Evaluation of Corticosteroid Therapy in Childhood Severe Sepsis - a Randomised Pilot Study

NCT00732277 | Completed Phase 2 DMC

• 3 other identifiers: RHM CHI 4342007-002788-2807/H0504/139
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 3

Brief Summary

Severe bacterial infections affecting multiple body organs, called severe sepsis (including meningococcal sepsis), remain an important cause of death and disability among children. Although early recognition, powerful antibiotics, and good intensive care have improved outcome, we need new ways to further reduce the number of deaths. Research in adults has shown that steroid replacement therapy might be useful. However, children are known to respond differently to adults and a definitive trial in children is needed because of the potentially harmful as well as beneficial effects of steroids. This pilot study will provide the necessary information to allow the rational design of a large trial conducted at multiple hospitals investigating the role of corticosteroid replacement therapy in childhood sepsis. The study will provide information on how to measure the effects of steroids, information on length of therapy and a better understanding of how steroids work in children. The results emerging from this study will ultimately allow paediatric intensive care clinicians to know whether or not steroids are safe and/or useful. The primary objective of this open-label study is therefore to gather clinical and laboratory data with which to inform the design of a large phase 3 double blind randomised controlled trial (RCT). The study will provide basic limited safety data, information on length of therapy and an assessment of possible clinical and laboratory endpoints to be used in addition to mortality. Definition of sepsis: Presence of a documented infection (eg clinical evidence of pneumonia, skin or soft tissue infection, purpura fulminans, urinary tract infection, abdominal infection) or a diagnostic positive blood culture (community or hospital acquired) within the last 72 hours and at least two of the following, one of which must be abnormal temperature or leucocyte count\[3\] core temperature of \>38.5°C or \<36°C; tachycardia (mean heart rate \>2 SD above normal for age); mean respiratory rate \> 2 SD above normal for age; leucocyte count elevated or depressed for age. Definition of severe sepsis: Sepsis plus cardiovascular organ dysfunction (the need for at least 5mcg/kg/min dopamine or dobutamine, or any amount of adrenaline or noradrenaline support), acute respiratory distress syndrome (ARDS), or 2 or more other organ dysfunctions.

Conditions

Sepsis

Keywords

sepsis; septicaemia; septicemia; paediatric; pediatric; children

Outcome Measures

Primary Outcomes (2)

• primary efficacy endpoint is all cause mortality

  28 days

• primary toxicity endpoint is Serious Adverse Events, excluding sepsis-related events specified as secondary outcomes

  28 days

Secondary Outcomes (11)

• PIM2

  entry

• PELOD

  daily to 28 days or PICU discharge

• ICU mortality

  28 days

• time until shock reversal, defined as cessation of inotropic support for 24 hours

  28 days

• time to resolution of multiorgan dysfunction

  28 days

Study Arms (2)

Treatment

EXPERIMENTAL

Patients in this arm will be given the following IMP intraveneously at 6 hour intervals - hydrocortisone (100mg/m2/24 hours)

Drug: hydrocortisone

Control

NO INTERVENTION

in each phase of study 15 patients will receive no IMP as control arm

Interventions

hydrocortisone DRUG

Patients will be assigned to treatment with hydrocortisone at 100mg/m2/24 hours in 4 divided doses (25 mg/m2/q 6 hourly) for 8 doses (48 hours) in phase 1 of study (45 patients, 30 receive IMP) or 20 doses (120 hours) in phase 2 (45 patients, 30 receive IMP).

Also known as: Solu-Cortef®, Hydrocortisone sodium succinate

Treatment

Eligibility Criteria

• Age: 3 Months - 14 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Severe sepsis where enrolment can occur within 20 hours of first contact with paediatric intensive care, or within 20 hours of the diagnosis of severe sepsis when this diagnosis is made on PICU. Randomisation should occur within 24 hours of first contact with paediatric intensive care, or within 24 hours of the diagnosis of severe sepsis when this diagnosis is made on PICU.
• Requiring mechanical ventilation (The subjects must be mechanically ventilated for entry into the study but this is not time limited. It is routine practice at study centres to pre-emptively ventilate children with evolving sepsis)

You may not qualify if:

• Concomitant steroid therapy, vasopressor treatment \>24 hrs or use of etomidate (not recommended for use in children less than 10 years and selectively inhibits 11 beta-hydroxylase)
• Patients who have a recognised indication for steroids
• Other immunosuppressive/immunomodulatory therapy (not including intravenous immunoglobulin which is considered standard therapy in toxic shock syndrome and may be given for this indication)
• Significant immunocompromise (eg HIV infection)
• Advanced malignancy
• Burns
• Cardiopulmonary resuscitation
• Children not likely to survive the time period of the maximum study intervention (5 days)
• Patients who have undergone organ transplantation (including bone marrow transplantation)
• Patients undergoing plasma exchange or whole blood exchange transfusion
• Treatment with an investigational drug or device within the last 30 days prior to enrolment.
• Patients who have experienced a prior episode of infection or sepsis during the current hospitalisation.
• Patients who are pregnant (a pregnancy test will be carried out for females of 11 years and above as is standard practice for clinical trials).
• Immediate families of investigators or site personnel directly affiliated with the study. Immediate family is defined as child or sibling, whether biological or legally adopted.

Sponsors & Collaborators

• University Hospital Southampton NHS Foundation Trust: lead
• Imperial College London: collaborator
• St Mary's NHS Trust: collaborator
• University of Bristol: collaborator
• University Hospitals Bristol and Weston NHS Foundation Trust: collaborator

Study Sites (3)

Bristol Royal Hospital for Children

Bristol, UK, BS2 8BJ, United Kingdom

Location

Imperial College Healthcare NHS Trust

London, UK, W2 1NY, United Kingdom

Location

Southampton University Hospitals NHS Trust

Southampton, UK, SO16 6YD, United Kingdom

Location

Related Publications (79)

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Related Links

• UK NIHR Medicines For Children Research Network

MeSH Terms

Conditions

Sepsis; Toxemia

Interventions

Hydrocortisone; hydrocortisone hemisuccinate

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; 11-Hydroxycorticosteroids; Hydroxycorticosteroids; Adrenal Cortex Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; 17-Hydroxycorticosteroids

Study Officials

• Saul N Faust, MBBS PhD

  University of Southampton

  STUDY CHAIR

• Simon Nadel, MB BS

  Imperial College London

  PRINCIPAL INVESTIGATOR

• Robert S Heyderman, MBBS PhD

  University of Liverpool

  STUDY DIRECTOR

• Diana M Gibb, MBChB MD

  Medical Research Council

  STUDY DIRECTOR

• Michael Levin, MBBCH PhD

  Imperial College London

  STUDY DIRECTOR

• Andrew Wolf, MBBChir MD

  Univeristy of Bristol

  PRINCIPAL INVESTIGATOR

• John V Pappachan, MB BChir

  University Hospital Southampton NHS Foundation Trust

  STUDY DIRECTOR

• Sarah Walker, MA PhD

  Medical Research Council

  STUDY DIRECTOR

• Carrol Gamble, PhD

  University of Liverpool / MCRN Clinical Trials Unit

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 7, 2008
• First Posted: August 11, 2008
• Study Start: April 1, 2008
• Primary Completion: April 1, 2012
• Study Completion: April 1, 2012
• Last Updated: May 6, 2016

Record last verified: 2016-05

Data Sharing

• IPD Sharing: Will not share

Locations

GB (3)