Seasonal influenza epidemics are important causes of morbidity and mortality. Cytokine dysregulation, with high levels of pro-inflammatory cytokines, occurs in patients with severe influenza. Early therapy with a neuraminidase inhibitor (NAI) is associated with better outcome in patients hospitalized with influenza, but significant mortality occurs despite use of antivirals. N-acetylcysteine (NAC) is a modified form of the amino acid cysteine, with anti-oxidant properties. NAC was shown to inhibit the production of pro-inflammatory molecules in lung epithelial cells infected with influenza viruses. Previous case report showed that high dose NAC, administered as continuous intravenous infusion, was effective and safe in improving the clinical outcomes. We aim to perform a randomized controlled trial to evaluate the therapeutic role of adjunctive NAC in the clinical management of patients with influenza complicated by lower respiratory tract involvement and abnormal respiratory status. Such information when available may reveal the potential of NAC for optimization of management of severe influenza, and provide important insights into future adjunctive therapy research.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
160
N-acetyl cysteine will be administered at 100 mg/kg daily as a continuous IV infusion (in 1000ml of 5% dextrose) over 24 hrs and oseltamivir 75 mg bid orally for 5 days. Extension of dosing to 10 days for oseltamivir and the study drug is allowed if there is slow recovery, lack of improvement, or deterioration.
5% dextrose 1 liter given over 24 hrs and oral oseltamivir 75 mg bid for 5 days. Extension of dosing to 10 days for oseltamivir and the study drug is allowed if there is slow recovery, lack of improvement, or deterioration.
Prince of Wales Hospital
Hong Kong, Hong Kong
RECRUITINGNormalization of respiratory status in day
oxygen saturation more than 93% or respiratory rate lower than 20/min on room air
Time frame: 28 days
viral ribonucleic acid (RNA) in copies per milliliter
All serially collected samples will be subjected to viral ribonucleic acid (RNA) quantification using quantitative reverse transcription PCR (qRTPCR) targeting the matrix (M)-gene ('viral load')
Time frame: 28 days
Interleukin 6 in pg/ml
Time frame: 10 days
interleukin-8 in pg/ml
Time frame: 10 days
interleukin 17 in pg/ml
Time frame: 10 days
Chemokine ligand 9 (CxCL9/MIG) in pg/ml
Time frame: 10 days
Soluble tumour necrosis factor receptor-1 (sTNFR-1) in pg/ml
Time frame: 10 days
interleukin 18 in pg/ml
Time frame: 10 days
CRP in mg/L
Time frame: 10 days
phospho-p38 and phospho-ERK (activated MAPKs) in mean fluorescence intensity(MFI)
Time frame: 10 days
phospho-inhibitor kB/IkB (NF-kB) in mean fluorescence intensity(MFI)
Time frame: 10 days
resolution of symptoms in days
A standard questionnaire will be used to collect baseline and serial clinical data. These include clinical manifestations/complications, symptom severity score, vital signs (e.g. temperature, respiratory rate, oxygen saturation), fever duration, requirements for supplemental oxygen therapy and invasive/non-invasive ventilation, duration of hospitalization, death, and occurrence of adverse events.
Time frame: 28 days
ICU admission in days
Time frame: 28 days
mortality in days
Time frame: 28 days
Incidence of Treatment-Emergent Adverse Events in numbers
Time frame: 28 days
a six step ordinal scale of clinical status
death, in ICU, ongoing hospitalisation on oxygen, hospital stay not on oxygen, discharged but not returned to normal activities, or discharged and returned to normal activities
Time frame: 7 days
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