Clinical trial NCT03901001: Adjunctive Sirolimus and Oseltamivir Versus Oseltamivir Alone for Treatment of Influenza
Official title: A Randomized Controlled Trial of Adjunctive Sirolimus and Oseltamivir Versus Oseltamivir Alone for Treatment of Influenza
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Influenza
Keywords: respiratory
Mortality
cytokines
chemokines
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
Intervention model description: randomized trial into either oseltamivir and adjunctive sirolimus or oseltamivir alone
Primary purpose: TREATMENT

Brief summary: Seasonal influenza epidemics are important causes of mortality and morbidity. Cytokine dysregulation, with high levels of pro-inflammatory cytokines, occurs in patients with severe influenza A(H1N1)pdm09 virus infection, A(H5N1) infection, and A(H7N9) infection. We aim to investigate the effects of adjunctive sirolimus in adults hospitalized with influenza A or B infections involving the lower respiratory tract.

Detailed description: The investigators aim to investigate the effects of adjunctive sirolimus in adults hospitalized with influenza A or B infections involving the lower respiratory tract. Patients will be randomized to either oseltamivir and adjunctive sirolimus or oseltamivir alone and assessed with reference to normalization of respiratory status (SaO2 ≥93% or respiratory rate ≤20/min on room air) as the primary endpoint,10 cytokines/chemokines and pro-inflammatory mediator changes, viral clearance, symptom resolution, ICU admission/death, day 28 mortality; safety profiles will also be assessed.

The investigators hypothesize that addition of sirolimus to oseltamivir would improve respiratory status and other endpoints more effectively than oseltamivir alone through reduction of inflammatory responses without affecting viral clearance.

Eligibility criteria: Inclusion Criteria:

* influenza A and B virus infections confirmed by 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, crepitations on auscultation, infiltrations or consolidations on chest radiograph) and 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 other immunosuppressants (e.g. post-chemotherapy, post-transplant, autoimmune diseases) other than systemic corticosteroids
* patients with known immuno-compromised conditions (e.g. active haematological malignancies, HIV/AIDS patients who are on antiretroviral therapy and CD4 cell count \< 200)
* pregnancy/lactation
* hepatic failure
* patients with surgery done/planned within 1 month
* patients who have received macrolide antibiotics and NSAID for 1 week prior to enrolment due to their immuno-modulating effects
* patients on drugs that may interact and alter sirolimus level (rifampicin, azole antifungals, phenytoin, diltiazem, verapamil, nicardipine, metoclopramide, phenobarbital, carbamazepine) will be excluded for safety purposes
* Use of investigational anti-influenza antivirals and blood products

Primary outcomes:
measure: normalisation of respiratory status
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
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
role: PRINCIPAL_INVESTIGATOR
References: