Adjunctive Sirolimus and Oseltamivir Versus Oseltamivir Alone for Treatment of Influenza

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

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.

Study Overview

• Status: Recruiting
• Conditions: Influenza
• Intervention / Treatment: Drug: sirolimus and oseltamivir; Drug: Oseltamivir

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.

• Study Type: Interventional
• Enrollment (Estimated): 160
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Ken Ka Pang Chan, MBChB; Phone Number: 3505 3532; Email: chankapang@cuhk.edu.hk

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong
    • Recruiting
    • Prince of Wales Hospital
    • Contact: Ken Ka Pang Chan; Phone Number: 3505 3532; Email: chankapang@cuhk.edu.hk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: oseltamivir and adjunctive sirolimus; 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; 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.
Placebo Comparator: oseltamivir alone; 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; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Chinese University of Hong Kong
• Investigators: Principal Investigator: David SC Hui, Chinese University of Hong Kong

Study record dates

Study Major Dates

• Study Start (Actual): May 8, 2023
• Primary Completion (Estimated): October 31, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: March 30, 2019
• First Submitted That Met QC Criteria: April 1, 2019
• First Posted (Actual): April 3, 2019

Study Record Updates

• Last Update Posted (Actual): November 27, 2023
• Last Update Submitted That Met QC Criteria: November 24, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Mortality; cytokines; respiratory; chemokines
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Orthomyxoviridae Infections; Influenza, Human; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Sirolimus; Oseltamivir
• Other Study ID Numbers: Sirolimus influenza/Hui/2019

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No