
18 weeks 
(± 2 weeks) 
 
 
 
 
Total N: Screen potential participants presenting with post-Covid19 smell loss with SIT 
test. Subjects with abnormal score will be offered participation in the study and informed 
consent will be obtained. 
Perform baseline assessments: 
History and head and neck exam including nasal endoscopy; 
Review SIT score, 
Administer drug or placebo (outpatient clinic)  
Outpatient follow-up visit in Otolaryngology clinic; 
Repeat SIT test; Questionnaire for Olfactory Disorders 
Outpatient follow-up visit in Otolaryngology clinic; 
Repeat administration of drug or placebo 
Data analysis 
And Interpretation 
Placebo 
n=10 
beclomethasone 
treatment, n=10 
Randomize 
Outpatient follow-up visit in Otolaryngology clinic; 
Repeat SIT test; Questionnaire for Olfactory Disorders 

DIRECTED TOPICAL DRUG DELIVERY FOR TREATMENT FOR PASC HYPOSMIA  
 
v.1.0, 1 March 2023  
 
Confidential and Proprietary 
 
Page 3 
1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
 
 
1.4 
TIME AND EVENTS KEY 
 
1      – Vital Sign measurements that will be collected are heart rate, blood pressure, temperature, height 
and weight at a minimum. (Note: that height will only be collected at Screening.) 
 
 
INTRODUCTION 
 
1.5 
STUDY RATIONALE  
 
COVID19 is a common cause of olfactory loss. Studies indicate that objective smell loss lasting > 3 month 
occurs in up to 10% of subjects with Covid smell loss. There are no effective drug treatments available, 
although olfactory training therapy has been used for some forms of post-viral smell loss with limited 
benefits. Our recent research has identified evidence for ongoing local inflammatory changes in the 
olfactory area of the nose in long-COVID smell loss patients. Nasal spray meds, such as steroids, are 
known to not reach this region of the nose well. Therefore, we propose to test this simple 
pharmacologic intervention in long-COVID smell loss patients with objective olfactory loss, to directly 
deliver  a topical nasal steroid to the olfactory cleft of the nose in an absorbable sponge. Both the 
medication and sponge are approved for use in the nose and sinuses. 
 
1.6 
BACKGROUND  
Procedures 
Screening 
Day -2 to 0 
Enrollment/Baseline 
Day 0 
Study Visit 2  
Day 14  +/-5 days 
Study Visit 3 
week 6 +/- 1 weeks 
Study Visit 4 
week 18+/- 2 weeks 
Informed consent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
Physical Exam 
X 
 
 
 
 
Vital Signs1 
X 
 
X 
X 
X 
Concomitant Medications Review 
X 
 
 
 
 
SIT (olfaction test) 
X 
 
 
X 
X 
QOD (questionnaire) 
X 
 
 
X 
X 
Randomization 
X 
 
 
 
 
Physical exam, with nasal 
endoscopy  
X 
 
 
 
 
Administer study intervention 
 
X 
X 
 
 
Adverse event review and 
evaluation 
 
X 
X 
X 
X 

DIRECTED TOPICAL DRUG DELIVERY FOR TREATMENT FOR PASC HYPOSMIA  
 
v.1.0, 1 March 2023  
 
Confidential and Proprietary 
 
Page 4 
Persistent anosmia (a loss of one’s sense of smell) affects an estimated 14 million people in the US1. 
Many persistent acquired forms of anosmia are thought to be due to neurodegenerative processes such 
as aging (presbyosmia) or damage to the nasal olfactory neuroepithelium (post-viral or post head 
trauma anosmia)2. Of these conditions, post-COVID smell loss has emerged as a major problem, 
impacting >30 million people globally.  Currently, we have no treatments for this problem.  
The pathogenesis of post-COVID smell loss is incompletely understood. Our recent research suggests 
that post-COVID hyposmics harbor ongoing local inflammation in the mucosa of the olfactory cleft of the 
nose, accompanied by fewer intact olfactory neurons. Normally, damaged olfactory neurons are 
replaced by basal progenitor cells, but it is thought that inflammation impairs this recovery process.  We 
hypothesize that an intervention to deliver anti-inflammatory medication directly to the olfactory 
area of the nose would help promote olfactory recovery. 
In considering possible therapeutic approaches, direct endoscopic application of an absorbable sponge 
impregnated with a steroid medicine is attractive. Steroids such as beclomethasone are FDA approved 
for both topical nasal administration and have a long track record of safe clinical use. Also, a dissolvable 
drug delivery microsponge (Vectra and PosiSep) is approved for nasal or sinus application. The use of a 
microsponge is ideal, since the olfactory area of the nose sits superiorly and a simple liquid would drip to 
the nasal floor if applied directly, and a self-administered spray does not efficiently reach this region of 
the nose. Given the safety record of the microsponge and steroid, we propose to undertake a human 
study testing this therapy for treatment of post-COVID persistent hyposmia. Identification of an effective 
therapy for certain forms of anosmia would be a significant advance, as there currently are no 
treatments available. 
1.7 
RISK/BENEFIT ASSESSMENT   
 
