Clinical trial NCT05184192
Conditions: COVID-19 Olfactory Disorder Anosmia Hyposmia Parosmia
Sponsor: Washington University School of Medicine
Start date: 2022-01-10; Completion date: 2023-08-29
Enrollment: 68 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will investigate the efficacy of oral gabapentin in olfactory improvement following Covid-19- associated olfactory dysfunction. This is a randomized, double-blinded, placebo-controlled trial.

Detailed description:
The drug will be given over a maximum 14 weeks with up to four weeks titrating up, eight weeks maintaining highest tolerable dose, and up to two weeks tapering down. Change in olfactory function from baseline to completion of 8-week fixed-dose period will be compared between the two study groups. Follow-up assessments will be conducted for both groups 4 weeks after completion of taper down.

Arms: arm 1: This arm will be given the active treatment, oral Letco (gabapentin) gelatin capsules of 300mg each.

Up to the first four weeks will be a titration period (week 1 300mg TID, week 2 600mg TID, week 3 900mg TID, week 4 1,200mg TID) as tolerated. If intolerable adverse reactions occur, the dosage will be decreased to prior tolerable dose (e.g., if 900mg TID is intolerable, dose will be decreased to 600mg TID).

The following eight weeks will be fixed dose, the highest tolerable dose from the titration period.

Up to two weeks will be a taper down tailored to the maximum dose the participant reached during the titration and fixed periods.

A maximum 14 weeks will mark the end of active treatment. Follow-up assessments will be conducted 4 weeks after completion of the taper-down period. arm 2: Placebo gelatin capsules that look, smell, and taste like gabapentin capsules will be given to the placebo arm.

To preserve double-blinding of the study, subjects will receive one capsule TID the first week, the second week two capsules TID, the third week three capsules TID, and fourth week four capsules TID as tolerated. If intolerable, the dose will be decreased to prior tolerable dose.

The next eight weeks will be a fixed amount of placebo based on the highest tolerable amount from the titration period.

Subjects will then taper-down placebo to imitate the gabapentin arm for maximum two weeks based on highest dose achieved during study.

4 weeks after completion of taper-down, follow-up assessments will be conducted.
Interventions: intervention 1: Gabapentin gelatin capsules 300mg intervention 2: Placebo
Intervention descriptions: intervention 1: Gabapentin is an anti-epileptic also used for nerve pain. This study will investigate the efficacy of gabapentin for olfactory nerve recovery and improvement in post-Covid-19 olfactory dysfunction. intervention 2: lactose monohydrate NF

