Early Intravenous Hydrocortisone in Sepsis (EARL-HYDRO)

Early Intravenous Hydrocortisone in Sepsis: a Randomized Control Trial

The goal of this clinical trial is to compare two timings of steroid treatment in patients with severe infection who develop low blood pressure.

The main question it aims to answer is:

• Which timing strategy is better between starting steroid treatment very early in the course of severe infection, or waiting until the patient does not respond to medicine that raises blood pressure according to the current guidelines?

Participants will receive either early steroid treatment or placebo right after they develop low blood pressure from infection. Both participants and treating doctors will not know which treatment participants received. When blood pressure goal is not reached after a moderate dose of drugs that raise blood pressure, an open-label steroid treatment will be given to participants as indicated in the current guidelines.

Study Overview

• Status: Recruiting
• Conditions: Shock, Septic; Sepsis Severe
• Intervention / Treatment: Drug: Early hydrocortisone; Drug: Open-label hydrocortisone; Drug: Normal saline placebo

Detailed Description

ENROLLMENT AND RANDOMIZATION Once patients meet the eligibility criteria, the treating physicians will notify one of the study investigators to invite the patients or the legal representatives to participate in the study. Written informed consent will be obtained before randomization. Each patient will be randomly assigned in a 1:1 ratio by the sequential enrollment numbers to receive early intravenous low-dose hydrocortisone (the EH group) or standard care. Randomization is performed using a computer-generated sequence in the permuted block of 4 by the investigator who is not involving patient enrollment and assessment. The other investigators, the patients or their representatives, and the treating physicians are all blinded to the group assignment. Patients may withdraw from the study for any reason at any time. The investigators or the treating physician may also withdraw the patients from the study for safety reasons at any time.

STUDY PROTOCOL AND INTERVENTIONS Blood will be drawn from the patients in both groups at the time of randomization for baseline interleukin-6, interleukin-10, tumor necrosis factor, procalcitonin, C-reactive protein, and cortisol levels. All patients will receive standard treatment and investigation for septic shock including standard laboratory analysis, antibiotics, infection source control, intravenous crystalloids, vasopressors, and organ support as directed by the treating physicians according to the Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021.

The study drug (low-dose hydrocortisone versus placebo) will be prepared by a pharmacist who has no role in the study, according to the sequential enrollment numbers. The study drugs will be packaged in identical containers labeled with sequential enrollment numbers. After randomization, the study drugs will be administered as soon as possible by the nurses who have no role in the study. For the early hydrocortisone (EH) group, 50 mg of hydrocortisone in 10 ml of normal saline will be given as an intravenous bolus, then 200 mg of hydrocortisone in 100 ml of normal saline will be given as continuous intravenous infusion in 24 hours for 2 consecutive days (total 250 mg in day 1 and 200 mg in day 2). For the standard care group, a bolus of 10 ml of normal saline will be given, then 100 ml of normal saline will be given as continuous intravenous infusion in 24 hours for 2 consecutive days as a sham control. After completion of the study drugs for 2 days, the study drug will be discontinued without tapering.

An open-label 50 mg of hydrocortisone given as an intravenous bolus followed by intravenous hydrocortisone 200 mg/day given as continuous infusion or divided bolus administration is suggested to be commenced in both study arms if the hemodynamic goal of the patient is not reached despite the dose of norepinephrine or epinephrine ≥ 0.25 mcg/kg/min at least 4 hours after the initiation of the vasopressors as recommended by the guideline. The study drug in each arm will be discontinued once an open-label hydrocortisone is initiated. Capillary or venous blood glucose will be tested at least every 6 hours for 2 days then at least once daily or more as appropriate for the first 7 days as a part of the study protocol.

The group allocation will be unblinded per request of the treating physicians or the principal investigators if the patient develops one of the following conditions: hyperglycemic emergencies, hypoglycemia, or active gastrointestinal hemorrhage within 7 days after randomization, undifferentiated hypotension or suspected adrenal insufficiency within 72 hours after the cessation of the study drug, and conditions related to hydrocortisone that the treating physicians concern to be harmful or potentially harmful to the patients.

The study protocol will be terminated if hyperglycemic emergencies, or active gastrointestinal hemorrhage develop during receiving the study drug. The investigators or the treating physician may also stop the study drug for safety reasons at any time.

STATISTICAL ANALYSIS Data will be analyzed according to an intention-to-treat principle for the primary analysis. The EH group will be compared against the usual care group for the main analysis of the primary outcomes and secondary outcomes. Continuous outcomes will be compared using an independent t-test or the Mann-Whitney U test as appropriate. The result will be reported as an absolute difference with a corresponding 95% confidence interval (CI). Chi-square or Fisher exact test will be employed as appropriate for comparing binary outcomes. Multivariate regression analyses will also be performed for the primary and secondary outcomes adjusted for potential confounders. Potential factors will be tested and selected as confounders for the model when the p-value is less than 0.2 in the univariate analysis. The result will be reported as adjusted OR (aOR) with 95% CI. For all statistical analyses, a p-value of less than 0.05 is considered statistically significant unless defined otherwise.

