Corticosteroid Therapy of Septic Shock - Corticus

Shock, Septic Clinical Trial

— Corticus  

Official title:

Corticosteroid Therapy of Septic Shock - Corticus. A Multi-National, Prospective, Double-Blind, Randomized, Placebo-Controlled Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00147004
• Other study ID #: QLK2-CT-2000-00589
• Secondary ID: EC- QLK2-CT-2000
• Status: Completed
• Phase: Phase 3
• First received: September 6, 2005
• Last updated: April 23, 2008
• Start date: March 2002
• Est. completion date: November 2005

Study information

• Verified date: April 2008
• Source: Hadassah Medical Organization
• Contact: n/a
• Is FDA regulated: No
• Health authority: Austria: Federal Ministry for Health and WomenBelgium: Federal Agency for Medicines and Health Products, FAMHPFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Germany: Federal Institute for Drugs and Medical DevicesIsrael: Israeli Health Ministry Pharmaceutical AdministrationItaly: National Monitoring Centre for Clinical Trials - Ministry of HealthNetherlands: The Central Committee on Research Involving Human Subjects (CCMO)Portugal: National Pharmacy and Medicines InstituteSpain: Spanish Agency of MedicinesUnited Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial Summary

The purpose of the study is to determine whether steroids decrease 28-day mortality in patients with septic shock.

Description:

The use of steroids in septic shock remains controversial. The purpose of this study is to determine whether hydrocortisone decreases 28-day mortality in patients with septic shock. The primary end point will be 28-day mortality in all the non-responders to ACTH (< or = 9 mcg/dl or 250 nmol/L post ACTH). Secondary endpoints will be 28 day all cause mortality in the total group and in responders, ICU and hospital mortality, one year mortality, organ system failure reversal especially shock, and duration of ICU and total hospitalisation.

In a double-blinded fashion (randomized on a 1:1 basis), patients receive 50 mg intravenously every 6 hours for 5 days. After 5 days, treatment will be tapered with 50 mg given intravenously every 12 hours for days 6-8, then 50 mg every 24 hours for days 9-11, and then stopped.

All concomitant treatments, including antibiotics, fluids, vasopressors and ancillary therapies will be given at the discretion of the primary care physician. Evidence-based guidelines for the management of severe sepsis and septic shock by the International Sepsis Forum (Intensive Care Med 2001;27:S124-S134) are encouraged to be followed.

All serious adverse events (SAE) which occur between days 0 and 28, which are unexpected and/or considered possibly or probably related to the study medication, must be documented and reported within 24 hours to the Safety and Efficacy Monitoring Committee. Non-serious adverse events will be listed on the case report form if they are unexpected and believed to be related to the study drug during days 0 to 14.

Specific adverse events which will be monitored closely because of their relationship to corticosteroids and shock are:

1. Use of corticosteroids, i.e. gastrointestinal bleeding and superinfection; hyperglycemia, hypernatremia, muscular weakness, etc.

2. Shock and use of vasopressors, i.e. stroke, acute myocardial infarction and peripheral ischemia.

In addition, substudies will include harmonization of cortisol by comparing cortisol levels measured in local laboratories and a central laboratory, immune and neuro-endocrine interactions, neuromuscular weakness and cytokines.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 500
• Est. completion date: November 2005
• Est. primary completion date: November 2005
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Clinical evidence of infection within the previous 72 hours (may be present longer than 72 hours) (a, b, c, or d - only 1 required)

1. Presence of polymorphonuclear cells in a normally sterile body fluid (excluding blood);

2. Culture or Gram stain of blood, sputum, urine or normally sterile body fluid positive for a pathogenic micro-organism;

3. Focus of infection identified by visual inspection (e.g. ruptured bowel with the presence of free air or bowel contents in the abdomen found at the time of surgery, wound with purulent drainage);

4. Other clinical evidence of infection - treated community acquired pneumonia, purpura fulminans, necrotising fascitis, etc.

2. Evidence of a systemic response to infection as defined by the presence of two or more of the following signs within the previous 24 hours. These signs may be present longer than 72 hours.

1. Fever (temperature >38.3°C) or hypothermia (rectal temperature < 35.6°C);

2. Tachycardia (heart rate of >90 beat/min);

3. Tachypnea (respiratory rate > 20 breaths/min, PaC02<32 mmHg) or patient requires invasive mechanical ventilation;

4. Alteration of the WBC count >12,000 cells/mm3, <4,000 cells/mm3 or >10% immature neutrophils (bands).

3. Evidence of shock defined by (A + B- both required within the previous 72 hours (may NOT be present longer than 72 hours).

A. A systolic blood pressure < 90 mmHg or a decrease in SBP of more than 50 mmHg from baseline in previous hypertensive patients (for at least one hour) despite adequate fluid replacement OR need for vasopressors for at least one hour (infusion of dopamine = 5 mcg/kg/min or any dose of adrenaline, noradrenaline, phenylephrine or vasopressin) to maintain a SBP = 90 mmHg;

B. Hypoperfusion or organ dysfunction which is not the result of underlying diseases or drugs, but is attributable to sepsis, including one of the following:

1. Sustained oliguria (urine output < 0.5 ml/kg/hr for a minimum of 1 hour)

2. Metabolic acidosis [pH of < 7.3, or a base deficit of > or = 5.0 mmol/L, or an increased lactic acid concentration (> 2 mmol/L)].

3. Arterial hypoxemia (Pa02/FI02<280 in the absence of pneumonia)(Pa02/FI02<200 in the presence of pneumonia).

4. Thrombocytopenia - platelet count = 100,000 cells/mm3.

5. Acute altered mental status (Glasgow Coma Scale < 14 or acute change from baseline).

4. Informed Consent

5. Cortisol level at baseline and 60 minutes after 0.25 mg cosyntropin

Exclusion Criteria:

1. Pregnancy

2. Age less than 18.

3. Underlying disease with a prognosis for survival of less than 3 months.

4. Cardiopulmonary resuscitation within 72 hours before study.

5. Drug-induced immunosuppression, including chemotherapy or radiation therapy within 4 weeks before the study.

6. Administration of chronic corticosteroids in the last 6 months or acute steroid therapy (any dose) within 4 weeks (including inhaled steroids). Topical steroids are not exclusions.

7. HIV positivity.

8. Presence of an advanced directive to withhold or withdraw life sustaining treatment (i.e. DNR).

9. Advanced cancer with a life expectancy less than 3 months.

10. Acute myocardial infarction or pulmonary embolus.

11. Another experimental drug study within the last 30 days.

12. Moribund patients likely to die within 24 hours.

13. Patients in the ICU for more than 2 months at the time of the start of septic shock.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Shock
• Shock, Septic

Intervention

Drug:
• hydrocortisone sodium succinate
50 mg intravenous bolus every six hours for 5 days, then tapered to 50 mg intravenously every 12 hours for days 6-8, 50 mg every 24 hours for days 9-11 and then stopped
• Placebo

Locations

Country	Name	City	State
Austria	LKH Feldkirch	Feldkirch
Austria	KH-BHS Linz	Linz
Austria	Krankenhaus der Barmherzigen Schwestern Ges. mbH	Linz
Austria	Universitaetsklinik fuer Innere Medizin II	Wien
Belgium	Hopital St. Joseph	Arlon
Belgium	Cliniques Universitaires St. Luc, UCL	Brussels
Belgium	University Hospital Erasme	Brussels
Belgium	CHU Charleroi	Charleroi
France	Hopital de Caen	Caen
France	Hopital Huriez	Lille
France	Hopital Caremeau	Nimes
France	Hopital Lariboisiere	Paris	Oarus
France	Hopital Raymond Poincare	Paris	Garches
France	Hopital Saint-Antoine	Paris
Germany	Zentralklinikum Augsburg	Augsburg
Germany	Charité - Campus Benjamin Franklin	Berlin
Germany	Charité - Campus Charité Mitte	Berlin
Germany	Charité Campus Mitte	Berlin
Germany	Charité Campus Virchow -Klinikum	Berlin
Germany	Charité Campus Virchow-Klinikum	Berlin
Germany	Charité- Campus Virchow- Klinikum	Berlin
Germany	Evangelisches Waldkrankenhaus Spandau	Berlin
Germany	St. Joseph Krankenhaus	Berlin
Germany	Vivantes-Klinikum im Friedrichshain	Berlin
Germany	Vivantes-Klinikum Neukoelln	Berlin
Germany	Vivantes-Klinikum Spandau	Berlin
Germany	Institute for Anaesthesia and Operative Intensive Care	Darmstadt
Germany	University Hospital Dresden	Dresden
Germany	Krankenhaus Hennigsdort	Hennigsdorf
Germany	Friedrich-Schiller Universitaet	Jena
Germany	Klinikum Kemptern-Oberallegaeu	Kempten
Germany	Klinikum Landshut	Landshut
Germany	Klinikum Mannheim, University of Heidelberg	Mannheim
Germany	Ludwig-Maximilian-Universitaet Muenchen	Muenchen
Germany	Staedtisches Krankenhaus Muenchen-Harlaching	Muenchen
Germany	Klinikum Grosshadern, LMU Munich	Munich
Germany	Univesitaet Erlangen-Namberg	Nurenberg
Germany	Klinikum Ernst von Bergman	Potsdam
Israel	Haemek Hospital	Afula
Israel	Hadassah Medical Organisation	Jerusalem
Israel	Beilinson Medical Centre	Petach Tikva
Israel	Ichilov Hospital	Tel Aviv
Italy	Centro di Rianimazione Ospedale S.Eugenio	Roma
Italy	Policlinico di Tor Vergata	Roma
Netherlands	Renier de Graaf Hospital	Delft
Netherlands	Erasmus University Medical Centre	Rotterdam
Portugal	Hospital de St. Antonio do Capuchos	Lisboa
Portugal	Hospital de Egas Moniz	Lisbon
Portugal	UCIP, Hospital de Desterro	Lisbon
United Kingdom	Aberdeen Royal Infirmary	Aberdeen
United Kingdom	Southend Hospital	Essex
United Kingdom	Ipswich Hospital	Ipswich
United Kingdom	Royal Lancaster Infirmary	Lancaster
United Kingdom	The General Infirmary at Leeds	Leeds
United Kingdom	Bloomsbury Institute of Intensive Care Medicine	London
United Kingdom	University of Manchester, Hope Hospital	Salford
United Kingdom	Southampton General Hospital	Southampton

Sponsors (4)

Lead Sponsor	Collaborator
Hadassah Medical Organization	European Society of Intensive Care Medicine, International Sepsis Forum, The Gorham Foundation

Countries where clinical trial is conducted

Austria,  Belgium,  France,  Germany,  Israel,  Italy,  Netherlands,  Portugal,  United Kingdom, 

References & Publications (2)

Annane D, Briegel J, Sprung CL. Corticosteroid insufficiency in acutely ill patients. N Engl J Med. 2003 May 22;348(21):2157-9. — View Citation

Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, Weiss YG, Benbenishty J, Kalenka A, Forst H, Laterre PF, Reinhart K, Cuthbertson BH, Payen D, Briegel J; CORTICUS Study Group. Hydrocortisone therapy for patients with septic shock. N Engl J Med — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	28 day mortality in all the non-responders to ACTH (< or = 9 mcg/dl or 250 nmol/L post ACTH)		28 days	Yes
Secondary	28 day all cause mortality in the total group.		28 days	Yes
Secondary	28 day all cause mortality in responders.		28 days	Yes
Secondary	One year mortality in nonresponders, total and responders.		one year	Yes
Secondary	ICU and hospital mortality.		one year	Yes
Secondary	Organ system failure reversal, especially shock.		one year	Yes
Secondary	Duration of ICU and total hospitalisation.		one year	Yes