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
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EFFICACY OF GABAPENTIN FOR POST-COVID-19 OLFACTORY 
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DYSFUNCTION 
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Principal Investigator: 
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Jay Piccirillo, MD, Department of Otolaryngology-Head and Neck Surgery 
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Version Date/Number:  
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06/20/22,V11 
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TABLE OF CONTENTS 
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A 
INTRODUCTION ............................................................................................................................... 4 
26 
A1 
STUDY ABSTRACT ......................................................................................................................... 4 
27 
A2 
PRIMARY HYPOTHESIS ................................................................................................................... 4 
28 
A3 
PURPOSE OF THE STUDY PROTOCOL .............................................................................................. 4 
29 
B 
BACKGROUND .................................................................................................................................. 4 
30 
B1 
PRIOR LITERATURE AND STUDIES .................................................................................................. 5 
31 
B2 
RATIONALE FOR THIS STUDY ......................................................................................................... 6 
32 
C 
STUDY OBJECTIVES ....................................................................................................................... 6 
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C1 
PRIMARY AIM ................................................................................................................................ 6 
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C2 
SECONDARY AIM ........................................................................................................................... 6 
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C3 
RATIONALE FOR THE SELECTION OF OUTCOME MEASURES ........................................................... 6 
36 
D 
INVESTIGATIONAL AGENT .......................................................................................................... 8 
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D1 
PRECLINICAL DATA ....................................................................................................................... 8 
38 
D2 
CLINICAL DATA TO DATE .............................................................................................................. 8 
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D3 
DOSE RATIONALE AND RISK/BENEFITS ......................................................................................... 8 
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E 
STUDY DESIGN ................................................................................................................................. 9 
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E1 
OVERVIEW OR DESIGN SUMMARY ................................................................................................. 9 
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E2 
SUBJECT SELECTION AND WITHDRAWAL ..................................................................................... 10 
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2.a 
Inclusion Criteria ................................................................................................................... 10 
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2.a 
Exclusion Criteria ................................................................................................................... 10 
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2.b 
Ethical Considerations ........................................................................................................... 10 
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2.c 
Subject Recruitment Plans and Consent Process ................................................................... 11 
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2.d 
Randomization Method and Blinding ..................................................................................... 11 
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2.e 
Risks and Benefits ................................................................................................................... 11 
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2.f 
Early Withdrawal of Subjects...................................................................................................... 12 
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2.g 
When and How to Withdraw Subjects ..................................................................................... 12 
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2.h 
Data Collection and Follow-up for Withdrawn Subjects ........................................................ 12 
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E3 
STUDY DRUG ............................................................................................................................... 12 
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3.a 
Description ............................................................................................................................. 12 
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3.b 
Treatment Regimen ................................................................................................................. 12 
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3.c 
Method for Assigning Subjects to Treatment Groups ............................................................. 13 
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3.d 
Preparation and Administration of Study Drug ...................................................................... 13 
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3.e 
Subject Compliance Monitoring ............................................................................................. 13 
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3.f 
Prior and Concomitant Therapy ................................................................................................. 13 
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3.g 
Packaging ............................................................................................................................... 13 
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3.h 
Blinding of Study Drug ........................................................................................................... 13 
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3.i 
Receiving, Storage, Dispensing and Return ................................................................................ 14 
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F 
STUDY PROCEDURES ................................................................................................................... 14 
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F1 
SCREENING FOR ELIGIBILITY ............................................................................................................ 14 
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F2 
SCHEDULE OF MEASUREMENTS ....................................................................................................... 14 
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F3 
SAFETY AND ADVERSE EVENTS ....................................................................................................... 17 
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3.a 
Safety and Compliance Monitoring ........................................................................................ 17 
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3.a 
Medical Monitoring ................................................................................................................ 18 
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Investigator only ..................................................................................................................................... 18 
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3.b 
Definitions of Adverse Events ................................................................................................. 18 
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i 
Relationship ............................................................................................................................................ 19 
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ii 
Severity ................................................................................................................................................... 19 
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iii 
Expectedness .......................................................................................................................................... 19 
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3.c 
Data Collection Procedures for Adverse Events .................................................................... 19 
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3.d 
Reporting Procedures ............................................................................................................. 20 
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3.e 
Adverse Event Reporting Period............................................................................................. 20 
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F4 
STUDY OUTCOME MEASUREMENTS AND ASCERTAINMENT ............................................................. 20 
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STATISTICAL PLAN ....................................................................................................................... 21 
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G1 
SAMPLE SIZE DETERMINATION AND POWER ................................................................................ 21 
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G2 
INTERIM MONITORING AND EARLY STOPPING ............................................................................. 21 
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G3 
STATISTICAL METHODS ............................................................................................................... 21 
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G4 
MISSING OUTCOME DATA ........................................................................................................... 22 
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G5 
UNBLINDING PROCEDURES .......................................................................................................... 22 
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H 
DATA HANDLING AND RECORD KEEPING ............................................................................ 22 
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H1 
CONFIDENTIALITY AND SECURITY ............................................................................................... 22 
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H2 
RECORDS RETENTION .................................................................................................................. 23 
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I 
STUDY ADMINISTRATION .......................................................................................................... 23 
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I1 
SUBJECT STIPENDS OR PAYMENTS ................................................................................................... 23 
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I2 
STUDY TIMETABLE .......................................................................................................................... 23 
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J 
PUBLICATION PLAN ..................................................................................................................... 23 
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ATTACHMENTS .............................................................................................................................. 23 
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K1 
QUESTIONNAIRES OR SURVEYS .................................................................................................... 23 
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L 
REFERENCES .................................................................................................................................. 24 
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A 
Introduction 
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A1 
Study Abstract 
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COVID-19 has now infected over 33 million people in the United States and 
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approximately 185 million worldwide.1,2 Of those, an estimated 85% have reported either 
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a new clinical diagnosis or subjective onset of olfactory dysfunction.3 While most 
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patients will recover their sense of smell within 7-14 days, others may not return to their 
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baseline function for months or at all.4 Viral infections that target the upper respiratory 
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system, such as COVID-19, often leave patients with diminished olfaction. This new-
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onset anosmia, hyposmia, and parosmia is theorized to be caused by damage to sensory 
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neurons following viral insult. Unfortunately, there is no treatment for post-COVID 
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olfactory dysfunction. Most patients are recommended to perform olfactory training with 
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essential oils,5but the evidence base to support this recommendation is not firm.6 Thus, 
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there is a very big need for effective treatments for patients suffering from post-COVID 
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olfactory dysfunction.  
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One potential therapy is gabapentin. Used as an antiepileptic and now first-line 
122 
medication for the treatment of diabetic neuropathy, gabapentin is known for reducing 
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pain secondary to diabetic neuropathy and post-herpetic neuralgia. Gabapentin works 
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mainly on voltage-gated calcium channels (VGCC) with an ability to cross the basement 
125 
membrane, a trait important for an antiepileptic. The α2δ2 subunit of VGCCs, with 
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increased expression in corticospinal neurons, has been associated with loss of regrowth 
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after spinal injuries. The α2δ2 blockage by gabapentin can allow increased nerve 
128 
regeneration and return of function.7 Inhibition of the α2δ2 subunit on VGCCs may allow 
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nerves to regenerate more rapidly than physiologically normal. This study will evaluate 
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the efficacy of gabapentin for olfactory dysfunction (anosmia, hyposmia, parosmia) in 
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post-COVID-19 patients.  
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A2 
Primary Hypothesis 
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We hypothesize that oral gabapentin will be more effective than placebo for COVID-19-
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related olfactory dysfunction (OD) improvement. 
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A3 
Purpose of the Study Protocol 
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This study will evaluate the efficacy of gabapentin for olfactory dysfunction (anosmia, 
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hyposmia, parosmia) in post-COVID-19 patients.  
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B 
Background 
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B1 
Prior Literature and Studies 
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The SARS-CoV-2 virus, has infected an estimated 78 million in the United States with 
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~85% of patients reporting some form of olfactory dysfunction.1,3 More recent studies 
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have shown an increased prevalence of olfactory change reported in women over men 
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and in Western countries when compared to Eastern countries.8,9 Moreover, the 
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percentage of patients with post-COVID-19 olfactory dysfunction is thought to be 
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underreported as patients need to individually report the symptom to their physician for it 
148 
to be recorded.9 
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Evidence has emerged to explain the pathophysiology of COVID-19 and its mechanism 
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of action on neurosensory pathways. Research suggests that COVID-19 affects two genes 
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commonly found in the human respiratory system, ACE2 and TMPRSS2.10. ACE2, 
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commonly associated with the renin-angiotensin-aldosterone system, has another role as 
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a receptor protein on cell surfaces – a receptor proven vital for SARS-CoV-2 to enter 
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respiratory cells.11 Similarly, TMPRSS2 also plays a role in SARS-CoV-2 entry into cells 
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and both genes are expressed in neuronal support cells.7 ACE2 and TMPRSS2 are found 
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only in support cells and not neurons. The support cells, such as sustentacular cells, 
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degenerate and are unable to sustain neurons. This lack of neuronal stability is what 
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likely causes the temporary neurosensory loss seen in post-COVID-19 patients. However, 
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evidence is now also supporting the theory that COVID-19-related olfactory dysfunction 
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may be due to direct damage to olfactory receptor neurons (ORNs) as well, which would 
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increase recovery time as neurons regenerate more slowly. Previous strains of human 
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coronavirus have also been proven to target ORNs causing olfactory dysfunction but 
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whether this direct damage to neurons is related to ACE2 and TMPRSS2 has yet to be 
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determined.10  
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Patients who do recover their sense of smell after infection tend to notice improvement in 
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just weeks, paralleling the rapid recovery rate of support cells. Those with lingering 
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olfactory dysfunction either return to new normalcy in months instead of weeks or have 
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yet to return to baseline. Some patients report a return of smell followed shortly by new 
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smell distortion. This observation of differing recovery rates supports the theory that 
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SARS-CoV-2 also damages olfactory receptor neurons directly leading to longer 
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recovery times. Research has demonstrated the possible utility in olfactory training, a 
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therapy thought to encourage neuroplasticity via repeat exposure to odors.6,12 However, 
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the evidence to support this treatment is not universally accepted and pharmacotherapy 
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options for post-COVID-19 olfactory dysfunction are still being explored; one potential 
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therapy is gabapentin.  
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Gabapentin is an antiepileptic medication now used as first-line therapy for diabetic 
180 
neuropathy and herpetic neuralgia. Gabapentin works by binding to VGCCs, which play 
181 
an important role in neuronal synaptic transmission. More specifically, gabapentin binds 
182 
to α2δ isoforms which have been associated with neuropathic pain. The postsynaptic α2δ1 
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subunit promotes spinogenesis, the development of neuronal dendritic spines, while the 
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α2δ2 works as a suppressor of axonal regeneration.13 Gabapentin functions as an inhibitor 
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of the α2δ2 subunit and therefore blocks the suppression of axonal regeneration leading to 
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increased neuronal regeneration and function. The medication is effective in the treatment 
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of chronic pain and burning mouth syndrome (BMS). The mode of action is thought to be 
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primarily due to the fact that gabapentin is highly lipophilic and can enter the central 
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nervous system (CNS) and iad in neuron regeneration.14 For these reasons, gabapentin is 
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thought to have the potential to improve post-COVID-19 olfactory dysfunction caused by 
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neuronal damage.  Our study will investigate the efficacy of gabapentin to increase 
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recovery of olfactory dysfunction secondary to post-COVID-19 infection.  
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194 
B2 
Rationale for this Study 
195 
Olfactory dysfunction is a major symptom of SARS-CoV-2 affecting up to 80% of 
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infected individuals. While most have a return to normal olfactory function in weeks, 
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some may not see full improvement for months and a small percentage may not recover 
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function and suffer long-term physical limitation and functional impairment. This 
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placebo-controlled, double-blinded pilot RCT will evaluate the efficacy of oral 
200 
gabapentin to improve chronic (>3 months) olfactory dysfunction secondary to COVID-
201 
19 infection. This study will provide data on the efficacy of gabapentin for the treatment 
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of OD.  
203 
 
