Randomized, double-blind, placebo-controlled clinical trial to assess the safety and effectiveness of a novel dual-action oral topical formulation against upper respiratory infections

Pranab K Mukherjee, Frank Esper, Ken Buchheit, Karen Arters, Ina Adkins, Mahmoud A Ghannoum, Robert A Salata, Pranab K Mukherjee, Frank Esper, Ken Buchheit, Karen Arters, Ina Adkins, Mahmoud A Ghannoum, Robert A Salata

Abstract

Background: Current prevention options for upper respiratory infections (URIs) are not optimal. We conducted a randomized, double-blinded, placebo-controlled pilot clinical trial to evaluate the safety and efficacy of ARMS-I™ (currently marketed as Halo™) in the prevention of URIs.

Methods: ARMS-I is patented novel formulation for the prevention and treatment of influenza, comprising a broad-spectrum antimicrobial agent (cetylpyridinium chloride, CPC) and components (glycerin and xanthan gum) that form a barrier on the host mucosa, thus preventing viral contact and invasion. Healthy adults (18-45 years of age) were randomized into ARMS-I or placebo group (50 subjects each). The drug was sprayed intra-orally (3× daily) for 75 days. The primary objectives were to establish whether ARMS-I decreased the frequency, severity or duration of URIs. Secondary objectives were to evaluate safety, tolerability, rate of virus detection, acceptability and adherence; effect on URI-associated absenteeism and medical visits; and effect of prior influenza vaccination on study outcomes.

Results: Of the 94 individuals who completed the study (placebo: n = 44, ARMS-I: n = 50), six presented with confirmed URI (placebo: 4, ARMS-I: 2), representing a 55% relative reduction, albeit this was statistically not significant). Influenza, coronavirus or rhinovirus were detected in three participants; all in the placebo group. Moreover, frequency of post-treatment exit visits was reduced by 55% in ARMS-I compared to the placebo group (N = 4 and 2, respectively). Fever was reported only in the placebo group. ARMS-I significantly reduced the frequency and severity of cough and sore throat, and duration of cough (P ≤ .019 for all comparisons). ARMS-I was safe, well tolerated, had high acceptability and high adherence to medication use. Medical visits occurred only in the placebo group while absenteeism did not differ between the two arms. Prior influenza vaccination had no effect on study outcome.

Conclusions: This randomized proof-of-concept clinical trial demonstrated that ARMS-I tended to provide protection against URIs in the enrolled study participants, while reducing severity and duration of cough and sore throat. A clinical trial with a larger number of study participants is warranted.

Trial registration: ClinicalTrials.gov NCT02644135 (retrospectively registered).

Keywords: Antiviral; Barrier formation; Cetylpyridinium chloride; Glycerin; Prophylaxis; Xanthan gum.

