search
Back to results

Efficacy of Gabapentin for Post-Covid-19 Olfactory Dysfunction (GRACE)

Primary Purpose

COVID-19, Olfactory Disorder, Anosmia

Status
Enrolling by invitation
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Gabapentin gelatin capsules 300mg
Placebo
Sponsored by
Washington University School of Medicine
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for COVID-19

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Men and women between the ages of 18 and 65 years
  • Residing within the states of Missouri or Illinois
  • Clinically diagnosed or subjective olfactory dysfunction (anosmia, hyposmia, or parosmia) of 3 months duration or longer diagnosed within 2 weeks of Covid-19 infection
  • UPSIT score consistent with diminished olfactory function (score ≤ 33 in men and ≤ 34 in women).
  • Willing to respond daily to study surveys, preferably through smartphone with unlimited texting plan
  • In possession of ALL 7 household items: soap, burnt candle, peanut butter, herb, garlic, lemon, and coffee

Exclusion Criteria:

  • Clinically diagnosed olfactory dysfunction secondary to genetic abnormalities or congenital dysfunction, trauma, non-Covid-19 viral infection, nasal polyps, neurodegenerative disorders
  • Current use of: azelastine, bromperidol, orophenadrine, oxomemazine, kratom, paraldehyde, or thalidomide
  • History of addiction to alcohol, cocaine, or opioids
  • Impaired renal function, myasthenia gravis, or myoclonus
  • Severe allergy to peanuts
  • Pregnancy or attempting pregnancy during study participation
  • Inability to participate in virtual trial due to lack of access to the internet or unlimited text messaging; inability to comprehend or use English language
  • Availability less than 6 months from time of enrollment
  • Residency in states other than Missouri or Illinois.

Sites / Locations

  • Washington University

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Gabapentin

Placebo

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Clinical Global Impression of Improvement Scale (CGI-I)
The CGI-Severity scale ranges from 1 to 7, where 1 is Very Much Improved and 7 is Very Much Worsened. This assessment will provide subjective data on patients' change in olfaction from baseline. Participants reporting 3 as Minimally Improved, 2 as Much Improved, or 1 as Very Much Improved in the CGI-I will be deemed responders to treatment, and the number of responders to non-responders will be compared between the two arms

Secondary Outcome Measures

University of Pennsylvania Smell Identification Test (UPSIT)
The UPSIT is composed of 40 strips of microencapsulated odorants, which are present on the bottom of each page, just below a four-alternative multiple-choice question. For a given item, the patient releases an odor by scratching the microencapsulated pad with a pencil tip, smells the pad, and indicates the odor quality from four alternatives. Even if no smell is perceived, a response is required (i.e., the test is forced-choice). The subject's total correct score out of the 40 items is determined and provides an objective measure of olfactory function.
Olfactory Dysfunction Outcomes Rating (ODOR)
The ODOR questionnaire is a 28-item disease-specific health status survey to assess the physical problems, functional impairments, and emotional consequences secondary to olfactory dysfunction. ODOR was developed and validated by Dr. Jake Lee and colleagues in the Clinical Outcomes Research Office at Washington University
NASAL-7
NASAL-7 is a simple diagnostic tool for olfactory dysfunction that is based on commonly found household items and can be used by adults who suspect olfactory dysfunction. The NASAL-7, contains 7 household items with each item scored as 0 for 'Cannot Smell', 1 for 'Smells Less Strong/Different Than Normal', and 2 for 'Smells Normal', for a total possible score ranging from 0-14. The following four categories of olfactory function were defined based on NASAL-7 score: anosmia (score 0-4), severe dysfunction (score 5-7), mild dysfunction (score 8-10), and normosmia (score 11-14).
Clinical Global Impression - Severity Scale for Parosmics (CGI-P)
The CGI-P Scale is a global rating of parosmia and the single global rating ranges from 1-5, where 1 is No Distortion, 2 is Mild Distortion, 3 is Moderate Distortion, 4 is Mostly Distorted, and 5 is Complete Distortion. The response on the CGI-P will provide information on the patient's perceived severity of the distortion of their smell.
Clinical Global Impression of Severity Scale (CGI-S)
The CGI-S Scale is a subjective rating of severity which ranges from 1 - 7 (1 is normal function and 7 is complete anosmia) to measure severity of smell loss.
Clinical Global Impression of Improvement Scale (CGI-I)
The CGI-Severity scale ranges from 1 to 7, where 1 is Very Much Improved and 7 is Very Much Worsened. This assessment will provide subjective data on patients' change in olfaction from baseline.