1.7.1 KNOWN POTENTIAL RISKS  
 
Risks from medication: beclomethasone is FDA approved, with many-year safety history. It is widely 
used for topical nasal delivery for allergy or rhinitis. Potential risks of long-term use include elevated 
ocular pressure in subjects with glaucoma, or possibly localized nasal irritation. The Vectra microsponge 
and PosiSep microsponge is approved for nasal and sinus application. It is widely used to place into a 
narrow sinus drainage region after surgery to soak with steroid for local delivery, in an effort to prevent 
swelling or blockage. The material dissolves generally within 6-7 days. Potential risks include tissue 
injury during endoscopic placement, although this is unlikely when applying it to the olfactory cleft 
region between the middle turbinate and nasal septum.  
Other risks: There is no economic risk, as we will supply the study medication. The pre-study work up 
and care is the standard-of-care, unchanged, and is no different for patients choosing or not choosing to 
participate in this study (nasal exam and psychophysical olfactory assessment using the Smell 
Identification Test (Sensonics). Psychologically, there is the risk of disappointment from possible lack of 
improvement or from treatment with placebo. However, the current standard-of-care is no treatment, 
so we will council patients regarding this. 
 

DIRECTED TOPICAL DRUG DELIVERY FOR TREATMENT FOR PASC HYPOSMIA  
 
v.1.0, 1 March 2023  
 
Confidential and Proprietary 
 
Page 5 
1.7.2 KNOWN POTENTIAL BENEFITS  
 
The immediate and long-range potential benefit is improvement in olfactory function. As stated, the 
standard of care for persistent post-COVID hyposmia is observation, and many patients do not recover 
olfaction. Translational research findings support the conclusion that effective treatment of olfactory 
cleft inflammation may help recovery. Thus, there is potential that olfactory neuron will improve with 
treatment in this study.  
 
1.7.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
Existing evidence is consistent with a very positive risk to benefit assessment. Prior clinical use of nasal 
steroids and the microsponge report no adverse effects. The treatment involves only 2 applications of 
medication. There are no existing alternatives. Basic science studies provide evidence for promoting 
recovery using this drug or approach. 
 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
To determine if topical intranasal 
treatment with beclomethasone on 
a microsponge results in improved 
olfactory function, compared to 
placebo. 
 
Olfactory function at 6 
weeks and 18 weekspost-
enrollment, as measured 
by Smell Identification 
Test (SIT). 
 
SIT is a validated test for olfaction. 
Time points were chosen to test 
for early recovery of olfactory 
neurons versus evidence for 
successful regeneration, 
respectively. 
Secondary 
 
 
To assess olfactory-specific quality 
of life measure in treated versus 
placebo groups. 
 
Questionnaire on olfactory 
dysfunction (QOD) scores 
at 6 weeks and 18 weeks .   
 
QOD is a validated tool for 
measuring quality of life related 
to olfactory loss. 
Tertiary/Exploratory  
 
 
N/A 
 
 
 
 
STUDY DESIGN  
 
1.8 
OVERALL DESIGN 
 
• 
Hypothesis: Treatment with topical intranasal beclomethasone on a microsponge applied to the 
olfactory region of the nasal cavity will result in improved olfactory function, compared to 
placebo. 
• 
Phase 2 trial.  

DIRECTED TOPICAL DRUG DELIVERY FOR TREATMENT FOR PASC HYPOSMIA  
 
v.1.0, 1 March 2023  
 
Confidential and Proprietary 
 
Page 6 
• 
Design: Randomized, placebo-controlled, double-blind study. 
• 
Study groups: Treatment versus Placebo. 
• 
Number of Sites: Single site. 
• 
Study Intervention: Beclomethasone on a microsponge 
 
1.9 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
We seek to determine if treatment with Beclomethasone on a microsponge will improve olfaction in 
post-COVID patients with persistent olfactory loss. To obtain high quality evidence, we chose a 
prospective randomized placebo control double blind approach. There is no standard of care treatment 
or drug that can be used for comparison; the current standard of care is observation. To avoid bias, a 
double blind approach will be used. Based on the best knowledge for mechanism of olfactory loss in 
these patients, we believe that directed topical nasal delivery of an anti-inflammatory to the olfactory 
area of the nasal cavity is likely to be effective. 
 