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C 
Study Objectives 
205 
 
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C1 
Primary Aim 
207 
To evaluate the efficacy of oral gabapentin on improvement of olfactory dysfunction in 
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patients with post-COVID-19 anosmia, hyposmia, or parosmia. Participants will receive a 
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maximum of 14weeks of either gabapentin or placebo with the first four weeks serving as 
210 
a titration phase and the last two weeks serving as a taper-down period. 
211 
C2 
Secondary Aim 
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Describe the adverse effects of gabapentin. All participants will be monitored for adverse 
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effects throughout the study.   
214 
C3 
Rationale for the Selection of Outcome Measures 
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Primary Outcome:  
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Clinical Global Impression of Improvement Scale (CGI-I). The response rate is 
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defined as the number of participants self-reporting minimal change or larger on 
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the Clinical Global Impression of Improvement Scale (CGI-I) scale, divided by 
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the number of participants in each group. The CGI-Improvement is a self-
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reported scale of improvement ranging from 1 to 7 (1 is Very Much Improved, 7 
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is Very Much Worsened) and will be measured after completing 8 weeks of the 
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fixed, highest-tolerable dose. Each rating is well defined to maximize accuracy. 
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Participants reporting 3 as Minimally Improved, 2 as Much Improved, or 1 as Very 
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Much Improved in the CGI-I will be deemed responders to treatment, and the 
226 
number of responders to non-responders will be compared between the two arms - 
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CGI-Severity (CGI-S) and CGI-Improvement (CGI-I). 
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Secondary Outcomes:  
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1. CGI-Severity. The CGI-Severity scale ranges from 1 to 7, where 1 is normal 
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function and 7 is complete anosmia. This assessment will provide subjective data 
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on patients’ baseline olfactory function prior to beginning the trial, after 8-week 
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Fixed-Dose period, and 4 weeks after completion of Taper-Down phase.  
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2. CGI-Improvement. The CGI Improvement will also be administered 4 weeks 
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after completion of Taper-Down phase which same analysis as described above.  
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3. University of Pennsylvania Smell Identification Test (UPSIT).15 The UPSIT is 
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composed of 40 strips of microencapsulated odorants, which are present on the 
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bottom of each page, just below a four-alternative multiple-choice question. For a 
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given item, the patient releases an odor by scratching the microencapsulated pad 
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with a pencil tip, smells the pad, and indicates the odor quality from four 
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alternatives. Even if no smell is perceived, a response is required (i.e., the test is 
243 
forced-choice).  The subject's total correct score out of the 40 items is 
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determined.16 
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The total UPSIT score can range from 0 to 40 and scores are interpreted as the 
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level of absolute smell function (i.e., normosmia, mild hyposmia, moderate 
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hyposmia, severe hyposmia, and anosmia), using the age- and sex-related 
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normative classification system described in the UPSIT manual (Table 1) The 
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minimal clinically important difference in UPSIT score is 4.  
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4. Olfactory Dysfunction Outcomes Rating (ODOR). The ODOR questionnaire is a 
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28-item disease-specific health status survey to assess the physical problems, 
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functional impairments, and emotional consequences secondary to olfactory 
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dysfunction. ODOR was developed and validated by Dr. Jake Lee and colleagues 
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in the Clinical Outcomes Research Office at Washington University. 
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5. NASAL-7.  NASAL-7 is a simple diagnostic tool for olfactory dysfunction that is 
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based on commonly found household items and can be used by adults who 
258 
suspect olfactory dysfunction.  The NASAL-7 was developed by Dr. Piccirillo and 
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colleagues in the Clinical Outcomes Research Office. The NASAL-7, contains 7 
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household items with each item scored as 0 for ‘Cannot Smell’, 1 for ‘Smells Less 
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Strong/Different Than Normal’, and 2 for ‘Smells Normal’, for a total possible 
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score ranging from 0-14.  The following four categories of olfactory function 
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were defined based on NASAL-7 score: anosmia (score 0-4), severe dysfunction 
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(score 5-7), mild dysfunction (score 8-10), and normosmia (score 11-14).  
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6. Clinical Global Impression-Severity Scale for Parosmics (CGI-P). The CGI-P 
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Scale is a global rating of parosmia and the single global rating ranges from 1-5, 
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where 1 is No Distortion, 2 is Mild Distortion, 3 is Moderate Distortion, 4 is 
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Mostly Distorted, and 5 is Complete Distortion. The response on the CGI-P will 
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8
provide information on the patient’s perceived severity of the distortion of their 
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smell. 
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D 
Investigational Agent  
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274 
D1 
Preclinical Data 
275 
Gabapentin is an antiepileptic medication now used as first-line therapy for diabetic 
276 
neuropathy and herpetic neuralgia. Gabapentin works by binding to voltage-gated 
277 
calcium channels (VGCCs), which play an important role in neuronal synaptic 
278 
transmission. More specifically, gabapentin binds to α2δ isoforms which have been 
279 
associated with neuropathic pain.  
280 
 
281 
The α2δ2 subunit of VGCCs, with increased expression in corticospinal neurons, has 
282 
been associated with loss of regrowth after spinal injuries. The postsynaptic α2δ1 subunit 
283 
promotes spinogenesis, the development of neuronal dendritic spines, while the α2δ2 
284 
works as a suppressor of axonal regeneration.13   The α2δ2 blockage by gabapentin can 
285 
allow increased nerve regeneration and return of function.7 Inhibition of the α2δ2 subunit 
286 
on VGCCs may allow nerves to regenerate more rapidly than physiologically normal.   
287 
D2 
Clinical Data to Date  
288 
Gabapentin is an antiepileptic medication now used as first-line therapy for diabetic 
289 
neuropathy and herpetic neuralgia. Gabapentin works by binding to voltage-gated 
290 
calcium channels (VGCCs), which play an important role in neuronal synaptic 
291 
transmission. More specifically, gabapentin binds to α2δ isoforms which have been 
292 
associated with neuropathic pain.  
293 
 
294 
The medication has also proven effective in treated chronic pain from Burning Mouth 
295 
Syndrome (BMS) since gabapentin is highly lipophilic and can enter the central nervous 
296 
system (CNS).14 For these reasons, gabapentin is thought to have the potential to improve 
297 
post-COVID-19 olfactory dysfunction caused by neuronal damage.  Gabapentin can 
298 
penetrate the blood-brain barrier and enter the CNS where it can aid in neuron 
299 
regeneration. 
300 
D3 
Dose Rationale and Risk/Benefits  
301 
Gabapentin dosing for this study mirrors dosing for the prior study “Relief of Idiopathic 
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Subjective Tinnitus” (IRB #02-0717) 
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Following randomization, participants in the gabapentin arm will take gradually titrated 
304 
dosages in order to achieve a dose of 3600mg/d or highest tolerable dose. The titration 
305 
schedule will span a maximum 4 weeks to reach 3600mg/d.  
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Week 1, 900 mg/d 
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Week 2, 1800 mg/d 
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Week 3, 2700 mg/d 
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Week 4, 3600 mg/d 
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Gabapentin (300 mg per capsule) and placebo will be supplied to patients in 
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identical opaque capsules in blinded fashion. The medications will be distributed in 4 
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separate vials representing each of the four weeks of the Titration Period.  All 
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participants will be provided an equal number of capsules and instructed to follow a TID 
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(i.e., 3 times per day) dosing schedule.  All participants’ dosages will be titrated to a 
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maximum dose of 3600 mg/d, regardless of any possible beneficial effect achieved at 
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lower dosages. If intolerable adverse reactions occur, the dosage will be decreased to 
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previous tolerable dose (e.g. if 2700mg/d is intolerable, dosage will be decreased to 1800 
319 
mg/d). If, during the first week, 900 mg/d is intolerable, dosing will be decreased by 300 
320 
mg/d per day until tolerable (i.e., 600 mg/d, 300mg/d) or until they are no longer taking 
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the medication. The dose established during the Titration Period will be maintained 
322 
throughout the Fixed-Dose period.  Participants receiving the matching placebo capsules 
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will be provided similar instructions for titration and de-escalation, should side effects 
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develop.   
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The potential benefit to the participant is improvement of their olfactory dysfunction 
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using this therapy. The potential benefit to the society is the use of the pilot study results 
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to initiate a larger trial to further evaluate the efficacy of gabapentin in the treatment of 
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post-COVID-19 olfactory dysfunction. 
330 
 
