Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Evidence of COVID-19 related anosmia and dysgeusia continues to accumulate daily.
Currently, up to 80% of patients report subjective olfactory dysfunction (OD), and prevalence using objective olfactory testing could be even higher.
We propose a phase II single-site, double-blinded, placebo-controlled randomized clinical trial to determine the efficacy and safety of intranasal theophylline, a known phosphodiesterase inhibitor in the treatment of asthma, as a possible treatment for COVID-19 related OD. Theophylline has shown benefit in similar clinical trials for post-viral OD.
Post-viral olfactory dysfunction has numerous known adverse effects such as loss of cortical gray matter and decrease in quality of life. COVID-19 related olfactory dysfunction has already been shown to be correlated with depression and decreased quality of life, so finding an effective treatment is imperative.
Intranasal and oral corticosteroids as well as olfactory training are currently used to treat post-viral OD; however they have demonstrated limited efficacy and there is no current gold standard of care. There is no current consensus on the pathogenesis of COVID-related anosmia; however evidence for post-viral olfactory dysfunction suggests sensory axonal regeneration and olfactory signaling may rely on elevated levels of secondary messengers cAMP and cGMP, a known effect of theophylline. In this phase II treatment trial, patients will be allocated 1:1 to receive either intranasal theophylline irrigation or placebo for six weeks. Various smell surveys and scratch-and-sniff tests will be utilized to capture changes in smell ability.
Due to COVID-19, this study will be conducted virtually, except for the first ten enrolled patients who will undergo one serum theophylline test. This study is limited to patients living in Missouri or Illinois.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Theophylline | Experimental | 400mg theophylline capsule diluted in 240 mL isotonic nasal saline lavage twice daily for six weeks. |
|
| Placebo | Placebo Comparator | 500mg lactose capsule diluted in 240 mL isotonic nasal saline lavage twice daily for six weeks. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Theophylline Powder | Drug | Twice daily nasal irrigation with 400 mg theophylline capsules and USP Grade Sodium Chloride & Sodium Bicarbonate Mixture (pH balanced, Isotonic & Preservative & Iodine Free) commercially prepared packets dissolved in 240 ml of distilled water. |
| Measure | Description | Time Frame |
|---|---|---|
| UPSIT | UPSIT 0-40 with higher scores indicating better results. The response rate defined as the number of participants in each group self-reporting of at least slightly better improvement in the Clinical Global Improvement Scale at 6 weeks post intervention as compared to baseline, devided by the total number of participants in that specific group. The CGI-Improvement Scale has seven response options (from 1 as Very Much Improved to 7 as Very Much Worsened) for answers to the question "Compared to your sense of smell before you started the nasal irrigations, how would you rate your sense of smell now" . 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 rate of responders will be compared between the two arms. | Comparison of response rate at 6 weeks post-intervention from baseline between the 2 study groups |
| Measure | Description | Time Frame |
|---|---|---|
| University of Pennsylvania Smell Identification Test (UPSIT) | UPSIT 0-40 with higher scores indicating better smell. This test is an objective, clinically validated 40-question forced-choice odor identification test where microencapsulated odorants on a strip are released by scratching. Out of a total of 40 points, normosmia is defined as ≥34 for males and ≥35 for females, and an increase in ≥4 points will be deemed a clinically significant improvement in symptoms. |
Not provided
Inclusion Criteria:
Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Jay F Piccirillo, M.D., FACS | Washington University School of Medicine | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Washington University School of Medicine in Saint Louis | St Louis | Missouri | 63110 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 34792577 | Background | Khan AM, Kallogjeri D, Piccirillo JF. Growing Public Health Concern of COVID-19 Chronic Olfactory Dysfunction. JAMA Otolaryngol Head Neck Surg. 2022 Jan 1;148(1):81-82. doi: 10.1001/jamaoto.2021.3379. | |
| 27287364 | Background | Hoffman HJ, Rawal S, Li CM, Duffy VB. New chemosensory component in the U.S. National Health and Nutrition Examination Survey (NHANES): first-year results for measured olfactory dysfunction. Rev Endocr Metab Disord. 2016 Jun;17(2):221-40. doi: 10.1007/s11154-016-9364-1. |
Not provided
Not provided
Not provided
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | Theophylline | 400mg theophylline capsule diluted in 240 mL isotonic nasal saline lavage twice daily. Theophylline Powder: Theophylline is a known phosphodiesterase inhibitor in the treatment of asthma. Evidence for post-viral olfactory dysfunction suggests sensory axonal regeneration and olfactory signaling may rely on elevated levels of secondary messengers cAMP and cGMP, a known effect of theophylline. Therefore it is hypothesized to help treat COVID-related smell dysfunction, especially if delivered intranasally. Twice daily nasal irrigation with 400 mg theophylline capsules and USP Grade Sodium Chloride & Sodium Bicarbonate Mixture (pH balanced, Isotonic & Preservative & Iodine Free) commercially prepared packets dissolved in 240 ml of distilled water. |
| FG001 | Placebo | 500mg lactose capsule diluted in 240 mL isotonic nasal saline lavage twice daily. Theophylline Powder: Theophylline is a known phosphodiesterase inhibitor in the treatment of asthma. Evidence for post-viral olfactory dysfunction suggests sensory axonal regeneration and olfactory signaling may rely on elevated levels of secondary messengers cAMP and cGMP, a known effect of theophylline. Therefore it is hypothesized to help treat COVID-related smell dysfunction, especially if delivered intranasally. Twice daily nasal irrigation with 400 mg theophylline capsules and USP Grade Sodium Chloride & Sodium Bicarbonate Mixture (pH balanced, Isotonic & Preservative & Iodine Free) commercially prepared packets dissolved in 240 ml of distilled water. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Theophylline | 400mg theophylline capsule diluted in 240 mL isotonic nasal saline lavage twice daily. Theophylline Powder: Theophylline is a known phosphodiesterase inhibitor in the treatment of asthma. Evidence for post-viral olfactory dysfunction suggests sensory axonal regeneration and olfactory signaling may rely on elevated levels of secondary messengers cAMP and cGMP, a known effect of theophylline. Therefore it is hypothesized to help treat COVID-related smell dysfunction, especially if delivered intranasally. Twice daily nasal irrigation with 400 mg theophylline capsules and USP Grade Sodium Chloride & Sodium Bicarbonate Mixture (pH balanced, Isotonic & Preservative & Iodine Free) commercially prepared packets dissolved in 240 ml of distilled water. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | UPSIT | UPSIT 0-40 with higher scores indicating better results. The response rate defined as the number of participants in each group self-reporting of at least slightly better improvement in the Clinical Global Improvement Scale at 6 weeks post intervention as compared to baseline, devided by the total number of participants in that specific group. The CGI-Improvement Scale has seven response options (from 1 as Very Much Improved to 7 as Very Much Worsened) for answers to the question "Compared to your sense of smell before you started the nasal irrigations, how would you rate your sense of smell now" . 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 rate of responders will be compared between the two arms. | This outcome measure could be assessed only from the participants that completed CGI-I at 6 weeks post intervention. | Posted | Number | percentage of participants | Comparison of response rate at 6 weeks post-intervention from baseline between the 2 study groups |
|
All participants were monitored for adverse events throughout participation in the study intervention (week 1 through week 6).
