Randomised, double-blind, multicentre, phase III clinical trial to evaluate the efficacy and safety of dexamethasone compared to placebo in patients with severe influenza (FLUDEX)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fundacion De La Comunitat Valenciana Para La Gestion Del Instituto De Investigacion Sanitaria Y Biomedica De Alicante

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08], Diseases [C] - Virus Diseases [C02]

Trial duration

20 Nov 2024 → ongoing

Decision date (initial)

2024-10-22

Transition trial

No

Low-intervention

Yes

Rare-disease indication

No

Vulnerable population

No

Funding sources

Carlos III Health Institute (ISCIII)

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

To compare the percentage of patients hospitalized with influenza according to treatment arm (oseltamivir-dexamethasone vs oseltamivir-placebo) with status 3 or higher according to the Hospital Recovery Scale (status 3: hospitalization with supplemental oxygen, or 4: ICU admission without invasive mechanical ventilation, or 5: with invasive mechanical ventilation, or 6: death) on day 7 after the start of treatment.

Secondary objectives 10

1. 1. To compare the time, in days, between initiation of treatment and clinical stability according to the NEWS2<2 scale for 24 hours or until hospital discharge, taking the value of the first of the two events to occur.
2. 2. To compare the frequency of serious adverse effects between groups (grades 3, 4 and 5 on the CTCAE scale).
3. 3. To evaluate the metabolic impact of dexamethasone by comparing the function of occurrence of sustained hyperglycemia level 1 and 2, and episodes of hyperglycemia during and at the end of dexamethasone treatment.
4. 4. To compare the average hospital stay (expressed in days) according to treatment group.
5. 5. To compare the function of occurrence over time of clinical failure, defined as progression to: need for ICU admission, need for intubation or death.
6. 6. To compare mortality at days 10, 30 and 90 post-randomization.
7. 7. To evaluate the impact of treatment on dependency (Barthel Index) and frailty (Clinical Frailty Score) at the time of discharge or at the end of treatment, and at 30 and 90 days after randomization.
8. 8. To evaluate the impact of steroid treatment on the evolution of the nasal microbiome expressed in alpha diversity.
9. 9. To evaluate the kinetics of influenza virus in nasopharyngeal swabs (using Ct and viral quantification per human cell) in both groups.
10. 10. To evaluate the impact of treatment on inflammatory markers (CRP, PCT, IL-6, IL-10).

Conditions and MedDRA coding

Severe Influenza

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Aged ≥ 18 years.
2. Diagnosis of influenza A or B virus infection by antigen or RT-PCR (local laboratory) at the time of entry or at 48 hours prior to randomization in respiratory specimens (nasopharyngeal swab or bronchoalveolar lavage).
3. Hospitalized patients with an estimated hospital stay of more than 24 hours.
4. In previous treatment or concomitant start of treatment with oseltamivir.
5. For women of childbearing age, use of contraceptive methods until day 30 after completion of treatment.
6. Signed informed consent.

Exclusion criteria 7

1. Patients with bronchial hyperresponsiveness that requires systemic corticosteroids for more than 24 hours.
2. Pre-inclusion treatment with corticosteroids for more than 24 hours at a dose equal to or higher than 1 mg/kg methyl-prednisolone (0.2 mg/kg dexamethasone or 1.25 mg/kg prednisone).
3. Inability to administer oral oseltamivir.
4. Patients on ECMO (extracorporeal membrane oxygenation).
5. Pre-existing condition or use of medication that, in the opinion of the local investigator, may pose a risk for the administration of corticosteroids.
6. Patients with severe comorbidity with life expectancy of less than six months in the opinion of the investigator.
7. Patients co-infected with SARS-CoV-2 or RSV.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Percentage of patients in status greater than or equal to 3 (3,4,5 or 6) according to the Hospital Recovery Scale (HRS) on day 7 after the start of treatment.

Secondary endpoints 14

1. Time elapsed in days between the start of treatment and clinical stability, defined by NEWS-2<2 scale for >24 hours or hospital discharge (first event).
2. Hospital stay: expressed in days, taken from the discharge date and date of admission.
3. Admission to the ICU: from any cause, and related or not to influenza (or its secondary complications) in the opinion of the researcher. Discharge date and date of admission.
4. Need or not for non-invasive mechanical ventilation (NIMV), with the start/end date.
5. Need or not for invasive mechanical ventilation (IMV) with the admission/discharge date.
6. Death: death from any cause, whether or not related to influenza (or its complications) in the opinion of the investigator.
7. Clinical failure: defined as clinical progression requiring admission to the ICU, invasive mechanical ventilation or death (from any cause) within 72 hours after the start of treatment in the control or experimental arm. Date.
8. Dependency index: measured with the Barthel index with a score from 0 to 100. Questionnaire that evaluates individual capabilities in 10 basic activities of daily living (Annex IV.-C). It will be measured at the baseline visit (with reference to the 15 days prior to admission), at the end of treatment or at hospital discharge (whichever comes first) and at follow-up visits 30 and 90.
9. Frailty index: measured by the Rockhood scale or Clinical Frailty Score that classifies on a scale of 1 to 8 according to the level of dependency and which serves as a global clinical measure of physical fitness and frailty (Annex IV.-D). It will be measured at the baseline visit (with reference to the 15 days prior to admission), at the end of treatment or at hospital discharge (whichever comes first) and at follow-up visits 30 and 90.
10. Evaluation of the impact of steroid treatment on the nasal microbiome: evaluation of alpha diversity variation (using Index of Shannon, number of ASV's) and determination of the differential taxa based on the outcome variables on day 10 post-randomization with respect to the baseline determination (Annex VI).
11. Shannon index, defined as the quantification index of diversity and richness of microbial species, evaluates quantity and equity of its distribution.
12. Amplicon Sequence Variants (ASV's), defined as specific DNA sequence obtained from techniques of massive sequencing and that identifies different taxa.
13. Evaluation of viral kinetics: quantification of viral load by Ct (cycle number 10-40) and total RNA/mcg DNA copies at basal level, day 2, 5 and 10 (Annex VI).
14. Evaluation of the impact of inflammation markers: measurement of leukocytes, lymphocytes, CRP, PCT (optional), total number of leukocytes and lymphocytes, IL-1 and IL6 will be carried out at baseline, day 2, 5, 7 and 10 (Annex VI).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fundacion De La Comunitat Valenciana Para La Gestion Del Instituto De Investigacion Sanitaria Y Biomedica De Alicante

Sponsor organisation

Fundacion De La Comunitat Valenciana Para La Gestion Del Instituto De Investigacion Sanitaria Y Biomedica De Alicante

Address

Edificio Gris, Avenida Pintor Baeza 12 Avenida Pintor Baeza 12

City

Alicante

Postcode

03010

Country

Spain

Scientific contact point

Organisation

Fundacion De La Comunitat Valenciana Para La Gestion Del Instituto De Investigacion Sanitaria Y Biomedica De Alicante

Contact name

Javier Mateo

Public contact point

Organisation

Fundacion De La Comunitat Valenciana Para La Gestion Del Instituto De Investigacion Sanitaria Y Biomedica De Alicante

Contact name

Javier Mateo

Locations

1 EU/EEA country · 11 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 13 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications