Combination of Corticotherapy and Intensive Insulin Therapy for Septic Shock

Study Overview
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Brief Summary
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This study will compare, in adults with septic shock, the safety and efficacy of a combination of moderate doses of corticosteroids and intensive insulin therapy to that of moderate doses of corticosteroids. In addition, this study will compare the efficacy and safety of hydrocortisone alone versus hydrocortisone plus fludrocortisone

Detailed Description
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Objectives: Comparison, in patients with septic shock, of efficacy and safety of the combination of moderate doses of corticosteroids and intensive insulin therapy to that of moderate doses of corticosteroids; and of efficacy and safety of hydrocortisone alone versus hydrocortisone plus fludrocortisone Methods Study design : This is a multicenter, prospective, randomised trial on parallel groups Study treatments : Experimental arm A: A1=50 mg iv every 6 hours of hydrocortisone (hemisuccinate), 50µg through the nasogastric tube of 9 alpha fludrocortisone, for 7 days AND strict control of blood glucose levels with a target of 4,4 to 6 mmol/L using continuous iv infusion of insulin up to intensive care unit discharge. A2=50 mg iv every 6 hours of hydrocortisone (hemisuccinate) for 7 days AND strict control of blood glucose levels with a target of 4,4 to 6 mmol/L using continuous iv infusion of insulin up to intensive care unit discharge. Control arm B: B1:50 mg iv every 6 hours of hydrocortisone (hemisuccinate), 50µg through the nasogastric tube of 9 alpha fludrocortisone, for 7 days. B2:50 mg iv every 6 hours of hydrocortisone (hemisuccinate)for 7 days. Study Primary outcome : In-hospital mortality Sample size calculation : The expected in-hospital mortality rate in the control group is 50%. To detect an absolute reduction in in-hospital mortality rate of 12.5 %, that is 37.5% in the experimental arm versus 50% in the control arm, and considering risk alpha of 0,05 and a risk beta of 0,20, 254 patients per treatment arms are needed, for a total of 508 patients.

Official Title
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Phase 3 Study of Corticotherapy (Hydrocortisone Alone Versus Hydrocortisone Plus Fludrocortisone) Versus Corticotherapy Plus Intensive Insulin Therapy for Septic Shock

Conditions
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Septic Shock

Intervention / Treatment
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* Drug: recombinant human insulin
* Drug: hydrocortisone
* Drug: fludrocortisone
* Drug: Hydrocortisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients admitted in intensive care units for septic shock and meeting all following criteria Proven infection Need for vasopressor to maintain systemic arterial tension above 90 mmHg Multiple organ dysfunction as defined by a SOFA score ³ 8. Need for treatment with moderate dose of corticosteroids Exclusion Criteria: One of the following : Pregnancy Less than 18 years old Moribund (i.e. expected to die on day of intensive care unit admission)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>Hydrocortisone and convention glycemic control | Drug: hydrocortisone<br>* 50 mg as iv bolus every 6 hours for 7 days<br>Drug: Hydrocortisone<br>* hydrocortisone 50mg q6 for 7 days<br>|
| Experimental: 2<br>Hydrocortisone and fludrocortisone and conventional glucose control | Drug: hydrocortisone<br>* 50 mg as iv bolus every 6 hours for 7 days<br>Drug: fludrocortisone<br>* 50 µg once a day via a nasogastric tube for seven days<br>|
| Experimental: 3<br>Hydrocortisone and intensive insulin therapy | Drug: recombinant human insulin<br>* intensive insulin therapy as a continuous infusion to maintain blood glucose levels between 4 and 6 mmol/l<br>Drug: hydrocortisone<br>* 50 mg as iv bolus every 6 hours for 7 days<br>|
| Experimental: 4<br>hydrocortisone, fludrocortisone and intensive insulin therapy | Drug: recombinant human insulin<br>* intensive insulin therapy as a continuous infusion to maintain blood glucose levels between 4 and 6 mmol/l<br>Drug: hydrocortisone<br>* 50 mg as iv bolus every 6 hours for 7 days<br>Drug: fludrocortisone<br>* 50 µg once a day via a nasogastric tube for seven days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| In-hospital mortality |  | Day 180 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary outcomes : |  | Day 180 | 
| 90-day and 180-day mortality. |  | Day 180 | 
| Duration of life-supporting treatments (i.e. vasopressors and mechanical ventilation) |  | Day 180 | 
| Time to resolve multiple organ dysfunction, i.e. to obtain a SOFA score < 8 |  | Day 180 | 
| Hospital length of stay. |  | Day 180 | 
| Number of hypoglycaemic events (blood glucose < 4 mmol/l) during insulin infusion |  | Day 180 | 
| Muscle weakness at discharge from intensive care unit, 90-day and 180-day |  | Day 180 | 
| Post traumatic stress disorders |  | Day 180 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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septic shock, adrenal insufficiency, glucose control, mineralocorticoids