Stellate Ganglion Block for the Treatment of COVID-19-Induced Parosmia: Double-Blinded, Placebo-Controlled Randomized Clinical Trial
Phase: PHASE2
Conditions: COVID-19-Induced Parosmia
Sponsor: Washington University School of Medicine

 
 
 
 
 
 
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Stellate Ganglion Block for the Treatment of COVID-19-
Induced Parosmia: Double-Blinded, Placebo-Controlled 
Randomized Clinical Trial  
Principal Investigator:   
Nyssa Farrell, MD 
 
Department of Otolaryngology – Head and Neck Surgery 
 
Co-Investigators: 
Jay F. Piccirillo, MD 
 
Department of Otolaryngology – Head and Neck Surgery 
 
Lara W. Crock, MD, PhD, MSCI 
Department of Anesthesiology 
 
Andrew M. Peterson, MD, MSCI 
 
Department of Otolaryngology – Head and Neck Surgery 
 
NCT06253806 
Version Date/Number: 06/18/2024 - Version 7 
 
 

 
 
 
 
 
 
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TABLE OF CONTENTS 
A 
INTRODUCTION ............................................................................................................................... 3 
A1 
STUDY ABSTRACT ......................................................................................................................... 3 
A2 
PRIMARY HYPOTHESIS ................................................................................................................... 3 
A3 
PURPOSE OF THE STUDY PROTOCOL .............................................................................................. 3 
B 
BACKGROUND AND RATIONALE ............................................................................................... 4 
C 
STUDY OBJECTIVES........................................................................................................................ 5 
C1 
PRIMARY AIM ................................................................................................................................ 5 
C2 
SECONDARY AIM ........................................................................................................................... 5 
C3 
RATIONALE FOR THE SELECTION OF OUTCOME MEASURES ........................................................... 5 
D 
INVESTIGATIONAL AGENT .......................................................................................................... 7 
D1 
CLINICAL DATA TO DATE .............................................................................................................. 7 
D2 
DOSE RATIONALE AND RISK/BENEFITS ......................................................................................... 8 
E 
STUDY DESIGN ................................................................................................................................. 9 
E1 
OVERVIEW OR DESIGN SUMMARY ................................................................................................. 9 
E2 
SUBJECT SELECTION ...................................................................................................................... 9 
2.a 
Inclusion Criteria ..................................................................................................................... 9 
2.a 
Exclusion Criteria ..................................................................................................................... 9 
2.b 
Ethical Considerations ............................................................................................................10 
2.c 
Subject Recruitment Plans and Consent Process ....................................................................10 
2.d 
Randomization Method and Blinding ......................................................................................10 
2.e 
Risks and Benefits ....................................................................................................................11 
2.f 
Early Withdrawal of Subjects ......................................................................................................12 
E3 
STUDY DRUG ................................................................................................................................12 
3.a 
Treatment Regimen ..................................................................................................................12 
F 
STUDY PROCEDURES ....................................................................................................................13 
F1 
SCREENING FOR ELIGIBILITY ........................................................................................................13 
F2 
SCHEDULE OF MEASUREMENTS ....................................................................................................13 
VISIT 1 13 
VISIT 2 13 
F3 
SAFETY AND ADVERSE EVENTS ....................................................................................................15 
3.a 
Safety and Compliance Monitoring .........................................................................................15 
3.b 
Adverse Events .........................................................................................................................15 
G 
STATISTICAL PLAN ........................................................................................................................15 
G1 
SAMPLE SIZE DETERMINATION AND POWER .................................................................................15 
G2 
INTERIM MONITORING AND EARLY STOPPING ..............................................................................16 
G3 
ANALYSIS PLAN............................................................................................................................16 
H 
DATA HANDLING AND RECORD KEEPING .............................................................................16 
H1 
CONFIDENTIALITY AND SECURITY ................................................................................................16 
I 
STUDY MONITORING, AUDITING, AND INSPECTING ..........................................................17 
I1 
STUDY MONITORING PLAN ...........................................................................................................17 
J 
ATTACHMENTS ...............................................................................................................................17 
J1 
QUESTIONNAIRES OR SURVEYS .....................................................................................................17 
K 
REFERENCES ...................................................................................................................................18 

 
 
 
 
 
 
