Stress Hydrocortisone In Pediatric Septic Shock

Septic Shock Clinical Trial

— SHIPSS  

Official title:

Stress Hydrocortisone In Pediatric Septic Shock

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03401398
• Other study ID #: IRB-P00027662
• Secondary ID: 1R01HD096901-01
• Status: Recruiting
• Phase: Phase 3
• Start date: March 11, 2019
• Est. completion date: December 31, 2026

Study information

• Verified date: May 2024
• Source: Seattle Children's Hospital
• Contact: Jerry J Zimmerman, MD, PhD
• Phone: 206-987-3862
• Email: jerry.zimmerman[@]seattlechildrens.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

SHIPSS is a multi-institutional, prospective, controlled, randomized, double-blinded interventional trial that will examine the potential benefits and risks of adjunctive hydrocortisone prescribed for children with fluid and vasoactive-inotropic refractory septic shock.

It is hypothesized that adjunctive hydrocortisone will significantly reduce the incidence of new and progressive organ dysfunction (primary outcome) and proportion of children with poor outcomes, defined as death or severely impaired health-related quality of life (HRQL) (secondary outcome), as assessed at 28 days following study enrollment (randomization).

Description:

Sepsis represents the most common cause of childhood mortality worldwide. In the United States alone, 200 cases of pediatric sepsis are diagnosed each day, with an associated hospital mortality rate of 5-10% and health care expenditures now approaching $5 billion annually. Moreover, nearly one third of children admitted to pediatric intensive care units (PICUs) for septic shock have not regained their baseline health-related quality of life one year following the sepsis event.

During early resuscitation of the child with septic shock, in addition to antibiotics, volume replacement, and vasoactive-inotropic support, the most recent pediatric treatment guidelines advise the practitioner to consider adjunctive hydrocortisone therapy if the patient "is at risk of absolute adrenal insufficiency or adrenal pituitary axis failure". However, the potential benefits and risks of this recommendation have not been rigorously examined. On the one hand, corticosteroids are inexpensive and have been frequently demonstrated to improve hemodynamic status in children and adults with sepsis. Conversely, this drug class is known to alter transcription of approximately 30% of the human genome. Notably, corticosteroids down regulate most aspects of the immune response, but particularly adaptive immunity. Moreover, recent data suggests that children with particular gene expression profiles in sepsis have increased likelihood of mortality when treated with corticosteroids.

SHIPSS (Stress Hydrocortisone In Pediatric Septic Shock) is a prospective, randomized, double-blinded, placebo-controlled trial examining the potential benefits and risks of adjunctive hydrocortisone prescribed to critically ill children with fluid and vasoactive-inotropic refractory septic shock. Up to 1,032 children will be enrolled, randomized, and evaluated at baseline, and 28 and 90 days following study enrollment.

The primary hypothesis is that hydrocortisone, compared to placebo, will decrease the the incidence of new or progressive organ dysfunction (primary outcome) and the proportion of subjects with poor outcomes, defined as death or severely impaired (≥25% decrease from baseline) HRQL (secondary outcome). Subjects will be monitored daily while receiving care in the PICU for the occurrence of adverse events, including the following protocol specified events:hyperglycemia treated with any insulin; gastrointestinal hemorrhage treated with blood product transfusion or vasopressin or octreotide infusion; delirium requiring medical treatment; and hospital-acquired infection treated with new antimicrobials. Finally, the investigators will test the hypothesis that biomarker-based prognostic and predictive enrichment strategies can improve our ability to identify which children with septic shock are more likely to benefit from adjunctive hydrocortisone, and which may be harmed. This trial will have a significant impact on public health by providing the heretofore missing evidence to inform guidelines regarding therapy for septic shock in children.

The SHIPSS trial will enroll patients from PICUs in Canada, the United States, Saudi Arabia, Israel, Brazil, Vietnam, Pakistan, Japan, China, Malaysia, and Singapore. Health Canada approval is not required as hydrocortisone is approved for use in septic shock in children, and this trial meets the criteria of a Phase IV study. In the United States, this trial is considered a Phase III trial as hydrocortisone is not approved for use in pediatric septic shock.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 500
• Est. completion date: December 31, 2026
• Est. primary completion date: September 30, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Month to 17 Years

Eligibility

Inclusion Criteria:

A child receiving treatment in a pediatric intensive care unit is eligible for recruitment into SHIPSS if she/he meets all of the following inclusion criteria:

1. Age is at least 1 month (with corrected gestational age =42 weeks), but less than 17 years and 8 months of age

2. A documented focus of infection or a strong suspicion of infection at PICU admission, or for patients who develop septic shock during PICU stay, at the onset of the septic shock event

3. Surveillance cultures (e.g. blood, urine, cerebral spinal fluid, wound) and/or other microbial diagnostic tests have been obtained

4. One or more antimicrobials have been prescribed

5. Core temperature >38.5 C or <36.0 C or leukocytosis or leukopenia (as defined by the local laboratory) or a left-shifted leukocyte differential (>10% immature granulocyte forms) or a neutrophil count of <0.5 x 109 cells per litre documented at least once within the 24 hours preceding screening

6. Treatment with a continuous infusion of vasoactive-inotropic agent(s) to maintain mean or systolic arterial blood pressure above the age-appropriate target set by the treating clinician

7. Administration of two or more vasoactive-inotropic agents at any dose or epinephrine or norepinephrine infusion(s) alone at greater than or equal to 0.10 mcg/kg/min for >1 hour.

Exclusion Criteria:

A child receiving treatment in a pediatric intensive care unit for sepsis is ineligible for enrollment into SHIPSS if she/he meets any of the following exclusion criteria:

1. All inclusion criteria have been present for > 12 hours

2. Attending physician expects to prescribe systemic corticosteroids for an indication other than septic shock

3. Patient has received any doses of systemic corticosteroids during treatment for sepsis

4. Enrolled concurrently in a competing interventional clinical trial (formal assessment to be conducted by SHIPSS Core Committee for each potential competing trial)

5. Etomidate or ketoconazole treatment within past 48 hours

6. Patient in whom steroids are contraindicated at time of screening (e.g. treatment for systemic fungal infection, cerebral malaria, strongyloides)

7. Known or suspected hypothalamic, pituitary or adrenal disease (including patient has received acute or chronic corticosteroid administration and the physician intends to provide corticosteroid for suspected adrenal suppression)

8. Attending physician, PICU care team, or legally recognized guardians not committed to full treatment and resuscitation at the time of screening

9. Patient documented to be pregnant

10. Previous enrollment in the SHIPSS study

11. Primary disease/injury is a thermal burn

12. (U.S. sites only) Patient in the custody of US protective services

13. Patient being evaluated for brain death

Related Conditions & MeSH terms

• Septic Shock
• Shock
• Shock, Septic

Intervention

Drug:
• Hydrocortisone, sodium succinate
Patients randomized to the hydrocortisone treatment arm will receive an initial bolus of 2 mg/kg IV hydrocortisone, followed by 1 mg/kg (maximum 50 mg) of hydrocortisone dosed every six hours for a maximum of seven days or until all vasoactive infusions have been discontinued for at least 12 hours, whichever comes first. When the hydrocortisone course is completed, the medication will be discontinued.
• Normal saline
Patients randomized to the placebo treatment arm will receive an equivalent volume of normal saline, with the identical dosing schedule to the intervention (hydrocortisone) arm.

