Adjunctive Sirolimus and Oseltamivir Versus Oseltamivir Alone for Treatment of Influenza

Influenza Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03901001
• Other study ID #: Sirolimus influenza/Hui/2019
• Status: Recruiting
• Phase: Phase 3
• Start date: May 8, 2023
• Est. completion date: December 31, 2025

Study information

• Verified date: November 2023
• Source: Chinese University of Hong Kong
• Contact: Ken Ka Pang Chan, MBChB
• Phone: 3505 3532
• Email: chankapang[@]cuhk.edu.hk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 160
• Est. completion date: December 31, 2025
• Est. primary completion date: October 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Influenza
• Influenza, Human

Intervention

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.
• 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.

Locations

Country	Name	City	State
Hong Kong	Prince of Wales Hospital	Hong Kong

Sponsors (1)

Lead Sponsor	Collaborator
Chinese University of Hong Kong

Country where clinical trial is conducted

Hong Kong, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	normalisation of respiratory status	SaO2 =93% or respiratory rate =20/min on room air	28 days
Secondary	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
Secondary	Interleukin 6 in pg/ml		10 days
Secondary	interleukin-8 in pg/ml		10 days
Secondary	interleukin 17 in pg/ml		10 days
Secondary	Chemokine ligand 9 (CxCL9/MIG) in pg/ml		10 days
Secondary	Soluble tumour necrosis factor receptor-1 (sTNFR-1) in pg/ml		10 days
Secondary	interleukin 18 in pg/ml		10 days
Secondary	CRP in mg/L		10 days
Secondary	phospho-p38 and phospho-ERK (activated MAPKs) in mean fluorescence intensity(MFI)		10 days
Secondary	phospho-inhibitor kB/IkB (NF-kB) in mean fluorescence intensity(MFI)		10 days
Secondary	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
Secondary	ICU admission in days		28 days
Secondary	mortality in days		28 days
Secondary	Incidence of Treatment-Emergent Adverse Events in numbers		28 days