Smell in COVID-19 and Efficacy of Nasal Theophylline (SCENT 3)

NCT05947643 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: 202209062
• Study Type: interventional
• Target: 77
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this Phase II trial is to test the effectiveness of intranasal theophylline irrigations for the treatment of COVID-19 related smell dysfunction. The investigators will compare the effect of theophylline nasal rinses versus placebo nasal rinses on smell symptoms. Participants will be asked to rinse their nose with a medication or placebo capsule dissolved in saltwater twice daily for 12 weeks and fill out surveys about smell before, during, and at the end of treatment. This study will also be used to describe adverse effects related to intranasal theophylline irrigation.

Conditions

COVID-19

Keywords

Nasal Theophylline; Olfactory disfunction; Anosmia; Gustatory disorders; Dysgeusia

Outcome Measures

Primary Outcomes (1)

• Clinical Global Impression - Improvement Scale

  The Clinical Global Impression-Improvement scale (CGI-I) is a subjective rating scale used to measure changes in a patient's condition over time. It ranges from 1 to 7, where 1 means "Very Much Improved," 2 means "Much Improved," 3 means "Minimally Improved," 4 means "No Change," 5 means "Minimally Worse," 6 means "Much Worse," and 7 means "Very Much Worsened." In this study, participants reporting scores of 1, 2, or 3 on the CGI-I are considered responders to treatment. The primary analysis will compare the proportion of responders between the theophylline and placebo groups assessing both within-subject changes over time and between-group differences. We will measure the response rate defined as the number of participants self-reporting minimal change or larger in the Clinical Global Impression Scale (CGI) scale, divided by the number of participants in each group.The main comparison will be focused on changes at 12-weeks

  week 12

Secondary Outcomes (4)

• Olfactory Dysfunction Outcomes Rating

  6 weeks and 12 week

• Assessment of Adherence

  12 weeks

• Assessment of Blind

  within first 3 weeks

• Adverse Effects

  up to 12 weeks

Study Arms (2)

Theophylline

EXPERIMENTAL

Participants will dissolve the contents of the 400 mg theophylline capsules (experimental) into the sinus rinse bottle containing nasal saline.

Drug: theophylline

Placebo

PLACEBO COMPARATOR

Participant will dissolve the contents of the identical-appearing lactose capsules (control) into the sinus rinse bottle containing nasal saline.

Drug: Placebo

Interventions

theophylline DRUG

capsules dissolved in intranasal irrigation

Theophylline

Placebo DRUG

identical-appearing lactose capsules dissolved in intranasal irrigation

Also known as: inactive medicine

Placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• males and females ages 18 to 75 years
• located within or willing to travel to the state of Missouri or Illinois
• Olfactory dysfunction that has persisted for \>3 months following suspected COVID-19 infection
• Baseline University of Pennsylvania Smell Identification Test (UPSIT) consistent with decreased olfactory function (\<= 34 in women, \<=33 in men). This test is a clinically validated 40-question forced-choice odor identification test where microencapsulated odorants on a strip are released by scratching.70 This will determine that patients have both subjectively and objectively diagnosed OD prior to undergoing treatment.
• Ability to read, write, and understand English and have access to email.

You may not qualify if:

• History of olfactory dysfunction prior to COVID-19 infection
• Any use of concomitant therapies specifically for the treatment of olfactory dysfunction
• Use of or participation in previous trials of intranasal theophylline.
• Known existence of nasal polyps, prior sinonasal, or anterior skull-based surgery
• Dependence on theophylline for comorbid conditions such as asthma and chronic obstructive pulmonary disease (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 (≥40%) interactions with theophylline, which include cimetidine, ciprofloxacin, disulfiram, enoxacin, fluvoxamine, interferon- alpha, lithium, mexiletine, phenytoin, propafenone, propranolol, tacrine, thiabendazole, ticlopidine, and troleandomycin.

Sponsors & Collaborators

• Washington University School of Medicine: lead

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Publications (66)

• Kaye R, Chang CWD, Kazahaya K, Brereton J, Denneny JC 3rd. COVID-19 Anosmia Reporting Tool: Initial Findings. Otolaryngol Head Neck Surg. 2020 Jul;163(1):132-134. doi: 10.1177/0194599820922992. Epub 2020 Apr 28.

  PMID: 32340555 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.

  PMID: 32563019 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.

  PMID: 31318413 BACKGROUND

• Dong E, Ratcliff J, Goyea TD, Katz A, Lau R, Ng TK, Garcia B, Bolt E, Prata S, Zhang D, Murray RC, Blake MR, Du H, Ganjkhanloo F, Ahmadi F, Williams J, Choudhury S, Gardner LM. The Johns Hopkins University Center for Systems Science and Engineering COVID-19 Dashboard: data collection process, challenges faced, and lessons learned. Lancet Infect Dis. 2022 Dec;22(12):e370-e376. doi: 10.1016/S1473-3099(22)00434-0. Epub 2022 Aug 31.

  PMID: 36057267 BACKGROUND

• Menni C, Valdes AM, Polidori L, Antonelli M, Penamakuri S, Nogal A, Louca P, May A, Figueiredo JC, Hu C, Molteni E, Canas L, Osterdahl MF, Modat M, Sudre CH, Fox B, Hammers A, Wolf J, Capdevila J, Chan AT, David SP, Steves CJ, Ourselin S, Spector TD. Symptom prevalence, duration, and risk of hospital admission in individuals infected with SARS-CoV-2 during periods of omicron and delta variant dominance: a prospective observational study from the ZOE COVID Study. Lancet. 2022 Apr 23;399(10335):1618-1624. doi: 10.1016/S0140-6736(22)00327-0. Epub 2022 Apr 7.

  PMID: 35397851 BACKGROUND

• Chen M, Pekosz A, Villano JS, Shen W, Zhou R, Kulaga H, Li Z, Smith A, Gurung A, Beck SE, Witwer KW, Mankowski JL, Ramanathan M Jr, Rowan NR, Lane AP. Evolution of nasal and olfactory infection characteristics of SARS-CoV-2 variants. J Clin Invest. 2024 Mar 14;134(8):e174439. doi: 10.1172/JCI174439.

  PMID: 38483537 BACKGROUND

• Sedaghat AR, Gengler I, Speth MM. Olfactory Dysfunction: A Highly Prevalent Symptom of COVID-19 With Public Health Significance. Otolaryngol Head Neck Surg. 2020 Jul;163(1):12-15. doi: 10.1177/0194599820926464. Epub 2020 May 5.

  PMID: 32366160 BACKGROUND

• Moein ST, Hashemian SM, Mansourafshar B, Khorram-Tousi A, Tabarsi P, Doty RL. Smell dysfunction: a biomarker for COVID-19. Int Forum Allergy Rhinol. 2020 Aug;10(8):944-950. doi: 10.1002/alr.22587. Epub 2020 Jun 18.

  PMID: 32301284 BACKGROUND

• Menni C, Sudre CH, Steves CJ, Ourselin S, Spector TD. Quantifying additional COVID-19 symptoms will save lives. Lancet. 2020 Jun 20;395(10241):e107-e108. doi: 10.1016/S0140-6736(20)31281-2. Epub 2020 Jun 4. No abstract available.

  PMID: 32505221 BACKGROUND

• Carfi A, Bernabei R, Landi F; Gemelli Against COVID-19 Post-Acute Care Study Group. Persistent Symptoms in Patients After Acute COVID-19. JAMA. 2020 Aug 11;324(6):603-605. doi: 10.1001/jama.2020.12603.

  PMID: 32644129 BACKGROUND

• Tan BKJ, Han R, Zhao JJ, Tan NKW, Quah ESH, Tan CJ, Chan YH, Teo NWY, Charn TC, See A, Xu S, Chapurin N, Chandra RK, Chowdhury N, Butowt R, von Bartheld CS, Kumar BN, Hopkins C, Toh ST. Prognosis and persistence of smell and taste dysfunction in patients with covid-19: meta-analysis with parametric cure modelling of recovery curves. BMJ. 2022 Jul 27;378:e069503. doi: 10.1136/bmj-2021-069503.

