Effect of nitazoxanide in adults and adolescents with acute uncomplicated influenza: a double-blind, randomised, placebo-controlled, phase 2b/3 trial

Jason Haffizulla, Aaron Hartman, Melanie Hoppers, Harvey Resnick, Steve Samudrala, Christine Ginocchio, Matthew Bardin, Jean-François Rossignol, US Nitazoxanide Influenza Clinical Study Group, Gregory Adams, Kevin Adkins, Patricia Alvarez, Saadat Ansari, Allan Aven, Matthew Beacom, K Alan Bean, Richard Beasley, Michael Bennett, Loray Blair-Britt, Edward Braun, John Calcagno, Venkata Challa, Steve Choi, Rita Chuang, Patrick Clay, Diane Combs, Michael Crawley, Mitchell Efros, Bryan Feldman, Thomas Fiel, Gene Fuller, Gary Gleason, William Gonte, Piyush Gupta, Jason Haffizulla, Wayne Harper, Hoadley Harris, Aaron Hartman, Delphanie Head, Archie Hearne, J Dwayne Helms, Martin Hollingsworth, Melanie Hoppers, Patricia Houser, Sergio Ibarra, William Jonakin, Grantley Joseph, Kishor Joshi, Jennifer Kay, Louise Lamarre, John Mageli, Acisclo Marxuach-Cuetera, Edward McCarthy, Derek Muse, Robert Onder, April Palmer, Dipti Patel, Frank Perrone, Norval Rasmussen, Keith Reisinger, Jefferson Hills, Harvey Resnick, Karin Rock, Luis Ruiz-Rivera, Gary Ruoff, S Steve Samudrala, Robert Saniuk, Darcy Scheeler, Shaukat Shah, Gerald Shockey, Dimitri Sirakoff, Christopher Smith, Jeffrey Smith, John Speer, Jack Stapleton, Jeffrey Stewart, Charles Tessier, Vincent Thompson, Mario Torres, Jan Vlach, Noel Williams, Gary Yeoman, Jason Haffizulla, Aaron Hartman, Melanie Hoppers, Harvey Resnick, Steve Samudrala, Christine Ginocchio, Matthew Bardin, Jean-François Rossignol, US Nitazoxanide Influenza Clinical Study Group, Gregory Adams, Kevin Adkins, Patricia Alvarez, Saadat Ansari, Allan Aven, Matthew Beacom, K Alan Bean, Richard Beasley, Michael Bennett, Loray Blair-Britt, Edward Braun, John Calcagno, Venkata Challa, Steve Choi, Rita Chuang, Patrick Clay, Diane Combs, Michael Crawley, Mitchell Efros, Bryan Feldman, Thomas Fiel, Gene Fuller, Gary Gleason, William Gonte, Piyush Gupta, Jason Haffizulla, Wayne Harper, Hoadley Harris, Aaron Hartman, Delphanie Head, Archie Hearne, J Dwayne Helms, Martin Hollingsworth, Melanie Hoppers, Patricia Houser, Sergio Ibarra, William Jonakin, Grantley Joseph, Kishor Joshi, Jennifer Kay, Louise Lamarre, John Mageli, Acisclo Marxuach-Cuetera, Edward McCarthy, Derek Muse, Robert Onder, April Palmer, Dipti Patel, Frank Perrone, Norval Rasmussen, Keith Reisinger, Jefferson Hills, Harvey Resnick, Karin Rock, Luis Ruiz-Rivera, Gary Ruoff, S Steve Samudrala, Robert Saniuk, Darcy Scheeler, Shaukat Shah, Gerald Shockey, Dimitri Sirakoff, Christopher Smith, Jeffrey Smith, John Speer, Jack Stapleton, Jeffrey Stewart, Charles Tessier, Vincent Thompson, Mario Torres, Jan Vlach, Noel Williams, Gary Yeoman

Abstract

Background: Influenza is an important cause of morbidity and mortality worldwide. Treatment options are scarce, and new drugs with novel mechanisms of action are needed. We aimed to assess the efficacy and safety of nitazoxanide, a thiazolide anti-infective, for treatment of acute uncomplicated influenza.