Figures

Fig. 1
Fig. 1
CONSORT flow figure for the conducted study

References

    1. Harper SA, Bradley JS, Englund JA, File TM, Gravenstein S, Hayden FG, McGeer AJ, Neuzil KM, Pavia AT, Tapper ML, et al. Seasonal influenza in adults and children--diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2009;48(8):1003–1032. doi: 10.1086/598513.
    1. Dasaraju PV, Liu C. Infections of the Respiratory System. 2011/03/18 1996.
    1. Torres HA, Aguilera EA, Mattiuzzi GN, Cabanillas ME, Rohatgi N, Sepulveda CA, Kantarjian HM, Jiang Y, Safdar A, Raad II, et al. Characteristics and outcome of respiratory syncytial virus infection in patients with leukemia. Haematologica. 2007;92(9):1216–1223. doi: 10.3324/haematol.11300.
    1. Bonten MJ, Gaillard CA, de Leeuw PW, Stobberingh EE. Role of colonization of the upper intestinal tract in the pathogenesis of ventilator-associated pneumonia. Clin Infect Dis. 1997;24(3):309–319. doi: 10.1093/clinids/24.3.309.
    1. Jaber R. Respiratory and allergic diseases: from upper respiratory tract infections to asthma. Prim Care. 2002;29(2):231–261. doi: 10.1016/S0095-4543(01)00008-2.
    1. Centers for Disease Control and Prevention Estimates of deaths associated with seasonal influenza --- United States, 1976–2007. MMWR Morb Mortal Wkly Rep. 2010;59(33):1057–1062.
    1. West JV. Acute upper airway infections. Br Med Bull. 2002;61:215–230. doi: 10.1093/bmb/61.1.215.
    1. Jain N, Lodha R, Kabra SK. Upper respiratory tract infections. Indian J Pediatr. 2001;68(12):1135–1138. doi: 10.1007/BF02722930.
    1. Molinari NA, Ortega-Sanchez IR, Messonnier ML, Thompson WW, Wortley PM, Weintraub E, Bridges CB. The annual impact of seasonal influenza in the US: measuring disease burden and costs. Vaccine. 2007;25(27):5086–5096. doi: 10.1016/j.vaccine.2007.03.046.
    1. Fendrick AM, Monto AS, Nightengale B, Sarnes M. The economic burden of non-influenza-related viral respiratory tract infection in the United States. Arch Intern Med. 2003;163(4):487–494. doi: 10.1001/archinte.163.4.487.
    1. Petrie JG, Cheng C, Malosh RE, VanWormer JJ, Flannery B, Zimmerman RK, Gaglani M, Jackson ML, King JP, Nowalk MP, et al. Illness Severity and Work Productivity Loss Among Working Adults With Medically Attended Acute Respiratory Illnesses: US Influenza Vaccine Effectiveness Network 2012–2013. Clin Infect Dis. 2016;62(4):448–455.
    1. Jacobs SE, Lamson DM, St George K, Walsh TJ. Human rhinoviruses. Clin Microbiol Rev. 2013;26(1):135–162. doi: 10.1128/CMR.00077-12.
    1. Carroll K, Reimer L. Microbiology and laboratory diagnosis of upper respiratory tract infections. Clin Infect Dis. 1996;23(3):442–448. doi: 10.1093/clinids/23.3.442.
    1. Lu PJ, Santibanez TA, Williams WW, Zhang J, Ding H, Bryan L, O’Halloran A, Greby SM, Bridges CB, Graitcer SB, et al. Surveillance of influenza vaccination coverage--United States, 2007–08 through 2011–12 influenza seasons. MMWR Surveill Summ. 2013;62(4):1–28.
    1. Flannery B, Thaker SN, Clippard J, Monto AS, Ohmit SE, Zimmerman RK, Nowalk MP, Gaglani M, Jackson ML, Jackson LA, et al. Interim estimates of 2013–14 seasonal influenza vaccine effectiveness - United States, february 2014. MMWR Morb Mortal Wkly Rep. 2014;63(7):137–142.
    1. Demicheli V, Jefferson T, Al-Ansary LA, Ferroni E, Rivetti A, Di Pietrantonj C. Vaccines for preventing influenza in healthy adults. Cochrane Database Syst Rev. 2014;3:CD001269.
    1. Appiah GD, Blanton L, D’Mello T, Kniss K, Smith S, Mustaquim D, Steffens C, Dhara R, Cohen J, Chaves SS, et al. Influenza activity - United States, 2014–15 season and composition of the 2015–16 influenza vaccine. MMWR Morb Mortal Wkly Rep. 2015;64(21):583–590.