The definition of adverse events/serious adverse events do not differ from the Clinical Trials definition.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Theophylline | 400mg theophylline capsule diluted in 240 mL isotonic nasal saline lavage twice daily. Theophylline Powder: Theophylline is a known phosphodiesterase inhibitor in the treatment of asthma. Evidence for post-viral olfactory dysfunction suggests sensory axonal regeneration and olfactory signaling may rely on elevated levels of secondary messengers cAMP and cGMP, a known effect of theophylline. Therefore it is hypothesized to help treat COVID-related smell dysfunction, especially if delivered intranasally. Twice daily nasal irrigation with 400 mg theophylline capsules and USP Grade Sodium Chloride & Sodium Bicarbonate Mixture (pH balanced, Isotonic & Preservative & Iodine Free) commercially prepared packets dissolved in 240 ml of distilled water. |
Not provided
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| fluid retension/extremity swelling | Blood and lymphatic system disorders | Non-systematic Assessment | Event was treated and was defined as mild and not related to study drug |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Research Statistician | Washington University in Saint Louis | 3143621077 | kallogjerid@wustl.edu |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Feb 20, 2021 | Dec 21, 2022 | Prot_SAP_000.pdf |
Not provided
Not provided
Not provided
| ID | Term |
|---|---|
| D000086382 | COVID-19 |
| D000086582 | Anosmia |
| D000370 | Ageusia |
| D000857 | Olfaction Disorders |
| ID | Term |
|---|---|
| D011024 | Pneumonia, Viral |
| D011014 | Pneumonia |
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
Not provided
Not provided
Not provided
Not provided
Not provided
The pharmacy will maintain the blind until the completion of the study.
|
| Placebo Comparator | Drug | Twice daily nasal irrigation with 500 mg lactose powder capsules and USP Grade Sodium Chloride & Sodium Bicarbonate Mixture (pH balanced, Isotonic & Preservative & Iodine Free) commercially prepared packets dissolved in 240 ml of distilled water. |
|
|
| Comparison at 6 weeks post-intervention from baseline |
| Change in Questionnaire for Olfactory Dysfunction (QOD) From Baseline to 6 Weeks Post Intervention | Questionnaire for Olfactory Dysfunction (QOD) assesses health-related quality of life of participants based on four factors such as eating, mental health, social interactions, or fear of dysfunction.. The survey also includes questions on parosmia, a phenomena of COVID-related OD. The QOD consists of 17 statements that participants score from 0-3, resulting in a total score from 0 to 51. Higher scores reflect better olfactory-specific QOL. | Comparison at 6 weeks post-intervention from baseline |
| 36-Item Short Form Health Survey (SF-36) | The SF-36 is a well-established 36-item questionnaire evaluating physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. This test allows us to study the overall quality of life for those suffering from COVID-19 related OD. There is no single overall score for SF-36. The SF 36 generates 8 subscales with scores ranging from 0 (worst) to 100 (best). General health domain scores are reported here. | Baseline assessment |
| Olfactory Dysfunction Outcomes Rating (ODOR) | The ODOR is a 28-item QOL instrument with a total score ranging from 0 to 112 points. Higher scores indicate worse QOL with higher degree of dysfunction and limitation. A decrease of 15 or more points is deemed to be a clinically significant improvement in QOL. | Comparison of response rate at 6 weeks post-intervention from baseline between the 2 study groups |
