Efficacy of Gabapentin For Post-COVID-19 Olfactory Dysfunction: The GRACE Randomized Clinical Trial.

Importance: The COVID-19 pandemic affected millions of people and has become a dominant etiology of olfactory dysfunction (OD). No interventions with definitive clinical utility exist. Gabapentin represents a potential therapy for COVID-19-induced OD. Objective: To evaluate the efficacy of oral gabapentin on olfactory function and olfaction-related quality of life in patients with COVID-19-induced OD. Design, Setting, and Participants: This pilot double-blinded, placebo-controlled randomized clinical trial (RCT) was conducted at Washington University School of Medicine in St Louis from January 7, 2022, to February 3, 2023. Adults with at least 3 months of OD after COVID-19 infection were eligible for inclusion. Participants with a history of other causes of OD or contraindications to gabapentin were excluded. Intervention: Patients were randomized 1:1 to oral gabapentin or placebo. All patients underwent titration to a maximum tolerable dose, which was maintained during an 8-week fixed-dose (FD) phase then tapered off. Participants were monitored for 4 weeks following cessation of study medication. Main Outcomes and Measures: Outcomes were assessed following the 8-week FD phase and 4 weeks after taper completion. The primary outcome measure was the response rate determined by subjective improvement in OD on the Clinical Global Impression of Improvement (CGI-I) after the FD phase. Other subjective and objective measures of olfactory function were also assessed as secondary outcome measures. Results: Sixty-eight participants were enrolled (34 randomized to each arm), a total of 44 participants completed the FD period and 20 (45.4%) reported response to treatment with at least slight improvement in olfaction from baseline. Of those randomized, 51 (75%) were women and 56 were White (82%) with a mean (SD) age of 43 (13.5) years. Baseline demographic features including age, sex, and race and ethnicity were not significantly different between the groups. Of the 18 participants in the gabapentin group, 8 (44%) were responders and of the 26 participants in the placebo group, 12 (46%) reported response to treatment (percent difference, 1.7%; 95% CI, -31.6% to 28.2%). Mixed-model analysis of all secondary outcome measures demonstrated no clinically meaningful or statistically significant difference between the gabapentin and placebo groups throughout the trial. There were no serious adverse events. Conclusions and Relevance: In this randomized clinical trial, gabapentin was not associated with statistically significant or clinically meaningful benefit over placebo and likely is not an efficacious therapy for COVID-19-induced OD. Trial Registration: ClinicalTrials.gov Identifier: NCT05184192.

Efficacy and Safety of Saline Nasal Irrigation Plus Theophylline for Treatment of COVID-19-Related Olfactory Dysfunction: The SCENT2 Phase 2 Randomized Clinical Trial.

Importance: Recent studies suggest that theophylline added to saline nasal irrigation (SNI) can be an effective treatment for postviral olfactory dysfunction (OD), a growing public health concern during the COVID-19 pandemic. Objective: To evaluate the efficacy and safety of theophylline added to SNI compared with placebo for COVID-19-related OD. Design, Setting, and Participants: This triple-blinded, placebo-controlled, phase 2 randomized clinical trial was conducted virtually between March 15 and August 31, 2021. Adults residing in Missouri or Illinois were recruited during this time period if they had OD persisting for 3 to 12 months following suspected COVID-19 infection. Data analysis was conducted from October to December 2021. Interventions: Saline sinus rinse kits and bottles of identical-appearing capsules with either 400 mg of theophylline (treatment) or 500 mg of lactose powder (control) were mailed to consenting study participants. Participants were instructed to dissolve the capsule contents into the saline rinse and use the solution to irrigate their nasal cavities in the morning and at night for 6 weeks. Main Outcomes and Measures: The primary outcome was the difference in the rate of responders between the treatment and the control arms, defined as a response of at least slightly better improvement in the Clinical Global Impression-Improvement scale posttreatment. Secondary outcome measures included changes in the University of Pennsylvania Smell Identification Test (UPSIT), the Questionnaire for Olfactory Disorders, the 36-Item Short Form Health Survey on general health, and COVID-19-related questions. Results: A total of 51 participants were enrolled in the study; the mean (SD) age was 46.0 (13.1) years, and 36 (71%) participants were women. Participants were randomized to SNI with theophylline (n = 26) or to SNI with placebo (n = 25). Forty-five participants completed the study. At the end of treatment, 13 (59%) participants in the theophylline arm reported at least slight improvement in the Clinical Global Impression-Improvement scale (responders) compared with 10 (43%) in the placebo arm (absolute difference, 15.6%; 95% CI, -13.2% to 44.5%). The median difference for the UPSIT change between baseline and 6 weeks was 3.0 (95% CI, -1.0 to 7.0) for participants in the theophylline arm and 0.0 (95% CI, -2.0 to 6.0) for participants in the placebo arm. Mixed-model analysis revealed that the change in UPSIT scores through study assessments was not statistically significantly different between the 2 study arms. Eleven (50%) participants in the theophylline arm and 6 (26%) in the placebo arm had a change of 4 or more points in UPSIT scores from baseline to 6 weeks. The difference in the rate of responders as measured by the UPSIT was 24% (95% CI, -4% to 52%) in favor of theophylline. Conclusions and Relevance: This randomized clinical trial suggests that the clinical benefit of theophylline nasal irrigations on olfaction in participants with COVID-19-related OD is inconclusive, though suggested by subjective assessments. Larger studies are warranted to investigate the efficacy of this treatment more fully. Trial Registration: ClinicalTrials.gov Identifier: NCT04789499.