Corticosteroid Therapy of Septic Shock - Corticus (Corticus)

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

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

Study Overview

• Status: Completed
• Conditions: Shock, Septic
• Intervention / Treatment: Drug: Placebo; Drug: hydrocortisone sodium succinate

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 500
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Feldkirch, Austria, A-6800
    • LKH Feldkirch
  • Linz, Austria, A-4010
    • KH-BHS Linz
  • Linz, Austria, A-4010
    • Krankenhaus der Barmherzigen Schwestern Ges. mbH
  • Wien, Austria, A 1090
    • Universitaetsklinik fuer Innere Medizin II
• Belgium
  • Arlon, Belgium, B-6700
    • Hôpital St. Joseph
  • Brussels, Belgium, B-1070
    • University Hospital Erasme
  • Brussels, Belgium, B-1200
    • Cliniques Universitaires St. Luc, UCL
  • Charleroi, Belgium, B-6000
    • Chu Charleroi
• France
  • Caen, France, 14033
    • Hôpital de Caen
  • Lille, France, F-59037
    • Hopital Huriez
  • Nimes, France, 30029 cedex 9
    • Hopital Caremeau
  • Paris, France, F-75571
    • Hopital Saint-Antoine
  • Garches
    • Paris, Garches, France, F-92380
      • Hôpital Raymond Poincaré
  • Oarus
    • Paris, Oarus, France, F-75010
      • Hopital Lariboisiere
• Germany
  • Augsburg, Germany, D-86155
    • Zentralklinikum Augsburg
  • Berlin, Germany, D-10117
    • Charité Campus Mitte
  • Berlin, Germany, D - 10249
    • Vivantes-Klinikum im Friedrichshain
  • Berlin, Germany, D - 13585
    • Vivantes-Klinikum Spandau
  • Berlin, Germany, D - 13589
    • Evangelisches Waldkrankenhaus Spandau
  • Berlin, Germany, D-12101
    • St. Joseph Krankenhaus
  • Berlin, Germany, D-12200
    • Charite - Campus Benjamin Franklin
  • Berlin, Germany, D-12313
    • Vivantes-Klinikum Neukoelln
  • Berlin, Germany, D-13353
    • Charité - Campus Charité Mitte
  • Berlin, Germany, D-13353
    • Charité Campus Virchow -Klinikum
  • Berlin, Germany, D-13353
    • Charité Campus Virchow-Klinikum
  • Berlin, Germany, D-13353
    • Charité- Campus Virchow- Klinikum
  • Darmstadt, Germany, D-64283
    • Institute for Anaesthesia and Operative Intensive Care
  • Dresden, Germany, D- 01307
    • University Hospital Dresden
  • Hennigsdorf, Germany, D-16761
    • Krankenhaus Hennigsdort
  • Jena, Germany, D - 07740
    • Friedrich-Schiller Universitaet
  • Kempten, Germany, D-87439
    • Klinikum Kemptern-Oberallegaeu
  • Landshut, Germany, D-84034
    • Klinikum Landshut
  • Mannheim, Germany, D- 68167
    • Klinikum Mannheim, University of Heidelberg
  • Muenchen, Germany, D- 81545
    • Staedtisches Krankenhaus Muenchen-Harlaching
  • Muenchen, Germany, D-81366
    • Ludwig-Maximilian-Universitaet Muenchen
  • Munich, Germany, D-81377
    • Klinikum Grosshadern, LMU Munich
  • Nurenberg, Germany, D-90471
    • Univesitaet Erlangen-Namberg
  • Potsdam, Germany, D-14467
    • Klinikum Ernst von Bergman
• Israel
  • Afula, Israel, 18101
    • Haemek Hospital
  • Jerusalem, Israel, 91120
    • Hadassah Medical Organisation
  • Petach Tikva, Israel, 491000
    • Beilinson Medical Centre
  • Tel Aviv, Israel, 64239
    • Ichilov Hospital
• Italy
  • Roma, Italy, 00133
    • Policlinico di Tor Vergata
  • Roma, Italy, 00144
    • Centro di Rianimazione Ospedale S.Eugenio
• Netherlands
  • Delft, Netherlands, 2600 GA
    • Renier de Graaf Hospital
  • Rotterdam, Netherlands, 3000 CA
    • Erasmus University Medical Centre
• Portugal
  • Lisboa, Portugal, 1150
    • Hospital de St. Antonio do Capuchos
  • Lisbon, Portugal, 1150
    • UCIP, Hospital de Desterro
  • Lisbon, Portugal, 1349-019
    • Hospital de Egas Moniz
• United Kingdom
  • Aberdeen, United Kingdom, AB25 2ZD
    • Aberdeen Royal Infirmary
  • Essex, United Kingdom, SSO ORY
    • Southend Hospital
  • Ipswich, United Kingdom, IP4 5PD
    • Ipswich Hospital
  • Lancaster, United Kingdom, LA1 4RP
    • Royal Lancaster Infirmary
  • Leeds, United Kingdom, LS1 3EX
    • The General Infirmary at Leeds
  • London, United Kingdom, W1T 3AA
    • Bloomsbury Institute of Intensive Care Medicine
  • Salford, United Kingdom, M6 8HD
    • University of Manchester, Hope Hospital
  • Southampton, United Kingdom
    • Southampton General Hospital

