Smell in Covid-19 and Efficacy of Nasal Theophylline

Covid19 Clinical Trial

— SCENT2  

Official title:

Smell in Covid-19 and Efficacy of Nasal Theophylline

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04789499
• Other study ID #: 202101190
• Status: Completed
• Phase: Phase 2
• Start date: March 15, 2021
• Est. completion date: December 30, 2021

Study information

• Verified date: April 2023
• Source: Washington University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 51
• Est. completion date: December 30, 2021
• Est. primary completion date: December 30, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Olfactory dysfunction that has persisted for >3 months following suspected COVID-19 infection

• Residing within the states of Missouri or Illinois.

• Can read, write, and understand English.

Exclusion Criteria:

• History of olfactory dysfunction prior to COVID-19 infection

• Use of concomitant therapies specifically for the treatment of olfactory dysfunction

• History of olfactory dysfunction longer than 12 months

• Known existence of nasal polyps, prior sinonasal, or anterior skull-based surgery

• Dependence on theophylline for comorbid conditions such as asthma and COPD

• History of an allergic reaction to theophylline or other methylxanthines

• History of neurodegenerative disease (ie. Alzheimer's dementia, Parkinson's disease, Lewy body dementia, frontotemporal dementia)

• Pregnant or breastfeeding mothers

• Current use of medications with significant interactions with theophylline, which include cimetidine, ciprofloxacin, disulfiram, enoxacin, fluvoxamine, interferon-alpha, lithium, mexiletine, phenytoin, propafenone, propranolol, tacrine, thiabendazole, ticlopidine, and troleandomycin.

• Pre-existing arrhythmias or seizures

Related Conditions & MeSH terms

• Ageusia
• Anosmia
• COVID-19
• Covid-19 Pandemic
• Covid19
• Hypogeusia
• Hyposmia
• Olfactory Disorder
• SARS-CoV-2 Infection

Intervention

Drug:
• Theophylline Powder
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.
• Placebo Comparator
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.

Locations

Country	Name	City	State
United States	Washington University School of Medicine in Saint Louis	Saint Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Washington University School of Medicine

Country where clinical trial is conducted

United States, 

References & Publications (46)

Anholt RR. Molecular neurobiology of olfaction. Crit Rev Neurobiol. 1993;7(1):1-22. — View Citation

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. — View Citation

Barnes PJ. Theophylline. Pharmaceuticals (Basel). 2010 Mar 18;3(3):725-747. doi: 10.3390/ph3030725. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Busner J, Targum SD. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry (Edgmont). 2007 Jul;4(7):28-37. — View Citation

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. — View Citation

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. — View Citation

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.

Hawkes C. Parosmia: treatment, mechanism, and types. BMJ. 2020 Dec 8;371:m4739. doi: 10.1136/bmj.m4739. No abstract available. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 46 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Comparison of response rate at 6 weeks post-intervention from baseline between the 2 study groups
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.	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.	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.	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.	Comparison of response rate at 6 weeks post-intervention from baseline between the 2 study groups