    1. Fine P. Science and society: vaccines and public health. Public Health. 2014;128(8):686–692. doi: 10.1016/j.puhe.2014.06.021.
    1. Dube E, Vivion M, MacDonald NE. Vaccine hesitancy, vaccine refusal and the anti-vaccine movement: influence, impact and implications. Expert Rev Vaccines. 2015;14(1):99–117. doi: 10.1586/14760584.2015.964212.
    1. Glezen WP. Prevention and Treatment of Seasonal Influenza. N Engl J Med. 2008;359(24):2579–2585. doi: 10.1056/NEJMcp0807498.
    1. Centers for Disease Control and Prevention (CDC) Antiviral Agents for the Treatment and Chemoprophylaxis of Influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP) Morb Mortal Wkly Rep. 2011;60(7 (RR-1)):1–24.
    1. Jefferson T, Jones MA, Doshi P, Del Mar CB, Heneghan CJ, Hama R, Thompson MJ. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev. 2012;1:CD008965.
    1. Smieja M. ACP Journal Club. Review: oseltamivir relieves symptoms but does not reduce hospitalizations in influenza. Ann Intern Med. 2012;157(6):JC3–5. doi: 10.7326/0003-4819-157-6-201209180-02005.
    1. Michiels B, Van Puyenbroeck K, Verhoeven V, Vermeire E, Coenen S. The value of neuraminidase inhibitors for the prevention and treatment of seasonal influenza: a systematic review of systematic reviews. PLoS One. 2013;8(4):e60348. doi: 10.1371/journal.pone.0060348.
    1. Samson M, Pizzorno A, Abed Y, Boivin G. Influenza virus resistance to neuraminidase inhibitors. Antiviral Res. 2013;98(2):174–185. doi: 10.1016/j.antiviral.2013.03.014.
    1. Hurt AC, Hardie K, Wilson NJ, Deng YM, Osbourn M, Gehrig N, Kelso A. Community transmission of oseltamivir-resistant A (H1N1) pdm09 influenza. N Engl J Med. 2011;365(26):2541–2542. doi: 10.1056/NEJMc1111078.
    1. Hu Y, Lu S, Song Z, Wang W, Hao P, Li J, Zhang X, Yen HL, Shi B, Li T, et al. Association between adverse clinical outcome in human disease caused by novel influenza A H7N9 virus and sustained viral shedding and emergence of antiviral resistance. Lancet. 2013;381(9885):2273–2279. doi: 10.1016/S0140-6736(13)61125-3.
    1. Hoffman KB, Demakas A, Erdman CB, Dimbil M, Doraiswamy PM. Neuropsychiatric adverse effects of oseltamivir in the FDA Adverse Event Reporting System, 1999–2012. BMJ. 2013;347:f4656. doi: 10.1136/bmj.f4656.
    1. Dobson J, Whitley RJ, Pocock S, Monto AS. Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials. Lancet. 2015;385(9979):1729–1737. doi: 10.1016/S0140-6736(14)62449-1.
    1. McKimm-Breschkin JL. Influenza neuraminidase inhibitors: antiviral action and mechanisms of resistance. Influenza Other Respir Viruses. 2013;7(Suppl 1):25–36. doi: 10.1111/irv.12047.
    1. Esper F, Mukherjee PK, Ghannoum AM, Salata RA, Ghannoum MA. In: 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) San Francisco: American Society for Microbiology; 2012. Barrier-Forming Formulation Containing Cetylpyridinium Chloride (fCPC) Possesses Anti-Infective Activity Against Influenza Virus.
    1. Esper FP, Dimaano ML, Popkin D, Fujioka H, Mukherjee PK, Ghannoum MA. In: ID Week 2015. San Diego: Infectious Diseases Society of America (IDSA); 2015. Novel Antiviral prevents Viral Upper Respiratory Infections in vitro and in vivo.
    1. Barrett B, Brown RL, Mundt MP, Thomas GR, Barlow SK, Highstrom AD, Bahrainian M. Validation of a short form Wisconsin Upper Respiratory Symptom Survey (WURSS-21) Health Qual Life Outcomes. 2009;7:76. doi: 10.1186/1477-7525-7-76.
    1. Mukherjee PK, Chandra J, Ghannoum AM, Sokol B, Ghannoum MA. In: 53nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) Denver: American Society for Microbiology; 2013. A Barrier-Forming Oral Formulation Exhibits Sustained Post-Antimicrobial Effect.
    1. Chandra J, Mukherjee PK, Jurevic RJ, Esper F, Ghannoum AM, Sokol B, Salata RA, Ghannoum MA. In: 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) San Francisco: American Society for Microbiology; 2012. Barrier-Forming Oral Formulation Containing Cetylpyridinium Chloride (fCPC) Exhibits Potent Activity Against Oral Pathogens.
    1. Landes MB, Neil RB, McCool SS, Mason BP, Woron AM, Garman RL, Smalley DL. The frequency and seasonality of influenza and other respiratory viruses in Tennessee: two influenza seasons of surveillance data, 2010–2012. Influenza Other Respir Viruses. 2013;7(6):1122–1127. doi: 10.1111/irv.12145.
    1. Eisfeld AJ, Neumann G, Kawaoka Y. Influenza A virus isolation, culture and identification. Nat Protoc. 2014;9(11):2663–2681. doi: 10.1038/nprot.2014.180.
    1. Brittain-Long R, Westin J, Olofsson S, Lindh M, Andersson LM. Prospective evaluation of a novel multiplex real-time PCR assay for detection of fifteen respiratory pathogens-duration of symptoms significantly affects detection rate. J Clin Virol. 2010;47(3):263–267. doi: 10.1016/j.jcv.2009.12.010.
    1. Brittain-Long R, Nord S, Olofsson S, Westin J, Anderson LM, Lindh M. Multiplex real-time PCR for detection of respiratory tract infections. J Clin Virol. 2008;41(1):53–56. doi: 10.1016/j.jcv.2007.10.029.
    1. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377–381. doi: 10.1016/j.jbi.2008.08.010.
    1. FDA DailyMed database []. Accessed 20 Aug 2013.
    1. Woodard G, Woodard MW, McNeely WH, Kovacs P, Cronin MT. Xanthan gum: safety evaluation by 2-year feeding studies in rats and dogs and a three-generation reproduction study in rats. Toxicol Appl Pharmacol. 1973;24(1):30–36. doi: 10.1016/0041-008X(73)90178-6.
    1. Farrer F. Sprays and lozenges for sore throats. SA Pharm J. 2011;78(4):26–31.
    1. EFSA Panel on Biological Hazards (BIOHAZ) EFSA Panel on Food Contact Materials Enzymes Flavourings and Processing Aids (CEF) Scientific Opinion on the evaluation of the safety and efficacy of Cecure® for the removal of microbial surface contamination of raw poultry products. EFSA J. 2012;10(3):2612. doi: 10.2903/j.efsa.2012.2612.
    1. British Industrial Biological Research Association (BIBRA) Toxicity Profile for Cetylpyridinium chloride. Carshalton: British Industrial Biological Research Association (BIBRA); 2005.
    1. Golberg L. Safety Evaluation of Cosmetics Ingredients. Food Cosmet Toxicol. 1963;1:215–216. doi: 10.1016/S0015-6264(63)80688-4.
    1. O’Neil J, Hughes S, Lourie A, Zweifler J. Effects of echinacea on the frequency of upper respiratory tract symptoms: a randomized, double-blind, placebo-controlled trial. Ann Allergy Asthma Immunol. 2008;100(4):384–388. doi: 10.1016/S1081-1206(10)60603-5.
    1. Bennett AL, Smith DW, Cummins MJ, Jacoby PA, Cummins JM, Beilharz MW. Influenza Other Respi Viruses. 2013. Low-dose oral interferon alpha as prophylaxis against viral respiratory illness: a double-blind, parallel controlled trial during an influenza pandemic year.
    1. Lakdawala SS, Jayaraman A, Halpin RA, Lamirande EW, Shih AR, Stockwell TB, Lin X, Simenauer A, Hanson CT, Vogel L, et al. The soft palate is an important site of adaptation for transmissible influenza viruses. Nature. 2015;526:122–5. doi: 10.1038/nature15379.

Source: PubMed

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