| 32432682 | Background | Whitcroft KL, Hummel T. Olfactory Dysfunction in COVID-19: Diagnosis and Management. JAMA. 2020 Jun 23;323(24):2512-2514. doi: 10.1001/jama.2020.8391. No abstract available. |
| 32617983 | Background | Speth MM, Singer-Cornelius T, Oberle M, Gengler I, Brockmeier SJ, Sedaghat AR. Mood, Anxiety and Olfactory Dysfunction in COVID-19: Evidence of Central Nervous System Involvement? Laryngoscope. 2020 Nov;130(11):2520-2525. doi: 10.1002/lary.28964. Epub 2020 Aug 12. |
| 34559820 | Background | Burges Watson DL, Campbell M, Hopkins C, Smith B, Kelly C, Deary V. Altered smell and taste: Anosmia, parosmia and the impact of long Covid-19. PLoS One. 2021 Sep 24;16(9):e0256998. doi: 10.1371/journal.pone.0256998. eCollection 2021. |
| 3164095 | Background | Schiffman SS, Warwick ZS. Flavor enhancement of foods for the elderly can reverse anorexia. Neurobiol Aging. 1988 Jan-Feb;9(1):24-6. doi: 10.1016/s0197-4580(88)80009-5. |
| 12425708 | Background | Murphy C, Schubert CR, Cruickshanks KJ, Klein BE, Klein R, Nondahl DM. Prevalence of olfactory impairment in older adults. JAMA. 2002 Nov 13;288(18):2307-12. doi: 10.1001/jama.288.18.2307. |
| 20231262 | Background | Bitter T, Gudziol H, Burmeister HP, Mentzel HJ, Guntinas-Lichius O, Gaser C. Anosmia leads to a loss of gray matter in cortical brain areas. Chem Senses. 2010 Jun;35(5):407-15. doi: 10.1093/chemse/bjq028. Epub 2010 Mar 15. |
| 25271633 | Background | Pinto JM, Wroblewski KE, Kern DW, Schumm LP, McClintock MK. Olfactory dysfunction predicts 5-year mortality in older adults. PLoS One. 2014 Oct 1;9(10):e107541. doi: 10.1371/journal.pone.0107541. eCollection 2014. |
| 31035288 | Background | Liu B, Luo Z, Pinto JM, Shiroma EJ, Tranah GJ, Wirdefeldt K, Fang F, Harris TB, Chen H. Relationship Between Poor Olfaction and Mortality Among Community-Dwelling Older Adults: A Cohort Study. Ann Intern Med. 2019 May 21;170(10):673-681. doi: 10.7326/M18-0775. Epub 2019 Apr 30. |
| 32153360 | Background | Van Regemorter V, Hummel T, Rosenzweig F, Mouraux A, Rombaux P, Huart C. Mechanisms Linking Olfactory Impairment and Risk of Mortality. Front Neurosci. 2020 Feb 21;14:140. doi: 10.3389/fnins.2020.00140. eCollection 2020. |
| 34830550 | Background | Schambeck SE, Crowell CS, Wagner KI, D'Ippolito E, Burrell T, Mijocevic H, Protzer U, Busch DH, Gerhard M, Poppert H, Beyer H. Phantosmia, Parosmia, and Dysgeusia Are Prolonged and Late-Onset Symptoms of COVID-19. J Clin Med. 2021 Nov 12;10(22):5266. doi: 10.3390/jcm10225266. |
| 32167747 | Background | Baig AM, Khaleeq A, Ali U, Syeda H. Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms. ACS Chem Neurosci. 2020 Apr 1;11(7):995-998. doi: 10.1021/acschemneuro.0c00122. Epub 2020 Mar 13. |
| 32563019 | Background | Meng X, Deng Y, Dai Z, Meng Z. COVID-19 and anosmia: A review based on up-to-date knowledge. Am J Otolaryngol. 2020 Sep-Oct;41(5):102581. doi: 10.1016/j.amjoto.2020.102581. Epub 2020 Jun 2. |
| 32469400 | Background | Politi LS, Salsano E, Grimaldi M. Magnetic Resonance Imaging Alteration of the Brain in a Patient With Coronavirus Disease 2019 (COVID-19) and Anosmia. JAMA Neurol. 2020 Aug 1;77(8):1028-1029. doi: 10.1001/jamaneurol.2020.2125. No abstract available. |
| 32790835 | Background | Morbini P, Benazzo M, Verga L, Pagella FG, Mojoli F, Bruno R, Marena C. Ultrastructural Evidence of Direct Viral Damage to the Olfactory Complex in Patients Testing Positive for SARS-CoV-2. JAMA Otolaryngol Head Neck Surg. 2020 Oct 1;146(10):972-973. doi: 10.1001/jamaoto.2020.2366. No abstract available. |
