Flufenamic Acid for Hospitalised Influenza Infection

A Double-blind Randomised Controlled Trial on Flufenamic Acid for Hospitalised Influenza Infection

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.

Study Overview

• Status: Unknown
• Conditions: Influenza A
• Intervention / Treatment: Drug: FFA, clarithromycin, oseltamivir; Drug: Oseltamivir alone

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.

• Study Type: Interventional
• Enrollment (Anticipated): 200
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Deborah Ho, BSc MSc; Phone Number: 22554049; Email: tipyin@yahoo.com.hk
• Study Contact Backup: Name: Teresa Tong, BSc; Phone Number: 22551674; Email: tongsma@hkucc.hku.hk

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong
    • Recruiting
    • Ivan Hung
    • Sub-Investigator: Kelvin To, MD FRCPath
    • Sub-Investigator: KY Yuen, MD FRCPath

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: FFA, clarithromycin, oseltamivir; oseltamivir 75mg + clarithromycin 500mg + FFA 200mg all twice daily for 2 days, followed by oseltamivir 75mg twice daily for 3 days	Drug: FFA, clarithromycin, oseltamivir; 2-day course of triple combination of clarithromycin 500mg, flufenamic acid 200mg and oseltamivir 75mg twice daily followed by oseltamivir 75mg twice daily for 3 days; Other Names: Antiviral combo
PLACEBO_COMPARATOR: Oseltamivir alone; 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	Drug: Oseltamivir alone; 2-day course of oseltamivir 75mg plus placebo capsules twice daily followed by oseltamivir 75mg twice daily for 3 days as control; Other Names: Antiviral

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	30-day mortality	30 days from commencement of treatment intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
NPA	nasopharyngeal aspirate viral load changes post treatment	5 days post treatment
PSI	Pneumonia severity index changes post treatment	5 days post treatment
Hospitalisation	Length of hospitalisation	Days of the subject hospitalised for the current admission up to 30 days
AE	Adverse events during treatment	2 weeks from subjects received treatment intervention
Long-term mortality	90-day mortality	90 days from commencement of treatment intervention

Collaborators and Investigators

• Sponsor: The University of Hong Kong
• Investigators: Principal Investigator: Ivan Hung, MD FRCP, The University of Hong Kong

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 8, 2018
• Primary Completion (ANTICIPATED): July 31, 2020
• Study Completion (ANTICIPATED): October 31, 2020

Study Registration Dates

• First Submitted: July 27, 2017
• First Submitted That Met QC Criteria: August 2, 2017
• First Posted (ACTUAL): August 3, 2017

Study Record Updates

• Last Update Posted (ACTUAL): October 22, 2019
• Last Update Submitted That Met QC Criteria: October 21, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: influenza; mortality; clarithromycin; FFA; hospitalisation
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Orthomyxoviridae Infections; Influenza, Human; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Protein Synthesis Inhibitors; Clarithromycin; Antiviral Agents; Oseltamivir
• Other Study ID Numbers: UW 16-418

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No