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

Influenza Clinical Trial

Official title:

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.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03900988
• Other study ID #: NAC Influenza/Hui/2019
• Status: Recruiting
• Phase: Phase 3
• Start date: May 8, 2023
• Est. completion date: December 31, 2025

Study information

• Verified date: November 2023
• Source: Chinese University of Hong Kong
• Contact: Ken Ka Pang Chan, MBChB
• Phone: 852 3505 3532
• Email: chankapang[@]cuhk.edu.hk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 160
• Est. completion date: December 31, 2025
• Est. primary completion date: October 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Influenza
• Influenza, Human

Intervention

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.
• 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.

Locations

Country	Name	City	State
Hong Kong	Prince of Wales Hospital	Hong Kong

Sponsors (1)

Lead Sponsor	Collaborator
Chinese University of Hong Kong

Country where clinical trial is conducted

Hong Kong, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Normalization of respiratory status in day	oxygen saturation more than 93% or respiratory rate lower than 20/min on room air	28 days
Secondary	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
Secondary	Interleukin 6 in pg/ml		10 days
Secondary	interleukin-8 in pg/ml		10 days
Secondary	interleukin 17 in pg/ml		10 days
Secondary	Chemokine ligand 9 (CxCL9/MIG) in pg/ml		10 days
Secondary	Soluble tumour necrosis factor receptor-1 (sTNFR-1) in pg/ml		10 days
Secondary	interleukin 18 in pg/ml		10 days
Secondary	CRP in mg/L		10 days
Secondary	phospho-p38 and phospho-ERK (activated MAPKs) in mean fluorescence intensity(MFI)		10 days
Secondary	phospho-inhibitor kB/IkB (NF-kB) in mean fluorescence intensity(MFI)		10 days
Secondary	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
Secondary	ICU admission in days		28 days
Secondary	mortality in days		28 days
Secondary	Incidence of Treatment-Emergent Adverse Events in numbers		28 days
Secondary	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