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

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ClinicalTrials.gov Identifier: NCT03900988
Recruitment Status : Not yet recruiting
First Posted : April 3, 2019
Last Update Posted : May 8, 2019
Sponsor:
Information provided by (Responsible Party):
Prof David Shu Cheong Hui, Chinese University of Hong Kong

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.

Condition or disease Intervention/treatment Phase
Influenza Drug: N-acetyl cysteine Drug: 5% Dextrose Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 160 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Primary Purpose: Treatment
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.
Estimated Study Start Date : August 1, 2019
Estimated Primary Completion Date : July 31, 2021
Estimated Study Completion Date : July 31, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Flu Flu Shot

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.




Primary Outcome Measures :
  1. Normalization of respiratory status in day [ Time Frame: 28 days ]
    oxygen saturation more than 93% or respiratory rate lower than 20/min on room air


Secondary Outcome Measures :
  1. viral ribonucleic acid (RNA) in copies per milliliter [ Time Frame: 28 days ]
    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')

  2. Interleukin 6 in pg/ml [ Time Frame: 10 days ]
  3. interleukin-8 in pg/ml [ Time Frame: 10 days ]
  4. interleukin 17 in pg/ml [ Time Frame: 10 days ]
  5. Chemokine ligand 9 (CxCL9/MIG) in pg/ml [ Time Frame: 10 days ]
  6. Soluble tumour necrosis factor receptor-1 (sTNFR-1) in pg/ml [ Time Frame: 10 days ]
  7. interleukin 18 in pg/ml [ Time Frame: 10 days ]
  8. CRP in mg/L [ Time Frame: 10 days ]
  9. phospho-p38 and phospho-ERK (activated MAPKs) in mean fluorescence intensity(MFI) [ Time Frame: 10 days ]
  10. phospho-inhibitor kB/IkB (NF-kB) in mean fluorescence intensity(MFI) [ Time Frame: 10 days ]
  11. resolution of symptoms in days [ Time Frame: 28 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.

  12. ICU admission in days [ Time Frame: 28 days ]
  13. mortality in days [ Time Frame: 28 days ]
  14. Incidence of Treatment-Emergent Adverse Events in numbers [ Time Frame: 28 days ]
  15. a six step ordinal scale of clinical status [ Time Frame: 7 days ]
    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



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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,
  • presenting within 5 days from illness onset,
  • 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)
  • ability to provide written informed consent.

Exclusion Criteria:

  • use of systemic corticosteroids (except for those who need low dose hydrocortisone 50mg qid for refractory septic shock)
  • use of other immunosuppressants (e.g. post-chemotherapy, post-transplant, autoimmune diseases)
  • known immuno-compromised conditions (e.g. active haematological malignancies, HIV/AIDS),
  • pregnancy
  • lactation,
  • end-stage renal failure
  • hepatic failure
  • cardiac failure
  • patients on anticoagulation,
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03900988


Contacts
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Contact: Susanna So-Shan Ng, MBChB 852 3505 2785 drsssng@gmail.com

Sponsors and Collaborators
Chinese University of Hong Kong
Investigators
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Principal Investigator: David SC Hui, MD Chinese University of Hong Kong

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Responsible Party: Prof David Shu Cheong Hui, Professor, Chinese University of Hong Kong
ClinicalTrials.gov Identifier: NCT03900988     History of Changes
Other Study ID Numbers: NAC Influenza/Hui/2019
First Posted: April 3, 2019    Key Record Dates
Last Update Posted: May 8, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Prof David Shu Cheong Hui, Chinese University of Hong Kong:
respiratory, mortality, cytokines, chemokines, N-acetylcysteine (NAC)

Additional relevant MeSH terms:
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Acetylcysteine
N-monoacetylcystine
Influenza, Human
Respiratory Tract Infections
Orthomyxoviridae Infections
RNA Virus Infections
Virus Diseases
Respiratory Tract Diseases
Infection
Oseltamivir
Antiviral Agents
Anti-Infective Agents
Expectorants
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Antidotes
Enzyme Inhibitors