Clinical trial NCT04952389
Conditions: Olfactory Dysfunction COVID-19
Sponsor: Mayo Clinic
Start date: 2021-12-07; Completion date: 2023-06-09
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is looking at the role of acupuncture as a treatment for olfactory dysfunction in patients who tested positive for COVID-19.

Detailed description:

Arms: arm 1: Subjects will undergo ten sessions of acupuncture therapy with a licensed acupuncturist in addition to the standard of care. arm 2: Subjects will be treated with two times daily budesonide rinses and olfactory (sense of smell) training. This is considered the current standard of care in the treatment of olfactory dysfunction.
Interventions: intervention 1: Acupuncture Therapy intervention 2: Budesonide intervention 3: Olfactory Training
Intervention descriptions: intervention 1: Consists of two treatments per week for five weeks intervention 2: Twice daily nasal rinses with steroid medication (budesonide) intervention 3: involves smelling 4 different essential oils (e.g. rose, lemon, clove, and eucalyptus) twice a day for 20 seconds each (after the nasal rinse)

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Acupuncture Therapy for COVID-Related 
Olfactory Loss 
 
NCT04952389 
 
March 23, 2021 


 
 
 
 
 
 
 
 
 
 
 
Page 1 of 10 
 
IRB Minimal Risk Protocol Template  
 
General Study Information 
 
Principal Investigator: Janalee K. Stokken       
 
 
 
 
 
 
 
 
Study Title: Acupuncture Therapy for COVID-Related Olfactory Loss 
 
Protocol version number and date: Version 1 – March 23rd, 2021     
 
Research Question and Aims 
 
Hypothesis: There will be no difference in improvement in olfaction in patients with COVID-related olfactory 
loss treated with acupuncture, steroid rinses, and olfactory retraining compared to those treated with steroid 
rinses and olfactory retraining. 
 
Aims, purpose, or objectives: 
 
Aim 1: Describe the incidence of COVID-related olfactory loss. 
Aim 2: Compare the effectiveness of acupuncture, steroid rinses, and olfactory training versus steroid rinses and 
olfactory training in the treatment of COVID-related olfactory loss. 
Aim 3: Recommend a treatment paradigm for patients with COVID-related olfactory loss. 
 
 
 
 
 
Background (Include relevant experience, gaps in current knowledge, preliminary data, etc.):   
 
Soon after the start of the COVID-19 pandemic, olfactory loss was identified as a common presenting symptom 
with anosmia reported in up to 75% of patients who tested positive for COVID-19 infection.1 The severity of 
alteration of the sense of smell or taste is mild to moderate in about two thirds of patients with COVID-19 
infection2 and complete recovery is seen in 64% of patients after symptom onset.3 In contrast, only 46% of 
patients with post-viral anosmia prior to the COVID-19 pandemic demonstrated clinically significant 
improvement in olfaction.4 The improved recovery rate seen in COVID-19 associated olfactory loss may be 
explained by the selective sparing of the olfactory sensory neurons, which lack the ACE2 receptor.5 
 
Olfactory training is the recommended treatment of post-viral olfactory dysfunction.6 Typical treatment 
includes exposure to four intense odors twice daily for twenty seconds each.7 Literature also supports the use of 
twice daily budesonide rinses in the treatment of olfactory dysfunction, with significant improvement seen in 
patients treated with budesonide irrigations and olfactory training compared to olfactory training alone.8 
Evidence supporting the use of systemic steroids is equivocal with one randomized trial showing no statistically 
significant improvement in odor detection threshold in patients with posttraumatic anosmia.9 Few studies have 
investigated the use of acupuncture in the treatment of post-viral olfactory dysfunction with one randomized 


 
 
 
 
 
 
 
 
 
 
 
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trial demonstrating significant improvement in olfactory function compared to controls.10 Acupuncture is a low 
risk intervention when performed by trained professionals. The risk of a serious adverse event is rare and below 
that of many common medical interventions. The occurrence of serious adverse events following acupuncture 
treatment is extremely rare when the acupuncture treatment is performed by a skilled and trained provider.  
Prospective studies of more than one million acupuncture treatments found that the risk of a serious adverse 
event is estimated to be 0.05 per 10,000 treatments and 0.55 per 10,000 individual patients.11 Acupuncture is 
generally safe for patients taking anticoagulant medications. A retrospective chart review found the occurrence 
rate of microbleeding (stopped within 30 s) was <4.8%.12 Additionally, acupuncture during pregnancy appears 
to be associated with few AEs (adverse events) when correctly applied.13 
 
Limited data is available regarding the treatment of COVID-19 associated olfactory dysfunction. The standard 
of care for olfactory dysfunction at our institution is olfactory retraining and twice daily budesonide rinses. The 
current study is designed to investigate the role of acupuncture in the treatment of post-viral olfactory 
dysfunction, specifically related to COVID-19 infection. By doing so, we hope to develop a treatment algorithm 
for COVID-19 related olfactory dysfunction that can be applied to clinical practice. 
 