Full Information

First Posted
January 6, 2022
Last Updated
May 24, 2023
Sponsor
Washington University School of Medicine
search

1. Study Identification

Unique Protocol Identification Number
NCT05184192
Brief Title
Efficacy of Gabapentin for Post-Covid-19 Olfactory Dysfunction
Acronym
GRACE
Official Title
Efficacy of Gabapentin for Post-Covid-19 Olfactory Dysfunction
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Enrolling by invitation
Study Start Date
January 10, 2022 (Actual)
Primary Completion Date
February 2024 (Anticipated)
Study Completion Date
March 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Washington University School of Medicine

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
COVID-19, Olfactory Disorder, Anosmia, Hyposmia, Parosmia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Double-blinded, randomized, placebo-controlled trial
Masking
ParticipantInvestigatorOutcomes Assessor
Masking Description
double-blinded, both participants and investigators will be blinded. Intervention will be packaged in blinded fashion by pharmacist before being shipped to participants by research assistant
Allocation
Randomized
Enrollment
50 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Gabapentin
Arm Type
Experimental
Arm Description
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 Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Gabapentin gelatin capsules 300mg
Other Intervention Name(s)
Letco
Intervention Description
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 Type
Drug
Intervention Name(s)
Placebo
Intervention Description
lactose monohydrate NF
Primary Outcome Measure Information:
Title
Clinical Global Impression of Improvement Scale (CGI-I)
Description
The CGI-Severity scale ranges from 1 to 7, where 1 is Very Much Improved and 7 is Very Much Worsened. This assessment will provide subjective data on patients' change in olfaction from baseline. Participants reporting 3 as Minimally Improved, 2 as Much Improved, or 1 as Very Much Improved in the CGI-I will be deemed responders to treatment, and the number of responders to non-responders will be compared between the two arms
Time Frame
After completion of eight-week fixed-dose period
Secondary Outcome Measure Information:
Title
University of Pennsylvania Smell Identification Test (UPSIT)
Description
The UPSIT is composed of 40 strips of microencapsulated odorants, which are present on the bottom of each page, just below a four-alternative multiple-choice question. For a given item, the patient releases an odor by scratching the microencapsulated pad with a pencil tip, smells the pad, and indicates the odor quality from four alternatives. Even if no smell is perceived, a response is required (i.e., the test is forced-choice). The subject's total correct score out of the 40 items is determined and provides an objective measure of olfactory function.
Time Frame
Baseline, after completion of eight-week fixed-dose period, and 4 weeks after completion of taper-down period
Title
Olfactory Dysfunction Outcomes Rating (ODOR)
Description
The ODOR questionnaire is a 28-item disease-specific health status survey to assess the physical problems, functional impairments, and emotional consequences secondary to olfactory dysfunction. ODOR was developed and validated by Dr. Jake Lee and colleagues in the Clinical Outcomes Research Office at Washington University
Time Frame
Baseline, after completion of eight-week fixed-dose period, and 4 weeks after completion of taper-down period
Title
NASAL-7
Description
NASAL-7 is a simple diagnostic tool for olfactory dysfunction that is based on commonly found household items and can be used by adults who suspect olfactory dysfunction. The NASAL-7, contains 7 household items with each item scored as 0 for 'Cannot Smell', 1 for 'Smells Less Strong/Different Than Normal', and 2 for 'Smells Normal', for a total possible score ranging from 0-14. The following four categories of olfactory function were defined based on NASAL-7 score: anosmia (score 0-4), severe dysfunction (score 5-7), mild dysfunction (score 8-10), and normosmia (score 11-14).
Time Frame
