Adjunctive Fludrocortisone in Septic Shock

Official title

Adjunctive Fludrocortisone in Septic Shock: a Multicenter, Double-blind, Randomized, Placebo-controlled Pilot Trial (AFLUDROS-1)

Overview

Sepsis is a life-threatening condition caused by the body's dysregulated response to an infection. While corticosteroids are known to help stabilize blood pressure in septic shock, their ability to reduce mortality is still debated. Recent analyses suggest that combining fludrocortisone with hydrocortisone may be more effective at saving lives than hydrocortisone alone. To test this hypothesis, a large, definitive international trial is needed. However, this research proposal is for a smaller pilot study (Phase II) involving 32 critically ill patients. The primary goal of this pilot is to determine the feasibility of conducting the subsequent large-scale trial that would compare hydrocortisone alone against the combination therapy and potentially change medical practice.

Detailed description

Design: Pilot, multicenter, randomized, double-blind, placebo-controlled trial on use of adjunctive fludrocortisone in critically ill patients with septic shock.

Objective: Determine feasibility of conducting a large, international, multicenter, double-blind, randomized, placebo controlled efficacy trial of adjunctive fludrocortisone to improve septic shock mortality.

Setting: 6 intensive care units (ICU) in Hong Kong, Australia and Singapore. Participants: 32 adult participants with suspected or confirmed septic shock within 24 hours of onset of shock and mechanical ventilation. Exclusion criteria are pregnancy, limitation of therapy, prescribed fludrocortisone for other medical condition, fludrocortisone cannot be administered within 24 hours of shock onset.

Interventions: Enteral 100 mcg fludrocortisone daily or placebo for up to 7 days or until death or discharge from ICU, whichever comes first.

Main outcome measures: Primary outcome is fulfillment of all pre-specified endpoints of feasibility criteria: protocol deviation \<15%, lost of concealment \<10%, drop out rate \<10% and missing data \<10%. Secondary outcomes include monthly recruitment rate, time to resolution of shock, 28-day mortality, days alive and free from organ support, severe electrolyte abnormality.

Data analysis: Each feasibility criterion will be assessed amongst all study participants. Intention to treat analysis will be used to calculate differences in secondary outcomes between treatment groups.

Expected results: Feasibility criteria will be met and demonstrate potential to scale-up to a large, international, multicenter, double-blind, randomized, placebo-controlled trial of adjunctive fludrocortisone to improve septic shock mortality.

Interventions

• Drug Fludrocortisone 100 mcg daily
  Patients will be given enteral fludrocortisone 100 mcg daily for 7 days or until discharge from ICU or death, whichever comes first. All patients will be treated with 7 days of intravenous hydrocortisone 50 mg every 6 hours for 7 days from randomization or until discharge from ICU or death, whichever comes first.
• Drug Placebo
  Patients will be given an enteral placebo tablet for 7 days or until discharge from ICU or death, whichever comes first. All patients will be treated with 7 days of intravenous hydrocortisone 50 mg every 6 hours for 7 days from randomization or until discharge from ICU or death, whichever comes first.

Primary outcome measures

• Number of Protocol deviations < 15% [Time frame: End of study approximately 20 months]
• Number of Lost of concealment < 10% [Time frame: End of study approximately 20 months]
• Number of Drop out < 10% [Time frame: End of study approximately 20 months]
• Number of Missing data < 10% [Time frame: End of study approximately 20 months]

Secondary outcome measures (9)

• Number of Monthly Recruitment [Time frame: End of study approximately 20 months]
• Time to resolution of shock [Time frame: Until patient discharge from ICU]
• 28-day mortality [Time frame: First 28 days after enrollment]
• Days alive and vasopressor-free until day 28 [Time frame: First 28 days after enrollment]
• Days alive and ventilator-free until day 28 [Time frame: First 28 days after enrollment]
• Days alive and dialysis-free until day 28 [Time frame: First 28 days after enrollment]
• Days alive and free from organ support [Time frame: First 28 days after enrollment]
• Number of new onset infections [Time frame: First 28 days after enrollment]
• Severe electrolyte abnormality [Time frame: First 7 days after enrollment]

Eligibility criteria

Inclusion criteria

• suspected or confirmed adult sepsis as defined by ≥ 2 increase in Sequential Organ Failure Assessment (SOFA) score due to infection
• ≥0.25 μg/kg/min of noradrenaline infusion or vasoactive-inotropic score (VIS) ≥25 to maintain mean arterial pressure (MAP) ≥65 mmHg for at least 1 hour
• onset of septic shock within 24 hours
• shock due to infection with no other proven or apparent cause
• hypoperfusion defined as arterial or venous lactate concentration >2.0 mmol/L
• mechanical ventilation

Exclusion criteria

• fludrocortisone cannot be administered within 24 hours of onset of septic shock
• death is deemed imminent or inevitable by treating clinicians
• limitation of therapy
• an underlying disease process with a life expectancy of less than 90 days
• pregnancy (confirmed or suspected)
• receiving immunomodulatory agents including hydrocortisone > 300mg/day
• enteral medication cannot be administered
• prescribed fludrocortisone for other medical condition
• contraindication to hydrocortisone or fludrocortisone

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Hong Kong · 5 centers

• North District Hospital — Hong Kong
• Pamela Youde Nethersole Hospital — Hong Kong
• Prince of Wales Hospital — Hong Kong
• Princess Margaret Hospital — Hong Kong
• Queen Mary Hospital — Hong Kong

Identifiers

NCT: NCT07451886 · 2024.398

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