| 33293264 | Background | Hawkes C. Parosmia: treatment, mechanism, and types. BMJ. 2020 Dec 8;371:m4739. doi: 10.1136/bmj.m4739. No abstract available. |
| 32937591 | Background | Brann DH, Tsukahara T, Weinreb C, Lipovsek M, Van den Berge K, Gong B, Chance R, Macaulay IC, Chou HJ, Fletcher RB, Das D, Street K, de Bezieux HR, Choi YG, Risso D, Dudoit S, Purdom E, Mill J, Hachem RA, Matsunami H, Logan DW, Goldstein BJ, Grubb MS, Ngai J, Datta SR. Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia. Sci Adv. 2020 Jul 31;6(31):eabc5801. doi: 10.1126/sciadv.abc5801. Epub 2020 Jul 24. |
| 3927168 | Background | Pace U, Hanski E, Salomon Y, Lancet D. Odorant-sensitive adenylate cyclase may mediate olfactory reception. Nature. 1985 Jul 18-24;316(6025):255-8. doi: 10.1038/316255a0. |
| 8467526 | Background | Anholt RR. Molecular neurobiology of olfaction. Crit Rev Neurobiol. 1993;7(1):1-22. |
| 9754114 | Background | Levy LM, Henkin RI, Lin CS, Hutter A, Schellinger D. Increased brain activation in response to odors in patients with hyposmia after theophylline treatment demonstrated by fMRI. J Comput Assist Tomogr. 1998 Sep-Oct;22(5):760-70. doi: 10.1097/00004728-199809000-00019. |
| 12086637 | Background | Neumann S, Bradke F, Tessier-Lavigne M, Basbaum AI. Regeneration of sensory axons within the injured spinal cord induced by intraganglionic cAMP elevation. Neuron. 2002 Jun 13;34(6):885-93. doi: 10.1016/s0896-6273(02)00702-x. |
| 16181424 | Background | Moon C, Simpson PJ, Tu Y, Cho H, Ronnett GV. Regulation of intracellular cyclic GMP levels in olfactory sensory neurons. J Neurochem. 2005 Oct;95(1):200-9. doi: 10.1111/j.1471-4159.2005.03356.x. |
| 18377763 | Background | Henkin RI, Velicu I. cAMP and cGMP in nasal mucus: relationships to taste and smell dysfunction, gender and age. Clin Invest Med. 2008;31(2):E71-7. doi: 10.25011/cim.v31i2.3366. |
| 18377764 | Background | Henkin RI, Velicu I. cAMP and cGMP in nasal mucus related to severity of smell loss in patients with smell dysfunction. Clin Invest Med. 2008;31(2):E78-84. doi: 10.25011/cim.v31i2.3367. |
| 19359985 | Background | Henkin RI, Velicu I, Schmidt L. An open-label controlled trial of theophylline for treatment of patients with hyposmia. Am J Med Sci. 2009 Jun;337(6):396-406. doi: 10.1097/MAJ.0b013e3181914a97. |
| 27713276 | Background | Barnes PJ. Theophylline. Pharmaceuticals (Basel). 2010 Mar 18;3(3):725-747. doi: 10.3390/ph3030725. |
| 23165381 | Background | Henkin RI, Schultz M, Minnick-Poppe L. Intranasal theophylline treatment of hyposmia and hypogeusia: a pilot study. Arch Otolaryngol Head Neck Surg. 2012 Nov;138(11):1064-70. doi: 10.1001/2013.jamaoto.342. |
| Background | Goldstein, M.F.; Hilditch, G.J.; Frankel, I.; Chambers, L.; Dvorin, D.J.; Belecanech, G. Intra-nasal theophylline for the treatment of chronic anosmia and hyposmia. Journal of Allergy & Clinical Immunology. 2017;139(2):AB252. |
| 28775001 | Background | Nigwekar SU, Weiser JM, Kalim S, Xu D, Wibecan JL, Dougherty SM, Mercier-Lafond L, Corapi KM, Eneanya ND, Holbrook EH, Brown D, Thadhani RI, Paunescu TG. Characterization and Correction of Olfactory Deficits in Kidney Disease. J Am Soc Nephrol. 2017 Nov;28(11):3395-3403. doi: 10.1681/ASN.2016121308. Epub 2017 Aug 3. |
| 34894449 | Background | Lee JJ, Peterson AM, Kallogjeri D, Jiramongkolchai P, Kukuljan S, Schneider JS, Klatt-Cromwell CN, Drescher AJ, Brunworth JD, Piccirillo JF. Smell Changes and Efficacy of Nasal Theophylline (SCENT) irrigation: A randomized controlled trial for treatment of post-viral olfactory dysfunction. Am J Otolaryngol. 2022 Mar-Apr;43(2):103299. doi: 10.1016/j.amjoto.2021.103299. Epub 2021 Dec 3. |
