Intravenous N-acetylcysteine and Oseltamivir Versus Oseltamivir in Adults Hospitalized With Influenza and Pneumonia

Study Overview
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Brief Summary
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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.

Official Title
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A Randomized, Double Blind, Placebo Controlled Trial of Intravenous N-acetylcysteine and Oseltamivir Versus Intravenous 5% Dextrose and Oseltamivir in Adults Hospitalized With Influenza Complicated by Lower Respiratory Tract Infection.

Conditions
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Influenza

Intervention / Treatment
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* Drug: N-acetyl cysteine
* Drug: 5% Dextrose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: influenza A and B virus infections confirmed by polymerase chain reaction (PCR) and/or immunofluorescence assays, hospitalized for the management of severe manifestations of influenza, initiation of oseltamivir, clinical evidence of lower respiratory tract infection (e.g. shortness of breath, tachypnea, oxygen desaturation <93% on room air, crepitations on auscultation, infiltrations or consolidations on chest radiograph) written informed consent (by the subjects, or from their next of kin if the subjects are unable to provide written consent at the time of enrollment) Exclusion Criteria: use of immunosuppressants (e.g. post-chemotherapy, post-transplant, autoimmune diseases) other than systemic corticosteroids known immuno-compromised conditions (e.g. active haematological malignancies, HIV/AIDS patients who are on antiretroviral therapy and CD4 cell count < 200), pregnancy lactation, end-stage renal failure hepatic failure cardiac failure patients on anticoagulation (except prophylactic dose of low molecular weight heparin), patients with scheduled major surgery within 2 weeks (NAC may affect blood clotting), patients who have received macrolide antibiotics and NSAID for 1 week prior to enrolment due to their immuno-modulating effects. Use of investigational anti-influenza antivirals and blood products

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: intravenous N-acetylcysteine (NAC) and oseltamivir<br> | Drug: N-acetyl cysteine<br>* 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.<br>|
| Placebo Comparator: intravenous 5% dextrose and oseltamivir<br> | Drug: 5% Dextrose<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Normalization of respiratory status in day | oxygen saturation more than 93% or respiratory rate lower than 20/min on room air | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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') | 28 days | 
| Interleukin 6 in pg/ml |  | 10 days | 
| interleukin-8 in pg/ml |  | 10 days | 
| interleukin 17 in pg/ml |  | 10 days | 
| Chemokine ligand 9 (CxCL9/MIG) in pg/ml |  | 10 days | 
| Soluble tumour necrosis factor receptor-1 (sTNFR-1) in pg/ml |  | 10 days | 
| interleukin 18 in pg/ml |  | 10 days | 
| CRP in mg/L |  | 10 days | 
| phospho-p38 and phospho-ERK (activated MAPKs) in mean fluorescence intensity(MFI) |  | 10 days | 
| phospho-inhibitor kB/IkB (NF-kB) in mean fluorescence intensity(MFI) |  | 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. | 28 days | 
| ICU admission in days |  | 28 days | 
| mortality in days |  | 28 days | 
| Incidence of Treatment-Emergent Adverse Events in numbers |  | 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 | 7 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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respiratory, mortality, cytokines, chemokines, N-acetylcysteine (NAC)