Prespecified subgroup analyses will be conducted based on the hypothesis that patients with higher inflammatory biomarkers would benefit more from early hydrocortisone. The median value of each inflammatory biomarker and cortisol level will be used as cut-off values for the exposures (highly-elevated versus low inflammatory biomarker groups). Subgroup analyses will be performed using multivariable logistic regression models adjusted for confounders with interaction terms. The result will be reported as adjusted OR (aOR) with 95% CI for each inflammatory biomarker.

A single interim analysis for risk monitoring and safety will be performed after a total recruitment of 115 patients (50% of the total sample size). A significance level of 0.001 is selected as a stopping rule for harm, based on Haybittle-Peto method. The trial will be stopped early if there is a significantly higher rate of 28-day mortality at the significance level of ≤ 0.001.

• Study Type: Interventional
• Enrollment (Estimated): 230
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Wasin Pansiritanachot, MD; Phone Number: 66896808508; Email: dr.wasinpan@gmail.com
• Study Contact Backup: Name: Chairat Permpikul, MD; Phone Number: +66 81-408-1676; Email: chairat.per@mahidol.ac.th

Study Locations

• Thailand
  • Bangkok
    • Bangkoknoi, Bangkok, Thailand, 10700
      • Recruiting
      • Faculty of Medicine Siriraj Hospital, Mahidol University
      • Sub-Investigator: Surat Tongyoo, MD
      • Contact: Wasin Pansiritanachot, MD; Phone Number: +66896808508; Email: dr.wasinpan@gmail.com
      • Contact: Chairat Permpikul, MD
      • Principal Investigator: Chairat Permpikul, MD
      • Sub-Investigator: Wasin Pansiritanachot, MD
      • Sub-Investigator: Tipa Chakorn, MD
      • Sub-Investigator: Patimaporn Wongprompitak, PhD
      • Sub-Investigator: Sansanee Senawong, MD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age of 18 years or older
• Suspected or definite sepsis Sepsis is defined by SEPSIS-3 definition as Sequential Organ Failure Assessment (SOFA) score ≥ 2 from baseline with suspected infection.2 Suspected sepsis is defined as patients with suspected infection who meet 2 or more criteria of quick SOFA (altered mentation, respiratory rate ≥ 22/min, systolic blood pressure ≤ 100 mmHg).
• Hypotension (mean arterial pressure < 65 mmHg)

Exclusion Criteria:

• Randomization and administration of the study drugs are not able to be executed within 3 hours after the onset of hypotension
• Causes of shock other than sepsis identified
• Immunocompromised A patient is considered immunocompromised if one of the following criteria is met: history of human immunodeficiency virus infection or acquired immunodeficiency syndrome, hematologic malignancy, receiving chemotherapy, active cancer receiving chemotherapy, current use of immunosuppressive medication)
• Hyperglycemic crisis (diabetic ketoacidosis, hyperosmolar hyperglycemic state)
• Pregnancy
• Post-cardiac arrest
• Received etomidate before randomization
• Systemic corticosteroids indicated for other conditions
• Received systemic corticosteroids within 4 weeks at any dose
• Cancer patients who are receiving palliative treatment
• Do-not-resuscitate order

