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


RESULTS
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.


CONCLUSIONS
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.


BACKGROUND
Romark Laboratories LC.
Sunrise Medical Research, Lauderdale Lakes, FL, USA.
Jason
J
Haffizulla
Virginia Research Center, Midlothian, VA, USA.
Aaron
A
Hartman
Clinical Research Solutions, Jackson, TN, USA.
Melanie
M
Hoppers
R D Clinical Research, Lake Jackson, TX, USA.
Harvey
H
Resnick
Clinical Research Solutions, Franklin, TN, USA.
Steve
S
Samudrala
BARC USA, Lake Success, NY, USA.
Christine
C
Ginocchio
Romark Laboratories, Tampa, FL, USA.
Matthew
M
Bardin
Romark Laboratories, Tampa, FL, USA. Electronic address: jrossignol@romark.com.
Jean-François
JF
Rossignol
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000890:Anti-Infective Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007251:Influenza, Human / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009574:Nitro Compounds; D013844:Thiazoles / Q000009:adverse effects / Q000627:therapeutic use*; D055815:Young Adult
D000890:Anti-Infective Agents; D009574:Nitro Compounds; D013844:Thiazoles; C041747:nitazoxanide