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

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.

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 Overview

• Status: Recruiting
• Conditions: Influenza
• Intervention / Treatment: Drug: N-acetyl cysteine; Drug: 5% Dextrose

• Study Type: Interventional
• Enrollment (Estimated): 160
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Ken Ka Pang Chan, MBChB; Phone Number: 852 3505 3532; Email: chankapang@cuhk.edu.hk

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong
    • Recruiting
    • Prince of Wales Hospital
    • Contact: Ken Ka Pang Chan; Phone Number: 3505 3532; Email: chankapang@cuhk.edu.hk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Chinese University of Hong Kong
• Investigators: Principal Investigator: David SC Hui, MD, Chinese University of Hong Kong

Study record dates

Study Major Dates

• Study Start (Actual): May 8, 2023
• Primary Completion (Estimated): October 31, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: March 31, 2019
• First Submitted That Met QC Criteria: April 1, 2019
• First Posted (Actual): April 3, 2019

Study Record Updates

• Last Update Posted (Actual): November 27, 2023
• Last Update Submitted That Met QC Criteria: November 24, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: respiratory, mortality, cytokines, chemokines, N-acetylcysteine (NAC)
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Orthomyxoviridae Infections; Influenza, Human; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Protective Agents; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Expectorants; Acetylcysteine; N-monoacetylcystine
• Other Study ID Numbers: NAC Influenza/Hui/2019

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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