| 35797023 | Background | Lee JJ, Gupta S, Kallogjeri D, Piccirillo JF. Safety of High-Dose Nasal Theophylline Irrigation in the Treatment of Postviral Olfactory Dysfunction: A Dose-Escalation Study. JAMA Otolaryngol Head Neck Surg. 2022 Sep 1;148(9):885-886. doi: 10.1001/jamaoto.2022.1574. |
| 6463130 | Background | Doty RL, Shaman P, Dann M. Development of the University of Pennsylvania Smell Identification Test: a standardized microencapsulated test of olfactory function. Physiol Behav. 1984 Mar;32(3):489-502. doi: 10.1016/0031-9384(84)90269-5. |
| 1593914 | Background | Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care. 1992 Jun;30(6):473-83. |
| 20526405 | Background | Busner J, Targum SD. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry (Edgmont). 2007 Jul;4(7):28-37. |
| 28653978 | Background | Dunlop BW, Gray J, Rapaport MH. Transdiagnostic Clinical Global Impression Scoring for Routine Clinical Settings. Behav Sci (Basel). 2017 Jun 27;7(3):40. doi: 10.3390/bs7030040. |
| 29719139 | Background | Mattos JL, Schlosser RJ, Mace JC, Smith TL, Soler ZM. Establishing the minimal clinically important difference for the Questionnaire of Olfactory Disorders. Int Forum Allergy Rhinol. 2018 Sep;8(9):1041-1046. doi: 10.1002/alr.22135. Epub 2018 May 2. |
| 3816016 | Background | Moscucci M, Byrne L, Weintraub M, Cox C. Blinding, unblinding, and the placebo effect: an analysis of patients' guesses of treatment assignment in a double-blind clinical trial. Clin Pharmacol Ther. 1987 Mar;41(3):259-65. doi: 10.1038/clpt.1987.26. |
| 34291813 | Background | O'Byrne L, Webster KE, MacKeith S, Philpott C, Hopkins C, Burton MJ. Interventions for the treatment of persistent post-COVID-19 olfactory dysfunction. Cochrane Database Syst Rev. 2021 Jul 22;7(7):CD013876. doi: 10.1002/14651858.CD013876.pub2. |
| 28040824 | Background | Sorokowska A, Drechsler E, Karwowski M, Hummel T. Effects of olfactory training: a meta-analysis. Rhinology. 2017 Mar 1;55(1):17-26. doi: 10.4193/Rhino16.195. |
| 31318413 | Background | Whitcroft KL, Hummel T. Clinical Diagnosis and Current Management Strategies for Olfactory Dysfunction: A Review. JAMA Otolaryngol Head Neck Surg. 2019 Sep 1;145(9):846-853. doi: 10.1001/jamaoto.2019.1728. |
| 29901865 | Background | Nguyen TP, Patel ZM. Budesonide irrigation with olfactory training improves outcomes compared with olfactory training alone in patients with olfactory loss. Int Forum Allergy Rhinol. 2018 Sep;8(9):977-981. doi: 10.1002/alr.22140. Epub 2018 Jun 14. |
| 29879268 | Background | Tait S, Kallogjeri D, Suko J, Kukuljan S, Schneider J, Piccirillo JF. Effect of Budesonide Added to Large-Volume, Low-pressure Saline Sinus Irrigation for Chronic Rhinosinusitis: A Randomized Clinical Trial. JAMA Otolaryngol Head Neck Surg. 2018 Jul 1;144(7):605-612. doi: 10.1001/jamaoto.2018.0667. |
| 23895713 | Background | Menorca RM, Fussell TS, Elfar JC. Nerve physiology: mechanisms of injury and recovery. Hand Clin. 2013 Aug;29(3):317-30. doi: 10.1016/j.hcl.2013.04.002. |
| 35115994 | Background | Wei G, Gu J, Gu Z, Du C, Huang X, Xing H, Li L, Zhang A, Hu X, Huo J. Olfactory Dysfunction in Patients With Coronavirus Disease 2019: A Review. Front Neurol. 2022 Jan 18;12:783249. doi: 10.3389/fneur.2021.783249. eCollection 2021. |
| 34752471 | Background | Jafar A, Lasso A, Shorr R, Hutton B, Kilty S. Olfactory recovery following infection with COVID-19: A systematic review. PLoS One. 2021 Nov 9;16(11):e0259321. doi: 10.1371/journal.pone.0259321. eCollection 2021. |