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A Introduction 
 
A1 Study Abstract 
 
Chronic olfactory dysfunction, both hyposmia and parosmia, from the COVID-19 
pandemic is a growing public health crisis with up to 1.2 million people in the United 
States affected. Olfactory dysfunction impacts one’s quality of life significantly by 
decreasing the enjoyment of foods, creating environmental safety concerns, and 
affecting one’s ability to perform certain jobs. Olfactory loss is also an independent 
predictor of anxiety, depression, and even mortality. Recent research by our group 
(unpublished data) suggests that parosmias, moreso than hyposmias, can result in 
increased rates of anxiety, depression, and even suicidal ideation. While the pandemic 
has increased the interest by the scientific community in combating the burgeoning 
health crisis, few effective treatments currently exist for olfactory dysfunction. Persistent 
symptoms after an acute COVID-19 infection, or “Long COVID” symptoms, have been 
hypothesized to be a result of sympathetic positive feedback loops and dysautonomia. 
Stellate ganglion blocks have been proposed to treat this hyper-sympathetic activation 
by blocking the sympathetic neuronal firing and resetting the balance of the autonomic 
nervous system. Studies prior to the COVID-19 pandemic have supported a beneficial 
effect of stellate ganglion blocks on olfactory dysfunction, and recent news reports and a 
published case series have described a dramatic benefit in both olfactory function and 
other long COVID symptoms in patients receiving stellate ganglion blocks. A previous 
pilot study using stellate ganglion blocks of 20 participants with persistent COVID-19 
olfactory dysfunction resulted modest improvements in subjective olfactory function, 
smell identification, and olfactory-specific quality-of-life, but it lacked a control group. 
Therefore, we propose a double-blinded, placebo-controlled randomized clinical trial 
assessing the efficacy of a stellate ganglion block versus saline injection in a total of up 
to 140 participants with persistent COVID-19-associated olfactory dysfunction.  
A2 Primary Hypothesis 
 
Stellate ganglion block (SGB) is effective and safe in improving olfactory dysfunction in 
patients with chronic COVID-19-induced parosmia. 
A3 Purpose of the Study Protocol 
 
The purpose of this study is to evaluate the efficacy of stellate ganglion blocks for the 
treatment of chronic COVID-19-associated parosmia in order to treat the growing 
population of people with long-term olfactory dysfunction as a result of the pandemic.  
 
 
 
 
 

 
 
 
 
 
 
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B Background and Rationale 
 
One of the hallmark symptoms of infection with SARS-CoV-2 is olfactory dysfunction 
(OD). While the majority of patients recover from COVID dysosmia, up to 15%-25% have 
long-term hyposmia1,2 and it is estimated that up to 1.2 million people in the United 
States will experience chronic OD from the COVID-19 pandemic.3 A unique feature of 
COVID-19-associated OD is the high rate of persistent parosmia. In one study of 222 
patients with COVID-19-associated olfactory dysfunction by Lerner et al, 148 (67%) of 
these patients experienced parosmia at some point, and estimates of persistent 
parosmia 6 months after COVID-19 infection range from 25% to 57%.4-6 Patients with 
OD have decreased quality-of-life and have described their lives as if “living in a box.”7 
These patients have concerns for environmental safety, decreased enjoyment of their 
food, depression, anxiety, and even a higher risk of mortality.7-9 Unpublished work by our 
group has demonstrated a relationship between parosmia and increased risk of 
screening positive for anxiety, depression, and suicidality. 
 
The COVID-19 pandemic has highlighted the importance of the sense of olfaction, but 
no standard of care treatment for post-viral OD exists. The most commonly used 
treatment for post-viral OD is olfactory training; however, a large proportion of patients 
do not receive benefit and continue to have persistent symptoms.10 A multitude of other 
therapies have been tried in randomized clinical trials with minimal success, including 
theophylline11, vitamin A12, sodium citrate13, and intranasal insulin.14,15 As a result, there 
is a critical need for the development of a novel intervention to address the large number 
of patients with OD due to the COVID-19 pandemic.  
 
 
The stellate ganglion block (SGB) is proposed to inhibit the sympathetic neural 
connections within the head, neck, and upper extremity, improve regional blood flow, 
reduce adrenal hormone concentration, and even reestablish circadian rhythms through 
modulation of melatonin.16-19 The SGB has been used successfully in a multitude of 
disorders, including post-traumatic stress disorder20, migraine21, and complex regional 
pain syndrome.22 A meta-analysis of 12 clinical trials found that SGB was superior to 
placebo in reducing pain scores among patients with various sympathetic hyperactivity-
associated disorders.23 Many “long COVID” symptoms, those that persist after recovery 
from acute COVID-19 infection, are hypothesized to be, at least in part, a result of 
sympathetic hyperactivity resulting in positive feedback loops.24 Therefore, the stellate 
ganglion block (SGB) is hypothesized to reset the balance of the autonomic nervous 
system and provide relief for long COVID symptoms, including OD.24 
 
The SGB was first proposed to treat OD by Lee et al in 2003, where 38 post-viral OD 
participants were treated with SGB and 13 participants remained untreated as controls.25 
Subjective olfactory function improved in 27 (71%) of the treated participants compared 
to zero (0%) of the controls. Olfactory perception was improved significantly in the SGB 
group assessed both by the butanol threshold test and odor identification test. Additional 
studies by Moon et al noted improvement in OD of various etiologies after repeated 
SGBs.26,27 However, each of these studies were limited by their use of unvalidated 
outcome measures in a heterogeneous OD population in the pre-COVID era, limiting 
their external validity to the present day.   
 