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Early hydrocortisone; After randomization, low-dose hydrocortisone will be administered as soon as possible	Drug: Early hydrocortisone; For the Early Hydrocortisone group, 50 mg of hydrocortisone in 10 ml of normal saline will be given as an intravenous bolus, then 200 mg of hydrocortisone in 100 ml of normal saline will be given as continuous intravenous infusion in 24 hours for 2 consecutive days (total 250 mg in day 1 and 200 mg in day 2). After completion of the study drugs for 2 days, the study drug will be discontinued without tapering.; Drug: Open-label hydrocortisone; An open-label 50 mg of hydrocortisone given as an intravenous bolus followed by intravenous hydrocortisone 200 mg/day given as continuous infusion or divided bolus administration is suggested to be commenced in both study arms if the hemodynamic goal of the patient is not reached despite the dose of norepinephrine or epinephrine ≥ 0.25 mcg/kg/min at least 4 hours after the initiation of the vasopressors as recommended by the guideline. The study drug in each arm will be discontinued once an open-label hydrocortisone is initiated. Capillary or venous blood glucose will be tested at least every 6 hours for 2 days then at least once daily or more as appropriate for the first 7 days as a part of the study protocol.
Placebo Comparator: Standard care; Low-dose hydrocortisone will be given when indicated according to the current Surviving Sepsis Campaign Guidelines	Drug: Open-label hydrocortisone; An open-label 50 mg of hydrocortisone given as an intravenous bolus followed by intravenous hydrocortisone 200 mg/day given as continuous infusion or divided bolus administration is suggested to be commenced in both study arms if the hemodynamic goal of the patient is not reached despite the dose of norepinephrine or epinephrine ≥ 0.25 mcg/kg/min at least 4 hours after the initiation of the vasopressors as recommended by the guideline. The study drug in each arm will be discontinued once an open-label hydrocortisone is initiated. Capillary or venous blood glucose will be tested at least every 6 hours for 2 days then at least once daily or more as appropriate for the first 7 days as a part of the study protocol.; Drug: Normal saline placebo; For the Standard Care group, a bolus of 10 ml of normal saline will be given, then 100 ml of normal saline will be given as continuous intravenous infusion in 24 hours for 2 consecutive days as a sham control. After completion of the study drugs for 2 days, the study drug will be discontinued without tapering.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
28-day mortality	Death within 28 days after randomization. Patients who are discharged alive before 28 days are considered to have no 28-day mortality.	From randomization to 28 days after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to shock control	Shock control is defined as achievement of sustained mean arterial pressure ≥ 65 mm Hg or higher for at least 30 minutes together with evidence of adequate tissue perfusion (urine flow at more than 0.5 ml/kg/h for 2 consecutive hours, or decreased in serum lactate by more than 10% from the initial lactate level)	From randomization to shock control, assessed up to 28 days
In-hospital mortality	Death during the current hospitalization	From randomization to the end of hospitalization, assessed up to 3 months
Hospital length of stay	Days from randomization to hospital discharge or death	From randomization to hospital discharge or death, assessed up to 3 months
Ventilator-free day	Ventilator-free day is defined as the number of days that patients were alive and free of ventilators up to day 28. Patients who die before day 28 will be assigned zero free day.	From randomization to 28 days after randomization
Vasopressor-free day	Vasopressor-free day is defined as the number of days that patients were alive and free of vasopressor up to day 28. Patients who die before day 28 will be assigned zero free day.	From randomization to 28 days after randomization
Number of participants with newly initiation of renal replacement therapy	Newly initiation of renal replacement therapy (RRT) includes the initiation of RRT in any modes in previously non-dialysis patients, or the initiation of sustained low-efficiency dialysis (SLED) or continuous RRT (CRRT) in previously hemodialysis patients. Routine hemodialysis in end-stage renal disease patients is not considered meeting a secondary outcome.	From randomization to hospital discharge or death, assessed up to 3 months
Fluid received in 24 hours	Fluid received in 24 hours includes resuscitation fluid (crystalloids and colloids) and maintenance fluid. Fluid used for dilution of intravenous drugs will not be included	From randomization to 24 hours after randomization
Fluid received in 72 hours	Fluid received in 72 hours includes resuscitation fluid (crystalloids and colloids) and maintenance fluid. Fluid used for dilution of intravenous drugs will not be included	From randomization to 72 hours after randomization
Highest vasopressor dose	The highest vasopressor dose will be reported as a norepinephrine-equivalent dose	From randomization to shock control, assessed up to 28 days
Number of participants with gastrointestinal hemorrhage	Gastrointestinal hemorrhage includes both upper and lower gastrointestinal tract bleeding.	From randomization to 28 days after randomization
Number of participants with superinfection	Superinfection is defined as a new infection occurring 48 hours or more after the initiation of a study drug.	48 hours after initiation of the study drug to 28 days after randomization
Number of participants with hyperglycemia	Hyperglycemia is defined as an episode of plasma glucose or capillary blood glucose > 180 mg/dL after the initiation of the study drug.	From initiation of the study drug to 7 days after randomization

Collaborators and Investigators

• Sponsor: Siriraj Hospital
• Investigators: Principal Investigator: Chairat Permpikul, MD, Mahidol University

Study record dates

Study Major Dates

• Study Start (Actual): June 25, 2024
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): September 1, 2026

Study Registration Dates

• First Submitted: December 29, 2023
• First Submitted That Met QC Criteria: January 11, 2024
• First Posted (Actual): January 23, 2024

Study Record Updates

• Last Update Posted (Actual): January 7, 2026
• Last Update Submitted That Met QC Criteria: January 5, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: shock; sepsis; hydrocortisone; early
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathological Conditions, Signs and Symptoms; Sepsis; Shock; Shock, Septic; Anti-Inflammatory Agents; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate
• Other Study ID Numbers: Si 917/2023

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices).
• IPD Sharing Time Frame: Beginning 3 months and ending 3 years following article publication
• IPD Sharing Access Criteria: Researchers who provide a methodologically sound proposal
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE; CSR

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