Locations

Country	Name	City	State
Canada	Alberta Children's Hospital	Calgary	Alberta
Canada	IWK Health Centre	Halifax	Nova Scotia
Canada	McMaster Children's Hospital	Hamilton	Ontario
Canada	London Health Sciences Centre	London	Ontario
Canada	Centre hospitalier universitaire Sainte-Justine	Montréal	Quebec
Canada	Montreal Children's Hospital	Montréal	Quebec
Canada	Children's Hospital of Eastern Ontario	Ottawa	Ontario
Canada	Centre hospitalier de l'Université Laval	Québec	Quebec
Canada	Royal University Hospital	Saskatoon	Saskatchewan
Canada	BC Children's Hospital	Vancouver	British Columbia
China	He Nan Children's hospital	Zhengzhou
Israel	Rambam Health Care Campus	Haifa
Israel	Hadassah University Medical Center, Ein Kerem	Jerusalem
Israel	Schneider Children's Medical Center of Israel	Petah Tikva
Japan	Kobe Children's Hospital	Kobe
Japan	Aichi Children's Health and Medical Center	Nagoya
Japan	Tokyo Metropolitan Children's Medical Center	Tokyo
Malaysia	UKM Specialist Children's Hospital	Kuala Lumpur
Malaysia	University Malaya Medical Centre	Kuala Lumpur
Malaysia	Sarawak General Hospital	Kuching
Pakistan	Shifa International Hospital	Islamabad
Pakistan	Aga Khan University Hospital	Karachi
Saudi Arabia	King Abdullah Specialist Children's Hospital	Riyadh
Singapore	KK Women's and Children's Hospital	Singapore
United States	Boston Children's Hospital	Boston	Massachusetts
United States	University of Chicago, Comer Children's Hospital	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Penn State Milton S. Hershey Children's Hospital	Hershey	Pennsylvania
United States	Saint Barnabas Medical Center	Livingston	New Jersey
United States	Children's Hospital of Los Angeles	Los Angeles	California
United States	University of Louisville, Norton Children's Hospital	Louisville	Kentucky
United States	University of Wisconsin Health/American Family Children's Hospital	Madison	Wisconsin
United States	Le Bonheur Children's Hospital	Memphis	Tennessee
United States	UCSF Benioff Children's Hospital - Oakland	Oakland	California
United States	The Children's Hospital at Oklahoma University Medical Center	Oklahoma City	Oklahoma
United States	Children's Hospital of Orange County	Orange	California
United States	The University of Illinois at Chicago/OSF Children's Hospital of Illinois	Peoria	Illinois
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	UCSF Benioff Children's Hospital - San Francisco	San Francisco	California
United States	Seattle Children's Hospital	Seattle	Washington
United States	University of Arizona Medical Centre	Tucson	Arizona
United States	Nemours Children's Health	Wilmington	Delaware
Vietnam	Vietnam National Children's Hospital	Hanoi
Vietnam	City Children's Hospital	Ho Chi Minh City

Sponsors (5)

Lead Sponsor	Collaborator
Jerry Zimmerman	Canadian Critical Care Trials Group, Canadian Institutes of Health Research (CIHR), Children's Hospital of Eastern Ontario, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Countries where clinical trial is conducted

United States,  Vietnam,  Canada,  China,  Israel,  Japan,  Malaysia,  Pakistan,  Saudi Arabia,  Singapore, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	SHIPSS specified adverse events	Occurrence of adverse events plausibly associated with corticosteroid administration. SHIPSS specified events include hyperglycemia, gastrointestinal hemorrhage, delirium, and hospital-acquired infection	28 days following study enrollment
Other	Risk stratification sepsis biomarkers and pediatric sepsis endotype	Risk stratification sepsis biomarkers will be measured in serum obtained at enrollment and on Day 2. The PERSEVERE (PEdiatRic SEpsis biomarkEr Risk modEl) will be used to determine the patient's risk of mortality. mRNA will be isolated from blood samples collected at enrollment and on Day 2 to classify the patient as pediatric septic shock Endotype B or A. A composite outcome of sepsis endotype and PERSEVERE risk of mortality will be used to determine if a biomarker-based prognostic model and predictive enrichment strategies allow identification of children with septic shock more likely to benefit from adjunctive hydrocortisone. We hypothesize that pediatric septic shock "endotype B" subjects having an intermediate to high Pediatric Sepsis Biomarker Risk Model (PERSEVERE)-based risk of mortality will derive significant benefit from adjunctive corticosteroids, compared to endotype B subjects having a low risk and endotype A subjects at all risk levels.	Enrollment and Day 2
Other	Trichotomous mortality/morbidity outcome	This is a 3-level ordinal endpoint, with levels death, survival with severely impaired HRQL (=25% decrease from baseline), and survival without severely impaired HRQL, assessed at 28 and 90 days. This approach is similar to that recently reported for assessment of functional status among children encountering critical illness, utilizing the Functional Status Scale. This endpoint is expected to be highly correlated with the primary efficacy endpoint.	28 and 90 days following study enrollment
Other	90-Day Death or =25% decrease in HRQL from baseline	Mortality or =25% decrease in PedsQL from baseline	90 days following study enrollment
Other	Vasoactive-inotropic infusion-free days through day 28	Vasoactive-inotropic infusion-free days through day 28 is defined as 28 minus duration of vasoactive-inotropic infusions. Subjects who die or are still receiving vasoactive-inotropic infusions by day 28 will be censored at 28 days and assigned zero vasoactive-inotropic infusion-free days.	28 days following study enrollment
Other	Mechanical ventilation-free days through day 28	Mechanical ventilation-free days through day 28 is defined as 28 minus duration of mechanical ventilation. Subjects who die, are still receiving mechanical ventilation, or are transferred from the PICU still receiving mechanical ventilation by day 28 will be censored at 28 days and assigned zero mechanical ventilation-free days.	28 days following study enrollment
Other	Utilization of acute renal replacement therapy (RRT)	Proportion of subjects receiving acute RRT. All types of acute RRT will be considered, including hemodialysis, continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis (CVVHD), and peritoneal dialysis. RRT in patients on chronic RRT will not be considered.	Enrollment to PICU discharge, an average of 2 weeks
Other	Utilization of extracorporeal membrane oxygenation (ECMO)	Proportion of subjects receiving ECMO	Enrollment to PICU discharge, an average of 2 weeks
Other	Functional status - POPC	Gross functional status category staging will be made using the Pediatric Overall Performance Category (POPC) score.	28 and 90 days following study enrollment
Other	Functional status - FSS	Functional Status Scale (FSS) will be employed to provide a more granular determination of changes in functional status.	28 and 90 days following study enrollment
Other	PICU-free days through day 28	PICU-free days through day 28 is defined as 28 minus duration of PICU stay. Subjects who die or are still in the PICU by day 28 will be censored at 28 days and assigned zero PICU-free days.	28 days following study enrollment
Other	Hospital-free days through day 28	Hospital-free days through day 28 is defined as 28 minus duration of hospital stay. Subjects who die or are still in the hospital by day 28 will be censored at 28 days and assigned zero hospital-free days through day 28.	28 days following study enrollment
Other	Hospital-free days through day 90	Hospital-free days through day 90 is defined as 90 minus duration of hospital stay. Subjects who die or are still in the hospital by day 90 will be censored at 90 days and assigned zero hospital-free days through day 90.	90 days following study enrollment
Other	Need for new medical devices at hospital discharge	New medical devices prescribed at hospital discharge will be collected from the hospital discharge summary.	At time of hospital discharge, expected to be an average of 21 days from time of enrollment
Other	Frequency of primary care, specialty care, and emergency department visits and hospital readmissions	Enumeration of additional health care evaluations following the index hospital admission will occur by telephone survey at 90 days.	90 days following study enrollment
Other	Disruption of family dynamics	The PedsQLTM 2.0 Family Impact Module will be used to quantify the impact of septic shock on family dynamics.	Enrollment and 90 days following study enrollment
Other	Cost Analysis - Cost of PICU admission for septic shock	The cost of each patients PICU admission will be determined by summing the cost of the following: PICU and hospital length of stay, frequency of primary care, specialty care, emergency department visits, and hospital readmissions up to 90 days following hospital discharge, new medical devices post hospital discharge and hospital costs of the admission for septic shock.	90 days following study enrollment
Primary	New or progressive multiple organ dysfunction syndrome as assessed utilizing the Pediatric Logistic Organ Dysfunction (PELOD-2) instrument.	Appearance of new or progression of existing organ dysfunctions according to PELOD-2 definitions. PELOD-2 considers 5 organ dysfunctions (neurological, cardiovascular, renal, respiratory, and hematological) with 10 total variables, with dysfunction scored 0 up to 6 for each organ category. Total minimum/maximal scores are 0/33, with increasing score indicating increasing risk of mortality. Logit (mortality) = -6.61 + 0.47 × PELOD-2 score. Probability of death = 1/(1 + exp [-logit(mortality)]). A new organ dysfunction or progression of organ dysfunction is defined as an increase score in any organ category from baseline.	28 days following study enrollment
Secondary	28-day hospital mortality or =25% decrease from baseline in health-related quality of life (HRQL) assessed utilizing the Pediatric Quality of Life Inventory, (PedsQL)	Mortality or =25% decrease in PedsQL from baseline	28 days following study enrollment

External Links

•   Website for SHIPSS investigation