Theophylline Nasal Spray for PD-Related Hyposmia and Anosmia

Summary

The goal of this study is to learn if intranasal theophylline (CYR-064) improves sense of smell in participants with hyposmia or anosmia related to the onset of Parkinson's Disease. Fifteen adults, age 19-80, years will participate for about 32 weeks. They will use the study nasal spray for 24 weeks. The nasal spray is given as 2 sprays to each side of the nose twice per day. They will be seen every 2 weeks during the first month of treatment, followed by monthly in-person visits. Tests about memory, Parkinson's Disease symptoms, and ability to detect and identify smells will be completed. Participants are monitored for any side effects.

Timeline

Start

2025-04

Primary completion

2026-06

Completion

2026-07

Outcome

Outcome not reported

Stopped: “sponsor discontinued site participation”

Publications

• Background CDC.gov. Weekly U.S. Influenza Surveillance Report. https://www.cdc.gov/flu/weekly/index.htm. Updated 29 April 2022. Accessed 04 May 2022.
• Background Centers for Disease Control and Prevention, National Center for Immunization and Respiratory Diseases (NCIRD). 2021-2022 U.S. Flu Season: Preliminary In-Season Burden Estimates. https://www.cdc.gov/flu/about/burden/preliminary-in-season-estimates.htm. Updated 29 April 2022. Accessed 04 May 2022.
• Background Choi JS, Jang SS, Kim J, Hur K, Ference E, Wrobel B. Association Between Olfactory Dysfunction and Mortality in US Adults. JAMA Otolaryngol Head Neck Surg. 2021 Jan 1;147(1):49-55. doi: 10.1001/jamaoto.2020.3502.
• Background Ciurleo R, De Salvo S, Bonanno L, Marino S, Bramanti P, Caminiti F. Parosmia and Neurological Disorders: A Neglected Association. Front Neurol. 2020 Nov 9;11:543275. doi: 10.3389/fneur.2020.543275. eCollection 2020.
• Background Coelho DH, Reiter ER, French E, Costanzo RM. Decreasing Incidence of Chemosensory Changes by COVID-19 Variant. Otolaryngol Head Neck Surg. 2023 Apr;168(4):704-706. doi: 10.1177/01945998221097656. Epub 2023 Feb 5.
• Background Croy I, Symmank A, Schellong J, Hummel C, Gerber J, Joraschky P, Hummel T. Olfaction as a marker for depression in humans. J Affect Disord. 2014 May;160:80-6. doi: 10.1016/j.jad.2013.12.026. Epub 2014 Jan 4.
• Background Dai Q, Pang Z, Yu H. Recovery of Olfactory Function in Postviral Olfactory Dysfunction Patients after Acupuncture Treatment. Evid Based Complement Alternat Med. 2016;2016:4986034. doi: 10.1155/2016/4986034. Epub 2016 Feb 29.
• Background FDA-4927905. FDA PIND Written Response Only (WRO) Meeting. 27 January 2022.
• Background FDA Guidance for industry COVID-19: Developing Drugs and Biological Products for Treatment or Prevention Guidance for Industry. 2021. Available from: https://www.fda.gov/media/137926/download.
• Background Amai M, Nojima M, Yuki Y, Kiyono H, Nagamura F. A review of criteria strictness in "Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials". Vaccine. 2023 Aug 31;41(38):5622-5629. doi: 10.1016/j.vaccine.2023.07.072. Epub 2023 Aug 1.
• Background Fonteyn S, Huart C, Deggouj N, Collet S, Eloy P, Rombaux P. Non-sinonasal-related olfactory dysfunction: A cohort of 496 patients. Eur Ann Otorhinolaryngol Head Neck Dis. 2014 Apr;131(2):87-91. doi: 10.1016/j.anorl.2013.03.006. Epub 2014 Mar 26.
• Background Harless L, Liang J. Pharmacologic treatment for postviral olfactory dysfunction: a systematic review. Int Forum Allergy Rhinol. 2016 Jul;6(7):760-7. doi: 10.1002/alr.21727. Epub 2016 Feb 16.