1. Passarelli PC, Lopez MA, Bonaviri GNM, Garcia-Godoy F, D’Addona A. Taste and smell as 
chemosensory dysfunctions in COVID-19 infection. Am J Dent. 2020;33:135-7. 
2. Borsetto D, Hopkins C, Philips V, et al. Self-reported alteration of sense of smell or taste in patients with 
COVID-19: a systematic review and meta-analysis on 3563 patients. Rhinology. 2020;58(5):430-6. 
3. Chary E, Carsuzaa F, Trijolet JP, et al. Prevalence and recovery from olfactory and gustatory 
dysfunctions in Covid-19 infection: a prospective multicenter study. Am J Rhinol Allergy. 
2020;34(5):686-93. 
4. Cavazzana A, Larsson M, Münch M, Hähner A, Hummel T. Postinfectious olfactory loss: a 
retrospective study on 791 patients. Laryngoscope. 2018;128(1):10-5. 
5. Brann DH, Tsukahara T, Weinreb C, et al. Non-neuronal expression of SARS-CoV-2 entry genes in the 
olfactory system suggests mechanisms underlying COVID-19-associated anosmia. Sci Adv. 
2020;6(31):eabc5801. 
6. Hura N, Xie DX, Choby GW, et al. Treatment of post-viral olfactory dysfunction: an evidence-based 
review with recommendations. Int Forum Allergy Rhinol. 2020;10(9):1065-86.  
7. Kattar N, Do TM, Unis GD, Migneron MR, Thomas AJ, McCoul ED. Olfactory training for postviral 
olfactory dysfunction: systematic review and meta-analysis. Otolaryngol Head Neck Surg. 
2021;164(2):244-54. 
8. Nguyen TP, Patel ZM. Budesonide irrigation with olfactory training improves outcomes compared with 
olfactory training alone in patients with olfactory loss. Int Forum Allergy Rhinol. 2018;8(9):977-81.  
9. Yan CH, Overdevest JB, Patel ZM. Therapeutic use of steroids in non-chronic rhinosinusitis olfactory 
dysfunction: a systematic evidence-based review with recommendations. Int Forum Allergy Rhinol. 
2019;9(2):165-76. 
10. Dai Q, Pang Z, Yu H. Recovery of olfactory function in postviral olfactory dysfunction patients after 
acupuncture treatment. Evid Based Complement Alternat Med. 2016;4986034. 
11. White A. A cumulative review of the range and incidence of significant adverse events associated with 
acupuncture. Acupunct Med. 2004;22(3):122-33. doi: 10.1136/aim.22.3.122. PMID: 15551936. 
12. Kim YJ, Kim SK, Cho SY, et al. Safety of acupuncture treatments for patients taking warfarin or 
antiplatelet medications: Retrospective chart review study. European Journal of Integrative 
Medicine 2014;6(4): 492-6. https://doi.org/10.1016/j.eujim.2014.04.004. 


 
 
 
 
 
 
 
 
 
 
 
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Study Design and Methods 
 
Methods:  Describe in lay terms, completely detailing the research activities that will be conducted by Mayo 
Clinic staff under this protocol. 
 
This study will be a prospective randomized controlled trial and will include subjects who present to the ENT 
clinics previously diagnosed with post-viral olfactory dysfunction secondary to COVID-19 infection and add 
newly diagnosed subjects in the future.  All patients with post-viral olfactory dysfunction of at least 4 weeks 
and a positive COVID PCR will be eligible to participate in the study. This study has received approval by the 
COVID-19 Research Task Force. Interested patients can complete the COVID-19 research interest form posted 
on an externally-facing Mayo Clinic COVID-19 Research website and will be directed for enrollment by the 
COVID-19 Research Clearinghouse staff if eligible. The Mayo social media accounts will also include 
recruitment phrases such as “If you have loss of sense of smell and a history of COVID-19 infection, then 
consider seeing our Rhinology team for treatment options” and “If you have an appointment in the Mayo Clinic 
ENT department and have a history of COVID-19 infection, your provider may ask you about loss of sense of 
smell and participation in a study looking at treatment options.” 
 
Phone, virtual, or in-person consents may be obtained by enrolling patients who are being seen by an ENT 
specialist at Mayo Clinic, or who previously saw a Mayo specialist who diagnosed them with olfactory loss 
from COVID-19 infection. For patients seen virtually, the following screening questions will be asked:  
• 
“Do you have purulent (colored or foul smelling) nasal or postnasal drainage?”  
• 
“Do you have worsening nasal obstruction over the past 6 months?”  
• 
“Do you use a steroid (budesonide or mometasone) nasal irrigation daily to treat chronic 
rhinosinusitis?”   
• 
“Have you been treated with an antibiotic for a sinus infection in the past 3 months?”  
If any of the above screening questions are positive, we would recommend an in-person appointment to rule out 
other causes of olfactory loss prior to treatment or enrollment in the study. If the patient does decide to be seen 
in person in the ENT department and it is determined by their provider that their olfactory loss is due to 
COVID-19 infection, they would then be approached about enrolling in the study. This in-person appointment 
would be billed to the patient or his/her insurance, as normal.  Patients who are seen via telemedicine with a 
negative screening will be offered enrollment in the study provided they are willing to travel to Mayo if selected 
into the treatment arm. 
 
Enrolled patients will be randomized into two groups at the time of accrual. The first group will undergo ten 
sessions of acupuncture therapy with a licensed acupuncturist, in addition to the twice daily budesonide 
irrigations and olfactory training. Mayo Clinic compounding pharmacy formulates a powdered version of 
budesonide that comes in capsules. We will mail it to patients who are not seen in person along with 
instructions on how to perform the nasal irrigations in person or electronically. The clinic nurse will also review 
the instructions with the patient during the in person or virtual visit. Acupuncture therapy will consist of two 
treatments per week for five weeks. Acupuncture points will include Du-20, Du-23, Li-20, Li-4, Lu-7, and St-36 
(see diagrams below of acupuncture points). There is one point, Li-4, which is contraindicated for pregnant 
patients because it is known to induce labor. This point will be avoided in all pregnant women randomized to 
acupuncture but will be used in everyone else. Needles will be left in place for 25 minutes per session. The 
second group will be treated only with twice daily budesonide rinses and olfactory training, which is considered 


 
 
 
 
 
 
 
 
 
 
 
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the standard of care. Patients can opt out of the study at any point. UPSIT will be used to assess the sense of 
smell at the initial visit and after three months of treatment. A clinically significant difference in UPSIT score is 
defined as a change in total score of 5 points.8 This is a scratch-and-sniff test where patients are given four 
multiple choice options to choose the correct answer to each scented box. The initial test will be mailed to the 
participant if consent is obtained by telemedicine appointment. If consent is obtained in person, the test may be 
delivered to the participant at the time of the appointment or mailed. The 3-month test will be mailed to all 
participants unless they are returning for follow-up at that time. If the UPSIT test is conducted remotely, we will 
provide verbal instructions during the initial telemedicine appointment on how to complete this. There are also 
instructions included in the test packet that is mailed to the patient instructing the patient to scratch, sniff, and 
fill in the corresponding multiple-choice bubble with the included pencil.  
 
Subjective measures of olfactory loss and sense of smell will also be obtained at the initial visit (virtual or in-
person) and at 3 months using the SNOT-22 questionnaire and 10-point visual analog scale with 0 representing 
no sense of smell and 10 representing normal smell. Both of these documents may be mailed to patients. Results 
will be analyzed based on original treatment group. We will also perform subgroup analysis for age, gender, and 
duration of olfactory loss of 1-4 months, 4-8 months, 8-12 months, and greater than 12 months. 
 
 


 
 
 
 
 
 
 
 
 
 
 
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Acupuncture Point Locations for Anosmia 
 
 
Du-20 is located at the top of the head. 
 
Du-23 is located approximately 1cm above the hairline. 
 
 


 
 
 
 
 
 
 
 
 
 
 
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Li-20 is located at the nasolabial groove. 
 
Lu-7 is located 1.5 inches above the crease of the wrist along the radius. 
 