1.10 JUSTIFICATION FOR DOSE 
 
Dose regimen is based on known pharmacology of beclomethasone and known time for microsponge to 
dissolve.  Beclomethasone is a longer-acting topical nasal glucocorticoid drug, compared to other 
available choices. The microsponge is designed to elute medication for about a week. We chose a single 
re-application at 2 weeks to deliver a total course of treatment that covers approximately one month. 
 
1.11 END OF STUDY DEFINITION 
 
The end of the study is defined as completion of the last visit shown in the SoA.  
 
STUDY POPULATION 
 
1.12 INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Presents to Duke HNSCS clinic with post-COVID hyposmia lasting greater than 3 months following 
COVID19 by history, with olfaction documented by University of Pennsylvania Smell Identification 
Test (SIT).  
2. Male or female, aged 18 years or older 
3. Provision of signed and dated informed consent form 
4. Stated willingness to comply with all study procedures and availability for the duration of the 
study 
1.13 EXCLUSION CRITERIA 

DIRECTED TOPICAL DRUG DELIVERY FOR TREATMENT FOR PASC HYPOSMIA  
 
v.1.0, 1 March 2023  
 
Confidential and Proprietary 
 
Page 7 
 An individual who meets any of the following criteria will be excluded from participation in this study: 
 
1. Pregnancy or lactation 
2. Known allergic reactions to components of microsponge or to beclomethasone 
3. Known diagnosis of glaucoma 
4. Febrile illness within 1 week  
5. Treatment with another investigational drug or other intervention within 3 months 
6. Active sinonasal disease by nasal exam, i.e. rhinosinusitis, nasal polyps 
7. Adults unable to consent 
8. Prisoners, employees or subordinates 
9. Individuals who are not yet adults (infants, children, teenagers). This population is excluded 
because the study problem is most common in adults. 
1.14 LIFESTYLE CONSIDERATIONS 
 
Not Applicable 
1.15 SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure participants, to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any serious adverse event (SAE). Re-screening will not be 
performed. 
 
1.16 STRATEGIES FOR RECRUITMENT AND RETENTION 
 
• 
Target study sample size: 10 subjects in each arm, 20 subjects total. No exclusions by gender, 
race and ethnicity.  Anticipated number to be screened in order to reach the target enrollment: 
50 subjects. 
• 
Anticipated accrual rate: 20 subjects 
• 
Anticipated number of sites: 1 
• 
Source of participants: outpatient. We routinely see smell loss subjects and expect to readily 
identify ample number of subjects, as no treatments are available. 
• 
Types of recruitment strategies planned: Will list trial on clinicaltrials.gov, and will notify patient 
advocacy groups (Smell and Taste Association of North America, STANA; 5th Sense) that help 
advise smell loss patients on possible trials. 
Specific strategies that will be used to recruit and retain historically under-represented populations in 
order to meet target sample size and conform with the NIH Policy on Inclusion of Women and Minorities 
as Participants In Research Involving Human Subjects: We will not exclude any demographic (other than 
children, as stated); our population in Durham County is quite diverse; the study population is 
anticipated to reflect this diversity. 
 

DIRECTED TOPICAL DRUG DELIVERY FOR TREATMENT FOR PASC HYPOSMIA  
 
v.1.0, 1 March 2023  
 
Confidential and Proprietary 
 
Page 8 
STUDY INTERVENTION 
 
1.17 STUDY INTERVENTION(S) ADMINISTRATION 
 
1.17.1 STUDY INTERVENTION DESCRIPTION 
 
Subjects will be randomized to receive either beclomethasone or placebo, to be prepared by our 
research pharmacy. Drug will be administered intranasally by an otolaryngologist at 2 outpatient visits, 
using a nasal endoscope to place the delivery microsponge in the olfactory region of the nasal cavity and 
then applying the drug or placebo onto the microsponge. This delivery method will direct the drug to 
the proper region of the nasal cavity and will prevent it from rapidly leaving this location (i.e., dripping 
inferiorly to the nasal floor). 
 
Beclomethasone is available by prescription as a topical nasal spray; one brand name is Beconase AQ, 
GlaxoSmithKline. This is a microcrystalline suspension of beclomethasone dipropionate, monohydrate 
equivalent to 42 mcg of beclomethasone dipropionate, calculated on the dried basis, in an aqueous 
medium containing microcrystalline cellulose, carboxymethylcellulose sodium, dextrose, benzalkonium 
chloride, polysorbate 80, and 0.25% v/w phenylethyl alcohol.  
 