 
A multitude of anecdotal news reports and published case series28-30 point to a possible 
beneficial effect of the SGB on both chronic COVID-19-induced OD and various other 

 
 
 
 
 
 
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long COVID symptoms. Numerous pain management clinics across the country are 
offering the SGB for long COVID with thousands of dollars of out-of-pocket costs to 
patients without adequate evidence to justify its use. One case series of 195 parosmic 
patients noted up to a 75% response rate after SGB.31  
 
Recently, our study team completed a prospective, pilot single-arm trial of 20 
participants with persistent COVID-19-associated OD who underwent bilateral stellate 
ganglion blocks and were followed for 1 month post-procedure. At 1-month, 10 (50%) 
participants experienced at least slight subjective improvement in their OD, 11 (55%) 
attained a clinically meaningful improvement in smell identification using the UPSIT, and 
7 (35%) achieved a clinically meaningful improvement in olfactory-specific QOL. 
Therefore, we propose a double-blinded, placebo-controlled randomized clinical trial 
assessing the efficacy of a stellate ganglion block versus saline injection in a total of 140 
participants with persistent COVID-19-associated parosmia.  
 
C Study Objectives 
 
C1 Primary Aim 
 
1. To determine the efficacy of a SGB in improving parosmia-related quality of 
life compared to saline injection 
C2 Secondary Aim 
 
1. To determine the efficacy of a SGB in improving self-reported parosmia 
compared to saline injection 
 
2. To determine the safety and tolerability of a SGB 
 
3. To determine if subjects who catastrophize their parosmia smell loss are 
more likely to respond to SGB 
 
4. To determine if subjects who screen positive for anxiety/depression are 
more likely to respond to SGB 
 
5. Explore if there is variation of SGB effect dependent on injection laterality 
(right versus left SGB) 
 
C3 Rationale for the Selection of Outcome Measures 
 
Parosmia Olfactory Dysfunction Outcomes Rating (DisODOR). The DisODOR is a 
disease-specific questionnaire that assesses for physical problems, functional 
limitations, and emotional consequences of parosmia secondary to any etiology. The 
instrument contains 29 total items with each scored on a 5-point Likert scale from 0 to 4.  
 

 
 
 
 
 
 
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Clinical Global Impression - Severity Scale (CGI-S). The baseline severity of 
parosmia will be measured with the CGI-S scale. The CGI-S scale measures disease 
severity in clinical condition based on a 5-point Likert scale.  
 
Clinical Global Impression - Improvement Scale (CGI-I). The overall response to 
treatment will be measured with the CGI-I scale. The CGI-I Scale measures response to 
treatment for a number of disorders and has good internal consistency and validity.32 
The CGI-I scale measures change in clinical condition based on a 7-point Likert scale. 
The CGI-I for parosmia asks, “Compared to before your stellate ganglion block, how 
would you describe your parosmia (things do not smell the same as you remember)?" 
Response options for each are: (1) Much better now than before, (2) Moderately better 
now than before, (3) Slightly better now than before, (4) About the same, (5) Slightly 
worse now than before, (6) Moderately worse now than before, and (7) Much worse now 
than before. Responders are defined as those who report “slightly better now than 
before” or greater.  
 
University of Pennsylvania Smell Identification Test (UPSIT, Sensonics, New 
Jersey). The UPSIT is a test of olfactory identification and consists of four 10-page 
booklets, with a total of 40 items. On each page, there is a different “scratch and sniff” 
strip and four choice options. Subjects are asked to scratch each strip with a pencil to 
release the scents, detect the smell, and identify the smell from the four choice options. 
The UPSIT comes from a scoring rubric that identifies the normalcy benchmark based 
on age and gender, which is >34 in women and >33 in men.33,34 The UPSIT is 
commercially available, takes 10-15 minutes to complete, and is the gold standard test 
to assess smell identification. The minimal clinically important difference of the UPSIT is 
4.  
 
Long-COVID Questionnaire (LCQ). Symptoms assessed via the LCQ are derived from 
the Symptom Burden Questionnaire for Long Covid35, which included tiredness/fatigue, 
shortness of breath, brain fogginess, headache, cough, depression, low-grade fevers, 
palpitations, dizziness, muscle pain, and joint pains. At baseline, participants are asked 
to rank the current severity of each problem on a 5-point Likert scale. At each follow-up 
visit, participants are asked to rank their overall improvement in each of the 11 
symptoms compared to their symptoms prior to their first SGB. The improvement options 
are based on the CGI-I 7-point Likert scale. 
 
Olfaction Catastrophizing Scale (OCS). The pain catastrophizing scale (PCS) was 
developed to measure the negative mental response to actual or anticipated pain. The 
OCS was derived from the validated PCS to similarly measure the negative mental 
response to smell dysfunctionloss. Multiple thoughts/feelings will be assessed on a 5-
point likert scale with a maximum score of 52. At each visit, subjects will be asked to 
complete the OCS. 
 