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The potential risk to participants during the study is an adverse event associated with the 
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medication use. Abrupt cessation of gabapentin may alter the seizure threshold; for this 
333 
reason, participants will be provided with a taper schedule specific to the gabapentin dose 
334 
at time of completion of the Fixed Dose period. Gabapentin has a slight risk of 
335 
dependence in patients with previous history of alcohol, cocaine, or opioid abuse so these 
336 
individuals will be excluded from the study. 17 
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E 
Study Design  
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340 
E1 
Overview or Design Summary 
341 
This study will be a double-blinded, placebo-controlled, randomized pilot clinical trial to 
342 
evaluate the efficacy of gabapentin to improve post-COVID-19 olfactory dysfunction. 
343 
This study will also describe adverse effects related to oral gabapentin use.  
344 
 
345 
This study will be conducted via virtual research guidelines and procedures. We will not 
346 
require in-person patient participation or evaluation. Following initial evaluation to 
347 
ensure potential participants meet all inclusion criteria and none of the exclusion criteria, 
348 
the research study will be explained in full via Zoom call, phone call if necessary. 
349 
Participants will then be randomized in a 1:1 allocation via permuted-block sequencing 
350 
into the oral gabapentin group or the placebo group. All assessments will be conducted 
351 
through a HIPAA-compliant online survey form. Baseline assessments will help us 
352 
determine subjective and objective rates of olfactory dysfunction. Assessments will be 
353 
conducted again after the 8-week Fixed-Dose period and 4 weeks after completing taper.  
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The primary objective of this study is to assess the efficacy of oral gabapentin in 
355 
improving olfactory dysfunction secondary to COVID-19. 
356 
E2 
Subject Selection and Withdrawal  
357 
 
358 
2.a 
Inclusion Criteria  
359 
Participants will be recruited based on the following inclusion criteria:   
360 
- 
Men and women between the ages of 18 and 65 years 
361 
- 
Residing within the states of Missouri or Illinois 
362 
- 
Clinically diagnosed or subjective olfactory dysfunction (anosmia, hyposmia, 
363 
or parosmia) of at least 3 months duration  associated with COVID-19 
364 
infection 
365 
- 
initial UPSIT score consistent with diminished olfactory function (score > 6 
366 
and  ≤ 33 in men and score > 6 and ≤ 34 in women). 
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Willing to respond daily to study surveys, preferably through smartphone with 
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unlimited texting plan. 
369 
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In possession of all 7 household items associated with NASAL-7: soap, burnt 
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candle, peanut butter, herb, garlic, lemon, and coffee 
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372 
2.a 
Exclusion Criteria  
373 
Individuals will not be allowed to participate in this study if they meet one or more of the 
374 
following exclusion criteria:  
375 
- 
Clinically diagnosed olfactory dysfunction secondary to non-COVID-19 viral 
376 
infection, genetic abnormalities or congenital dysfunction, trauma, nasal 
377 
polyps, neurodegenerative disorders 
378 
- 
Current use of: azelastine, bromperidol, orophenadrine, oxomemazine, 
379 
kratom, paraldehyde, or thalidomide 
380 
- 
History of addiction to alcohol, cocaine, or opioids 
381 
- 
Impaired renal function, myasthenia gravis, or myoclonus  
382 
- 
Severe allergy to peanuts 
383 
- 
Pregnancy or attempting pregnancy during study participation 
384 
- 
Inability to participate in virtual trial due to lack of access to the; inability to 
385 
comprehend or use English language 
386 
- 
Availability less than 18 weeks from time of enrollment 
387 
- 
Residency in states other than Missouri or Illinois. 
388 
2.b 
Ethical Considerations  
389 
This study relies on participation of human subjects. Informed consent will be 
390 
obtained from each participant to ensure their safety, minimize risk, and ensure full 
391 
confidentiality. All assessments will be conducted virtually via HIPAA-compliant online 
392 
surveys at baseline and then throughout the study course. Selection of participants for the 
393 
study will consider the variability in response to COVID-19 as well as response to 
394 
gabapentin by ensuring the two groups are matched 1:1 by permuted block 
395 
randomization. Gabapentin has a slight risk of dependence in individuals with previous 
396 


 
 
 
 
 
 
______________________________________________________________________________________ 
 
11
history of alcohol, cocaine, or opioid abuse so these patients will be excluded from the 
397 
study.17The study team will be available at all times for participants during the full course 
398 
of the trial.  
399 
2.c 
Subject Recruitment Plans and Consent Process 
400 
Recruitment will be done at the Washington University Department of Otolaryngology-
401 
Head and Neck Surgery outpatient clinics. Advertisements will also be sent to all 
402 
members of the St. Louis ENT Club, and otolaryngologists whose practices are within 
403 
150 miles of Washington University Medical Center (WUMC). Direct recruitment of 
404 
potential participants will also be achieved through use of the Washington University 
405 
Volunteers for Health Research Participant Registry, and the Otolaryngology Research 
406 
Participant Registry. This recruitment strategy has been successful for two current trials 
407 
of treatment for COVID-associated anosmia VOLT (IRB ID# 202011046) and SCENT2 
408 
(IRB ID# 202101190). We may also attempt to recruit potential participants from past 
409 
studies in our lab, such as the CODS trial (IRB ID# 202004146). Additionally, due to the 
410 
focus on virtual research at this time, we may also use website postings and work with 
411 
anosmia support groups such as AbScent and FifthSense to share the trial. 
412 
2.d 
Randomization Method and Blinding 
413 
Participants who remain eligible at the end of the screening period will be randomized in 
414 
a double-blind fashion, according to a computer-generated random code, to receive either 
415 
placebo or gabapentin. Dr. Kallogjeri will provide the randomization table to the BJH 
416 
Research Pharmacist, who will prepare both gabapentin and placebo for the entire study.  
417 
The research assistants will collect the gabapentin and placebo in a blinded fashion from 
418 
the research pharmacist for distribution to the participants via FedEx.   
419 
2.e 
Risks and Benefits 
420 
The potential benefit to the participant is improvement of their olfactory dysfunction 
421 
using this therapy. The potential benefit to the society is the use of the pilot study results 
422 
to initiate a larger trial to further evaluate the efficacy of gabapentin in the treatment of 
423 
post-COVID-19 olfactory dysfunction.  
424 
 
425 
The potential risk to participants during the study is an adverse event associated with the 
426 
medication use. Abrupt cessation of gabapentin may alter the seizure threshold; for this 
427 
reason, participants will be provided with a taper schedule specific to the gabapentin dose 
428 
at time of cessation. Gabapentin has a slight risk of dependence in individuals with 
429 
previous history of alcohol, cocaine, or opioid abuse so these individuals will be excluded 
430 
from the study. 17 
431 
 
432 
The consent process informs a volunteer about the study, indicates that participation is 
433 
voluntary, and that he/she has the right to stop at any time. Risks are listed in the 
434 
informed consent form and described orally during the consent process.  
435 
 
436 


 
 
 
 
 
 
______________________________________________________________________________________ 
 
12
2.f 
Early Withdrawal of Subjects  
437 
If a subject decides to withdraw from all components of the research study, the 
438 
investigator will discontinue all of the current and scheduled research activities in the 
439 
study. Participants taking an intervention medication at the time of withdrawal will be 
440 
provided with a taper-down schedule based on maximum intervention dose achieved.  
441 
 
442 
2.g 
When and How to Withdraw Subjects  
443 
A participant can withdraw consent for the study at any time. Participants will be allowed 
444 
to end participation in the study at any point should they desire. If a participant must be 
445 
withdrawn due to a drug-related serious adverse event, then blind will be broken and, if 
446 
on gabapentin, drug withdrawal will be tapered or completely stopped based on the 
447 
clinical judgement of the PI. All participants will have an exit interview to ascertain any 
448 
adverse effects and discuss the reason for ending participation. The study team will 
449 
follow them for safety reasons up to 30 days after stopping use of the study drug.  
450 
 
451 
2.h 
Data Collection and Follow-up for Withdrawn Subjects  
452 
If a participant has ended participation, the only data that will be collected are the data 
453 
from the exit interview and the data collected prior to withdrawal.  There will not be any 
454 
other follow-up or data collected from these subjects.   
455 
 
