Adaptive RCT of Corticosteroids for Severe Influenza Pneumonia in Adults (CAPSTONE-IFV)

An Embedded Adaptive Randomized Controlled Trial of Corticosteroid Therapy for Severe Influenza Community-Acquired Pneumonia in Adults

Severe community-acquired pneumonia caused by influenza virus (hereafter referred to as severe influenza pneumonia) is a major etiology of community-acquired pneumonia leading to acute respiratory failure and ICU admission. It can rapidly progress to profound hypoxemia, acute respiratory distress syndrome (ARDS), and multiple organ dysfunction, and remains associated with substantial mortality. Although antiviral therapy-typically neuraminidase inhibitors-and well-established organ-support strategies are currently available, outcomes in a subset of critically ill patients remain poor despite antiviral and supportive care alone, with ICU mortality reported to be as high as 20-30%. Therefore, identifying effective adjunctive interventions beyond standard care to further reduce mortality in severe influenza pneumonia is of great clinical importance for improving outcomes in critically ill patients and alleviating the burden on families and society.

However, the use of systemic corticosteroids in influenza-associated community-acquired pneumonia (CAP) has long been highly controversial. Multiple studies have suggested that corticosteroid therapy may increase mortality among patients with H1N1 influenza. During the early phase of the COVID-19 pandemic, treatment strategies drew on this evidence and generally advised caution regarding corticosteroid use; subsequently, randomized controlled trials (RCTs) such as RECOVERY and REMAP-CAP demonstrated that low-dose corticosteroids (e.g., dexamethasone 6 mg/day) reduce mortality in patients with pneumonia requiring oxygen therapy. Recently, the U.S. Centers for Disease Control and Prevention (CDC) has emphasized the urgent need for RCTs evaluating low- to moderate-dose corticosteroids or other immunomodulatory agents to clarify their role in the management of influenza-associated CAP. Collectively, these observations underscore the urgency of pathogen-directed anti-inflammatory strategies for CAP-associated acute respiratory failure.

Accordingly, we plan to conduct an adaptive, randomized, open-label, controlled trial to evaluate the efficacy and safety of adjunctive corticosteroid regimens at different doses, in addition to early standard supportive care (including guideline-concordant antiviral therapy and organ support), for reducing mortality in patients with severe influenza pneumonia.

Study Overview

• Status: Not yet recruiting
• Conditions: Influenza
• Intervention / Treatment: Drug: Saline (0.9%, sterile, for infusion); Drug: low dose Methylprednisolone; Drug: Moderate dose Methylprednisolone

• Study Type: Interventional
• Enrollment (Estimated): 496
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 18 years.
• Admission to the Intensive Care Unit (ICU).
• Meeting the diagnostic criteria for community-acquired pneumonia (CAP).

• Meeting at least one of the major diagnostic criteria for severe pneumonia:

  (i) Requirement for endotracheal intubation and mechanical ventilation;

(ii) Septic shock requiring vasopressor therapy after adequate fluid resuscitation.

-Or simultaneously fulfilling three of the minor criteria:

(i) Respiratory rate ≥ 30 breaths/min;

(ii) PaO₂/FiO₂ ≤ 250 mmHg;

(iii) Multilobar infiltrates;

(iv) Altered mental status and/or disorientation;

(v) Blood urea nitrogen ≥ 20 mg/dL (7.12 mmol/L);

(vi) Leukopenia (white blood cell count < 4 × 10⁹/L);

(vii) Thrombocytopenia (platelet count < 100 × 10⁹/L);

(viii) Hypothermia (core temperature < 36 °C);

(ix) Hypotension (systolic blood pressure < 90 mmHg) requiring aggressive fluid resuscitation.

• Confirmed influenza virus etiology: at least one positive nucleic acid test (RT-PCR/PCR) or next-generation sequencing (NGS) result for influenza virus in respiratory specimens (respiratory secretions, throat swabs, or bronchoalveolar lavage fluid).
• Severe community-acquired pneumonia (SCAP) patients admitted to the emergency department/ward/ICU due to respiratory failure within < 72 hours.
• Signed informed consent.

Exclusion Criteria:

• Patients receiving vasopressor therapy for septic shock at the time of enrollment.
• Terminally ill patients (expected survival <30 days, e.g., advanced malignancy).
• Clinical history suggesting overt aspiration.
• Documented active gastrointestinal bleeding.
• Presence of cystic fibrosis, obstructive pneumonia, active influenza, pulmonary tuberculosis, or fungal infection.
• Active viral hepatitis or active herpesvirus infection.
• Bone marrow suppression or HIV infection.
• Refusal of mechanical ventilation and endotracheal intubation.
• Uncontrolled hyperglycemia (diabetic ketoacidosis with blood ketones >3 mmol/L, or hyperosmolar hyperglycemic state with blood glucose >33.3 mmol/L and elevated osmolality).
• Known allergy to corticosteroids.
• Patients requiring anti-inflammatory corticosteroids or replacement hydrocortisone for any reason, or those already receiving prednisone >15 mg/day (or equivalent dose of another corticosteroid).
• Pregnant or breastfeeding women.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Standard of Care; Control group	Drug: Saline (0.9%, sterile, for infusion); Sailine as control
Experimental: Low dose steroids; treated with low dose corticosteroids	Drug: low dose Methylprednisolone; Methylprednisolone 0.5mg/kg ivgtt qd
Experimental: Moderate dose steroids; treated with moderate dose corticosteroids	Drug: Moderate dose Methylprednisolone; Methylprednisolone 1.0mg/kg ivgtt qd

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
28-day all cause mortality	28 days from inclusion

Collaborators and Investigators

• Sponsor: Qingyuan Zhan

Study record dates

Study Major Dates

• Study Start (Estimated): January 15, 2026
• Primary Completion (Estimated): November 30, 2028
• Study Completion (Estimated): November 30, 2028

Study Registration Dates

• First Submitted: January 12, 2026
• First Submitted That Met QC Criteria: January 12, 2026
• First Posted (Actual): January 20, 2026

Study Record Updates

• Last Update Posted (Actual): January 20, 2026
• Last Update Submitted That Met QC Criteria: January 12, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Influenza; corticosteroids; community-acquired pneumonia; adaptive randomised controled trial
• Additional Relevant MeSH Terms: Respiratory Tract Infections; Infections; Orthomyxoviridae Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Pneumonia; Community-Acquired Infections; Influenza, Human; Community-Acquired Pneumonia; Polycyclic Compounds; Inorganic Chemicals; Chlorine Compounds; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Pregnadienetriols; Prednisolone; Sodium Compounds; Chlorides; Hydrochloric Acid; Methylprednisolone; Sodium Chloride
• Other Study ID Numbers: 2025-I2M-C&T-B-090C

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

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