Hospital Anxiety and Depression Scale (HADS). The HADS was developed for 
screen for anxiety and depression in the general population. It consists of 7 questions for 
anxiety and 7 questions for depression each ranked on a 4-point Likert Scale. A score of 
0-7 is considered normal, 8-10 is borderline abnormal anxiety or depression, and a score 
of 11-21 corresponds with screening positive for anxiety or depression. Subjects will be 
screened for anxiety and depression at eachtheir initial visit. 
 

 
 
 
 
 
 
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Pre-Intervention Expectations. A significant number of social media and news stories 
have discussed anecdotal success of stellate ganglion blocks for COVID-19-induced 
olfactory dysfunction. As a result, we propose that participants may have a distorted pre-
operative expectation that may affect their subjective rating of improvement in olfaction. 
Therefore, participants will be asked at baseline, “How confident are you that the stellate 
ganglion block will improve your smell loss or smell distortion?” Possible answer 
choices: Not at all, Slightly confident, Somewhat confident, Very confident, Extremely 
confident.  
 
Patient Satisfaction with Treatment. Participants will be asked at the 1-month virtual 
visit, “Overall, how satisfied were you with the stellate ganglion block treatment for your 
parosmia?” Possible answer choices: 1) Completely dissatisfied, 2) Mostly dissatisfied, 
3) Somewhat dissatisfied, 4) Neither satisfied or dissatisfied, 5) Somewhat satisfied, 6) 
Mostly satisfied, 7) Completely satisfied. Patients will also be asked at the final visit, 
“Would you recommend this treatment to a family member or close friend who also 
suffers from chronic smell loss due to COVID-19?” Possible answer choices: 1) Yes, 2) 
No. 
 
Assessment of the Blind. Immediately after the initial injection, participants will be 
asked, “Which intervention do you think you received?” Answer choices: 1) Mepivacaine 
(active medication) 2) Saline (placebo). 
 
Parosmia Trigger Question. “How many different items trigger parosmia?" This will be 
assessed on a 5-point Likert scale.  
 
D Investigational Agent  
 
D1 Clinical Data to Date  
 
The SGB was first proposed to treat OD by Lee et al in 2003, where 38 post-viral OD 
participants were treated with SGB and 13 participants remained untreated as controls.25 
Subjective olfactory function improved in 27 (71%) of the treated participants compared 
to zero (0%) of the controls. Olfactory perception was improved significantly in the SGB 
group assessed both by the butanol threshold test and odor identification test. Additional 
studies by Moon et al noted improvement in OD of various etiologies after repeated 
SGBs.26,27 However, each of these studies were limited by their use of unvalidated 
outcome measures in a heterogeneous OD population in the pre-COVID era, limiting 
their external validity to the present day.   
 
 
A multitude of anecdotal news reports and published case series28-30 point to a possible 
beneficial effect of the SGB on both chronic COVID-19-induced OD and various other 
long COVID symptoms. Most recently, a case series of 195 patients with parosmia noted 
up to 75% response rate after SGB.31 Numerous pain management clinics across the 
country are offering the SGB for long COVID with thousands of dollars of out-of-pocket 
costs to patients without adequate evidence to justify its use. Recently, our study team 
completed a prospective, pilot single-arm trial of 20 participants with persistent COVID-
19-associated OD who underwent bilateral stellate ganglion blocks and were followed for 

 
 
 
 
 
 
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1 month post-procedure. At 1-month, 10 (50%) participants experienced at least slight 
subjective improvement in their OD, 11 (55%) attained a clinically meaningful 
improvement in smell identification using the UPSIT, and 7 (35%) achieved a clinically 
meaningful improvement in olfactory-specific QOL.  
D2 Dose Rationale and Risk/Benefits  
 
The stellate ganglion block has been used for decades with the assistance of 
fluoroscopy and has been modified in the present day by using ultrasound to improve 
visualization. Substantial data has been generated on the safety and tolerability of the 
procedure in other conditions, such as post-traumatic stress disorder (PTSD). One study 
of 250 SGBs for PTSD performed by an experienced pain management provider 
resulted in zero post-procedural or delayed complications. Of 110 participants in the 
study who returned completed surveys, 100% of the patients said they would 
recommend the procedure to a friend, and 95% stated that they would be willing to 
undergo as many repeat procedures as necessary based on the minimal discomfort and 
tolerable side effects.36 A temporary Horner's syndrome is an expected outcome of SGB 
and improves over the course of a few hours.  
 
Our 20-participant pilot study demonstrated the following safety data for the SGB. There 
were no serious adverse events and all adverse events were transient. A total of 11 
(55%) of the participants reported being satisfied with the SGB and 17 (85%) said that 
they would recommend the treatment to a close friend or family member. 
 