456 
Data collected up to this point will not be used in the analysis, and further data will not be 
457 
collected from these participants.  
458 
 
459 
E3 
Study Drug  
460 
 
461 
3.a 
Description  
462 
Gabapentin is an antiepileptic medication now used as first-line therapy for diabetic 
463 
neuropathy and herpetic neuralgia. Gabapentin works by binding to voltage-gated 
464 
calcium channels (VGCCs), which play an important role in neuronal synaptic 
465 
transmission. More specifically, gabapentin binds to α2δ isoforms which have been 
466 
associated with neuropathic pain.  
467 
3.b 
Treatment Regimen  
468 
During the titration period of maximum 4 weeks, participants randomized to 
469 
the gabapentin arm will take gradually titrated dosages of gabapentin as follows:  
470 
 
Week 1, 900 mg/d (300 mg TID) 
471 
 
Week 2, 1800 mg/d (600 mg TID) 
472 
 
Week 3, 2700 mg/d (900 mg TID) 
473 
 
Week 4, 3600 mg/d (1200 mg TID) 
474 
 
475 
If intolerable effects occur, dosage will be decreased by 1 dose (300 mg) step (e.g. if 
476 
2700 mg/d is intolerable, dosage will be decreased to 2400 mg/d).  Further de-escalation 
477 


 
 
 
 
 
 
______________________________________________________________________________________ 
 
13
will be determined by PI clinical judgement to prior tolerable dose. The highest tolerable 
478 
dose established during the Titration Period will be maintained throughout the 8-week 
479 
Fixed-Dose period.   
480 
3.c 
Method for Assigning Subjects to Treatment Groups  
481 
The participants will be divided using permuted block randomization in a 1:1 allocation 
482 
between two arms: the oral gabapentin group and the oral lactose placebo group with 20 
483 
persons in each group. 
484 
3.d 
Preparation and Administration of Study Drug  
485 
Gabapentin (300 mg per capsule) and placebo will be supplied to patients in identical 
486 
opaque capsules in blinded fashion.  The medications will be distributed in 4 separate 
487 
vials representing each of the four weeks of the Titration Period and distributed in 8 
488 
separate vials prior to the Fixed-Dose period.  
489 
3.e 
Subject Compliance Monitoring  
490 
There will be check-ins with the study participants every two weeks conducted virtually 
491 
through the participant’s preferred communication method (i.e. phone call or video call) 
492 
to answer questions and ensure participants are adhering to medication schedule. Subjects 
493 
will be asked to keep a paper calendar for daily notes of pill count, side/adverse effects, 
494 
and study barriers. The paper calendar will be mailed back to the RA after study 
495 
completion. 
496 
3.f 
Prior and Concomitant Therapy  
497 
Patients receiving concomitant therapy specifically for the treatment of olfactory 
498 
dysfunction will not be eligible for the trial unless they are able to stop taking those 
499 
therapies during the conduct of the study. Participants who have tried previous therapies 
500 
for their olfactory dysfunction, including over-the-counter treatments such as vitamin A 
501 
or omega-3 fatty acids will be eligible for the trial. Information will be gathered on their 
502 
use of prior or current therapies, and if needed, a sensitivity or subgroup analysis may be 
503 
considered.  
504 
 
505 
3.g 
Packaging  
506 
The Research Pharmacist will deliver the gabapentin and placebo in a blinded fashion to 
507 
the research assistant for distribution to the participants via FedEx.   
508 
3.h 
Blinding of Study Drug  
509 
Participants will be divided into two groups; one group will be given oral gabapentin 
510 
while the other group will be given oral placebo. The research pharmacist will receive the 
511 
randomization assignment code from the biostatistician. The RA will pick up the study 
512 
drug in blinded fashion from research pharmacist and distribute it to the participant via 
513 
FedEx delivery. In this way, only the Research Pharmacist will know participant 
514 
assignment.  Adequate taper of gabapentin will be provided for those on gabapentin while 
515 
the placebo group will receive additional placebo for taper in order to maintain the blind.  
516 


 
 
 
 
 
 
______________________________________________________________________________________ 
 
14
3.i 
Receiving, Storage, Dispensing and Return  
517 
The services of the Investigational Pharmacy at Barnes-Jewish Hospital will be used for 
518 
this trial.  The product used in this trial will be managed by the pharmacist according to 
519 
the pharmacy SOP. 
520 
F 
Study Procedures  
521 
 
522 
F1 
Screening for Eligibility 
523 
Individuals who reach out with interest in the study after seeing the approved study flyer 
524 
or who have contacted RA for participation in similar studies for which recruitment has 
525 
ended will asked to complete an online screening questionnaire (survey titled: 
526 
“ScreeningSurvey”) to ensure he or she meets all the inclusion criteria and does not meet 
527 
any exclusion criteria. Following eligibility confirmation, the RA will collect information 
528 
required to mail screening smell identification test (UPSIT).  Once received, the 
529 
participant will complete the UPSIT and provide their response virtually through the 
530 
REDCap survey.  Once eligibility is confirmed based on UPSIT score, participants will 
531 
be provided through REDCap an online consent form to review and complete. The RA 
532 
will offer each participant the option to review the consent form independently or with 
533 
the RA via zoom or phone call (zoom as the preferred option). Once the participant 
534 
electronically signs the consent form, the RA will review it and sign.  The REDCap 
535 
software will automatically email the participant a copy of their completed form. 
536 
F2 
Schedule of Measurements 
537 
Following the recruitment period and successful enrollment, baseline survey completion 
538 
(survey titled Week0BaselineSurvey) and randomization of participants will occur. The 
539 
timeline for measurements can be seen below.  
540 
 
541 
Gabapentin Study Flow Chart 
542 
 
543 
 
544 
 
545 
 
546 
 
547 
 
548 


 
 
 
 
 
 
______________________________________________________________________________________ 
 
15
 
549 
 
550 
 
551 
 
552 
 
553 
a. Federal guidelines require timely reporting (within 15 calendar days) of an 
554 
unanticipated or life-threatening event or death occurring within 30 days of 
555 
active study participation. 
556 
 
557 
 
558 
Titration Period: maximum duration 4 weeks 
559 
 
560 
Placebo.  In this study, we plan to use an inert placebo and not an active drug 
561 
or non-active drug with side effects similar to gabapentin.  Participants randomized to the 
562 
Placebo arm will participate in a 4-week Titration Period. Placebo will be supplied to 
563 
patients in opaque capsules in blinded fashion.  The medications will be distributed in 4 
564 
separate vials representing each of the four weeks of the Titration Period.  If intolerable 
565 
adverse reactions occur, the dosage will be decreased to prior tolerable dose. 
566 
Gabapentin.  Participants randomized to the gabapentin arm will take 
567 
gradually titrated dosages of gabapentin as follows:  
568 
 
569 
 
Week 1, 900 mg/d (300 mg TID) 
570 
 
Week 2, 1800 mg/d (600 mg TID) 
571 
 
Week 3, 2700 mg/d (900 mg TID) 
572 
 
Week 4, 3600 mg/d (1200 mg TID) 
573 
 
574 
Gabapentin (300 mg per capsule) will be supplied to participants in opaque 
575 
capsules in blinded fashion identical to the supply of Placebo.  The medications will be 
576 
distributed in 4 separate vials representing each of the four weeks of the Titration Period. 
577 
All participants’ dosages will be titrated to a maximum dose of 3600 mg/d, regardless of 
578 
any effect achieved at lower dosages. If intolerable effects occur, dosage will be 
579 
decreased by 1 dose (300 mg) step (e. g. if 2700 mg/d is intolerable, dosage will be 
580 
decreased to 2400 mg/d).  Further de-escalation will be determined by PI clinical 
581 
judgement to prior tolerable dose. Participants with intolerable effects may have a lower 
582 
maximum dose than 3600mg/d and may complete the Titration Period in less than 4 
583 
weeks. The dose established during the Titration Period will be maintained throughout 
584 
the Fixed-Dose period.     
585 


