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Stress Hydrocortisone In Pediatric Septic Shock (SHIPSS)

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ClinicalTrials.gov Identifier: NCT03401398
Recruitment Status : Recruiting
First Posted : January 17, 2018
Last Update Posted : May 9, 2019
Sponsor:
Collaborators:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Canadian Institutes of Health Research (CIHR)
Canadian Critical Care Trials Group
Children's Hospital of Eastern Ontario
Information provided by (Responsible Party):
Jerry Zimmerman, Seattle Children's Hospital

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 proportion of children with poor outcomes, defined as death or severely impaired health-related quality of life (HRQL), as assessed at 28 days following study enrollment (randomization).


Condition or disease Intervention/treatment Phase
Septic Shock Drug: Hydrocortisone, sodium succinate Drug: Normal saline Phase 3

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 1,032 children will be enrolled, randomized, and evaluated at baseline, PICU discharge, and 28 and 90 days following study enrollment.

The primary hypothesis is that hydrocortisone, compared to placebo, will decrease the proportion of subjects with poor outcomes, defined as death or severely impaired (≥25% decrease from baseline) HRQL. Subjects will be monitored daily while receiving care in the PICU, for collection of data on organ dysfunction, hemodynamic support, mechanical ventilation, renal replacement therapy, extracorporeal membrane oxygenation (ECMO) and occurrence of adverse events. 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 Canada and the US. 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 approved for use in septic shock but not specifically approved for use in pediatric septic shock.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1032 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
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.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Subjects, families, critical care providers and investigators will be blinded to study drug administration. Only the local performance site research pharmacist will be un-blinded.
Primary Purpose: Treatment
Official Title: Stress Hydrocortisone In Pediatric Septic Shock
Actual Study Start Date : March 11, 2019
Estimated Primary Completion Date : September 20, 2023
Estimated Study Completion Date : December 30, 2023


Arm Intervention/treatment
Active Comparator: 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.
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.
Other Name: SOLU-CORTEF- hydrocortisone sodium succinate injection

Placebo Comparator: 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.
Drug: 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.




Primary Outcome Measures :
  1. 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) [ Time Frame: 28 days following study enrollment ]
    Mortality or ≥25% decrease in PedsQL from baseline


Secondary Outcome Measures :
  1. New or progressive multiple organ dysfunction syndrome as assessed utilizing the Pediatric Logistic Organ Dysfunction (PELOD-2) instrument. [ Time Frame: 28 days following study enrollment ]
    Appearance of new or progression of existing organ dysfunctions according to PELOD-2 definitions


Other Outcome Measures:
  1. SHIPSS specified adverse events [ Time Frame: 28 days following study enrollment ]
    Occurrence of adverse events plausibly associated with corticosteroid administration. SHIPSS specified events include hyperglycemia, gastrointestinal hemorrhage, delirium, and hospital-acquired infection

  2. Risk stratification sepsis biomarkers and Pediatric sepsis endotype [ Time Frame: Enrollment and Day 2 ]
    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.

  3. Trichotomous mortality/morbidity outcome [ Time Frame: 28 and 90 days following study enrollment ]
    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.

  4. 90-Day Death or ≥25% decrease in HRQL from baseline [ Time Frame: 90 days following study enrollment ]
    Mortality or ≥25% decrease in PedsQL from baseline

  5. Vasoactive-inotropic infusion-free days through day 28 [ Time Frame: 28 days following study enrollment ]
    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.

  6. Mechanical ventilation-free days through day 28 [ Time Frame: 28 days following study enrollment ]
    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.

  7. Utilization of acute renal replacement therapy (RRT) [ Time Frame: Enrollment to PICU discharge, an average of 2 weeks ]
    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.

  8. Utilization of extracorporeal membrane oxygenation (ECMO) [ Time Frame: Enrollment to PICU discharge, an average of 2 weeks ]
    Proportion of subjects receiving ECMO

  9. Functional status - POPC [ Time Frame: 28 and 90 days following study enrollment ]
    Gross functional status category staging will be made using the Pediatric Overall Performance Category (POPC) score.

  10. Functional status - FSS [ Time Frame: 28 and 90 days following study enrollment ]
    Functional Status Scale (FSS) will be employed to provide a more granular determination of changes in functional status.

  11. PICU-free days through day 28 [ Time Frame: 28 days following study enrollment ]
    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.