1.17.2 DOSING AND ADMINISTRATION 
 
Drug will be administered intranasally by an otolaryngologist at 2 outpatient visits, using a nasal 
endoscope to place the delivery microsponge in the olfactory region of the nasal cavity and then 
applying the drug or placebo onto the microsponge. 
1.18 PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
1.18.1 ACQUISITION AND ACCOUNTABILITY 
 
Randomization, drug and placebo preparation, and packaging will be done Duke research pharmacy 
following their established protocols for double-blind studies. When ordered, the dose will be 
administered by a physician otolaryngologist in outpatient clinic.  
 
1.18.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Research pharmacy will prepare and label study drug or placebo appropriately for double-blind study. 
 
1.18.3 PRODUCT STORAGE AND STABILITY 
 
Drug is to be stored at room temperature.  
 
 
1.18.4 PREPARATION 
 

DIRECTED TOPICAL DRUG DELIVERY FOR TREATMENT FOR PASC HYPOSMIA  
 
v.1.0, 1 March 2023  
 
Confidential and Proprietary 
 
Page 9 
No preparation will be required. Drug or placebo will be administered ontranasally by physician at 2 
visits. 
 
1.19 MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
To minimize bias, this will be a randomized double-blind trial. We will use the Duke Research Pharmacy 
to prepare study drug or placebo, using their randomization procedures and labeling. Trial 
randomization codes will be maintained until planned enrollment is reached and the final patient has 
completed the planned follow up visits. There are no planned lab studies or measures that would be 
expected to lead to inadvertent unblinding. If there are serious adverse events (SAEs), this will be 
reported to the PI and unblinding for the affected subject would be performed. 
 
 
1.20 STUDY INTERVENTION COMPLIANCE 
 
Since the drug or placebo will be applied intranasally by the physician at 2 visits, there is no need for 
compliance checks or verification of delivery. 
 
1.21 CONCOMITANT THERAPY 
 
Concomitant medications will not be restricted, except that we will ask subjects to avoid using other 
intrnasal spray medications such as nasal saline, nasal decongestants or allergy sprays.  
 
1.21.1 RESCUE MEDICINE 
 
Not Applicable 
 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
Participants may withdraw voluntarily from the study or the PI may discontinue a participant from the 
study.  In addition, participants may discontinue the study intervention, but remain in the study for 
follow-up, especially for safety and efficacy study endpoints (if applicable).  
 
1.22 DISCONTINUATION OF STUDY INTERVENTION 
 
If a patient notes a possible adverse effect, such as allergic reaction to study medication, we will 
discontinue study medication. Any new clinically relevant finding will be reported as an adverse event 
(AE). Because the outpatient course of study medication is only 6 days, we will not restart study 
medication in that short timeframe and instead will withdraw the patient from this study. Such patients 
will still be offered planned follow up and the planned outcome measures will still be collected. 
 
The data to be collected at the time of study intervention discontinuation will include the following: 

DIRECTED TOPICAL DRUG DELIVERY FOR TREATMENT FOR PASC HYPOSMIA  
 
v.1.0, 1 March 2023  
 
Confidential and Proprietary 
 
Page 10 
• 
Details of possible adverse event, and appropriate care as indicated (for example ER 
assessment). 
 
1.23 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
• 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
The reason for participant discontinuation or withdrawal from the study will be recorded on the Case 
Report Form (CRF). Subjects who sign the informed consent form and are randomized but do not receive 
the study intervention may be replaced.  Subjects who sign the informed consent form, and are 
randomized and receive the study intervention, and subsequently withdraw, or are withdrawn or 
discontinued from the study, will be replaced. Patients who do not complete the full course of study 
drug/placebo will be noted in the results tables, and they will not be included in the statistical analysis of 
outcome measures, since this is a simple comparison of SIT score between patients receiving 2 
applications of drug versus placebo. 
1.24 LOST TO FOLLOW-UP 
 
 
 A participant will be considered lost to follow-up if he or she fails to return for the 2 scheduled follow 
up Otolaryngology clinic visits and is unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit within 2 weeks 
and counsel the participant on the importance of maintaining the assigned visit schedule. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s medical record or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
 
SAFETY ASSESSMENTS 
 
1.25 EFFICACY ASSESSMENTS  

DIRECTED TOPICAL DRUG DELIVERY FOR TREATMENT FOR PASC HYPOSMIA  
 
v.1.0, 1 March 2023  
 
Confidential and Proprietary 
 
Page 11 
The primary outcome measure is olfactory ability at 6 weeks and 18 weeks, measured via the SIT. There 
are only 3 procedures involved in the study to assess efficacy: (1) SIT measures (2) Administration of 
study medication or placebo, (3) the QOD quality of life questionnaire. 
 
