Combination of Corticotherapy and Intensive Insulin Therapy for Septic Shock (COIITSS)

Study Description

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Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Septic Shock	Drug: recombinant human insulin; Drug: hydrocortisone; Drug: fludrocortisone; Drug: Hydrocortisone	Phase 3

Detailed Description:

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	508 participants
Allocation:	Randomized
Intervention Model:	Factorial Assignment
Masking:	Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	Phase 3 Study of Corticotherapy (Hydrocortisone Alone Versus Hydrocortisone Plus Fludrocortisone) Versus Corticotherapy Plus Intensive Insulin Therapy for Septic Shock
Study Start Date :	January 2006
Actual Primary Completion Date :	January 2009
Actual Study Completion Date :	February 2009

Arms and Interventions

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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

Outcome Measures

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Primary Outcome Measures :

1. In-hospital mortality [ Time Frame: Day 180 ]

Secondary Outcome Measures :

1. Secondary outcomes : [ Time Frame: Day 180 ]
2. 90-day and 180-day mortality. [ Time Frame: Day 180 ]
3. Duration of life-supporting treatments (i.e. vasopressors and mechanical ventilation) [ Time Frame: Day 180 ]
4. Time to resolve multiple organ dysfunction, i.e. to obtain a SOFA score < 8 [ Time Frame: Day 180 ]
5. Hospital length of stay. [ Time Frame: Day 180 ]
6. Number of hypoglycaemic events (blood glucose < 4 mmol/l) during insulin infusion [ Time Frame: Day 180 ]
7. Muscle weakness at discharge from intensive care unit, 90-day and 180-day [ Time Frame: Day 180 ]
8. Post traumatic stress disorders [ Time Frame: Day 180 ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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)

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

France
Hôpital Avicenne
Bobigny, France
Hôpital Jean Verdier
Bondy, France
CHU Grenoble
Grenoble, France
Hôpital central
Nancy, France
Hôpital Saint Louis
Paris, France, 75
Hôpital Bichat Claude Bernard
Paris, France
hôpital Cochin
Paris, France
Hôpital Delafontaine
Saint Denis, France, 93

Sponsors and Collaborators

University of Versailles

Assistance Publique - Hôpitaux de Paris

Investigators

Study Chair:	Djillali annane, MD, PhD	Assistance Publique Hôpitaux de Paris - University of Versailles

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications of Results:

COIITSS Study Investigators, Annane D, Cariou A, Maxime V, Azoulay E, D'honneur G, Timsit JF, Cohen Y, Wolf M, Fartoukh M, Adrie C, Santré C, Bollaert PE, Mathonet A, Amathieu R, Tabah A, Clec'h C, Mayaux J, Lejeune J, Chevret S. Corticosteroid treatment and intensive insulin therapy for septic shock in adults: a randomized controlled trial. JAMA. 2010 Jan 27;303(4):341-8. doi: 10.1001/jama.2010.2. Erratum in: JAMA. 2010 May 5;303(17):1698.

Responsible Party:	Djillali Annane, AP-HP - University of Versailles SQY
ClinicalTrials.gov Identifier:	NCT00320099 History of Changes
Other Study ID Numbers:	AOM04100; P040421
First Posted:	May 3, 2006
Last Update Posted:	April 6, 2010
Last Verified:	April 2010

Keywords provided by University of Versailles:

septic shock; adrenal insufficiency; glucose control; mineralocorticoids

Additional relevant MeSH terms:

Shock; Shock, Septic; Pathologic Processes; Sepsis; Infection; Systemic Inflammatory Response Syndrome; Inflammation; Insulin, Globin Zinc; Insulin	Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Cortisol succinate; Hydrocortisone; Fludrocortisone; Hypoglycemic Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents