Hydrocortisone for Pediatric Septic Shock

(SHIPSS Trial)

Recruiting at 55 trial locations

Overseen By Kusum Menon, MD, MSc

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: Jerry Zimmerman

Must be taking: Vasoactive-inotropic agents

Must not be taking: Systemic corticosteroids, Etomidate, Ketoconazole

Disqualifiers: Pregnancy, Brain death, Dengue, others

Stay on Your Current Meds You can continue your current medications while participating

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 28

Duration: 28 days

500 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether hydrocortisone, a type of steroid medication, can aid children in intensive care in recovering from septic shock, a severe body-wide infection that can lead to organ failure. Researchers aim to determine if hydrocortisone can reduce new organ problems and improve survival and quality of life. Children battling a severe infection in a pediatric intensive care unit (PICU) and already receiving certain strong medications to support blood pressure might be suitable for this study. Participants will receive either hydrocortisone or a placebo (a treatment with no active medicine) to compare outcomes. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially life-saving treatment advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are taking systemic corticosteroids or certain other medications like etomidate or ketoconazole, you may not be eligible to participate.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that hydrocortisone treats septic shock in children, a serious condition where blood pressure drops significantly due to infection. Hydrocortisone helps stabilize blood pressure.

Some side effects have been noted, including muscle weakness, high sodium levels, and high blood sugar. Despite these potential side effects, hydrocortisone is generally considered safe enough for inclusion in treatment guidelines.

Furthermore, its approval for use in children with septic shock provides additional reassurance about its safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for septic shock?

Most treatments for pediatric septic shock focus on managing symptoms and stabilizing the patient, often using antibiotics and fluids. However, unlike these standard options, hydrocortisone is unique because it targets the body's inflammatory response directly. Researchers are excited about hydrocortisone since it could help reduce inflammation more effectively, potentially leading to quicker stabilization and recovery for children. This approach might offer a more precise method to control the severe immune reaction seen in septic shock, which is what sets it apart from current treatments.

What evidence suggests that hydrocortisone might be an effective treatment for pediatric septic shock?

In this trial, participants will be randomized to receive either hydrocortisone or a placebo. Research has shown that hydrocortisone might help children with septic shock. One study found that using hydrocortisone significantly lowered the risk of death and improved survival rates by 2.5 times. Experts recommend hydrocortisone for treating septic shock in children, suggesting it can be effective. While more information is needed, these findings support its potential benefits for this condition. ^{1 3 6 7 8}

Who Is on the Research Team?

Mihir R Atreya, MD, MPH

Principal Investigator

Children's Hospital Medical Center, Cincinnati

Jerry J Zimmerman MD, MD, PhD

Principal Investigator

Seattle Children's Hospital, University of Washington School of Medicine

Michael Agus, MD

Principal Investigator

Boston Children's Hospital, Harvard Medical School

David Wypij, PhD

Principal Investigator

Boston Children's Hospital, Harvard Medical School

Kusum Menon, MD

Principal Investigator

Children's Hospital of Eastern Ontario

Are You a Good Fit for This Trial?

This trial is for children aged 1 month to less than 17 years and 8 months with severe septic shock, who have had certain tests done, are on multiple medications to support blood pressure, and show signs of infection. It's not for those treated with specific drugs recently, pregnant, in US protective custody, or with certain diseases like adrenal disorders.

Inclusion Criteria

I am younger than 17 years and 8 months old.

I have been prescribed antibiotics.

I have been given two or more heart medications or high-dose adrenaline infusions for over an hour.

Exclusion Criteria

All inclusion criteria have been present for > 12 hours

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

I have or might have a condition affecting my hormone glands and may need steroids.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive either hydrocortisone or placebo for septic shock management

28 days

Daily monitoring in PICU

Follow-up

Participants are monitored for safety and effectiveness after treatment

90 days

Assessments at 28 and 90 days post-enrollment

Long-term Follow-up

Evaluation of health-related quality of life and functional status

90 days

What Are the Treatments Tested in This Trial?

Interventions

• Hydrocortisone

Trial Overview The SHIPSS study is testing if hydrocortisone can help kids with septic shock get better outcomes compared to a normal saline placebo. Kids will be randomly assigned to either the drug or placebo group without knowing which one they're getting.

How Is the Trial Designed?

Group I: Treatment Active Control 1 Intervention

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.

Group II: Placebo Placebo Group 1 Intervention

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.

Who Is Running the Clinical Trial?

Jerry Zimmerman

Lead Sponsor

Trials

1

Recruited

500+

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Collaborator

Trials

2,103

Recruited

2,760,000+

Canadian Critical Care Trials Group

Collaborator

Trials

32

Recruited

227,000+

Children's Hospital of Eastern Ontario

Collaborator

Trials

134

Recruited

61,000+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

Published Research Related to This Trial

In a study of 499 patients with septic shock, hydrocortisone did not significantly improve survival rates compared to placebo, regardless of the patients' response to corticotropin testing.

While hydrocortisone did lead to a quicker reversal of shock symptoms, it was associated with a higher incidence of superinfections, including new cases of sepsis and septic shock.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hydrocortisone therapy for patients with septic shock. Sprung, CL., Annane, D., Keh, D., et al.[2022]

In a study of 6,693 pediatric patients with severe sepsis, the use of systemic corticosteroids was associated with increased mortality, suggesting that they do not improve outcomes in critically ill infants and children.