• 
The SIT is a self-administered 40-item test involving microencapsulated (scratch-and-sniff) odors 
with a forced-choice design. There are 4 booklets with 10 questions each, asking the subject to 
identify which of 4 answers best described the odor. Total scores are categorized, based on 
normative data, as normal, mild hyposmia, moderate hyposmia, severe hposmia, total anosmia, 
or probable malingering. The test was developed at University of Pennsylvania as part of an NIH-
funded program project and is widely used as a standard assessment of olfactory function. 
 
• 
The QOD is a validated olfactory-specific quality of life questionnaire and is attached. 
 
1.26 SAFETY AND OTHER ASSESSMENTS 
 
The potential patient safety issue for the study is the possibility of adverse reaction to study medication. 
The dosage regimen we are using has been used as standard for this drug, as prescribed for metered 
dose nasal spray for rhinitis or nasal polyps. Patients will receive instructions and contact information to 
inform the coordinator or PI promptly of any potential problems. At follow up visit, we will collect any 
comments or notes regarding possible side effects. 
   
1.27 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
1.27.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
1.27.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include allergic reaction requiring 
intensive treatment in an emergency room or at home. 
 
 
1.27.3 CLASSIFICATION OF AN ADVERSE EVENT 
 

DIRECTED TOPICAL DRUG DELIVERY FOR TREATMENT FOR PASC HYPOSMIA  
 
v.1.0, 1 March 2023  
 
Confidential and Proprietary 
 
Page 12 
1.27.3.1 SEVERITY OF EVENT 
 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
 
1.27.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below. In a clinical trial, the 
study product must always be suspect.  
 
• 
Related – The AE is known to occur with the study intervention, there is a reasonable possibility 
that the study intervention caused the AE, or there is a temporal relationship between the study 
intervention and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention 
and event onset, or an alternate etiology has been established. 
 
 
1.27.3.3 EXPECTEDNESS  
 
PI will be responsible for determining whether an adverse event (AE) is expected or unexpected.  An AE 
will be considered unexpected if the nature, severity, or frequency of the event is not consistent with 
the risk information previously described for the study intervention. 
 
1.27.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs 

DIRECTED TOPICAL DRUG DELIVERY FOR TREATMENT FOR PASC HYPOSMIA  
 
v.1.0, 1 March 2023  
 
Confidential and Proprietary 
 
Page 13 
occurring while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
PI will record all reportable events with start dates occurring any time after informed consent is 
obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation.  At 
each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit.  Events 
will be followed for outcome information until resolution or stabilization. 
 
1.27.5 ADVERSE EVENT REPORTING  
 
Adverse Event reporting will adhere to all established guidelines, as described below. 
 
1.27.6 SERIOUS ADVERSE EVENT REPORTING  
 
The study clinician will immediately report to the Duke Human Subjects Research Office any serious 
adverse event, whether or not considered study intervention related, including those listed in the 
protocol or investigator brochure and must include an assessment of whether there is a reasonable 
possibility that the study intervention caused the event. Study endpoints that are serious adverse events 
(e.g., all-cause mortality) must be reported in accordance with the protocol unless there is evidence 
suggesting a causal relationship between the study intervention and the event (e.g., death from 
anaphylaxis). In that case, the investigator must immediately report the event to the sponsor. 
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable.  
 
1.27.7 REPORTING EVENTS TO PARTICIPANTS  
 
Any subjects who have not yet completed their first follow up visit will be contacted by phone to inform 
them of any Serious Adverse Events, if any occur. 
 
1.27.8 EVENTS OF SPECIAL INTEREST  
 
Not Applicable 
 
1.27.9 REPORTING OF PREGNANCY  
 
N/A 
 

DIRECTED TOPICAL DRUG DELIVERY FOR TREATMENT FOR PASC HYPOSMIA  
 
v.1.0, 1 March 2023  
 
Confidential and Proprietary 
 
Page 14 
1.28 UNANTICIPATED PROBLEMS 
 
1.28.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
Unanticipated problems involving risks to participants or others include, in general, any incident, 
experience, or outcome that meets all of the following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
 
1.28.2  UNANTICIPATED PROBLEM REPORTING  
 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) and to the Data Coordinating Center (DCC)/lead principal investigator (PI). The UP report will 
include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and to the DCC/study 
sponsor within 5 days of the investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB and to the DCC/study sponsor within 1 week of the 
investigator becoming aware of the problem.  
• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), within 1 week of the 
IRB’s receipt of the report of the problem from the investigator. 
 