  PMID: 35896188 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.

  PMID: 32432682 BACKGROUND

• Catton G, Gardner A. COVID-19 Induced Taste Dysfunction and Recovery: Association with Smell Dysfunction and Oral Health Behaviour. Medicina (Kaunas). 2022 May 26;58(6):715. doi: 10.3390/medicina58060715.

  PMID: 35743978 BACKGROUND

• Sungnak W, Huang N, Becavin C, Berg M, Queen R, Litvinukova M, Talavera-Lopez C, Maatz H, Reichart D, Sampaziotis F, Worlock KB, Yoshida M, Barnes JL; HCA Lung Biological Network. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat Med. 2020 May;26(5):681-687. doi: 10.1038/s41591-020-0868-6. Epub 2020 Apr 23.

  PMID: 32327758 BACKGROUND

• Rockx B, Kuiken T, Herfst S, Bestebroer T, Lamers MM, Oude Munnink BB, de Meulder D, van Amerongen G, van den Brand J, Okba NMA, Schipper D, van Run P, Leijten L, Sikkema R, Verschoor E, Verstrepen B, Bogers W, Langermans J, Drosten C, Fentener van Vlissingen M, Fouchier R, de Swart R, Koopmans M, Haagmans BL. Comparative pathogenesis of COVID-19, MERS, and SARS in a nonhuman primate model. Science. 2020 May 29;368(6494):1012-1015. doi: 10.1126/science.abb7314. Epub 2020 Apr 17.

  PMID: 32303590 BACKGROUND

• Zou L, Ruan F, Huang M, Liang L, Huang H, Hong Z, Yu J, Kang M, Song Y, Xia J, Guo Q, Song T, He J, Yen HL, Peiris M, Wu J. SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients. N Engl J Med. 2020 Mar 19;382(12):1177-1179. doi: 10.1056/NEJMc2001737. Epub 2020 Feb 19. No abstract available.

  PMID: 32074444 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.

  PMID: 32167747 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.

  PMID: 32937591 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.

  PMID: 32790835 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.

  PMID: 32469400 BACKGROUND

• Pekala K, Chandra RK, Turner JH. Efficacy of olfactory training in patients with olfactory loss: a systematic review and meta-analysis. Int Forum Allergy Rhinol. 2016 Mar;6(3):299-307. doi: 10.1002/alr.21669. Epub 2015 Dec 1.

  PMID: 26624966 BACKGROUND

• Wilson DA, Best AR, Sullivan RM. Plasticity in the olfactory system: lessons for the neurobiology of memory. Neuroscientist. 2004 Dec;10(6):513-24. doi: 10.1177/1073858404267048.

  PMID: 15534037 BACKGROUND

• Kollndorfer K, Kowalczyk K, Hoche E, Mueller CA, Pollak M, Trattnig S, Schopf V. Recovery of olfactory function induces neuroplasticity effects in patients with smell loss. Neural Plast. 2014;2014:140419. doi: 10.1155/2014/140419. Epub 2014 Dec 3.

  PMID: 25544900 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.

  PMID: 27287364 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.

  PMID: 31035288 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.

  PMID: 25271633 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.

  PMID: 32153360 BACKGROUND

• Soler ZM, Patel ZM, Turner JH, Holbrook EH. A primer on viral-associated olfactory loss in the era of COVID-19. Int Forum Allergy Rhinol. 2020 Jul;10(7):814-820. doi: 10.1002/alr.22578. Epub 2020 Jun 1.

  PMID: 32271490 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.

  PMID: 20231262 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.

  PMID: 12425708 BACKGROUND

• Cho SH. Clinical Diagnosis and Treatment of Olfactory Dysfunction. Hanyang Med Rev. 2014;34(3):107-115.

  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.

  PMID: 3164095 BACKGROUND

• Hendriks AP. Olfactory dysfunction. Rhinology. 1988 Dec;26(4):229-51.

  PMID: 3070710 BACKGROUND

• Reden J, Mueller A, Mueller C, Konstantinidis I, Frasnelli J, Landis BN, Hummel T. Recovery of olfactory function following closed head injury or infections of the upper respiratory tract. Arch Otolaryngol Head Neck Surg. 2006 Mar;132(3):265-9. doi: 10.1001/archotol.132.3.265.

  PMID: 16549746 BACKGROUND

• RECOVERY Collaborative Group; Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, Staplin N, Brightling C, Ustianowski A, Elmahi E, Prudon B, Green C, Felton T, Chadwick D, Rege K, Fegan C, Chappell LC, Faust SN, Jaki T, Jeffery K, Montgomery A, Rowan K, Juszczak E, Baillie JK, Haynes R, Landray MJ. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021 Feb 25;384(8):693-704. doi: 10.1056/NEJMoa2021436. Epub 2020 Jul 17.

  PMID: 32678530 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.

  PMID: 28040824 BACKGROUND

• Konstantinidis I, Tsakiropoulou E, Bekiaridou P, Kazantzidou C, Constantinidis J. Use of olfactory training in post-traumatic and postinfectious olfactory dysfunction. Laryngoscope. 2013 Dec;123(12):E85-90. doi: 10.1002/lary.24390. Epub 2013 Oct 4.

  PMID: 24114690 BACKGROUND

• Konstantinidis I, Tsakiropoulou E, Constantinidis J. Long term effects of olfactory training in patients with post-infectious olfactory loss. Rhinology. 2016 Jun;54(2):170-5. doi: 10.4193/Rhino15.264.

  PMID: 27017331 BACKGROUND

• Hura N, Xie DX, Choby GW, Schlosser RJ, Orlov CP, Seal SM, Rowan NR. Treatment of post-viral olfactory dysfunction: an evidence-based review with recommendations. Int Forum Allergy Rhinol. 2020 Sep;10(9):1065-1086. doi: 10.1002/alr.22624. Epub 2020 Jun 25.

  PMID: 32567798 BACKGROUND

• Cerebrolycin for Treatment of Covid-related Anosmia and Ageusia.

  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.

  PMID: 16181424 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.

  PMID: 3927168 BACKGROUND

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

  PMID: 27713276 BACKGROUND

• Ronnett GV, Parfitt DJ, Hester LD, Snyder SH. Odorant-sensitive adenylate cyclase: rapid, potent activation and desensitization in primary olfactory neuronal cultures. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2366-9. doi: 10.1073/pnas.88.6.2366.

  PMID: 2006174 BACKGROUND

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

  PMID: 8467526 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.

  PMID: 12086637 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.

  PMID: 18377763 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.

  PMID: 18377764 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.

  PMID: 19359985 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.

  PMID: 9754114 BACKGROUND

• AlAjmi MF, Azhar A, Owais M, Rashid S, Hasan S, Hussain A, Rehman MT. Antiviral potential of some novel structural analogs of standard drugs repurposed for the treatment of COVID-19. J Biomol Struct Dyn. 2021 Oct;39(17):6676-6688. doi: 10.1080/07391102.2020.1799865. Epub 2020 Jul 30.

  PMID: 32729392 BACKGROUND

• Elzupir AO. Caffeine and caffeine-containing pharmaceuticals as promising inhibitors for 3-chymotrypsin-like protease of SARS-CoV-2. J Biomol Struct Dyn. 2022 Mar;40(5):2113-2120. doi: 10.1080/07391102.2020.1835732. Epub 2020 Oct 23.

  PMID: 33094705 BACKGROUND

• Tomita K, Chikumi H, Tokuyasu H, Yajima H, Hitsuda Y, Matsumoto Y, Sasaki T. Functional assay of NF-kappaB translocation into nuclei by laser scanning cytometry: inhibitory effect by dexamethasone or theophylline. Naunyn Schmiedebergs Arch Pharmacol. 1999 Apr;359(4):249-55. doi: 10.1007/pl00005349.

  PMID: 10344522 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.

  PMID: 23165381 BACKGROUND

• Goldstein MF, Hilditch GJ, Frankel I, Chambers L, Dvorin DJ, Belecanech G. Intra-Nasal Theophylline for the Treatment of Chronic Anosmia and Hyposmia. Journal of Allergy and Clinical Immunology. 2017;139(2):AB252.

  BACKGROUND

• 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.

  PMID: 35797024 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.

  PMID: 28653978 BACKGROUND

• Barnes PJ. Theophylline in chronic obstructive pulmonary disease: new horizons. Proc Am Thorac Soc. 2005;2(4):334-9; discussion 340-1. doi: 10.1513/pats.200504-024SR.

  PMID: 16267358 BACKGROUND

• Tzelepis GE, Bascom AT, Safwan Badr M, Goshgarian HG. Effects of theophylline on pulmonary function in patients with traumatic tetraplegia. J Spinal Cord Med. 2006;29(3):227-33. doi: 10.1080/10790268.2006.11753878.

  PMID: 16859226 BACKGROUND

• Yu TJ, Liu YC, Chu CM, Hu HC, Kao KC. Effects of theophylline therapy on respiratory muscle strength in patients with prolonged mechanical ventilation: A retrospective cohort study. Medicine (Baltimore). 2019 Jan;98(2):e13982. doi: 10.1097/MD.0000000000013982.

  PMID: 30633180 BACKGROUND

• McKay SE, Howie CA, Thomson AH, Whiting B, Addis GJ. Value of theophylline treatment in patients handicapped by chronic obstructive lung disease. Thorax. 1993 Mar;48(3):227-32. doi: 10.1136/thx.48.3.227.

  PMID: 8497820 BACKGROUND

• Hosein W, Henkin RI. Therapeutic diminution of Interleukin-10 with intranasal theophylline administration in hyposmic patients. Am J Otolaryngol. 2022 Mar-Apr;43(2):103375. doi: 10.1016/j.amjoto.2022.103375. Epub 2022 Jan 28.

  PMID: 35124402 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.

  PMID: 34894449 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.

  PMID: 35797023 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.

  PMID: 6463130 BACKGROUND

• Theophylline in Dextrose [package insert]. Lake Forest, IL: Hospira, INC;2008

  BACKGROUND

Related Links

• Anosmia Rehabilitation in Patients Post Coronavirus Disease (COVID 19).
• COVID-19 Anosmia Study.
• Corticosteroid Nasal Spray in COVID-19 Anosmia.

MeSH Terms

Conditions

COVID-19; Anosmia; Dysgeusia

Interventions

Theophylline

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Olfaction Disorders; Sensation Disorders; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Taste Disorders

Intervention Hierarchy (Ancestors)

Xanthines; Alkaloids; Heterocyclic Compounds; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Limitations and Caveats

The exact pathogenesis of COVID-related anosmia remains unclear, complicating targeted treatment development. Prior treatments like corticosteroids and olfactory training have shown limited or variable efficacy, and no gold standard exists.

Results Point of Contact

• Title: Dorina Kallogjeri, Assoc.Professor of Otolaryngology
• Organization: Washington University, Department of Otolaryngology - Head and Neck Surgery

kallgjerid@wustl.edu

314-362-1077

Study Officials

• Jay F Piccirillo, MD

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Double-blinded, meaning neither the subjects nor the investigators will be aware of the intervention received by any subject.
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Single-site, double-blinded, placebo-controlled randomized clinical trial performed at a tertiary academic medical center.

Study Record Dates

• First Submitted: July 13, 2023
• First Posted: July 17, 2023
• Study Start: November 22, 2022
• Primary Completion: April 24, 2025
• Study Completion: August 4, 2025
• Last Updated: August 20, 2025
• Results First Posted: August 20, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)