Adverse Effecta 
No. (%)  
All completed procedures (n = 40) 
Horner syndrome 
39 (97.5) 
Hoarseness 
17 (42.5) 
Globus 
14 (35) 
Brief lightheadedness 
9 (22.5) 
Numbness of the face 
8 (20) 
Mild shortness of breath 
7 (17.5) 
Nasal congestion 
6 (15) 
Pain at the injection site 
6 (15) 
Fatigueb,c 
5 (12.5) 
Cough 
2 (10) 
Weakness of the arm 
2 (10) 
Weakness of the neck/back 
2 (10) 
Tightness of the neck 
2 (10) 
Arm heaviness 
1 (5) 
Bruising of the injection site 
1 (5) 
Chest heaviness 
1 (5) 
Headache 
1 (5) 
Palpitations 
1 (5) 
Tightness of the shoulderb 
1 (5) 
 
a Displayed adverse effects were all found to be at least possibly related to the study, three additional 
adverse effects, bruising of the eyelid, persistent numbness of the neck, and photosensitivity, were also 
reported but their relatedness to the study was determined to be unlikely 
b Adverse effect was determined to be unexpected and was reported to the institutional review board 

 
 
 
 
 
 
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c One instance of persistent fatigue was reported and was determined to be unexpected; all other instances 
of fatigue were brief and were determined to be expected 
 
E Study Design  
 
E1 Overview or Design Summary 
 
The study will be a single center, double-blinded, placebo-controlled randomized clinical 
trial conducted at Washington University School of Medicine. 
 
E2 Subject Selection  
2.a 
Inclusion Criteria  
1) 
Adults age 18 to 70 
2) 
Diagnosis of COVID at least 6 months prior to study enrollment 
with self-reported parosmia 
3) 
Ability to read, write, and understand English 
4) 
Score of at least 40 on DiSODOR during screening and at least 25 
during Visit 1 
 
2.a 
Exclusion Criteria  
1) 
History of smell loss or change prior to COVID-19 infection 
2) 
History of conditions known to impact olfactory function: 
a. Chronic rhinosinusitis 
i. If individual notes a history of chronic rhinosinusitis or 
prior endoscopic sinus surgery, they may be eligible if 
they can a note from their otolaryngology (ENT) 
physician stating the following: 
      1. Patient's chronic rhinosinusitis is controlled 
      2. There are no polyps/masses/scarring of the 
olfactory cleft 
      3. The otolaryngologist feels that the patient’s 
parosmia is secondary to COVID-19 
b. History of prior sinonasal or skull base surgery 
c. Neurodegenerative disorders (Parkinson’s disease, 
Huntington’s disease, Amyotrophic lateral sclerosis, Lewy 
body dementia, frontotemporal dementia) 
3) 
Currently using concomitant therapies specifically for the 
treatment of olfactory dysfunction 
4) 
Inability to tolerate a needle injection into the neck 
5) 
History of coexisting conditions that make SGB contraindicated: 
a. Unilateral vocal cord paralysis 
b. Severe COPD (FEV1 between 30-50% of predicted) 
c. Recent myocardial infarction within the last year 

 
 
 
 
 
 
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d. Glaucoma 
e. Cardiac conduction block of any degree 
6) 
Currently taking blood thinners or antiplatelet agents, including     
> 81mg aspirin 
7) 
Allergy to local anesthetic 
8) 
Inability to extend the neck for any reason (e.g., severe arthritis) 
9) 
History of prior stellate ganglion block 
 
2.b 
Ethical Considerations  
 
Patients will be informed in the informed consent process that they may or may not 
personally benefit from the study and that the data obtained from the study will be used 
to inform the future care patients with chronic COVID-19-induced olfactory dysfunction. 
There will be phone assistance available 24/7 during the study period to report any 
possible adverse reactions. There are no financial conflicts of interest. 
2.c 
Subject Recruitment Plans and Consent Process 
 
Study recruitment strategies include: 
- 
Approaching adult patients with chronic COVID-19-induced olfactory dysfunction 
being seen at Washington University Medical Center  
o CARES clinic will provide list of potentially eligible patients to be 
contacted by the study team 
- 
Searching the electronic medical record (Epic) to identify potentially eligible 
patients to be contacted by a study team member  
- 
Contacting participants from previous COVID related research studies who 
agreed to be contacted for future studies 
- 
Distributing study recruitment flier to ENT physicians/offices  
- 
Posting study recruitment flier to social media sites 
- 
WU Volunteer for Health database email blast and Study Search post 
 
Eligible patients who present to clinic, contact the study team, or are contacted by the 
study team will be approached by a research team member for study screening and, if 
eligible, to review the informed consent form and thoroughly discuss the research 
protocol, potential benefits, and risks of the study.  The informed consent discussion will 
take place with the potential participant and any available family members over the 
phone or in person, whichever the potential participant prefers. Any subsequent 
questions or concerns from the potential participant about the study will also be 
addressed at that time and they will be reminded that participation is voluntary and will 
not affect their current or future care.  If interested, written consent will be obtained a the 
initial study visit and prior to commencement of any research activities.  
 
2.d 
Randomization Method and Blinding 
 
After informed consent, participants will be randomized using permuted blocks of varying 
sizes to receive either a stellate ganglion block or a placebo saline injection near the 
stellate ganglion. Randomization will ocurr as 2:1 active versus placebo injection. 
 

