Corticosteroid Therapy of Septic Shock - Corticus

NCT ID: NCT00147004

Last Updated: 2008-04-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 500 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2002-03-31
• Study Completion Date: 2005-11-30

Brief Summary

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

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.

Conditions

Shock, Septic

Keywords

Septic shock; Steroids; Hydrocortisone; Mortality; Reversal of shock; Adrenal insufficiency

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

1

hydrocortisone sodium succinate

Group Type: EXPERIMENTAL

hydrocortisone sodium succinate

Intervention Type: DRUG

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

2

Placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Interventions

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

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

European Society of Intensive Care Medicine

OTHER

Sponsor Role: collaborator

International Sepsis Forum

OTHER

Sponsor Role: collaborator

The Gorham Foundation

UNKNOWN

Sponsor Role: collaborator

Hadassah Medical Organization

OTHER

Sponsor Role: lead

Responsible Party

Hadassah Medical Organization

Principal Investigators

Charles L Sprung, MD

Role: STUDY_CHAIR

Hadasah Medical Organization

Djillali Annane, MD

Role: STUDY_DIRECTOR

Hopital Raymond Poincare

Josef Briegel, MD

Role: STUDY_DIRECTOR

Ludwig-Maximilian-Universitaet Muenchen

Didier Keh, MD

Role: STUDY_DIRECTOR

Charite Campus Virchow-Klinikum

Rui Moreno, MD

Role: STUDY_DIRECTOR

Hospital de St. António dos Capuchos

Didier Pittet, MD

Role: STUDY_DIRECTOR

University Hospital, Geneva

Mervyn Singer, MD

Role: STUDY_DIRECTOR

University College, London

Locations

LKH Feldkirch

Feldkirch, , Austria

KH-BHS Linz

Linz, , Austria

Krankenhaus der Barmherzigen Schwestern Ges. mbH

Linz, , Austria

Universitaetsklinik fuer Innere Medizin II

Vienna, , Austria

Hopital St. Joseph

Arlon, , Belgium

University Hospital Erasme

Brussels, , Belgium

Cliniques Universitaires St. Luc, UCL

Brussels, , Belgium

CHU Charleroi

Charleroi, , Belgium

Hopital Raymond Poincare

Paris, Garches, France

Hopital Lariboisiere

Paris, Oarus, France

Hopital de Caen

Caen, , France

Hopital Huriez

Lille, , France

Hopital Caremeau

Nîmes, , France

Hopital Saint-Antoine

Paris, , France

Zentralklinikum Augsburg

Augsburg, , Germany

Vivantes-Klinikum im Friedrichshain

Berlin, , Germany

Vivantes-Klinikum Spandau

Berlin, , Germany

Evangelisches Waldkrankenhaus Spandau

Berlin, , Germany

Charité Campus Mitte

Berlin, , Germany

St. Joseph Krankenhaus

Berlin, , Germany

Charité - Campus Benjamin Franklin

Berlin, , Germany

Vivantes-Klinikum Neukoelln

Berlin, , Germany

Charité - Campus Charité Mitte

Berlin, , Germany

Charité Campus Virchow -Klinikum

Berlin, , Germany

Charité Campus Virchow-Klinikum

Berlin, , Germany

Charité- Campus Virchow- Klinikum

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

Klinikum Grosshadern, LMU Munich

Munich, , Germany

Staedtisches Krankenhaus Muenchen-Harlaching

München, , Germany

Ludwig-Maximilian-Universitaet Muenchen

München, , Germany

Univesitaet Erlangen-Namberg

Nuremberg, , Germany

Klinikum Ernst von Bergman

Potsdam, , Germany

Haemek Hospital

Afula, , Israel

Hadassah Medical Organisation

Jerusalem, , Israel

Beilinson Medical Centre

Petah Tikva, , Israel

Ichilov Hospital

Tel Aviv, , Israel

Policlinico di Tor Vergata

Roma, , Italy

Centro di Rianimazione Ospedale S.Eugenio

Roma, , Italy

Renier de Graaf Hospital

Delft, , Netherlands

Erasmus University Medical Centre

Rotterdam, , Netherlands

Hospital de St. Antonio do Capuchos

Lisbon, , Portugal

UCIP, Hospital de Desterro

Lisbon, , Portugal

Hospital de Egas Moniz

Lisbon, , Portugal

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, , United Kingdom

Countries

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

References

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.

Reference Type: BACKGROUND

PMID: 12761380 (View on PubMed)

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.

Reference Type: RESULT

PMID: 18184957 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 22073145 (View on PubMed)

Other Identifiers

EC- QLK2-CT-2000-00589

Identifier Type: -

Identifier Source: secondary_id

QLK2-CT-2000-00589

Identifier Type: -

Identifier Source: org_study_id