Clinical trial NCT03401398: Stress Hydrocortisone In Pediatric Septic Shock
Official title: Stress Hydrocortisone In Pediatric Septic Shock
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Septic Shock
Keywords: hydrocortisone
refractory septic shock
sepsis
new/progressive MODS
mortality
health-related quality of life
corticosteroid adverse events
sepsis biomarkers
Lead sponsor: Seattle Children's Hospital
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: Canadian Institutes of Health Research (CIHR)
name: Canadian Critical Care Trials Group
name: Children's Hospital of Eastern Ontario
First posted: 2018-01-17
Enrollment: 500
Sex: ALL
Minimum age (years): 1
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients randomized to the hydrocortisone treatment arm will receive an initial bolus of 2 mg/kg IV hydrocortisone (maximum 100 mg), 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. Patients randomized to the placebo treatment arm will receive an equivalent volume of normal saline, with the identical dosing schedule outlined above.
Primary purpose: TREATMENT

Brief 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).

Detailed 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 500 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, 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.

Eligibility criteria: 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. Patient admitted directly to the PICU with a thermal burn who has been in the PICU for \<72 hours prior to meeting SHIPSS inclusion criteria.
12. (U.S. sites only) Patient in the custody of US protective services
13. Patient being evaluated for brain death
14. Vasoactive-inotropic agents prescribed solely for an indication other than septic shock
15. Confirmed dengue fever

Primary outcomes:
measure: New or progressive multiple organ dysfunction syndrome as assessed utilizing the Pediatric Logistic Organ Dysfunction (PELOD-2) instrument.
timeFrame: 28 days following study enrollment
Secondary outcomes:
measure: 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)
timeFrame: 28 days following study enrollment
Other outcomes:
measure: SHIPSS specified adverse events
timeFrame: 28 days following study enrollment
measure: Risk stratification sepsis biomarkers and pediatric sepsis endotype
timeFrame: Enrollment and Day 2
measure: Trichotomous mortality/morbidity outcome
timeFrame: 28 and 90 days following study enrollment
measure: 90-Day Death or ≥25% decrease in HRQL from baseline
timeFrame: 90 days following study enrollment
measure: Vasoactive-inotropic infusion-free days through day 28
timeFrame: 28 days following study enrollment
measure: Mechanical ventilation-free days through day 28
timeFrame: 28 days following study enrollment
measure: Utilization of acute renal replacement therapy (RRT)
timeFrame: Enrollment to PICU discharge, an average of 2 weeks
measure: Utilization of extracorporeal membrane oxygenation (ECMO)
timeFrame: Enrollment to PICU discharge, an average of 2 weeks
measure: Functional status - POPC
timeFrame: 28 and 90 days following study enrollment
measure: Functional status - FSS
timeFrame: 28 and 90 days following study enrollment
measure: PICU-free days through day 28
timeFrame: 28 days following study enrollment
measure: Hospital-free days through day 28
timeFrame: 28 days following study enrollment
measure: Hospital-free days through day 90
timeFrame: 90 days following study enrollment
measure: Need for new medical devices at hospital discharge
timeFrame: At time of hospital discharge, expected to be an average of 21 days from time of enrollment
measure: Frequency of primary care, specialty care, and emergency department visits and hospital readmissions
timeFrame: 90 days following study enrollment
measure: Disruption of family dynamics
timeFrame: Enrollment and 90 days following study enrollment
measure: Cost Analysis - Cost of PICU admission for septic shock
timeFrame: 90 days following study enrollment
Locations:
city: Tucson
country: United States
facility: University of Arizona Medical Centre
state: Arizona
city: Los Angeles
country: United States
facility: Children's Hospital of Los Angeles
state: California
city: Oakland
country: United States
facility: UCSF Benioff Children's Hospital - Oakland
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: San Francisco
country: United States
facility: UCSF Benioff Children's Hospital - San Francisco
state: California
city: Wilmington
country: United States
facility: Nemours Children's Health
state: Delaware
city: Chicago
country: United States
facility: University of Chicago, Comer Children's Hospital
state: Illinois
city: Peoria
country: United States
facility: The University of Illinois at Chicago/OSF Children's Hospital of Illinois
state: Illinois
city: Louisville
country: United States
facility: University of Louisville, Norton Children's Hospital
state: Kentucky
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Livingston
country: United States
facility: Saint Barnabas Medical Center
state: New Jersey
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Oklahoma City
country: United States
facility: The Children's Hospital at Oklahoma University Medical Center
state: Oklahoma
city: Hershey
country: United States
facility: Penn State Milton S. Hershey Children's Hospital
state: Pennsylvania
city: Memphis
country: United States
facility: Le Bonheur Children's Hospital
state: Tennessee
city: Salt Lake City
country: United States
facility: Primary Children's Hospital
state: Utah
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Madison
country: United States
facility: University of Wisconsin Health/American Family Children's Hospital
state: Wisconsin
city: Bahia
country: Brazil
facility: Santa Casa de Misericordia Da Bahia
city: Rio de Janeiro
country: Brazil
facility: Hospital Jutta Batista - Rio de Janeiro
city: Rio de Janeiro
country: Brazil
facility: Hospital Jutta Batista
city: São Paulo
country: Brazil
facility: Hospital Alvorada Taguatinga LTDA
city: São Paulo
country: Brazil
facility: HOSPITAL SINO BRASILEIRO - Hospital São Luiz Osasco
city: São Paulo
country: Brazil
facility: Real e Benemérita Associação Portuguesa de Beneficência/SP
city: São Paulo
country: Brazil
facility: REDE D'OR SAO LUIZ S.A. - Hospital São Luiz Anália Franco
city: São Paulo
country: Brazil
facility: REDE D'OR SAO LUIZ S.A. - Hospital São Luiz Vila Lobos
city: Calgary
country: Canada
facility: Alberta Children's Hospital
state: Alberta
city: Vancouver
country: Canada
facility: BC Children's Hospital
state: British Columbia
city: Halifax
country: Canada
facility: IWK Health Centre
state: Nova Scotia
city: Hamilton
country: Canada
facility: McMaster Children's Hospital
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Ottawa
country: Canada
facility: Children's Hospital of Eastern Ontario
state: Ontario
city: Montréal
country: Canada
facility: Centre hospitalier universitaire Sainte-Justine
state: Quebec
city: Montréal
country: Canada
facility: Montreal Children's Hospital
state: Quebec
city: Québec
country: Canada
facility: Centre hospitalier de l'Université Laval
state: Quebec
city: Saskatoon
country: Canada
facility: Royal University Hospital
state: Saskatchewan
city: Haifa
country: Israel
facility: Rambam Health Care Campus
city: Jerusalem
country: Israel
facility: Hadassah University Medical Center, Ein Kerem
city: Petah Tikva
country: Israel
facility: Schneider Children's Medical Center of Israel
city: Kobe
country: Japan
facility: Kobe Children's Hospital
city: Nagoya
country: Japan
facility: Aichi Children's Health and Medical Center
city: Tokyo
country: Japan
facility: Tokyo Metropolitan Children's Medical Center
city: Kuala Lumpur
country: Malaysia
facility: UKM Specialist Children's Hospital
city: Kuala Lumpur
country: Malaysia
facility: University Malaya Medical Centre
city: Kuching
country: Malaysia
facility: Sarawak General Hospital
city: Islamabad
country: Pakistan
facility: Shifa International Hospital
city: Karachi
country: Pakistan
facility: Aga Khan University Hospital
city: Riyadh
country: Saudi Arabia
facility: King Abdullah Specialist Children's Hospital
city: Singapore
country: Singapore
facility: KK Women's and Children's Hospital
city: Hanoi
country: Vietnam
facility: Vietnam National Children's Hospital
city: Ho Chi Minh City
country: Vietnam
facility: City Children's Hospital
Study officials:
affiliation: Seattle Children's Hospital, University of Washington School of Medicine
name: Jerry J Zimmerman MD, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Boston Children's Hospital, Harvard Medical School
name: Michael Agus, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital Medical Center, Cincinnati
name: Hector R Wong, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Boston Children's Hospital, Harvard Medical School
name: David Wypij, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital of Eastern Ontario
name: Kusum Menon, MD, MSc
role: PRINCIPAL_INVESTIGATOR
References: