Adjunctive Sirolimus and Oseltamivir Versus Oseltamivir Alone for Treatment of Influenza

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomized Controlled Trial of Adjunctive Sirolimus and Oseltamivir Versus Oseltamivir Alone for Treatment of Influenza

Conditions
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Influenza

Intervention / Treatment
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* Drug: sirolimus and oseltamivir
* Drug: Oseltamivir


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: randomized trial into either oseltamivir and adjunctive sirolimus or oseltamivir alone
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: oseltamivir and adjunctive sirolimus<br>Sirolimus 1 mg daily and oseltamivir 75 mg bid for 5 days, both given orally. Extension of dosing to 10 days for oseltamivir and the study drug is allowed if there is slow recovery, lack of improvement, or deterioration. | Drug: sirolimus and oseltamivir<br>* Sirolimus 1 mg daily and oseltamivir 75 mg bid for 5 days, both given orally. Extension of dosing to 10 days for oseltamivir and the study drug is allowed if there is slow recovery, lack of improvement, or deterioration.<br>|
| Placebo Comparator: oseltamivir alone<br>oral oseltamivir 75 mg bid alone 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. | Drug: Oseltamivir<br>* oral oseltamivir 75 mg bid alone 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| normalisation of respiratory status | SaO2 ≥93% or respiratory rate ≤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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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respiratory, Mortality, cytokines, chemokines