Clinical trial NCT03238612: Flufenamic Acid for Hospitalised Influenza Infection
Official title: A Double-blind Randomised Controlled Trial on Flufenamic Acid for Hospitalised Influenza Infection
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Influenza A
Keywords: influenza
FFA
clarithromycin
mortality
hospitalisation
Lead sponsor: The University of Hong Kong
Sponsor class: OTHER
First posted: 2017-08-03
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective Randomised Controlled Trial
Primary purpose: TREATMENT

Brief summary: It is well recognized that respiratory viruses cause substantial disease burden every year. Among all known respiratory viruses, influenza virus is the greatest cause of disability-adjusted life years lost, excess hospitalizations, and deaths in the elderly and patients with chronic illness. These patients are frequently hospitalized for pneumonia secondary to these respiratory viral infection. Recently, macrolide antimicrobial clarithromycin and flufenamic acid (FFA) have been shown to inhibit seasonal influenza virus infection in human airway epithelial cells with additional anti-inflammatory effect.

The investigators therefore plan to conduct a 3-year prospective study among adult patients hospitalized in Queen Mary Hospital for influenza with secondary pneumonia and randomized them to receive a course of oseltamivir + FFA + clarithromycin (as treatment) vs. a course of oseltamivir (current standard treatment as control). The objective of this prospective double-blind randomized controlled trial is to evaluate the efficacy of clarithromycin and FFA antiviral therapy in patients diagnosed to have pneumonia secondary to influenza infection.

Detailed description: This double blind randomized-controlled trial will assess the clinical efficacy, mortality reduction and viral load reduction of clarithromycin and FFA in patients hospitalized for pneumonia secondary to influenza infection.

The investigators plan to enroll at least 200 adult patients. Enrolled patients will be randomized into 2 groups. Group 1: oseltamivir 75mg + clarithromycin 500mg + FFA 200mg all twice daily for 2 days, followed by oseltamivir 75mg twice daily for 3 days ; Group 2: oseltamivir 75mg + two placebo capsules (identical in appearance to clarithromycin and FFA capsules respectively) twice daily for 2 days, followed by oseltamivir 75mg twice daily for 3 days. The placebo capsules will contain inactive starch. All patients will receive a 5-day course of amoxicillin-clavulanate 1g bid for empirical coverage of community acquired pneumonia and esomeprazole 20mg daily for prevention of non-steroidal anti-inflammatory drugs related gastropathy.

Randomized treatment will be double blinded. Patients will be assigned to serial number by the study-coordinator. Each serial number will be linked to a computer-generated randomization list assigning the antiviral treatment regimens. The study medications will be dispensed by the hospital pharmacy and then to the patients by the medical ward nurses who will not know the treatment regimen of any subsequent patients. Enrolled patients could not differentiate the study or the placebo medication capsule which will be identical in appearance. The placebo capsules will contain inactive starch.

There will be 50% chance of random assignment into one of the treatment or control arms.

Clinical data, nasopharyngeal aspirate (NPA) and blood specimens will be collected daily if possible from admission till discharge, transfer to convalescent hospitals or death. All enrolled patients will be invited to the Infectious Disease outpatient clinic in Queen Mary Hospital for follow-up at 1 and 3 months after discharge. The investigators will retrieve your clinical information from the Clinical Medical System in the Queen Mary Hospital during follow-up.

Eligibility criteria: Inclusion Criteria:

1. Recruited subjects include all adult patients ≥18 years hospitalised for virologically confirmed influenza infection.
2. Auditory temperature ≥38°C with at least one of the following symptoms (cough, sputum production, sore-throat, nasal discharge, myalgia, headache or fatigue) upon admission
3. Symptom duration ≤72 hours
4. Radiological changes of pulmonary infiltrate by chest radiography or computerised tomography
5. All subjects give written informed consent. Subjects must be available to complete the study and comply with study procedures. Willingness to allow for serum samples to be stored beyond the study period, for potential additional future testing to better characterise immune response.

Exclusion Criteria:

1. Inability to comprehend and to follow all required study procedures.
2. Allergy or severe reactions including renal or hepatic dysfunctions to clarithromycin, FFA, oseltamivir, amoxicillin-clavulanate or esomeprazole will be excluded
3. Patient with moderate renal impairment (creatinine clearance \<30mL/min)
4. Prolonged QT or ventricular cardiac arrhythmias, including torsade de pointes.
5. Patient with a history of cholestatic jaundice and/or liver dysfunction associated with prior clarithromycin use
6. Patient on cisapride, pimozide, astemizole, terfenadine, ergotamine, dihyroergotamine, or statins medications which could not be stopped
7. Patient on colchicine with renal or hepatic impairment.
8. Pregnant or lactating women
9. Inability to comprehend and to follow all required study procedures
10. Have known human immunodeficiency virus infection
11. Received an experimental agent (vaccine, drug, biologic, device, blood product, or medication) within 1 month prior to recruitment in this study or expect to receive an experimental agent during this study. Unwilling to refuse participation in another clinical study through the end of this study.
12. Have a history of alcohol or drug abuse in the last 5 years. Have any condition that the investigator believes may interfere with successful completion of the study.

Primary outcomes:
measure: Mortality
timeFrame: 30 days from commencement of treatment intervention
Secondary outcomes:
measure: NPA
timeFrame: 5 days post treatment
measure: PSI
timeFrame: 5 days post treatment
measure: Hospitalisation
timeFrame: Days of the subject hospitalised for the current admission up to 30 days
measure: AE
timeFrame: 2 weeks from subjects received treatment intervention
measure: Long-term mortality
timeFrame: 90 days from commencement of treatment intervention
Other outcomes:
Locations:
city: Hong Kong
country: Hong Kong
facility: Ivan Hung
Study officials:
affiliation: The University of Hong Kong
name: Ivan Hung, MD FRCP
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hung IFN, To KKW, Chan JFW, Cheng VCC, Liu KSH, Tam A, Chan TC, Zhang AJ, Li P, Wong TL, Zhang R, Cheung MKS, Leung W, Lau JYN, Fok M, Chen H, Chan KH, Yuen KY. Efficacy of Clarithromycin-Naproxen-Oseltamivir Combination in the Treatment of Patients Hospitalized for Influenza A(H3N2) Infection: An Open-label Randomized, Controlled, Phase IIb/III Trial. Chest. 2017 May;151(5):1069-1080. doi: 10.1016/j.chest.2016.11.012. Epub 2016 Nov 22.
citation: Hung IFN, To KKW, Lee CK, Lee KL, Yan WW, Chan K, Chan WM, Ngai CW, Law KI, Chow FL, Liu R, Lai KY, Lau CCY, Liu SH, Chan KH, Lin CK, Yuen KY. Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection. Chest. 2013 Aug;144(2):464-473. doi: 10.1378/chest.12-2907.
citation: Li IW, Hung IF, To KK, Chan KH, Wong SS, Chan JF, Cheng VC, Tsang OT, Lai ST, Lau YL, Yuen KY. The natural viral load profile of patients with pandemic 2009 influenza A(H1N1) and the effect of oseltamivir treatment. Chest. 2010 Apr;137(4):759-68. doi: 10.1378/chest.09-3072. Epub 2010 Jan 8.
citation: Hung IF, To KK, Lee CK, Lee KL, Chan K, Yan WW, Liu R, Watt CL, Chan WM, Lai KY, Koo CK, Buckley T, Chow FL, Wong KK, Chan HS, Ching CK, Tang BS, Lau CC, Li IW, Liu SH, Chan KH, Lin CK, Yuen KY. Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection. Clin Infect Dis. 2011 Feb 15;52(4):447-56. doi: 10.1093/cid/ciq106. Epub 2011 Jan 19.