 
 
 
 
 
 
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11
Blinding. Blinding will be achieved through two primary means. First, the Barnes Jewish 
Hospital investigational drug pharmacy will produce identical appearing mepivacaine and 
saline vials of which the entire research team will be unaware of the participant’s 
intervention assignment. Second, a single-use eye patch will be placed prior to the 
procedure. Additionally, a cool compress will be applied to each participant’s ipsilateral 
eye prior to the procedure and kept in place throughout the procedure and during the 
post-procedure recovery for a total of up to 20 min of cool compress application. Once 
subjects have been approved for discharge from the CTRU, participants will be asked to 
to wear the single-use eye patch for an additional 2 hours prior to patch removal. All 
subjects will be informed that Horner’s syndrome can occur regardless of injection of 
mepivacaine or placebo. 
2.e 
Risks and Benefits 
 
Risks of lidocaine/mepivacaine injection (SGB) include:  
 
• 
allergic reactions like skin rash, itching or hives, swelling of the face, lips, or 
tongue 
• 
breathing problems 
• 
changes in vision 
• 
chest pain 
• 
feeling faint or lightheaded, falls 
• 
headache 
• 
seizures 
• 
slow, irregular heartbeat 
• 
trembling or shaking 
• 
unusually weak or tired 
• 
confusion 
• 
ringing in your ears 
 
If a participant experiences any side effect listed above following the injection, the post-
injection observation period will last up to 2 hours. Vital signs (heart rate and breathing) 
will be monitored throughout the observation period. 
 
Side effects that are expected, common, usually lasting up to 24 hours and usually do 
not require medical attention: 
 
• 
Horner syndrome - constricted pupil (miosis), drooping of the upper eyelid 
(ptosis), absence of sweating of the face (anhidrosis), and sinking of the eyeball 
into the bony cavity that protects the eye (enophthalmos).  
• 
anxiety or nervousness 
• 
backache 
• 
feelings of cold, heat, or numb 
• 
irritation at site where injected 
• 
nausea, vomiting 
• 
hoarseness 
• 
mild shortness of breath 
• 
dysphagia (difficulty swallowing) 
• 
globus (feeling of something stuck in the throat) 

 
 
 
 
 
 
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• 
congestion- nasal  
• 
temporary weakness in the arm 
• 
blurry vision 
• 
droopy eye lid 
• 
eye redness 
• 
neck pain or pain at injection site 
 
However, these side effects are all rare when used at the maximum total combined dose 
of 4.5mg/kg lidocaine and 4.5mg/kg mepivacaine. We will strictly following this dosing 
guideline. 
 
Participants may or may not directly benefit from the stellate ganglion blocks and will be 
aware that they may receive the saline injection (without active medication). Regardless 
of the results, our findings will help direct future care of patients with a similar condition. 
 
 
2.f 
Early Withdrawal of Subjects  
 
During the informed consent process, participants will be informed that they may 
withdraw at anypoint during the study, including before, during, or after their SGB. 
Participants will face no penalty or negative consequences for withdrawaling from the 
study.  
 
E3 Study Drug  
3.a 
Treatment Regimen  
 
Stellate Ganglion Block. All SGBs will be performed by a board-certified 
anesthesiologist and pain management specialist with extensive experience performing 
SGBs (Dr. Lara Crock). Laterality of the SGB will be randomized between the left and 
right sides of the neck. Participants will be asked to remain NPO for 8 hours prior to the 
SGB. Using ultrasound-guidance, the transverse process of the C6 vertebra is identified. 
Color-doppler is used to identify blood vessels. A 27-gauge needle is used to 
anesthetize the superficial skin with 1% lidocaine. Then, a 21-gauge ultrasound needle 
is advanced using an in-plane technique from lateral to medial with careful avoidance of 
neurovascular structures. After negative aspiration, 6-8 mL of 1% mepivacaine is 
deposited beneath the prevertebral fascia and above the longus coli muscle into the 
stellate ganglion.  
 
The presence of a transient Horner syndrome (ipsilateral miosis, anhidrosis, and ptosis) 
5-15 minutes after the SGB is expected. Post-procedure adverse effects will be 
documented. If participants develop globus or dysphagia they are asked to remain NPO 
for an additional 2 hours post-procedure. 
 
All participants will be monitored for adverse effects prior to, during, and immediately 
following each SGB. A continuous electrocardiogram (ECG) is run from just prior to the 
start of the procedure until ten minutes following its completion. Vital signs, including 
pulse oximetry, blood pressure, heart rate, and respiratory rate will be obtained prior to 
the beginning of the procedure and repeated until ten minutes post-procedure. 

 
 
 
 
 
 
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13
 
Placebo Injection. The placebo sham injection will be performed in an identical fashion 
as the stellate ganglion block by Dr. Crock with the exception of using 6-8 mL of 0.9% 
saline injection instead of mepivacaine. A Horner syndrome is not expected after 
placebo injection, but its presence has been noted in prior studies with sham SGBs.  
 
