Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
PHASE3
500 participants
INTERVENTIONAL
2019-03-11
2026-12-31
Brief Summary
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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).
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
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Treatment
Approximately half of the subjects randomized into SHIPSS will be randomized into the Treatment Group and will receive hydrocortisone sodium succinate according to a predetermined dosing schedule.
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.
Placebo
Approximately half of the subjects randomized into SHIPSS will be randomized into the Placebo Group and will receive equivalent study drug volumes of normal saline.
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.
Interventions
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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.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
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.
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
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
1 Month
17 Years
ALL
No
Sponsors
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Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
NIH
Canadian Institutes of Health Research (CIHR)
OTHER_GOV
Canadian Critical Care Trials Group
OTHER
Children's Hospital of Eastern Ontario
OTHER
Jerry Zimmerman
OTHER
Responsible Party
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Jerry Zimmerman
Professor of Pediatrics/Anesthesiology, University of Washington School of Medicine
Principal Investigators
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Jerry J Zimmerman MD, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Seattle Children's Hospital, University of Washington School of Medicine
Michael Agus, MD
Role: PRINCIPAL_INVESTIGATOR
Boston Children's Hospital, Harvard Medical School
Mihir R Atreya, MD, MPH
Role: PRINCIPAL_INVESTIGATOR
Children's Hospital Medical Center, Cincinnati
David Wypij, PhD
Role: PRINCIPAL_INVESTIGATOR
Boston Children's Hospital, Harvard Medical School
Kusum Menon, MD, MSc
Role: PRINCIPAL_INVESTIGATOR
Children's Hospital of Eastern Ontario
Locations
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University of Arizona Medical Centre
Tucson, Arizona, United States
Children's Hospital of Los Angeles
Los Angeles, California, United States
UCSF Benioff Children's Hospital - Oakland
Oakland, California, United States
Children's Hospital of Orange County
Orange, California, United States
UCSF Benioff Children's Hospital - San Francisco
San Francisco, California, United States
Nemours Children's Health
Wilmington, Delaware, United States
University of Chicago, Comer Children's Hospital
Chicago, Illinois, United States
The University of Illinois at Chicago/OSF Children's Hospital of Illinois
Peoria, Illinois, United States
University of Louisville, Norton Children's Hospital
Louisville, Kentucky, United States
Boston Children's Hospital
Boston, Massachusetts, United States
Saint Barnabas Medical Center
Livingston, New Jersey, United States
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States
The Children's Hospital at Oklahoma University Medical Center
Oklahoma City, Oklahoma, United States
Penn State Milton S. Hershey Children's Hospital
Hershey, Pennsylvania, United States
Le Bonheur Children's Hospital
Memphis, Tennessee, United States
Primary Children's Hospital
Salt Lake City, Utah, United States
Seattle Children's Hospital
Seattle, Washington, United States
University of Wisconsin Health/American Family Children's Hospital
Madison, Wisconsin, United States
Santa Casa de Misericordia Da Bahia
Bahia, , Brazil
Hospital Jutta Batista - Rio de Janeiro
Rio de Janeiro, , Brazil
Alberta Children's Hospital
Calgary, Alberta, Canada
BC Children's Hospital
Vancouver, British Columbia, Canada
IWK Health Centre
Halifax, Nova Scotia, Canada
McMaster Children's Hospital
Hamilton, Ontario, Canada
London Health Sciences Centre
London, Ontario, Canada
Children's Hospital of Eastern Ontario
Ottawa, Ontario, Canada
Centre hospitalier universitaire Sainte-Justine
Montreal, Quebec, Canada
Montreal Children's Hospital
Montreal, Quebec, Canada
Centre hospitalier de l'Université Laval
Québec, Quebec, Canada
Royal University Hospital
Saskatoon, Saskatchewan, Canada
Rambam Health Care Campus
Haifa, , Israel
Hadassah University Medical Center, Ein Kerem
Jerusalem, , Israel
Schneider Children's Medical Center of Israel
Petah Tikva, , Israel
Kobe Children's Hospital
Kobe, , Japan
Aichi Children's Health and Medical Center
Nagoya, , Japan
UKM Specialist Children's Hospital
Kuala Lumpur, , Malaysia
University Malaya Medical Centre
Kuala Lumpur, , Malaysia
Sarawak General Hospital
Kuching, , Malaysia
Shifa International Hospital
Islamabad, , Pakistan
Aga Khan University Hospital
Karachi, , Pakistan
King Abdullah Specialist Children's Hospital
Riyadh, , Saudi Arabia
KK Women's and Children's Hospital
Singapore, , Singapore
Vietnam National Children's Hospital
Hanoi, , Vietnam
City Children's Hospital
Ho Chi Minh City, , Vietnam
Countries
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Central Contacts
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Facility Contacts
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Katri Typpo, MD
Role: primary
Christopher Newth, MD
Role: primary
Natalie Cvijanovich, MD
Role: primary
Adam Schwarz, MD
Role: primary
Catherine Madurski, MD
Role: primary
Grace Chong, MD
Role: primary
Sandeep Tripath, MD
Role: primary
John Berkenbosch, MD
Role: primary
Michael Agus, MD
Role: primary
Shira J Gertz, MD
Role: primary
Ranjit R Chima, MD
Role: primary
Christine Allen, MD
Role: primary
Robert Kavanagh, MD
Role: primary
Samir Shah, MD
Role: primary
Jennifer Workman, MD
Role: primary
Jerry J Zimmerman, MD, PhD
Role: primary
Pelin Cengiz, MD
Role: primary
Megan Mahoney, MD
Role: primary
Neeraj Verma, MD
Role: primary
Karen Choong, MD
Role: primary
Douglas Fraser, MD
Role: primary
Marisa Tucci, MD
Role: primary
Matthew Weiss, MD
Role: primary
Amir Hadash, MD
Role: primary
Asaf Mandel, MD
Role: primary
Elhanan Nahum, PhD
Role: primary
Hiroshi Kurosawa, MD
Role: primary
Takanari Ikeyama, MD
Role: primary
Swee Fong Tang, MD
Role: primary
Chin Seng Gan, MD
Role: primary
Olive Pei Ee Lee, MD
Role: primary
Humaira Rafique, MD
Role: primary
Ejaz Ahmed Khan, MD
Role: backup
Qalab Abbas, MD
Role: primary
Yasser Kazzaz, MD
Role: primary
Lee Jan Hau, MD
Role: primary
Loh Sin Wee, MD
Role: backup
Phuc Huu Phan, MD
Role: primary
Nam Tran Nguyen, MD
Role: primary
References
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Basu S, Habet V, Delgado M, Chiu P, Knox D, Thibault E, Shukla A, Harrington E, Bailey V, Lipsitz S, Fu Y, Agus M, Kheir J, Sasaki J, Moynihan K. Adjunctive Corticosteroids for Hypotension in the Pediatric Cardiac ICU: Single-Center Retrospective Study, 2020-2021. Pediatr Crit Care Med. 2025 Jul 1;26(7):e877-e888. doi: 10.1097/PCC.0000000000003757. Epub 2025 May 1.
Related Links
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Website for SHIPSS investigation
Other Identifiers
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IRB-P00027662
Identifier Type: -
Identifier Source: org_study_id
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