 
 
 
 
 
 
______________________________________________________________________________________ 
 
16
 
586 
Gabapentin (300 mg pill) Titration Schedule 
587 
 
588 
If at any point during the Titration Period, the participant wishes to discontinue 
589 
the medication for any reason, they will be instructed to follow the taper down schedule 
590 
(see below) in order to safely stop the medication.  The participant will be informed that 
591 
any abrupt stoppage of gabapentin could cause serious adverse effects. 
592 
Participants will be contacted by telephone or video call by the Research Assistant 
593 
(RA) at the end of Titration period.  The purpose of this call will be to query the 
594 
participants about adverse effects.  Participants will be provided with a paper calendar 
595 
and asked to maintain diaries of olfactory and taste symptoms and adverse effects 
596 
possibly related to the intervention. 
597 
Participants will not complete any forms at the completion of Titration period. 
598 
Instead, they will proceed directly to Fixed-Dose Period. 
599 
 
600 
Fixed-Dose Period: duration 8 weeks  
601 
During the Fixed-Dose period, participant’s dose will remain at their maximum tolerated 
602 
dosage established during the Titration phase.  The study drug will be distributed in eight 
603 
separate vials representing the eight weeks of the Fixed-Dose period.  The RA will 
604 
contact the participants at the end of Week 4 to administer the blind assessment using 
605 
REDCap (survey titled: “Blind Assessment”). Participants will complete the following 
606 
forms after completing the Fixed-Dose Period (survey titled: “FixedDoseSurvey”): 
607 
 
608 
1.) Clinical Global Impression of Severity Scale (CGI-S). 
609 
2.) Clinical Global Impression of Improvement Scale (CGI-I) 
610 
3.) University of Pennsylvania Smell Identification Test (UPSIT) 
611 
4.) Olfactory Dysfunction Outcomes Rating (ODOR) 
612 
5.) NASAL-7 
613 
6.) Clinical Global Impression-Severity Scale for Parosmics (CGI-P) 
614 
7.) Adverse Event assessment 
615 
8.) Compliance 
616 
 
617 
Adverse events. Any unintentional or unfavorable clinical sign or symptom, any new 
618 
illness or disease or the deterioration of existing disease or illness, or any clinically 
619 
significant deterioration in any laboratory assessments or clinical tests while participating 
620 
in this study will be captured. The study coordinator will contact participants virtually to 
621 
answer questions and assess adverse effects after Titration period, Fixed-Dose period, 
622 
and 4 weeks after Taper. 
623 
 
624 


 
 
 
 
 
 
______________________________________________________________________________________ 
 
17
Taper Down: maximum duration 2 weeks    
625 
Upon completion of the Fixed-Dose period, all participants in the study will be 
626 
titrated off study drug through a taper down period of maximum 2 weeks. Taper schedule 
627 
will directly relate to maximum gabapentin dose achieved during trial and is described in 
628 
the Table below. The study drug will be distributed in 2 separate vials representing each 
629 
of the two weeks of the Taper-Down Period. It should be noted, participants randomized 
630 
to placebo will also receive sufficient capsules to complete a taper down. In this way, the 
631 
blind will be maintained.  
632 
 
633 
Gabapentin Taper Down Schedule 
634 
 
635 
End of Study Intervention: Exit Interview/ Data Collection: 4 weeks after 
636 
completing Taper Down   
637 
The RA will contact the participants to query participants about compliance 
638 
with taper-down schedule and maintenance of diaries. Participants will complete the 
639 
following forms (survey titled: “FinalSurvey”):  
640 
1. Clinical Global Impression of Severity Scale (CGI-S). 
641 
2. Clinical Global Impression of Improvement Scale (CGI-I) 
642 
3. University of Pennsylvania Smell Identification Test (UPSIT) 
643 
4. Olfactory Dysfunction Outcomes Rating (ODOR) 
644 
5. NASAL-7 
645 
6. Clinical Global Impression-Severity Scale for Parosmics (CGI-P) 
646 
 
647 
F3 
Safety and Adverse Events  
648 
 
649 
3.a 
Safety and Compliance Monitoring 
650 
The specific monitoring plan for this study is based on the potential risk of participation 
651 
and size and complexity of the planned investigation.  Based on these considerations, this 
652 
study will have a monitoring committee comprised of Dr. Piccirillo, Ms. Kukuljan, and 
653 
Dr. Kallogjeri, the study biostatistician. All reports of a Serious Adverse Event (SAE) or 
654 


 
 
 
 
 
 
______________________________________________________________________________________ 
 
18
an Unexpected Adverse Event (UAE) will be investigated by the monitoring team and 
655 
reported to Washington University HRPO according to the reporting requirements.  
656 
 
657 
Participants who experience serious adverse effects with gabapentin therapy will be 
658 
removed from the study. Participants with serious adverse effects will be instructed to 
659 
call 911, seek immediate medical care and discontinue all further gabapentin treatment. If 
660 
tolerated, all participants will complete the Titration period (≤ 4 weeks), Fixed-Dose 
661 
period (8 weeks), and Taper-Down period (2 weeks) for maximum 14 weeks of active 
662 
participation.  In addition, there will be a 4-week, post-Taper completion follow-up for 
663 
maximum total of 18-week trial duration. 
664 
3.a 
Medical Monitoring  
665 
 
666 
i 
Investigator only 
667 
The PI and the study team will be monitoring patients for any safety concerns, such as 
668 
SAE or UAE, in real time for the duration of the 18-week study. In addition, participants 
669 
will be specifically asked about any adverse events after the Fixed-Dose period via 
670 
REDCap. Participants will be able to get in touch with a member of the study team 24/7 
671 
via phone or pager for the duration of the 18-week clinical trial. The study biostatistician 
672 
will hold the randomization codes and remain blinded to the intervention assignment. In 
673 
the event of an SAE or UAE in which the blind needs to be broken, the Research 
674 
Pharmacist will be contacted by the PI or a member of the study team.  The participant 
675 
will receive appropriate care and will be removed from the trial. A description of the 
676 
event will be included in the report of adverse events for the clinical study. 
677 
 
678 
3.b 
Definitions of Adverse Events 
679 
Adverse event (AE) means any untoward medical occurrence associated with the use of a 
680 
drug in humans, whether or not considered drug related (21 CFR 312.32(a)). 
681 
 
682 
An adverse event (also referred to as an adverse experience) can be any unfavorable and 
683 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily 
684 
associated with the use of a drug, without any judgment about causality or relationship to 
685 
the drug. 
686 
 
687 
An adverse event can arise from any use of the drug (e.g., off-label use, use in 
688 
combination with another drug) and from any route of administration, formulation, or 
689 
dose, including an overdose. 
690 
 
691 
Serious adverse events (SAEs) are special cases of an adverse event where adverse 
692 
outcomes are severe. SAEs include the following events: 
693 
 
694 
• Death of any of the participants associated with a clinical trial. 
695 
• An event which can lead to life-threatening complications or put the life of 
696 
participants at risk as a result of participation in a clinical trial. 
697 


 
 
 
 
 
 
______________________________________________________________________________________ 
 
19
• Events that result in such a condition where the participants may require 
698 
immediate hospitalization or increase the duration of hospitalization. 
699 
• Any events that lead to a permanent or temporary physical disability in the body 
700 
of the participants. Any sort of incapacity is also regarded as SAE. 
701 
• Any events that lead to any type of congenital abnormalities. It also includes any 
702 
cases of birth defects resulting from the clinical trials. 
703 
• Any events where an investigator or team of investigators finds feel that it can 
704 
lead to significant hazards. 
705 
 