Methods: We did a double-blind, randomised, placebo-controlled, phase 2b/3 trial in 74 primary care clinics in the USA between Dec 27, 2010, and April 30, 2011. We enrolled participants aged 12-65 years with fever, at least one respiratory symptom, and one constitutional symptom of influenza within 48 h of symptom onset. We randomly assigned participants to receive either nitazoxanide 600 mg, nitazoxanide 300 mg, or placebo twice daily for 5 days, (ratio 1:1:1) and followed them up for 28 days. Randomisation lists were computer generated and done in blocks of three. Sponsor, investigators, study monitors, patients, and laboratory personnel were all masked to treatment allocation in the study. The primary endpoint was the time from first dose to alleviation of symptoms. The primary analysis was by intention-to-treat for participants with influenza infection confirmed by RT-PCR or culture at baseline. This trial is registered with ClinicalTrials.gov, number NCT01227421.

Findings: Of 650 participants screened, 624 (96%) were enrolled. Of these, 212 were randomly assigned to receive placebo twice a day, 201 to receive nitazoxanide 300 mg twice a day, and 211 to receive nitazoxanide 600 mg a day. The median duration of symptoms for participants receiving placebo was 116·7 h (95% CI 108·1-122·1) compared with 95·5 h (84·0-108·0; p=0·0084) for those receiving 600 mg nitazoxanide and 109·1 h (96·1-129·5, p=0·52) for those receiving 300 mg nitazoxanide. Adverse events were similar between the three groups, the most common being headache reported by 24 (11%) of 212 patients enrolled in placebo group, 12 (6%) of 201 patients in the low-dose group, and 17 (8%) of 211 patients in the high-dose group, or diarrhoea, reported by seven (3%) patients in the placebo group, four (2%) patients enrolled in the low-dose group, and 17 (8%) patients in the high-dose group.

Interpretation: Treatment with nitazoxanide 600 mg twice daily for 5 days was associated with a reduction of the duration of symptoms in participants with acute uncomplicated influenza. Further studies are warranted to confirm these findings and to assess efficacy of the drug alone or in combination with existing drugs in seriously ill patients and those at risk of influenza complications.

Funding: Romark Laboratories LC.

Copyright © 2014 Elsevier Ltd. All rights reserved.

Figures

Figure 1
Figure 1
Trial profile
Figure 2
Figure 2
Kaplan-Meier plot of time from first dose to alleviation of symptoms for patients with confirmed influenza
Figure 3
Figure 3
Mean change in TCID50 viral titre from baseline Analysis of change in TCID50 viral titre for participants with confirmed influenza that we took daily nasopharyngeal swabs from. Statistical comparison with mixed model for repeated measures including baseline viral titre, treatment group, and geographic location: p=0·0006 for the difference between nitazoxanide 600 mg and placebo, p=0·1553 for the difference between nitazoxanide 300 mg and placebo.