Baseline, after completion of eight-week fixed-dose period, and 4 weeks after completion of taper-down period
Title
Clinical Global Impression - Severity Scale for Parosmics (CGI-P)
Description
The CGI-P Scale is a global rating of parosmia and the single global rating ranges from 1-5, where 1 is No Distortion, 2 is Mild Distortion, 3 is Moderate Distortion, 4 is Mostly Distorted, and 5 is Complete Distortion. The response on the CGI-P will provide information on the patient's perceived severity of the distortion of their smell.
Time Frame
Baseline, after completion of eight-week fixed-dose period, and 4 weeks after completion of taper-down period
Title
Clinical Global Impression of Severity Scale (CGI-S)
Description
The CGI-S Scale is a subjective rating of severity which ranges from 1 - 7 (1 is normal function and 7 is complete anosmia) to measure severity of smell loss.
Time Frame
Baseline, after completion of eight-week fixed-dose period, and 4 weeks after completion of taper-down period
Title
Clinical Global Impression of Improvement Scale (CGI-I)
Description
The CGI-Severity scale ranges from 1 to 7, where 1 is Very Much Improved and 7 is Very Much Worsened. This assessment will provide subjective data on patients' change in olfaction from baseline.
Time Frame
4 weeks after completion of Taper-Down Period.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Men and women between the ages of 18 and 65 years Residing within the states of Missouri or Illinois Clinically diagnosed or subjective olfactory dysfunction (anosmia, hyposmia, or parosmia) of 3 months duration or longer diagnosed within 2 weeks of Covid-19 infection UPSIT score consistent with diminished olfactory function (score ≤ 33 in men and ≤ 34 in women). Willing to respond daily to study surveys, preferably through smartphone with unlimited texting plan In possession of ALL 7 household items: soap, burnt candle, peanut butter, herb, garlic, lemon, and coffee Exclusion Criteria: Clinically diagnosed olfactory dysfunction secondary to genetic abnormalities or congenital dysfunction, trauma, non-Covid-19 viral infection, nasal polyps, neurodegenerative disorders Current use of: azelastine, bromperidol, orophenadrine, oxomemazine, kratom, paraldehyde, or thalidomide History of addiction to alcohol, cocaine, or opioids Impaired renal function, myasthenia gravis, or myoclonus Severe allergy to peanuts Pregnancy or attempting pregnancy during study participation Inability to participate in virtual trial due to lack of access to the internet or unlimited text messaging; inability to comprehend or use English language Availability less than 6 months from time of enrollment Residency in states other than Missouri or Illinois.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jay F Piccirillo, MD
Organizational Affiliation
Washington University School of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Washington University
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
32253535
Citation
Lechien JR, Chiesa-Estomba CM, De Siati DR, Horoi M, Le Bon SD, Rodriguez A, Dequanter D, Blecic S, El Afia F, Distinguin L, Chekkoury-Idrissi Y, Hans S, Delgado IL, Calvo-Henriquez C, Lavigne P, Falanga C, Barillari MR, Cammaroto G, Khalife M, Leich P, Souchay C, Rossi C, Journe F, Hsieh J, Edjlali M, Carlier R, Ris L, Lovato A, De Filippis C, Coppee F, Fakhry N, Ayad T, Saussez S. Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study. Eur Arch Otorhinolaryngol. 2020 Aug;277(8):2251-2261. doi: 10.1007/s00405-020-05965-1. Epub 2020 Apr 6.
Results Reference
background
PubMed Identifier
32614442
Citation
Boscolo-Rizzo P, Borsetto D, Fabbris C, Spinato G, Frezza D, Menegaldo A, Mularoni F, Gaudioso P, Cazzador D, Marciani S, Frasconi S, Ferraro M, Berro C, Varago C, Nicolai P, Tirelli G, Da Mosto MC, Obholzer R, Rigoli R, Polesel J, Hopkins C. Evolution of Altered Sense of Smell or Taste in Patients With Mildly Symptomatic COVID-19. JAMA Otolaryngol Head Neck Surg. 2020 Aug 1;146(8):729-732. doi: 10.1001/jamaoto.2020.1379.
Results Reference
background
PubMed Identifier
19235739
Citation
Hummel T, Rissom K, Reden J, Hahner A, Weidenbecher M, Huttenbrink KB. Effects of olfactory training in patients with olfactory loss. Laryngoscope. 2009 Mar;119(3):496-9. doi: 10.1002/lary.20101.