706 
Classification of Events 
707 
 
708 
i 
Relationship 
709 
An AE or SAE may or may not be causally related to the study intervention. A causal 
710 
relationship means that the intervention caused (or is reasonably likely to have caused) 
711 
the AE. This usually implies a relationship in time between the intervention and the AE 
712 
(e.g., the AE occurred shortly after the participant received the intervention).  For all 
713 
AEs, it is the responsibility of the Principal Investigator who examines and evaluates the 
714 
patient to determine the relatedness of the event to the study intervention. 
715 
 
716 
ii 
Severity 
717 
Severity refers to the intensity of a specific event and is a matter of individual clinical 
718 
judgment.  
719 
• Grade 1:  Asymptomatic or mild symptoms; clinical or diagnostic observations 
720 
only; no intervention indicated 
721 
• Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
722 
age-appropriate instrumental activities of daily living (ADL) 
723 
• Grade 3: Severe; or medically significant but not immediately life- threatening; 
724 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
725 
self-care ADL 
726 
• Grade 4: Life-threatening; urgent intervention indicated. 
727 
• Grade 5: Death related to an AE 
728 
 
729 
iii 
Expectedness 
730 
 
731 
An adverse event or suspected adverse reaction is considered "unexpected" if it is not 
732 
consistent with the risk information described in this protocol or on the informed consent 
733 
or is not listed at the specificity or severity that has been observed; or, if an investigator 
734 
brochure is not required or available, is not consistent with the risk information described 
735 
in the general investigational plan or elsewhere in the current application, as amended. 
736 
3.c 
Data Collection Procedures for Adverse Events 
737 
All adverse events and suspected adverse reactions are collected from ‘source 
738 
documentation’ and the research coordinator will abstract the events.  Documentation can 
739 


 
 
 
 
 
 
______________________________________________________________________________________ 
 
20
be within Washington University EPIC medical records, but at times the research 
740 
coordinator will also need to have the subject or family send outside source 
741 
documentation. 
742 
 
743 
3.d 
Reporting Procedures 
744 
The Principal Investigator (PI) will be responsible for ensuring participants’ safety on a 
745 
daily basis and for reporting Serious Adverse Events and Unanticipated Problems to the 
746 
Institutional Review Board (IRB) as required. 
747 
 
748 
All SAEs will be reported immediately to the Principal Investigator upon identification. 
749 
3.e 
Adverse Event Reporting Period 
750 
 
751 
All AEs and unanticipated problems will be reported to the IRB in a prompt and timely 
752 
manner to protect other subjects from avoidable harm. The appropriate time frame for 
753 
satisfying the requirement for prompt reporting will vary depending on the specific nature 
754 
of the unanticipated problem.  For this study, unanticipated problems that are serious 
755 
adverse events will be reported to the IRB within 1 week of the investigator becoming 
756 
aware of the event.  Any other unanticipated problem will be reported to the IRB within 2 
757 
weeks of the investigator becoming aware of the problem.   
758 
 
759 
Determining the appropriate time frame for reporting a particular unanticipated problem 
760 
requires careful judgment by the Research Coordinator and the Principal Investigator 
761 
knowledgeable about human subject protections.  The primary consideration in making 
762 
these judgments is the need to take timely action to prevent avoidable harms to other 
763 
subjects.   
764 
 
765 
F4 
Study Outcome Measurements and Ascertainment 
766 
Participants will complete an assessment of blind after completion of 4 weeks of 
767 
the 8-week Fixed-Dose period using REDCap (survey titled: “Blind Assessment”) 
768 
 
769 
Participants will also complete the following forms using REDCap (survey titled 
770 
“FixedDoseSurvey”) after completing the 8-week Fixed-Dose Period: 
771 
 
772 
1.) Clinical Global Impression of Severity Scale (CGI-S). 
773 
2.) Clinical Global Impression of Improvement Scale (CGI-I) 
774 
3.) University of Pennsylvania Smell Identification Test (UPSIT) 
775 
4.) Olfactory Dysfunction Outcomes Rating (ODOR) 
776 
5.) NASAL-7 
777 
6.) Clinical Global Impression-Severity Scale for Parosmics (CGI-P) 
778 
7.) Adverse Event assessment 
779 
8.) Compliance 
780 
 
781 


 
 
 
 
 
 
______________________________________________________________________________________ 
 
21
Participants will also complete the following forms using REDCap (survey titled 
782 
FinalSurvey) 4 weeks after completing the Taper Period. 
783 
1) Clinical Global Impression of Severity Scale (CGI-S). 
784 
2) Clinical Global Impression of Improvement Scale (CGI-I) 
785 
3) University of Pennsylvania Smell Identification Test (UPSIT) 
786 
4) Olfactory Dysfunction Outcomes Rating (ODOR) 
787 
5) NASAL-7 
788 
6) Clinical Global Impression-Severity Scale for Parosmics (CGI-P) 
789 
 
790 
 
791 
G Statistical Plan  
792 
 
793 
G1 
 Sample Size Determination and Power 
794 
To date there have been no studies investigating efficacy of gabapentin in COVID-19 
795 
related olfactory dysfunction. Due to the lack of preliminary data and effect size, 
796 
estimates of the sample size for this study will be determined based on feasibility. For 
797 
this pilot study, we plan to enroll 60 subjects. The sample size of 60 subjects is feasible 
798 
given the incidence of COVID-19 cases in Missouri and considering a conservative 
799 
estimate of a 10% rate of permanent olfactory dysfunction among those (~50%) who 
800 
experience olfactory dysfunction as one of the presenting symptoms. Using a 33% drop 
801 
out rate, we estimate that the sample size of 60 subjects randomized in a balanced way 
802 
between the two treatment groups will provide us with 40 evaluable cases. A previous 
803 
study exploring a different treatment for COVID-19 related anosmia in our lab showed 
804 
that 30% of the participants randomized to placebo reported improvement at the end of 
805 
the trial as compared to baseline.  We aim to observe a 25% difference in the response 
806 
rate between gabapentin and placebo groups. Assuming that this will be the response rate 
807 
in the placebo group of our trial, the sample size of 20 subjects per group will provide us 
808 
with a 95% Confidence Interval -5% to 55% around the desired proportion difference of 
809 
25% between gabapentin and placebo groups.   
810 
 
811 
G2 
 Interim Monitoring and Early Stopping 
812 
There will not be a planned interim monitoring, nor will there be early stopping rules. 
813 
G3 
Statistical Methods  
814 
An intention-to-treat analysis will be used for the primary analysis of the data. All 
815 
participants will be examined in the groups to which they were initially assigned. 
816 
Standard descriptive statistics will be used to assess the demographics, clinical 
817 
characteristics, and olfactory test results of the study population. The difference in rate of 
818 
responders after Fixed-Dose period will estimate the effect size of the primary outcome 
819 
measure, and the 95% CI around that point estimate will measure precision. In each 
820 
group, the frequency and relative frequency of the participants’ response to the global 
821 
rating of smell change will be reported for each Likert category. Fisher’s exact test will 
822 
be used for comparing the responders’ rates between the 2 groups. Histograms and 
823 


 
 
 
 
 
 
______________________________________________________________________________________ 
 
22
Shapiro-Wilks test will be used to test the normal distribution assumption of the 
824 
continuously measured UPSIT scores and the differences pre-post treatment in each of 
825 
the groups. Independent samples t-test or its nonparametric equivalent Mann-Whitney U 
826 
test will be used to compare the change in UPSIT scores between the two groups. Mixed 
827 
effects model will be used to test whether the change in UPSIT score from baseline to 
828 
end of treatment is significantly different between 2 groups. Subjects will be treated as 
829 
random factors, and group and time will be used as fixed factors in the model. Interaction 
830 
of group by time will be explored.  Effect sizes with 95% CIs will be reported for each 
831 
analysis. All statistical analyses will be conducted in SPSS 28 (IBM Corp., Armonk, 
832 
NY). 
833 
 
834 
G4 
 Missing Outcome Data 
835 
All attempts will be made using Good Clinical Practice and through the reduction of the 
836 
complexity and number of assessments to minimize the occurrence of missing outcome 
837 
data. It will be assumed that all missing data will be at random. As this is a small pilot 
838 
study, no computational techniques will be employed to adjust analyses for missing data. 
839 
G5 
Unblinding Procedures  
840 
The blind will be broken for individual participants for safety concerns. Knowledge of 
841 
the treatment received is necessary for interpreting the event, may be essential for the 
842 
medical management of the subject, and may provide critical safety information about 
843 
gabapentin that could have implications for the ongoing conduct of the trial (e.g., 
844 
monitoring, informed consent).  For unblinding, the research coordinator will contact the 
845 
research pharmacist and provide the study ID number for the participant to be unblinded.  
846 
The research pharmacist will contact the PI directly and reveal the intervention 
847 
assignment.  The research coordinator will remain blinded. 
848 
 
849 
H Data Handling and Record Keeping  
850 
 
851 
H1 
Confidentiality and Security 
852 
Procedures that are in place to curb risks of breaches in confidentiality and privacy are 1) 
853 
formal training protocols centered on the maintenance of confidentiality for all study 
854 
team members and  secure storage for identified data such as completed questionnaires 
855 
and UPSIT exams; and communication with study team via secure email, phone line, or 
856 
televideo call. 
857 
 
858 
Only members of the study team will have access to the electronic research files. All 
859 
research data files will be stored on secure Washington University servers with computer, 
860 
network, and database-level passwords that will only be accessible to study team 
861 
members. Accordingly, these mechanisms intend to limit access to information that can 
862 
link clinical data to individual participants. No participant identifying information will be 
863 
revealed in any publications or presentations. 
864 
 
865 


 
 
 
 
 
 
______________________________________________________________________________________ 
 
23
Case report forms will be created as electronic documents and stored within each study 
866 
participants electronic file. Original hard-copy source documents will be electronically 
867 
scanned and stored in the participants electronic file and stored in a locked file cabinet. 
868 
H2 
Records Retention 
869 
All records will be retained for a minimum of six years after completion of the study and 
870 
closure with the WU IRB. 
871 
I 
Study Administration 
872 
 
873 
I1 
Subject Stipends or Payments  
874 
Participants will be provided a Forte/Advarra debit card. They will receive $60 for 
875 
completing all study requirements. If participants do not complete all requirements, they 
876 
will be paid proportionally for the work they have completed. 
877 
 
878 
I2 
 Study Timetable 
879 
 
880 
January 2022: IRB approval process and acquisition of resources 
881 
February 2022 - March 2022: Rolling recruitment 
882 
February 2022 - August 2022: 18-week clinical trial 
883 
September 2022: Statistical analysis and publication of results 
884 
 
885 
J 
Publication Plan  
886 
 
887 
We plan to analyze accumulated data throughout the month of September 2022 and 
888 
publish the results by the end of September 2022. This data includes the analysis of the 
889 
CGI-I, UPSIT, ODOR, NASAL-7, and CGI-P as well as a discussion of the potential 
890 
adverse effects associated with oral gabapentin therapy for treatment of post-COVID-19 
891 
olfactory dysfunction.  
892 
 
893 
K  Attachments  
894 
K1 
Questionnaires or surveys 
895 
- 
Screening Survey  
896 
- 
Screening UPSIT 
897 
- 
Week0BaselineSurvey 
898 
- 
Blind Assessment 
899 
- 
FixedDoseSurvey 
900 
- 
FinalSurvey 
901 
 
902 
 
903 


 
 
 
 
 
 
______________________________________________________________________________________ 
 
24
L 
References 
904 
 
905 
 
906 
1. 
Prevention CfDCa. COVID Data Tracker. https://covid.cdc.gov/covid-data-
907 
tracker/#datatracker-home. Published 2021. Accessed. 
908 
2. 
Organization WH. WHO Coronavirus (COVID-19) Dashboard. 
909 
https://covid19.who.int/. Published 2021. Accessed. 
910 
3. 
Lechien JR, Chiesa-Estomba CM, De Siati DR, et al. Olfactory and gustatory 
911 
dysfunctions as a clinical presentation of mild-to-moderate forms of the 
912 
coronavirus disease (COVID-19): a multicenter European study. Eur Arch 
913 
Otorhinolaryngol. 2020. 
914 
4. 
Boscolo-Rizzo P, Borsetto D, Fabbris C, et al. Evolution of Altered Sense of 
915 
Smell or Taste in Patients With Mildly Symptomatic COVID-19. JAMA 
916 
Otolaryngol Head Neck Surg. 2020. 
917 
5. 
Hummel T, Rissom K, Reden J, Hahner A, Weidenbecher M, Huttenbrink KB. 
918 
Effects of olfactory training in patients with olfactory loss. Laryngoscope. 
919 
2009;119(3):496-499. 
920 
6. 
Turner JH. Olfactory training: what is the evidence? Int Forum Allergy Rhinol. 
921 
2020;10(11):1199-1200. 
922 
7. 
Biole C, Bianco M, Nunez-Gil IJ, et al. Gender Differences in the Presentation 
923 
and Outcomes of Hospitalized Patients With COVID-19. J Hosp Med. 
924 
2021;16(6):349-352. 
925 
8. 
Butowt R, von Bartheld CS. Anosmia in COVID-19: Underlying Mechanisms and 
926 
Assessment of an Olfactory Route to Brain Infection. Neuroscientist. 
927 
2020:1073858420956905. 
928 
9. 
Bilinska K, Butowt R. Anosmia in COVID-19: A Bumpy Road to Establishing a 
929 
Cellular Mechanism. ACS Chem Neurosci. 2020;11(15):2152-2155. 
930 
10. 
Kuba K, Imai Y, Penninger JM. Multiple functions of angiotensin-converting 
931 
enzyme 2 and its relevance in cardiovascular diseases. Circ J. 2013;77(2):301-
932 
308. 
933 
11. 
Mollica V, Rizzo A, Massari F. The pivotal role of TMPRSS2 in coronavirus 
934 
disease 2019 and prostate cancer. Future Oncol. 2020;16(27):2029-2033. 
935 
12. 
Damm M, Pikart LK, Reimann H, et al. Olfactory training is helpful in 
936 
postinfectious olfactory loss: a randomized, controlled, multicenter study. 
937 
Laryngoscope. 2014;124(4):826-831. 
938 
13. 
Schopf CL, Ablinger C, Geisler SM, et al. Presynaptic alpha2delta subunits are 
939 
key organizers of glutamatergic synapses. Proc Natl Acad Sci U S A. 
940 
2021;118(14). 
941 
14. 
Lopez-D'alessandro E, Escovich L. Combination of alpha lipoic acid and 
942 
gabapentin, its efficacy in the treatment of Burning Mouth Syndrome: a 
943 
randomized, double-blind, placebo controlled trial. Med Oral Patol Oral Cir 
944 
Bucal. 2011;16(5):e635-640. 
945 
15. 
Doty RL, Shaman P, Dann M. Development of the University of Pennsylvania 
946 
Smell Identification Test: A standardized microencapsulated test of olfactory 
947 
function. Physiol Behav. 1984;32(3):489-502. 
948 


 
 
 
 
 
 
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25
16. 
Doty RL. Olfactory dysfunction and its measurement in the clinic. World J 
949 
Otorhinolaryngol Head Neck Surg. 2015;1(1):28-33. 
950 
17. 
Mersfelder TL, Nichols WH. Gabapentin: Abuse, Dependence, and Withdrawal. 
951 
Ann Pharmacother. 2016;50(3):229-233. 
952