 
1.28.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
N/A 
 

DIRECTED TOPICAL DRUG DELIVERY FOR TREATMENT FOR PASC HYPOSMIA  
 
v.1.0, 1 March 2023  
 
Confidential and Proprietary 
 
Page 15 
STATISTICAL CONSIDERATIONS  
 
1.29 STATISTICAL HYPOTHESES 
 
• 
Primary Efficacy Endpoint(s):  
 
To determine if treatment with topical beclomethasone applied on microsponge to the olfactory cleft  
results in improved olfactory function in long-COVID hyposmics, compared to placebo. Type of 
comparison: superiority. Time period: 6 weeks and 18 weeks post-enrollment. 
 
Null hypothesis: There is no difference in SIT score with drug treatment or placebo. 
Alternative hypothesis: Drug treatment results in improved SIT score. 
 
• 
Secondary Efficacy Endpoint(s): 
 
To assess olfactory-specific quality of life measure in treated versus placebo groups. 
Type of comparison: superiority. Time period: 6 weeks and 18 weeks post-enrollment. 
 
Null hypothesis: There is no difference in QOD score with drug treatment or placebo. 
Alternative hypothesis: Drug treatment results in improved QOD score. 
 
1.30 SAMPLE SIZE DETERMINATION 
Number of participants to enroll to have adequate power to test the key hypotheses for the study:  
Placebo group: 10 
Treatment group: 10 
 
• 
Target study sample size: 10 subjects in each arm, 20 subjects total. Anticipated number to be 
screened in order to reach the target enrollment: 50 subjects  
• 
Outcome measure used for calculations: SIT score  
• 
Test statistic: t-test 
• 
Null and alternative hypotheses: 
- 
Null hypothesis: There is no difference in SIT score with drug treatment or placebo. 
- 
Alternative hypothesis: NAC treatment results in improved SIT score. 
 
• 
Type I error rate (alpha): 0.05 
• 
Power level: 0.8 
• 
Assumed mean and variance: 
- 
Placebo group, mu1: SIT=24 ± 4 
- 
Treatment group, mu2: SIT=29 ± 4 
 
Reference: “Hypothesis Testing: Two-Sample Inference - Estimation of Sample Size and Power for 
Comparing Two Means” in Rosner, Bernard Fundamentals of Biostatistics, Belmont, Calif. : Duxbury 
Press, [1995]. 
 

DIRECTED TOPICAL DRUG DELIVERY FOR TREATMENT FOR PASC HYPOSMIA  
 
v.1.0, 1 March 2023  
 
Confidential and Proprietary 
 
Page 16 
SIT score of 24 is used for the placebo group because this is a score categorized as severe hyposmia 
(reduced olfaction). Based on published reports and our experience with long-COVID hyposmia 
subjects, we anticipate identifying and enrolling patients with a mean score of approximately 24 and 
a variance of approximately 4.  
 
In terms of estimated possible improvement in SIT score with drug treatment, we have chosen an 
increase of 5 ± 4 points, because a jump of more than a few points on a repeat SIT test after one 
month is considered to be greater than just random chance3; (and Doty, R., personal communication). 
There are no published data available for specifically measuring olfactory change following treatment 
with beclomethasone applied to the olfactory cleft topically for post-viral hyposia.  
 
• 
Anticipated impact of dropout rates, withdrawal, missing data, etc. on study power: to 
compensate for such issues, we have increased our sample size by 1 subject per group.  
 
• 
Secondary endpoint: We have included a secondary endpoint to measure quality of life via a 
validated questionnaire (QOD). We have no specific guides for mean or variance for the 
questionnaire in terms of possible beclamethasone or placebo treatment, so no calculations are 
possible. Nonetheless, a simple questionnaire poses no cost or risk, such that we see no reason 
to not collect these data. 
1.31 POPULATIONS FOR ANALYSES 
 
• 
Intention-to-Treat (ITT) Analysis Dataset (i.e., all randomized participants): 
 
Placebo group (n=10) 
Beclamethasone treated group (n=10) 
 
1.32 STATISTICAL ANALYSES 
 
General Approach 
1.32.1 DATA 
Data (SIT scores, QOD scores) will be presented as means with standard deviations, as well as range. 
Placebo and drug-treated groups will be compared statistically, with p<0.05 considered significant, via 
two-tailed t-test. If data are not normally distributed, nonparametric testing or appropriate post-hoc 
corrections will be applied. 
 
1.32.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
Primary endpoint is SIT score at 6 weeks and18 weeks. 
Placebo and drug-treated groups will be compared. SIT (mean ± sd) will be compared via two-tailed t-
test. SIT scores may range from 0-40, and normal scores are well-established. An assignment of 
normosmia, mild hyposmia, moderate hyposmia, severe hyposmia, anosmia, or probable malingering 
can be made based on SIT score. 
 