  12. Hospital-free days through day 28 [ Time Frame: 28 days following study enrollment ]
    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.

  13. Hospital-free days through day 90 [ Time Frame: 90 days following study enrollment ]
    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.

  14. Need for new medical devices at hospital discharge [ Time Frame: At time of hospital discharge, expected to be an average of 21 days from time of enrollment ]
    New medical devices prescribed at hospital discharge will be collected from the hospital discharge summary.

  15. Frequency of primary care, specialty care, and emergency department visits and hospital readmissions [ Time Frame: 90 days following study enrollment ]
    Enumeration of additional health care evaluations following the index hospital admission will occur by telephone survey at 90 days.

  16. Disruption of family dynamics [ Time Frame: Enrollment and 90 days following study enrollment ]
    The PedsQLTM 2.0 Family Impact Module will be used to quantify the impact of septic shock on family dynamics.

  17. Cost Analysis - Cost of PICU admission for septic shock [ Time Frame: 90 days following study enrollment ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   1 Month to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 17.5 years.
  2. A focus of infection has been documented or there is a strong suspicion of infection upon admission to the PICU.
  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 <500 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 >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. Treatment for systemic fungal infection at time of screening
  7. Documented cerebral malaria at time of screening
  8. Documented strongyloides at time of screening
  9. 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)
  10. Attending physician, PICU care team, or legally recognized guardians not committed to full treatment and resuscitation
  11. Patient documented to be pregnant
  12. Previous enrollment in the SHIPSS study
  13. Primary disease/injury is a thermal burn
  14. (U.S. sites only) Patient in the custody of US protective services.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03401398


Contacts
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Contact: Jerry J Zimmerman, MD, PhD 206-987-3862 jerry.zimmerman@seattlechildrens.org
Contact: Kusum Menon, MD, MSc 613-737-7600 ext 2538 menon@cheo.on.ca

  Show 31 Study Locations
Sponsors and Collaborators
Jerry Zimmerman
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Canadian Institutes of Health Research (CIHR)
Canadian Critical Care Trials Group
Children's Hospital of Eastern Ontario
Investigators
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Principal Investigator: Jerry J Zimmerman MD, MD, PhD Seattle Children's Hospital, University of Washington School of Medicine
Principal Investigator: Michael Agus, MD Boston Children's Hospital, Harvard Medical School
Principal Investigator: Hector R Wong, MD Children's Hospital Medical Center, Cincinnati
Principal Investigator: David Wypij, PhD Boston Children's Hospital, Harvard Medical School
Principal Investigator: Kusum Menon, MD, MSc Children's Hospital of Eastern Ontario

Additional Information:
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Responsible Party: Jerry Zimmerman, Professor of Pediatrics/Anesthesiology, University of Washington School of Medicine, Seattle Children's Hospital
ClinicalTrials.gov Identifier: NCT03401398     History of Changes
Other Study ID Numbers: IRB-P00027662
1R01HD096901-01 ( U.S. NIH Grant/Contract )
First Posted: January 17, 2018    Key Record Dates
Last Update Posted: May 9, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Per NIH policy, the SHIPSS investigators will provide a de-identified dataset and all the data-related documentation necessary to utilize the study data (dictionary, calculated variables, and standard operating procedures) to the NIH no later than 3 years after the final 90-day assessment or 2 years after the primary paper has been published, whichever comes first. The investigators will submit this dataset to the NICHD data repository, Data and Specimen Hub (DASH). In addition, final datasets and statistical analyses will be archived.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code
Time Frame: No later than 3 years after the final 90-day assessment or 2 years after the primary paper has been published, whichever comes first.
Access Criteria: Anyone can access NICHD DASH, which is a public website with free access to the scientific research community. All users may browse and view information about studies and data archived in NICHD DASH. Users who are interested in submitting or requesting study data must register for a free account.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Jerry Zimmerman, Seattle Children's Hospital:
hydrocortisone
refractory septic shock
sepsis
new/progressive MODS
mortality
health-related quality of life
corticosteroid adverse events
sepsis biomarkers

Additional relevant MeSH terms:
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Shock
Shock, Septic
Pathologic Processes
Sepsis
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Hydrocortisone
Hydrocortisone 17-butyrate 21-propionate
Hydrocortisone acetate
Hydrocortisone hemisuccinate
Anti-Inflammatory Agents