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:

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: 2; Placebo	Drug: Placebo
Experimental: 1; hydrocortisone sodium succinate	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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
28 day mortality in all the non-responders to ACTH (< or = 9 mcg/dl or 250 nmol/L post ACTH)	28 days

Secondary Outcome Measures

Outcome Measure	Time Frame
28 day all cause mortality in the total group.	28 days
28 day all cause mortality in responders.	28 days
One year mortality in nonresponders, total and responders.	one year
ICU and hospital mortality.	one year
Organ system failure reversal, especially shock.	one year
Duration of ICU and total hospitalisation.	one year

Collaborators and Investigators

• Sponsor: Hadassah Medical Organization
• Collaborators: European Society of Intensive Care Medicine; International Sepsis Forum; The Gorham Foundation
• Investigators: Study Chair: Charles L Sprung, MD, Hadasah Medical Organization; Study Director: Djillali Annane, MD, Hôpital Raymond Poincaré; Study Director: Josef Briegel, MD, Ludwig-Maximilian-Universitaet Muenchen; Study Director: Didier Keh, MD, Charité Campus Virchow-Klinikum; Study Director: Rui Moreno, MD, Hospital de St. António dos Capuchos; Study Director: Didier Pittet, MD, University Hospital, Geneva; Study Director: Mervyn Singer, MD, University College, London

Publications and helpful links

General Publications

• Annane D, Briegel J, Sprung CL. Corticosteroid insufficiency in acutely ill patients. N Engl J Med. 2003 May 22;348(21):2157-9. doi: 10.1056/NEJM200305223482123. No abstract available.
• 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. 2008 Jan 10;358(2):111-24. doi: 10.1056/NEJMoa071366.
• Polito A, Sonneville R, Guidoux C, Barrett L, Viltart O, Mattot V, Siami S, Lorin de la Grandmaison G, Chretien F, Singer M, Gray F, Annane D, Brouland JP, Sharshar T. Changes in CRH and ACTH synthesis during experimental and human septic shock. PLoS One. 2011;6(11):e25905. doi: 10.1371/journal.pone.0025905. Epub 2011 Nov 3.

Study record dates

Study Major Dates

• Study Start: March 1, 2002
• Primary Completion (Actual): November 1, 2005
• Study Completion (Actual): November 1, 2005

Study Registration Dates

• First Submitted: September 6, 2005
• First Submitted That Met QC Criteria: September 6, 2005
• First Posted (Estimate): September 7, 2005

Study Record Updates

• Last Update Posted (Estimate): April 24, 2008
• Last Update Submitted That Met QC Criteria: April 23, 2008
• Last Verified: April 1, 2008

More Information

Terms related to this study

• Keywords: Septic shock; Mortality; Hydrocortisone; Steroids; Adrenal insufficiency; Reversal of shock
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Shock, Septic; Shock; Anti-Inflammatory Agents; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate
• Other Study ID Numbers: QLK2-CT-2000-00589; EC- QLK2-CT-2000-00589