• Background Hendeles L, Bighley L, Richardson RH, Hepler CD, Carmichael J. Frequent toxicity from IV aminophylline infusions in critically ill patients. 1977. Ann Pharmacother. 2006 Jul-Aug;40(7-8):1417-23. doi: 10.1345/aph.140027. No abstract available.
• Background Henkin RI, Levy LM, Fordyce A. Taste and smell function in chronic disease: a review of clinical and biochemical evaluations of taste and smell dysfunction in over 5000 patients at The Taste and Smell Clinic in Washington, DC. Am J Otolaryngol. 2013 Sep-Oct;34(5):477-89. doi: 10.1016/j.amjoto.2013.04.006. Epub 2013 Jun 2.
• Background Henkin RI. Comparative monitoring of oral theophylline treatment in blood serum, saliva, and nasal mucus. Ther Drug Monit. 2012 Apr;34(2):217-21. doi: 10.1097/FTD.0b013e3182492a20.
• Background Henkin RI. Growth Factors in Olfaction. In: Preedy VR, editor. Handbook of Growth and Growth Monitoring in Health and Disease. New York, NY: Springer New York; 2012. p. 1417-36.
• Background Henkin RI, Abdelmeguid M. Improved Smell and Taste Dysfunction with Intranasal Theophylline. Am J Otolaryngol Head Neck Surg. 2019;2(9):1070.
• Background Henkin RI, Hosein S, Stateman WA, Knoppel AB, Abdelmeguid M. Improved smell function with increased nasal mucus sonic hedgehog in hyposmic patients after treatment with oral theophylline. Am J Otolaryngol. 2017 Mar-Apr;38(2):143-147. doi: 10.1016/j.amjoto.2016.11.010. Epub 2016 Nov 23.
• 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 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.
• 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.
• Background Henkin RI, Velicu I, Schmidt L. Relative resistance to oral theophylline treatment in patients with hyposmia manifested by decreased secretion of nasal mucus cyclic nucleotides. Am J Med Sci. 2011 Jan;341(1):17-22. doi: 10.1097/MAJ.0b013e3181f1fdc8.
• 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.
• Background Hummel T, Kobal G, Gudziol H, Mackay-Sim A. Normative data for the "Sniffin' Sticks" including tests of odor identification, odor discrimination, and olfactory thresholds: an upgrade based on a group of more than 3,000 subjects. Eur Arch Otorhinolaryngol. 2007 Mar;264(3):237-43. doi: 10.1007/s00405-006-0173-0. Epub 2006 Sep 23.
• Background Hummel T, Whitcroft KL, Andrews P, Altundag A, Cinghi C, Costanzo RM, Damm M, Frasnelli J, Gudziol H, Gupta N, Haehne A, Holbrook E, Hong SC, Hornung D, Huttenbrink KB, Kamel R, Kobayashi M, Konstantinidis I, Landis BN, Leopold DA, Macchi A, Miwa T, Moesges R, Mullol J, Mueller CA, Ottaviano G, Passali GC, Philpott C, Pinto JM, Ramakrishnan VJ, Rombaux P, Roth Y, Schlosser RA, Shu B, Soler G, Stjarne P, Stuck BA, Vodicka J, Welge-Luessen A. Position paper on olfactory dysfunction. Rhinol Suppl. 2017 Mar;54(26):1-30. doi: 10.4193/Rhino16.248.
• 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.
• Background Jafek BW, Hartman D, Eller PM, Johnson EW, Strahan RC, Moran DT. Postviral Olfactory Dysfunction. Am J Rhinol. 1990;4(3):91-100.
• Background Keller A, Malaspina D. Hidden consequences of olfactory dysfunction: a patient report series. BMC Ear Nose Throat Disord. 2013 Jul 23;13(1):8. doi: 10.1186/1472-6815-13-8.
