Early Intravenous Hydrocortisone in Sepsis

Shock, Septic Clinical Trial

Official title:

Early Intravenous Hydrocortisone in Sepsis: a Randomized Control Trial

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06217939
• Other study ID #: Si 917/2023
• Status: Not yet recruiting
• Phase: N/A
• Start date: April 2024
• Est. completion date: July 2025

Study information

• Verified date: March 2024
• Source: Siriraj Hospital
• Contact: Wasin Pansiritanachot, MD
• Phone: 66896808508
• Email: dr.wasinpan[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 230
• Est. completion date: July 2025
• Est. primary completion date: March 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Sepsis
• Shock, Septic
• Toxemia

Intervention

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.
• 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.
• 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.

Locations

Country	Name	City	State
Thailand	Faculty of Medicine Siriraj Hospital, Mahidol University	Bangkoknoi	Bangkok

Sponsors (1)

Lead Sponsor	Collaborator
Siriraj Hospital

Country where clinical trial is conducted

Thailand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	In-hospital mortality	Death during the current hospitalization	From randomization to the end of hospitalization, assessed up to 3 months
Secondary	Hospital length of stay	Days from randomization to hospital discharge or death	From randomization to hospital discharge or death, assessed up to 3 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Number of participants with gastrointestinal hemorrhage	Gastrointestinal hemorrhage includes both upper and lower gastrointestinal tract bleeding.	From randomization to 28 days after randomization
Secondary	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
Secondary	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