| 35797024 | Derived | Gupta S, Lee JJ, Perrin A, Khan A, Smith HJ, Farrell N, Kallogjeri D, Piccirillo JF. Efficacy and Safety of Saline Nasal Irrigation Plus Theophylline for Treatment of COVID-19-Related Olfactory Dysfunction: The SCENT2 Phase 2 Randomized Clinical Trial. JAMA Otolaryngol Head Neck Surg. 2022 Sep 1;148(9):830-837. doi: 10.1001/jamaoto.2022.1573. |
| BG001 | Placebo | 500mg lactose capsule diluted in 240 mL isotonic nasal saline lavage twice daily. Theophylline Powder: Theophylline is a known phosphodiesterase inhibitor in the treatment of asthma. Evidence for post-viral olfactory dysfunction suggests sensory axonal regeneration and olfactory signaling may rely on elevated levels of secondary messengers cAMP and cGMP, a known effect of theophylline. Therefore it is hypothesized to help treat COVID-related smell dysfunction, especially if delivered intranasally. Twice daily nasal irrigation with 400 mg theophylline capsules and USP Grade Sodium Chloride & Sodium Bicarbonate Mixture (pH balanced, Isotonic & Preservative & Iodine Free) commercially prepared packets dissolved in 240 ml of distilled water. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG000 | Theophylline | 400mg theophylline capsule diluted in 240 mL isotonic nasal saline lavage twice daily. Theophylline Powder: Theophylline is a known phosphodiesterase inhibitor in the treatment of asthma. Evidence for post-viral olfactory dysfunction suggests sensory axonal regeneration and olfactory signaling may rely on elevated levels of secondary messengers cAMP and cGMP, a known effect of theophylline. Therefore it is hypothesized to help treat COVID-related smell dysfunction, especially if delivered intranasally. Twice daily nasal irrigation with 400 mg theophylline capsules and USP Grade Sodium Chloride & Sodium Bicarbonate Mixture (pH balanced, Isotonic & Preservative & Iodine Free) commercially prepared packets dissolved in 240 ml of distilled water. |
| OG001 | Placebo | 500mg lactose capsule diluted in 240 mL isotonic nasal saline lavage twice daily. Theophylline Powder: Theophylline is a known phosphodiesterase inhibitor in the treatment of asthma. Evidence for post-viral olfactory dysfunction suggests sensory axonal regeneration and olfactory signaling may rely on elevated levels of secondary messengers cAMP and cGMP, a known effect of theophylline. Therefore it is hypothesized to help treat COVID-related smell dysfunction, especially if delivered intranasally. Twice daily nasal irrigation with 400 mg theophylline capsules and USP Grade Sodium Chloride & Sodium Bicarbonate Mixture (pH balanced, Isotonic & Preservative & Iodine Free) commercially prepared packets dissolved in 240 ml of distilled water. |
|
|
| Secondary | University of Pennsylvania Smell Identification Test (UPSIT) | UPSIT 0-40 with higher scores indicating better smell. This test is an objective, clinically validated 40-question forced-choice odor identification test where microencapsulated odorants on a strip are released by scratching. Out of a total of 40 points, normosmia is defined as ≥34 for males and ≥35 for females, and an increase in ≥4 points will be deemed a clinically significant improvement in symptoms. | The outcome measure could be assessed only on subjects that completed UPSIT test at 6 weeks post-intervention | Posted | Median | 95% Confidence Interval | score on a scale | Comparison at 6 weeks post-intervention from baseline |
|
|
|
| Secondary | Change in Questionnaire for Olfactory Dysfunction (QOD) From Baseline to 6 Weeks Post Intervention | Questionnaire for Olfactory Dysfunction (QOD) assesses health-related quality of life of participants based on four factors such as eating, mental health, social interactions, or fear of dysfunction.. The survey also includes questions on parosmia, a phenomena of COVID-related OD. The QOD consists of 17 statements that participants score from 0-3, resulting in a total score from 0 to 51. Higher scores reflect better olfactory-specific QOL. | Since the outcome is measuring the change in QOD, only the data from participant completing QOD at baseline and 6 weeks were included | Posted | Median | 95% Confidence Interval | score on a scale | Comparison at 6 weeks post-intervention from baseline |
|
|
|
| Secondary | 36-Item Short Form Health Survey (SF-36) | The SF-36 is a well-established 36-item questionnaire evaluating physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. This test allows us to study the overall quality of life for those suffering from COVID-19 related OD. There is no single overall score for SF-36. The SF 36 generates 8 subscales with scores ranging from 0 (worst) to 100 (best). General health domain scores are reported here. | This was a baseline assessment only, so all randomized participants are analyzed. | Posted | Median | Full Range | score on a scale | Baseline assessment |
|
|
|
| Secondary | Olfactory Dysfunction Outcomes Rating (ODOR) | The ODOR is a 28-item QOL instrument with a total score ranging from 0 to 112 points. Higher scores indicate worse QOL with higher degree of dysfunction and limitation. A decrease of 15 or more points is deemed to be a clinically significant improvement in QOL. | This outcome is assessed only for participants that have ODOR assessed at baseline and at 6 months. | Posted | Median | 95% Confidence Interval | score on a scale | Comparison of response rate at 6 weeks post-intervention from baseline between the 2 study groups |
|
|
|
| 0 |
| 26 |
| 0 |
| 26 |
| 7 |
| 26 |
| EG001 | Placebo | 500mg lactose capsule diluted in 240 mL isotonic nasal saline lavage twice daily. Theophylline Powder: Theophylline is a known phosphodiesterase inhibitor in the treatment of asthma. Evidence for post-viral olfactory dysfunction suggests sensory axonal regeneration and olfactory signaling may rely on elevated levels of secondary messengers cAMP and cGMP, a known effect of theophylline. Therefore it is hypothesized to help treat COVID-related smell dysfunction, especially if delivered intranasally. Twice daily nasal irrigation with 400 mg theophylline capsules and USP Grade Sodium Chloride & Sodium Bicarbonate Mixture (pH balanced, Isotonic & Preservative & Iodine Free) commercially prepared packets dissolved in 240 ml of distilled water. | 0 | 25 | 0 | 25 | 11 | 25 |
|
| Parosmia and Headache | General disorders | Non-systematic Assessment | Event was deemed mild and probably related to study drug |
|
| Lightheadedness | General disorders | Non-systematic Assessment |
|
| Nausea | Gastrointestinal disorders | Non-systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | Non-systematic Assessment |
|
| Abdominal pain | General disorders | Non-systematic Assessment |
|
| Insomnia | General disorders | Non-systematic Assessment |
|
| Tremors | Nervous system disorders | Non-systematic Assessment |
|
| Tachycardia | Cardiac disorders | Non-systematic Assessment |
|
Not provided
Not provided
| D014777 |
| Virus Diseases |
| D018352 | Coronavirus Infections |
| D003333 | Coronaviridae Infections |
| D030341 | Nidovirales Infections |
| D012327 | RNA Virus Infections |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D012678 | Sensation Disorders |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D013651 | Taste Disorders |