1.32.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 

DIRECTED TOPICAL DRUG DELIVERY FOR TREATMENT FOR PASC HYPOSMIA  
 
v.1.0, 1 March 2023  
 
Confidential and Proprietary 
 
Page 17 
Secondary endpoint is QOD score at 6 weeks and18 weeks. 
Placebo and drug-treated groups will be compared. QOD (mean ± sd) will be compared via two-tailed t-
test.  
QOD scores may range from 0-75. There are 25 quality of life questions, scored 0-3 each. A lower score 
implies more severe dysfunction. 
 
1.32.4 SAFETY ANALYSES 
 
There is no formal safety endpoint being evaluated. AEs will be counted per event and will be presented 
as number of AEs and severity.  
 
1.32.5 BASELINE DESCRIPTIVE STATISTICS 
 
The baseline characteristics of the placebo group and the drug-treated groups will be presented. Data 
will include age (mean ± sd) and SIT score (mean ± sd) on enrollment. Also, gender, ethnicity, and details 
of the Covid19 history (i.e., timing, duration, severity) will be captured.  
 
1.32.6 PLANNED INTERIM ANALYSES  
 
Not Applicable 
 
1.32.7 SUB-GROUP ANALYSES 
 
Although no differences are anticipated based on gender, we will capture this information and present 
mean SIT scores for males or females. The primary endpoint will include both genders. 
 
1.32.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
A Table containing individual patient data will be included. 
 
1.32.9 EXPLORATORY ANALYSES 
 
Not Applicable 
 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
1.33 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
 
1.33.1 INFORMED CONSENT PROCESS 
 
1.33.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 
The consent form that will be used for this study is attached. 

DIRECTED TOPICAL DRUG DELIVERY FOR TREATMENT FOR PASC HYPOSMIA  
 
v.1.0, 1 March 2023  
 
Confidential and Proprietary 
 
Page 18 
 
 
1.33.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. All subjects must provide written 
consent prior to participating in this study. Potential participants will be given an ICF containing 
information in a language understandable to them, which meets all federal, local, ICH and HIPAA 
requirements, and is approved by an Institutional Review Board (IRB). 
 
Informed consent will be obtained using processes that comply with all federal and local regulations. 
Patients evaluated at Duke otolaryngology clinic for post-COVID smell loss, with documented hyposmia 
by University of Pennsylvania Smell Identification Test (SIT) will be identified and approached by the 
treating physician. The Investigator (or designee) will carefully review the ICF with potential subject, 
which includes a review of the purpose, scope, procedures, and potential consequences to the subject. 
Patients will be informed that participation in the study is completely voluntary, and they may withdraw 
from the study at any time with no penalty or loss of benefits. Likewise, the quality of their medical care 
will not be adversely affected if they decline to participate in this study.  
 
Participants will have the opportunity to carefully review the written consent form and ask questions 
prior to signing. The participants should have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate. The participant will sign the informed 
consent document prior to any procedures being done specifically for the study. 
 
The potential study subject (or healthcare proxy) and Investigator (or designee) must sign and date the 
ICF before the subject can participate in the study. The original will be retained on file at the study site, 
and the subject will receive a copy.  
 
Should the ICF be amended during the study, the site must use the amended ICF for all new subjects and 
repeat the consent process with the amended ICF for any ongoing subjects. Spanish speaking subjects 
will be provided a translated consent. 
 
1.33.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the PI to study participants and the Institutional Review Board (IRB) and will provide the 
reason(s) for the termination or suspension.  
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 

DIRECTED TOPICAL DRUG DELIVERY FOR TREATMENT FOR PASC HYPOSMIA  
 
v.1.0, 1 March 2023  
 
Confidential and Proprietary 
 
Page 19 
Study may resume once concerns about safety, protocol compliance, or data quality are addressed and 
satisfy the IRB. 
 
 
1.33.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their interventions. Each subject’s name will remain strictly confidential 
and shall be excluded from the database, only subjects’ initials, assigned identifier number, and 
birthdate shall be entered, uploaded, or otherwise documented in the database. The Investigator will 
retain a cross-referencing record of each subject’s name and assigned identifier number. 
All study data and results will be stored in an electronic database. Each study subject will give explicit 
consent for representatives of the IRB/IEC and regulatory authorities to inspect and verify each subject’s 
medical records and collected information. Each study subject will be assured that all their personal 
information will be maintained in the strictest of confidence, and in compliance with HIPAA, and all 
other federal and local laws regulating privacy and data protection. 
All research activities will be conducted in as private a setting as possible. 
The study participants’ contact information will be securely stored at the clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 
1.33.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be analyzed and stored at the PI’s office at Duke University.  
There are no specimens or biologic samples collected for this study. 
 
1.33.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Medical Monitor 
Bradley J. Goldstein, MD, PhD 
Associate Professor, Head and Neck Surgery & 
Communication Sciences 
 
Duke University School of Medicine 
Duke University School of Medicine 
40 Duke Medicine Circle, Clinic 1F, Durham, 
NC 27710 
40 Duke Medicine Circle, Clinic 1F, Durham, 
NC 27710 
919-684-6595 
 
Bradley.goldstein@duke.edu 
 
 
1.33.6 CLINICAL MONITORING 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/amendment(s), with International 
Conference on Harmonization Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s).  
 

DIRECTED TOPICAL DRUG DELIVERY FOR TREATMENT FOR PASC HYPOSMIA  
 
v.1.0, 1 March 2023  
 
Confidential and Proprietary 
 
Page 20 
• 
On-site monitoring, by the research manager of the Department will be planned throughout the 
study. This will included a targeted review of with verification of endpoint and safety, and the 
distribution of monitoring reports will be provided to the PI. Study coordinator will help 
following the regulations in every aspect of the study. 
• 
Independent audits will not be conducted, for this relatively small study. 
 
 
1.33.7 QUALITY ASSURANCE AND QUALITY CONTROL 
 
An individualized quality management plan will be developed to describe a site’s quality management. 
No specimens are to be collected for this study, and the data that are to be collected for primary 
endpoint include SIT scores. Thus, we will focus on monitoring that SITs, a self-administered test, are 
being collected and scored properly. 
 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
 
 
1.33.8 DATA HANDLING AND RECORD KEEPING  
 
1.33.8.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
This is a Single-Center study. Data collection is the responsibility of the clinical trial staff under the 
supervision of the PI. The PI is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data.  Records will be kept in the EMR at Duke, known as Epic. This will include demographics, vital 
signs, and initial H&P. Relevant data will be summarized on a visit worksheet, including information on 
initial SIT score, COVID19 history, and key exam findings. 
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) will be then entered into the EMR system. The data system includes password protection and 
internal quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate. Clinical data will be entered directly from the source documents. Data will 
include the drug administration information, SIT scores and QOD scores. 
 
 
1.33.8.2 STUDY RECORDS RETENTION  
 
Study documents will be retained until at least 2 years have elapsed since the formal discontinuation of 
clinical development of the study intervention. These documents should be retained for a longer period, 

DIRECTED TOPICAL DRUG DELIVERY FOR TREATMENT FOR PASC HYPOSMIA  
 
v.1.0, 1 March 2023  
 
Confidential and Proprietary 
 
Page 21 
however, if required by local regulations. No records will be destroyed without the written consent of 
the sponsor, if applicable. It is the responsibility of the sponsor to inform the investigator when these 
documents no longer need to be retained. 
 
1.33.9 PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within 30 working days of identification of the protocol deviation, or within 30 working days 
of the scheduled protocol-required activity.  All deviations must be addressed in study source 
documents.  Protocol deviations must be sent to the reviewing Institutional Review Board (IRB) per their 
policies. The site investigator is responsible for knowing and adhering to the reviewing IRB 
requirements.  
 
1.33.10 
PUBLICATION AND DATA SHARING POLICY 
 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
This trial will be registered at ClinicalTrials.gov, and results information from this trial will be submitted 
to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed journals.  
Data from this study may be requested from other researchers 3 years after the completion of the 
primary endpoint by contacting the PI, Bradley Goldstein, MD, PhD.  
 
 
1.33.11 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.  The study 
leadership in conjunction with Duke University has established policies and procedures for all 
researchers to disclose all conflicts of interest and, will establish a mechanism for the management of all 
reported dualities of interest. 
 

DIRECTED TOPICAL DRUG DELIVERY FOR TREATMENT FOR PASC HYPOSMIA  
 
v.1.0, 1 March 2023  
 
Confidential and Proprietary 
 
Page 22 
1.34 ADDITIONAL CONSIDERATIONS 
N/A 
 
 

DIRECTED TOPICAL DRUG DELIVERY FOR TREATMENT FOR PASC HYPOSMIA  
 
v.1.0, 1 March 2023  
 
Confidential and Proprietary 
 
Page 23 
1.35 ABBREVIATIONS 
 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
EMR 
Electronic Medical Record 
FDA 
Food and Drug Administration 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
QOD 
Questionnaire on Olfactory Disorders 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SIT 
Smell Identification Test 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
 

DIRECTED TOPICAL DRUG DELIVERY FOR TREATMENT FOR PASC HYPOSMIA  
 
v.1.0, 1 March 2023  
 
Confidential and Proprietary 
 
Page 24 
1.36 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

DIRECTED TOPICAL DRUG DELIVERY FOR TREATMENT FOR PASC HYPOSMIA  
 
v.1.0, 1 March 2023  
 
Confidential and Proprietary 
 
Page 25