F Study Procedures  
 
F1 Screening for Eligibility 
 
To determine potential eligibility for the study, the research team will query the medical 
record and our team’s contact database of COVID-19-induced olfactory dysfunction 
patients based on the inclusion/exclusion criteria. For those meeting the selection 
criteria, we will access name, telephone number, age, sex, and date/time of any 
upcoming clinic visits. For interested and potentially eligible individuals, including those 
contacting the study team, eligibility will be determined based on the inclusion/exclusion 
criteria and completion of the DisODOR questionnaire.  If they have been treated at the 
medical center for COVID, their medical record will be accessed. 
 
F2 Schedule of Measurements 
 
The first visit will be completed at the Clinical and Translational Research Unit (CTRU). 
The second and third visits will be completed virtually. 
 
Role of the CTRU: Nursing staff will be needed for assistance in completion of the SGB. 
Additionally, all subjects will have vital signs monitored with serial blood pressures, 
respiratory rate, heart rate, and pulse oximetry within the CTRU for a minimum of 10 
minutes after completion of the block to ensure patient stability prior to discharge.  
Additional monitoring will be provided as needed based on patient response to the 
procedure. Participants will be discharged once stability is determined and instructed to 
continue wearing an eye patch for an additional 2 hours. It will be ensured that they have 
someone to drive them home prior to discharge.  
Visit 1  
 
At the initial visit, demographic information, including age, sex, race, and length of time 
of parosmia will be collected from each enrolled patient. Prior to undergoing the first 
SGB, participants will complete the Parosmia trigger question, DisODOR, UPSIT, CGI-S 
for Parosmia, OCS, HADS, and Pre-Intervention Expectations Questionnaire. The 
assessment of the blind will occur just prior to discharge from the first visit. 
Visit 2 
 
The second visit will be virtual and will occur approximately 1 month after the first visit. 
Participants must have access to email and the internet to receive a link which will 

 
 
 
 
 
 
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14
connect them with the questionnaires to complete about their smell ability and how they 
are feeling.Their answers will be saved in saved in REDCap. Participants will be asked 
to fill out the Parosmia trigger question and the DisODOR. They will also complete the 
CGI-I for Olfactory Dysfunction, the LCQ, the Participants Satisfaction with Treatment 
Questionnaire, OCS, HADS, and Adverse Events Assessment. 
 
 
Visit 3 
 
The third and final visit will be virtual and will occur approximately 3 months after the 
injection. Participants must have access to email and the internet to receive a link which 
will connect them with the questionnaires to complete about their smell ability and how 
they are feeling.Their answers will be saved in saved in REDCap. At 3-months post-
SGB, participants will virtually complete the Parosmia trigger question, DisODOR, CGI-I 
for Olfactory Dysfunction, LCQ, Participant Satisfaction with Treatment Questionnaire, 
OCS, HADS, and Adverse Events Questionnaire.  
 
 
Schedule of Events 
Visit 1 
 
Visit 2  
1 Month post 
SGB 
(=+/- 7 days) 
 
Visit 3  
3 Months post 
SGB 
(+/- 7 days) 
Screening* 
Baseline 
Informed Consent 
X 
 
 
 
Demographics 
Questionnaire** 
X 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
Parosmia trigger 
question 
 
X 
X 
X 
CGI-S for Parosmia  
 
X 
 
 
University of 
Pennsylvania Smell 
Identification Test 
(UPSIT) 
 
X 
 
 
Pre-Intervention 
Expectations 
Questionnaire  
 
 
X 
 
 
Parosmia Olfactory 
Dysfunction Outcomes 
Rating (DisODOR) 
X 
X 
X 
X 
Olfaction 
Catastrophizing Scale 
(OCS) 
 
X 
X 
X 
Hospital Anxiety and 
Depression Scale 
(HADS) 
 
X 
X 
X 
Long-COVID 
Questionnaire  
 
X 
X 
X 
SGB or Placebo 
Injection 
 
 
X 
 
 

 
 
 
 
 
 
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15
Assessment of the Blind 
 
X 
 
 
CGI-I for Parosmia 
 
 
X 
X 
Participant Satisfaction 
with Treatment 
Questionnaire 
 
 
X 
X 
Adverse Events 
Assessment 
 
X 
X 
X 
*Screening and Visit 1 may occur at the same visit 
**Demographic variables include date of birth, sex, race, ethnicity, home address, date of (+) 
COVID-19 test 
***The assessment of the blind will occur just prior to discharge from the first visit. 
 
