Clinical trial NCT03900988: Intravenous N-acetylcysteine and Oseltamivir Versus Oseltamivir in Adults Hospitalized With Influenza and Pneumonia
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.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Influenza
Keywords: respiratory, mortality, cytokines, chemokines, N-acetylcysteine (NAC)
Lead sponsor: Chinese University of Hong Kong
Sponsor class: OTHER
First posted: 2019-04-03
Enrollment: 160
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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

Primary outcomes:
measure: Normalization of respiratory status in day
timeFrame: 28 days
Secondary outcomes:
measure: viral ribonucleic acid (RNA) in copies per milliliter
timeFrame: 28 days
measure: Interleukin 6 in pg/ml
timeFrame: 10 days
measure: interleukin-8 in pg/ml
timeFrame: 10 days
measure: interleukin 17 in pg/ml
timeFrame: 10 days
measure: Chemokine ligand 9 (CxCL9/MIG) in pg/ml
timeFrame: 10 days
measure: Soluble tumour necrosis factor receptor-1 (sTNFR-1) in pg/ml
timeFrame: 10 days
measure: interleukin 18 in pg/ml
timeFrame: 10 days
measure: CRP in mg/L
timeFrame: 10 days
measure: phospho-p38 and phospho-ERK (activated MAPKs) in mean fluorescence intensity(MFI)
timeFrame: 10 days
measure: phospho-inhibitor kB/IkB (NF-kB) in mean fluorescence intensity(MFI)
timeFrame: 10 days
measure: resolution of symptoms in days
timeFrame: 28 days
measure: ICU admission in days
timeFrame: 28 days
measure: mortality in days
timeFrame: 28 days
measure: Incidence of Treatment-Emergent Adverse Events in numbers
timeFrame: 28 days
measure: a six step ordinal scale of clinical status
timeFrame: 7 days
Other outcomes:
Locations:
city: Hong Kong
country: Hong Kong
facility: Prince of Wales Hospital
Study officials:
affiliation: Chinese University of Hong Kong
name: David SC Hui, MD
role: PRINCIPAL_INVESTIGATOR
References: