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

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

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

Study Overview

• Status: Completed
• Conditions: Septic Shock
• Intervention / Treatment: Drug: hydrocortisone; Drug: fludrocortisone; Drug: recombinant human insulin; Drug: Hydrocortisone

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 Type: Interventional
• Enrollment (Actual): 508
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Bobigny, France
    • Hôpital Avicenne
  • Bondy, France
    • Hôpital Jean Verdier
  • Grenoble, France
    • CHU Grenoble
  • Nancy, France
    • Hôpital Central
  • Paris, France
    • Hopital Cochin
  • Paris, France
    • Hopital Bichat Claude Bernard
  • Paris, France, 75
    • Hopital Saint Louis
  • Saint Denis, France, 93
    • Hopital DELAFONTAINE

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: FACTORIAL
• Masking: TRIPLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: 1; Hydrocortisone and convention glycemic control	Drug: hydrocortisone; 50 mg as iv bolus every 6 hours 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: hydrocortisone; 50 mg as iv bolus every 6 hours for 7 days; Drug: recombinant human insulin; intensive insulin therapy as a continuous infusion to maintain blood glucose levels between 4 and 6 mmol/l
EXPERIMENTAL: 4; hydrocortisone, fludrocortisone and intensive insulin therapy	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; Drug: recombinant human insulin; intensive insulin therapy as a continuous infusion to maintain blood glucose levels between 4 and 6 mmol/l

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
In-hospital mortality	Day 180

Secondary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: University of Versailles
• Collaborators: Assistance Publique - Hôpitaux de Paris

Publications and helpful links

General Publications

• COIITSS Study Investigators; Annane D, Cariou A, Maxime V, Azoulay E, D'honneur G, Timsit JF, Cohen Y, Wolf M, Fartoukh M, Adrie C, Santre 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.

Study record dates

Study Major Dates

• Study Start: January 1, 2006
• Primary Completion (ACTUAL): January 1, 2009
• Study Completion (ACTUAL): February 1, 2009

Study Registration Dates

• First Submitted: April 27, 2006
• First Submitted That Met QC Criteria: April 27, 2006
• First Posted (ESTIMATE): May 3, 2006

Study Record Updates

• Last Update Posted (ESTIMATE): April 6, 2010
• Last Update Submitted That Met QC Criteria: April 5, 2010
• Last Verified: April 1, 2010

More Information

Terms related to this study

• Keywords: septic shock; glucose control; adrenal insufficiency; mineralocorticoids
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Shock, Septic; Shock; Hypoglycemic Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Insulin; Insulin, Globin Zinc; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate; Fludrocortisone
• Other Study ID Numbers: AOM04100; P040421