F3 Safety and Adverse Events  
3.a 
Safety and Compliance Monitoring 
 
The specific monitoring plan for this study is based on the potential risk of participation 
and size and complexity of the planned investigation. Based on these considerations, 
this study will have a monitoring board comprised of Dr. Farrell, Dr. Crock, Dr. Piccirillo, 
Ms. Kukuljan, and Dr. Kallogjeri, the study biostatistician. The monitoring board will meet 
to review data after enrollment of 20 participants. All reports of a Serious Adverse Event 
(SAE) or an Unexpected Adverse Event will be investigated by the monitoring team and 
reported to Washington University HRPO according to the reporting requirements. 
3.b 
Adverse Events 
 
Adverse events will be tracked from the time of dose administration through post dose 
and at the follow up visit 3 for drug-related adverse events. All adverse events will be 
documented and assessed for relatedness to the study medication. The study team will 
monitor for adverse events on an ongoing basis. Once the team becomes aware of an 
adverse event, the AE will be reported according to institutional guidelines. 
 
G Statistical Plan  
 
G1  Sample Size Determination and Power 
 
Sample size estimate for the proposed study is based on our team’s previous pilot study 
with 50% of participants reporting slightly improved olfactory dysfunction at 1 month.  
 
A power analysis was performed using Fisher’s exact test in G-Power 3.1.2. Our recently 
completed SGB trial showed that 1 month after injection, 35% of the participants had an 
improvement of 15 points of more in ODOR total score. Using a clinically important 
difference of 25% in proportions of responders between active treatment and control 
group, we estimated using an exact test that a sample size of 114 subjects (38 controls 

 
 
 
 
 
 
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16
and 76 cases) will be needed to detect with 80% power at the 2-sided alpha level of 
0.05. 
 
Considering a 20% drop-out rate the total sample size to enroll is up to 140 participants. 
 
G2 Interim Monitoring and Early Stopping 
 
We plan to perform an interim futility analysis. The recruitment will be halted and we will 
perform interim analysis when the first 40 subjects randomized and who have 
successfully completed treatment will have completed their 1-month post treatment 
assessment. Comparison of the primary endpoint between the 2 study groups will be 
evaluated for the interim futility analysis.  Fisher’s exact test will be used for the analysis 
given the small sample size. Conditional power (CP) with is the probability of finding 
statically significant results at the end of the trial, given the information obtained at 
interim analysis will be calculated using Mehta & Pocock CP equation. If CP<20% the 
result will be considered as suggestive of futility and it will serve only as a guideline that 
initiates more comprehensive discussion as to whether the course of the study should be 
modified. The data will be frozen for analysis and will be saved, so that additional 
analyses may be performed, or the analyses recreated, if necessary. Interim 
comparative data will be considered confidential and the results will be provided in a 
blinded fashion to research team members. 
G3  Analysis Plan 
 
Standard descriptive statistics will be used to describe distribution of baseline 
characteristics in each of the study groups. The effect of the intervention will be 
measured as the between-subject change in DisODOR.    
 
The 95% confidence interval around this effect size will be determined to assess the 
precision of the observed effect and whether a clinically meaningful difference is 
plausible given the observed results. The DisODOR has an MCID of 15 points. A 
difference of at least 25% from the saline group is considered clinically meaningful. If a 
greater than 25% proportion difference in responder rate is achieved in favor of 
the SGB group, we will offer the SGB to the placebo group at the conclusion of the 
study. This will be submitted as a modification to the study. 
 
Appropriate analyses will be performed for the secondary outcome measures.  
 
H Data Handling and Record Keeping  
 
H1 Confidentiality and Security 
 
The secure REDCap database will be used to store data. Only study team members will 
have access to the database.  
 

 
 
 
 
 
 
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17
I Study Monitoring, Auditing, and Inspecting  
 
I1 
Study Monitoring Plan  
The regulatory coordinator with the assistance of the study team will: 
• 
Review of credentials, training records, and delegation of responsibility logs. 
• 
Review of Consent Forms: 
o 100% reviewed for studies with < 100 subjects. 
• 
Review reports on missed events, missing data, and protocol deviations for a 
determined sample of subjects. 
• 
Compare source documentation and CRFs (REDCap database) to ensure 
data are accurate and complete.   
• 
Regulatory review of IRB approvals in the Investigator Site File.  
 
Monitoring Schedule: 
• 
The first monitoring activities will occur within 1 month after first subject is 
enrolled. 
• 
Interim monitoring activities will occur after 20 participants are enrolled and 
again when enrollment is met and all visits for all participants are completed.  
• 
Ad hoc or for-cause monitoring as needed or requested. 
 
J  Attachments  
 
J1 Questionnaires or surveys 
- 
Assessment of the Blind 
- 
Parosmia trigger question 
- 
Parosmia Olfactory Dysfunction Outcomes Rating (DisODOR) 
- 
CGI-S for Parosmia  
- 
CGI-I for Parosmia 
- 
Long-COVID Questionnaire  
- 
Olfactory Catastrophizing Scale (OCS) 
- 
Hospital Anxiety and Depression Scale (HADS) 
- 
Pre-Intervention Expectations Questionnaire 
- 
Participants Satisfaction with Treatment Questionnaire 
- 
University of Pennsylvania Smell Identification Test (UPSIT) 
 
 

 
 
 
 
 
 
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18
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