Independent predictors of mortality included older age, hematologic-oncologic diagnoses, and the use of steroids, indicating that clinicians should be cautious in using corticosteroids for severe sepsis until further randomized clinical trials are conducted.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective cohort study of prognostic factors associated with outcome in pediatric severe sepsis: what is the role of steroids? Markovitz, BP., Goodman, DM., Watson, RS., et al.[2022]

In a study of 70 critically ill children with catecholamine-dependent septic shock, stress dose hydrocortisone therapy was found to correlate more with the severity of illness rather than random serum total cortisol levels, indicating that the therapy may not be beneficial for all patients.

The use of stress dose hydrocortisone was associated with worse outcomes, including higher PICU mortality and longer hospital stays, particularly in children with higher baseline cortisol levels, suggesting that this treatment may need to be reconsidered in certain cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hydrocortisone Therapy in Catecholamine-Resistant Pediatric Septic Shock: A Pragmatic Analysis of Clinician Practice and Association With Outcomes. Nichols, B., Kubis, S., Hewlett, J., et al.[2019]

In a pilot study involving 38 children with septic shock, low-dose intravenous hydrocortisone showed a trend towards faster shock reversal and reduced need for inotropic support compared to normal saline, although these results were not statistically significant.

The study suggests that while low-dose hydrocortisone may be beneficial in managing pediatric septic shock, further research with a larger sample size is needed to confirm its efficacy, especially considering factors like malnutrition and delayed treatment in developing countries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose hydrocortisone in pediatric septic shock: an exploratory study in a third world setting. Valoor, HT., Singhi, S., Jayashree, M.[2022]

In a study involving 75 adrenalectomized rats with lethal septic shock, the combination of low-dose hydrocortisone and the antibiotic ertapenem significantly improved survival compared to either treatment alone.

Hydrocortisone treatment reversed sepsis-induced immunosuppression by altering gene expression related to immune response, which included increasing TNF production and decreasing bacterial burden in the kidneys.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose hydrocortisone prolongs survival in a lethal sepsis model in adrenalectomized rats. Doulias, T., Quickert, S., Weis, S., et al.[2019]

In a study of 3411 patients with septic shock, those treated with hydrocortisone had higher illness severity, indicated by higher lactate levels and APACHE III scores, compared to those who did not receive the treatment.

Although patients receiving hydrocortisone experienced longer vasopressor duration and higher hospital mortality rates, multivariable analysis showed no significant association between hydrocortisone use and increased mortality, suggesting that the observed outcomes may be influenced by the patients' overall severity of illness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Utilization of Stress Dose Hydrocortisone in Adult Patients With Septic Shock: A Retrospective Observational Study at a Large Academic Medical Center. Sacha, GL., Chen, AY., Palm, NM., et al.[2023]

In a study of 29 patients with severe burn and septic shock, hydrocortisone treatment significantly increased both systolic and diastolic blood pressure, indicating its efficacy in managing blood pressure in these patients.

Despite the positive response in blood pressure, the mortality rate remained unchanged, suggesting that while hydrocortisone can improve hemodynamics, it may not impact overall survival in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Blood pressure alterations in burn patients with septic shock under hydro-cortisone treatment. Alinejad, F., Momeni, M., Fatemi, MJ., et al.[2020]

In a study of 1,470 patients with vasopressor-dependent septic shock, initiating hydrocortisone treatment within the first 12 hours after shock onset was associated with better outcomes, including more days alive and free from vasopressors.

Delaying hydrocortisone treatment beyond 48 hours was linked to higher ICU mortality, emphasizing the importance of timely intervention in septic shock management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of the Initiation Timing of Hydrocortisone in Adult Patients With Septic Shock. Sacha, GL., Chen, AY., Palm, NM., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11676778/

Corticosteroids in Pediatric Septic Shock: A Narrative Review Until further data are available, hydrocortisone (50 to 100 mg/kg/d) has been recommended for use in pediatric septic shock, including in ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6513143/

Relative Adrenal Insufficiency in Pediatric Septic Shock - PMC In the same study, the treatment with hydrocortisone reduced the risk for mortality by an adjusted hazard ratio of 2.5 (95% confidence interval: 1.11–5.56).

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03401398

Stress Hydrocortisone In Pediatric Septic Shock (SHIPSS) 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.

4. sciencedirect.com sciencedirect.com/science/article/pii/S0007091223005895

Glucocorticoids with or without fludrocortisone in septic shock A reduction in mortality has been reported in septic shock when adjunctive hydrocortisone is administered in combination with fludrocortisone. The mechanisms ...

5. publications.aap.org publications.aap.org/pediatrics/article/153/1/e2023062967/196195/Pediatric-Sepsis-Diagnosis-Management-and-Sub

Pediatric Sepsis Diagnosis, Management, and Sub- ... These findings suggest that a favorable response to hydrocortisone in pediatric septic shock may be limited to high-risk patients biologically ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39728068/

Corticosteroids in Pediatric Septic Shock: A Narrative Review Regarding side effects, muscle weakness, hypernatremia, and hyperglycemia are the most observed. Conclusions: The literature does not give ...

7. elsevier.health elsevier.health/en-US/preview/hydrocortisone

Hydrocortisone Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children.

8. clinicaltrials.ucsf.edu clinicaltrials.ucsf.edu/trial/NCT03401398

Stress Hydrocortisone In Pediatric Septic Shock The primary hypothesis is that hydrocortisone, compared to placebo, will decrease the the incidence of new or progressive organ dysfunction (primary outcome) ...