References

    1. WHO Influenza (Seasonal). Fact sheet number 211. March 2009. (accessed April 29, 2013).
    1. Thompson WW, Shay DK, Weintraub E. Influenza-associated hospitalizations in the United States. JAMA. 2004;292:1333–1340.
    1. Centers for Disease Control and Prevention Estimates of deaths associated with seasonal influenza—United States, 1976–2007. MMWR. 2010;59:1057–1062.
    1. Rossignol JF, La Frazia S, Chiappa L, Ciucci A, Santoro MG. Thiazolides, a new class of anti-influenza molecules targeting viral hemagglutinin at the post-translational level. J Biol Chem. 2009;43:29798–29808.
    1. Belardo G, La Frazia S, Cenciarelli O, Carta S, Rossignol JF, Santoro MG. Nitazoxanide, a novel potential anti-influenza drug, acting in synergism with neuraminidase inhibitors. 49th Infectious Disease Society of America Annual Meeting; Boston, MA, USA; Oct 20–23 2011; [cited 2013 Apr 29]
    1. Romark Laboratories, LC. Alinia prescribing information. Tampa, FL; October, 2011.
    1. US Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER) Guidance for Industry, Influenza: Developing Drugs for Treatment and/or Prophylaxis. Silver Spring: 2011. (accessed April 29, 2013).
    1. Treanor JJ, Hayden FG, Vrooman PS. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza. JAMA. 2000;283:1016–1024.
    1. Nicholson KG, Aoki FY, Ostherhaus AD. Efficacy and safety of oseltamivir in treatment of acute influenza: a randomized controlled trial. Neuraminidase Inhibitor Flu Treatment Investigator Group. Lancet. 2000;355:1845–1850.
    1. Hayden FG, Osterhaus AD, Treanor JJ. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenzavirus infections. GG167 Influenza Study Group. N Engl J Med. 1997;337:874–880.
    1. The MIST (Management of Influenza in the Southern Hemisphere Trialists) Study Group Randomised trial of efficacy and safety of inhaled zanamivir in treatment of influenza A and B virus infections. Lancet. 1998;352:1877–1881.
    1. Mäkelä MJ, Pauksens K, Rostila T. Clinical efficacy and safety of the orally inhaled neuraminidase inhibitor zanamivir in the treatment of influenza: a randomized, double-blind, placebo-controlled European study. J Infect. 2000;40:42–48.
    1. Stockis A, De Bruyn S, Gengler C, Rosillon D. Nitazoxanide pharmacokinetics and tolerability in man during 7 days of 0.5 g and 1 g bid dosing with food. Int J Clin Pharmacol Ther. 2002;40:221–227.
    1. Harper SA, Bradley JS, Englund JA. 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;48:1003–1032.
    1. Centers for Disease Control and Prevention Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010. MMWR. 2010;59:1–62.
    1. Centers for Disease Control and Prevention CDC realtime RTPCR (rRTPCR) protocol for detection and characterization of swine influenza (version 2009) (accessed April 29, 2013).
    1. Ebell MH, Call M, Shinholser J. Effectiveness of oseltamivir in adults: a meta-analysis of published and unpublished clinical trials. Fam Pract. 2013;30:125–133.
    1. Kohno S, Kida H, Mizuguchi M, Shimada J, S-021812 Clinical Study Group Efficacy and safety of intravenous peramivir for treatment of seasonal influenza virus infection. Antimicrob Agents Chemother. 2010;54:4568–4574.
    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:e60348.
    1. Wang K, Shun-Shin M, Gill P, Perera R, Harnden A. Neuraminidase inhibitors for preventing and treating influenza in children (published trials only) Cochrane Database Syst Rev. 2012;4 CD002744.
    1. Hsu J, Santesso N, Mustafa R. Antivirals for treatment of influenza: a systematic review and meta-analysis of observational studies. Ann Intern Med. 2012;156:512–524.
    1. Jefferson T, Jones MA, Doshi P. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev. 2012;1 CD008965.
    1. Wang K, Shun-Shin M, Gill P, Perera R, Harnden A. Neuraminidase inhibitors for preventing and treating influenza in children. Cochrane Database Syst Rev. 2012;1 CD002744.
    1. Jefferson T, Jones M, Doshi P, Del Mar C. Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis. BMJ. 2009;339:b5106.
    1. Burch J, Corbett M, Stock C. Prescription of anti-influenza drugs for healthy adults: a systematic review and meta-analysis. Lancet Infect Dis. 2009;9:537–545.
    1. Shun-Shin M, Thompson M, Heneghan C, Perera R, Harnden A, Mant D. Neuraminidase inhibitors for treatment and prophylaxis of influenza in children: systematic review and meta-analysis of randomised controlled trials. BMJ. 2009;339:b3172.
    1. Moscona A. Neuraminidase inhibitors for influenza. N Engl J Med. 2005;353:1363–1373.

Source: PubMed

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