Results Reference
background
PubMed Identifier
32776673
Citation
Turner JH. Olfactory training: what is the evidence? Int Forum Allergy Rhinol. 2020 Nov;10(11):1199-1200. doi: 10.1002/alr.22681. Epub 2020 Sep 3. No abstract available.
Results Reference
background
PubMed Identifier
34129486
Citation
Biole C, Bianco M, Nunez-Gil IJ, Cerrato E, Spirito A, Roubin SR, Viana-Llamas MC, Gonzalez A, Castro-Mejia AF, Eid CM, Fernandez-Perez C, Uribarri A, Alfonso-Rodriguez E, Ugo F, Guerra F, Feltes G, Akin I, Fernandez-Rozas I, Blasco-Angulo N, Huang J, Aguado MG, Pepe M, Romero R, Becerra-Munoz VM, Estrada V, Macaya C. Gender Differences in the Presentation and Outcomes of Hospitalized Patients With COVID-19. J Hosp Med. 2021 Jun;16(6):349-352. doi: 10.12788/jhm.3594.
Results Reference
background
PubMed Identifier
32914699
Citation
Butowt R, von Bartheld CS. Anosmia in COVID-19: Underlying Mechanisms and Assessment of an Olfactory Route to Brain Infection. Neuroscientist. 2021 Dec;27(6):582-603. doi: 10.1177/1073858420956905. Epub 2020 Sep 11.
Results Reference
background
PubMed Identifier
32673476
Citation
Bilinska K, Butowt R. Anosmia in COVID-19: A Bumpy Road to Establishing a Cellular Mechanism. ACS Chem Neurosci. 2020 Aug 5;11(15):2152-2155. doi: 10.1021/acschemneuro.0c00406. Epub 2020 Jul 16.
Results Reference
background
PubMed Identifier
23328447
Citation
Kuba K, Imai Y, Penninger JM. Multiple functions of angiotensin-converting enzyme 2 and its relevance in cardiovascular diseases. Circ J. 2013;77(2):301-8. doi: 10.1253/circj.cj-12-1544. Epub 2013 Jan 18.
Results Reference
background
PubMed Identifier
32658591
Citation
Mollica V, Rizzo A, Massari F. The pivotal role of TMPRSS2 in coronavirus disease 2019 and prostate cancer. Future Oncol. 2020 Sep;16(27):2029-2033. doi: 10.2217/fon-2020-0571. Epub 2020 Jul 13. No abstract available.
Results Reference
background
PubMed Identifier
23929687
Citation
Damm M, Pikart LK, Reimann H, Burkert S, Goktas O, Haxel B, Frey S, Charalampakis I, Beule A, Renner B, Hummel T, Huttenbrink KB. Olfactory training is helpful in postinfectious olfactory loss: a randomized, controlled, multicenter study. Laryngoscope. 2014 Apr;124(4):826-31. doi: 10.1002/lary.24340. Epub 2013 Sep 19.
Results Reference
background
PubMed Identifier
33782113
Citation
Schopf CL, Ablinger C, Geisler SM, Stanika RI, Campiglio M, Kaufmann WA, Nimmervoll B, Schlick B, Brockhaus J, Missler M, Shigemoto R, Obermair GJ. Presynaptic alpha2delta subunits are key organizers of glutamatergic synapses. Proc Natl Acad Sci U S A. 2021 Apr 6;118(14):e1920827118. doi: 10.1073/pnas.1920827118.
Results Reference
background
PubMed Identifier
20711135
Citation
Lopez-D'alessandro E, Escovich L. Combination of alpha lipoic acid and gabapentin, its efficacy in the treatment of Burning Mouth Syndrome: a randomized, double-blind, placebo controlled trial. Med Oral Patol Oral Cir Bucal. 2011 Aug 1;16(5):e635-40. doi: 10.4317/medoral.16942.
Results Reference
background
PubMed Identifier
6694486
Citation
Doty RL, Shaman P, Kimmelman CP, Dann MS. University of Pennsylvania Smell Identification Test: a rapid quantitative olfactory function test for the clinic. Laryngoscope. 1984 Feb;94(2 Pt 1):176-8. doi: 10.1288/00005537-198402000-00004.
Results Reference
background
PubMed Identifier
29204537
Citation
Doty RL. Olfactory dysfunction and its measurement in the clinic. World J Otorhinolaryngol Head Neck Surg. 2015 Oct 26;1(1):28-33. doi: 10.1016/j.wjorl.2015.09.007. eCollection 2015 Sep.
Results Reference
background
PubMed Identifier
26721643
Citation
Mersfelder TL, Nichols WH. Gabapentin: Abuse, Dependence, and Withdrawal. Ann Pharmacother. 2016 Mar;50(3):229-33. doi: 10.1177/1060028015620800. Epub 2015 Dec 31.
Results Reference
background
Links:
URL
http://covid.cdc.gov/covid-data-tracker/#datatracker-home
Description
CDC Covid-19 data tracker
URL
http://covid19.who.int/
Description
World Health Organization Covid-19 Dashboard

Learn more about this trial

Efficacy of Gabapentin for Post-Covid-19 Olfactory Dysfunction

We'll reach out to this number within 24 hrs