 
 
 
 
 
 
 
 
 
 
 
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Li-4 is located on the dorsal side of the hand between the thumb and index finger.  
 


 
 
 
 
 
 
 
 
 
 
 
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St-36 is located 3 inches below the knee on the lateral side of the tibia.  
 
 
 
 
Subject Information 
 
Target accrual is the proposed total number of subjects to be included in this study at Mayo Clinic. A “Subject” 
may include medical records, images, or specimens generated at Mayo Clinic and/or received from external 
sources.    
 
Target accrual: 100 patients 
 
Subject population (children, adults, groups): Adults 
 


 
 
 
 
 
 
 
 
 
 
 
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Inclusion Criteria: 18 years or older, including pregnant/breastfeeding women. Acupuncture is safe before, 
during, and after pregnancy and is associated with few adverse events when correctly applied.13 Additionally, 
patients must have post-viral olfactory dysfunction > 4 weeks and a history of positive COVID-19 PCR. 
 
Exclusion Criteria: Less than 18 years of age; active sinus infection, new diagnosis of untreated CRS, prior 
diagnosis of dementia or Parkinson’s, prior head trauma or neurosurgical procedure resulting in 
olfactory loss, patients who do not speak or read English, patients unable to understand and sign the 
study consent 
 
 
Biospecimens 
 
Collection of blood samples. When multiple groups are involved copy and paste the appropriate section below 
for example repeat section b when drawing blood from children and adults with cancer.  
 
a. From healthy, non-pregnant, adult subjects who weigh at least 110 pounds. For a minimal risk 
application, the amount of blood drawn from these subjects may not exceed 550ml in an 8 week period 
and collection may not occur more frequently than 2 times per week. 
Volume per blood draw: _____ml   
Frequency of blood draw (e.g. single draw, time(s) per week, per year, etc.) ___________ 
 
b. From other adults and children considering age, weight, and health of subject. For a minimal risk 
application, the amount of blood drawn from these subjects may not exceed the lesser of 50 ml or 3 ml 
per kg in an 8 week period, and collection may not occur more frequently than 2 times per week.   
Volume per blood draw: _____ml 
Frequency of blood draw (e.g. single draw, time(s) per week, per year, etc.) ___________  
 
Prospective collection of biological specimens other than blood: ______________________________ 
 
 
Review of medical records, images, specimens  
 
 
Check all that apply (data includes medical records, images, specimens).  
 
  Only data that exists before the IRB submission date will be collected.   
 
Date Range for Specimens and/or Review of Medical Records:   
Examples: 01/01/1999 through 12/31/2015, or all records through mm/dd/yyyy.  
 
Note: The Date Range must include the period for collection of baseline data, as well as follow-up data, 
if applicable. 


 
 
 
 
 
 
 
 
 
 
 
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  The study involves data that exist at the time of IRB submission and data that will be generated after IRB 
submission. Include this activity in the Methods section.  
 
  The study will use data that have been collected under another IRB protocol. Include in the Methods section 
and enter the IRB number from which the research material will be obtained. When appropriate, note when 
subjects have provided consent for future use of their data and/or specimens as described in this protocol.  
 
Enter one IRB number per line, add more lines as needed 
 
 Data    
 Specimens  
 Data & Specimens  ______________________________________ 
 
 Data    
 Specimens  
 Data & Specimens  ______________________________________ 
 
 Data    
 Specimens  
 Data & Specimens  ______________________________________ 
 
 
Data Analysis 
 
 
Power analyses may not be appropriate if this is a feasibility or pilot study, but end-point analysis plans are 
always appropriate even if only exploratory. Provide all information requested below, or provide justification if 
not including all of the information.  
 
Power Statement:   
This is novel work so estimates for change in UPSIT score for the 2 groups are unavailable. Therefore, no 
power/sample size calculation is possible. 
 
Data Analysis Plan:  
Differences in demographic/history/clinic factors between groups to be compared will be analyzed using chi-
square or fisher’s exact as appropriate for categorical factors and Wilcoxon rank sum test for continuous factors. 
 
Analysis of Covariance (ANCOVA) will be used to model differences in change in UPSIT score from baseline 
between the case and control group while accounting, where able, for any demographic/historical/clinical 
factors that are found to be significantly associated with UPSIT score. 
 
Endpoints 
Primary: Post-treatment UPSIT scores 
Secondary: Patient-reported subjective olfactory loss