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)

INTERVENTION: Product Name: , Product Code:SCP10332310, Pharmaceutical Form: , Other descriptive name: , Strength: , Product Name: , Product Code:SCP259874, Pharmaceutical Form: , Other descriptive name: , Strength: , Product Name: CELLULOSE, MICROCRYSTALLINE, Product Code:SUB12626MIG, Pharmaceutical Form: ORAL POWDER, Other descriptive name: , Strength: , Pharmaceutical form of the placebo: ORAL POWDER CONDITION: Severe Influenza ; MedDRA version: 24.0Level: PTClassification code: 10069767Term: H1N1 influenza Class: 100000004862 Therapeutic area: Diseases [C] ‐ Respiratory Tract Diseases [C08] Therapeutic area: Diseases [C] ‐ Virus Diseases [C02] INCLUSION CRITERIA: Aged = 18 years., 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)., Hospitalized patients with an estimated hospital stay of more than 24 hours., In previous treatment or concomitant start of treatment with oseltamivir., For women of childbearing age, use of contraceptive methods until day 30 after completion of treatment., Signed informed consent. PRIMARY OUTCOME: Main Objective: 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. Primary end point(s): 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 Objective: 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. To compare the frequency of serious adverse effects between groups (grades 3, 4 and 5 on the CTCAE scale)., 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. To compare the average hospital stay (expressed in days) according to treatment group., 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. To compare mortality at days 10, 30 and 90 post‐randomization., 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. To evaluate the impact of steroid treatment on the evolution of the nasal microbiome expressed in alpha diversity., 9. To evaluate the kinetics of influenza virus in nasopharyngeal swabs (using Ct and viral quantification per human cell) in both groups., 10. To evaluate the impact of treatment on inflammatory markers (CRP, PCT, IL‐6, IL‐10). SECONDARY OUTCOME: Secondary end point(s):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. Secondary end point(s):Amplicon Sequence Variants (ASV's), defined as specific DNA sequence obtained from techniques of massive sequencing and that identifies different taxa. Secondary end point(s):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. Secondary end point(s):Death: death from any cause, whether or not related to influenza (or its complications) in the opinion of the investigator. Secondary end point(s):Dependency index: measured with the Barthel inde Xwith a score from 0 to 100. Questionnaire that evaluates individual capabilities in 10 basic activities of daily living (Anne XIV.‐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. Secondary end point(s):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 (Anne XVI). Secondary end point(s):Evaluation of the impact of steroid treatment on the nasal microbiome: evaluation of alpha diversity variation (using Inde Xof 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 (Anne XVI). Secondary end point(s):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 (Anne XVI). Secondary end point(s):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 (Anne XIV.‐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. Secondary end point(s):Hospital stay: expressed in days, taken from the discharge date and date of admission. Secondary end point(s):Need or not for invasive mechanical ventilation (IMV) with the admission/discharge date. Secondary end point(s):Need or not for non‐invasive mechanical ventilation (NIMV), with the start/end date. Secondary end point(s):Shannon index, defined as the quantification inde Xof diversity and richness of microbial species, evaluates quantity and equity of its distribution. Secondary end point(s):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).