• Background Lechien JR, Chiesa-Estomba CM, Beckers E, Mustin V, Ducarme M, Journe F, Marchant A, Jouffe L, Barillari MR, Cammaroto G, Circiu MP, Hans S, Saussez S. Prevalence and 6-month recovery of olfactory dysfunction: a multicentre study of 1363 COVID-19 patients. J Intern Med. 2021 Aug;290(2):451-461. doi: 10.1111/joim.13209. Epub 2021 Jan 5.
• 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.
• 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.
• Background Miwa T, Furukawa M, Tsukatani T, Costanzo RM, DiNardo LJ, Reiter ER. Impact of olfactory impairment on quality of life and disability. Arch Otolaryngol Head Neck Surg. 2001 May;127(5):497-503. doi: 10.1001/archotol.127.5.497.
• 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.
• Background Mori I, Goshima F, Imai Y, Kohsaka S, Sugiyama T, Yoshida T, Yokochi T, Nishiyama Y, Kimura Y. Olfactory receptor neurons prevent dissemination of neurovirulent influenza A virus into the brain by undergoing virus-induced apoptosis. J Gen Virol. 2002 Sep;83(Pt 9):2109-2116. doi: 10.1099/0022-1317-83-9-2109.
• Background Mori I, Nishiyama Y, Yokochi T, Kimura Y. Virus-induced neuronal apoptosis as pathological and protective responses of the host. Rev Med Virol. 2004 Jul-Aug;14(4):209-16. doi: 10.1002/rmv.426.
• 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.
• 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.
• Background Saniasiaya J, Islam MA, Abdullah B. Prevalence and Characteristics of Taste Disorders in Cases of COVID-19: A Meta-analysis of 29,349 Patients. Otolaryngol Head Neck Surg. 2021 Jul;165(1):33-42. doi: 10.1177/0194599820981018. Epub 2020 Dec 15.
• Background Seiden AM. Postviral olfactory loss. Otolaryngol Clin North Am. 2004 Dec;37(6):1159-66. doi: 10.1016/j.otc.2004.06.007.
• Background Theophylline [package insert]. Hospira, Inc., Lake Forest, IL 60045 USA; July 2008.
• Background Vaira LA, Hopkins C, Salzano G, Petrocelli M, Melis A, Cucurullo M, Ferrari M, Gagliardini L, Pipolo C, Deiana G, Fiore V, De Vito A, Turra N, Canu S, Maglio A, Serra A, Bussu F, Madeddu G, Babudieri S, Giuseppe Fois A, Pirina P, Salzano FA, De Riu P, Biglioli F, De Riu G. Olfactory and gustatory function impairment in COVID-19 patients: Italian objective multicenter-study. Head Neck. 2020 Jul;42(7):1560-1569. doi: 10.1002/hed.26269. Epub 2020 May 21.
• Background Vaira LA, Lechien JR, Khalife M, Petrocelli M, Hans S, Distinguin L, Salzano G, Cucurullo M, Doneddu P, Salzano FA, Biglioli F, Journe F, Piana AF, De Riu G, Saussez S. Psychophysical Evaluation of the Olfactory Function: European Multicenter Study on 774 COVID-19 Patients. Pathogens. 2021 Jan 12;10(1):62. doi: 10.3390/pathogens10010062.
• Background Vent J, Wang DW, Damm M. Effects of traditional Chinese acupuncture in post-viral olfactory dysfunction. Otolaryngol Head Neck Surg. 2010 Apr;142(4):505-9. doi: 10.1016/j.otohns.2010.01.012.
• Background Welge-Lussen A, Wolfensberger M. Olfactory disorders following upper respiratory tract infections. Adv Otorhinolaryngol. 2006;63:125-132. doi: 10.1159/000093758.
• Background Yamagishi M, Fujiwara M, Nakamura H. Olfactory mucosal findings and clinical course in patients with olfactory disorders following upper respiratory viral infection. Rhinology. 1994 Sep;32(3):113-8.
• Background Zeidman A, Gardyn J, Fradin Z, Fink G, Mittelman M. [Therapeutic and toxic theophylline levels in asthma attacks--is there a need for additional theophylline?]. Harefuah. 1997 Jul;133(1-2):3-5, 80. Hebrew.

Drugs

Indications