Clinical trial NCT00147004: Corticosteroid Therapy of Septic Shock - Corticus
Official title: Corticosteroid Therapy of Septic Shock - Corticus. A Multi-National, Prospective, Double-Blind, Randomized, Placebo-Controlled Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Shock, Septic
Keywords: Septic shock
Steroids
Hydrocortisone
Mortality
Reversal of shock
Adrenal insufficiency
Lead sponsor: Hadassah Medical Organization
Sponsor class: OTHER
Collaborators: name: European Society of Intensive Care Medicine
name: International Sepsis Forum
name: The Gorham Foundation
First posted: 2005-09-07
Enrollment: 500
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: 28 day mortality in all the non-responders to ACTH (< or = 9 mcg/dl or 250 nmol/L post ACTH)
timeFrame: 28 days
Secondary outcomes:
measure: 28 day all cause mortality in the total group.
timeFrame: 28 days
measure: 28 day all cause mortality in responders.
timeFrame: 28 days
measure: One year mortality in nonresponders, total and responders.
timeFrame: one year
measure: ICU and hospital mortality.
timeFrame: one year
measure: Organ system failure reversal, especially shock.
timeFrame: one year
measure: Duration of ICU and total hospitalisation.
timeFrame: one year
Other outcomes:
Locations:
city: Feldkirch
country: Austria
facility: LKH Feldkirch
city: Linz
country: Austria
facility: KH-BHS Linz
city: Linz
country: Austria
facility: Krankenhaus der Barmherzigen Schwestern Ges. mbH
city: Wien
country: Austria
facility: Universitaetsklinik fuer Innere Medizin II
city: Arlon
country: Belgium
facility: Hopital St. Joseph
city: Brussels
country: Belgium
facility: University Hospital Erasme
city: Brussels
country: Belgium
facility: Cliniques Universitaires St. Luc, UCL
city: Charleroi
country: Belgium
facility: CHU Charleroi
city: Paris
country: France
facility: Hopital Raymond Poincare
state: Garches
city: Paris
country: France
facility: Hopital Lariboisiere
state: Oarus
city: Caen
country: France
facility: Hopital de Caen
city: Lille
country: France
facility: Hopital Huriez
city: Nimes
country: France
facility: Hopital Caremeau
city: Paris
country: France
facility: Hopital Saint-Antoine
city: Augsburg
country: Germany
facility: Zentralklinikum Augsburg
city: Berlin
country: Germany
facility: Vivantes-Klinikum im Friedrichshain
city: Berlin
country: Germany
facility: Vivantes-Klinikum Spandau
city: Berlin
country: Germany
facility: Evangelisches Waldkrankenhaus Spandau
city: Berlin
country: Germany
facility: Charité Campus Mitte
city: Berlin
country: Germany
facility: St. Joseph Krankenhaus
city: Berlin
country: Germany
facility: Charité - Campus Benjamin Franklin
city: Berlin
country: Germany
facility: Vivantes-Klinikum Neukoelln
city: Berlin
country: Germany
facility: Charité - Campus Charité Mitte
city: Berlin
country: Germany
facility: Charité Campus Virchow -Klinikum
city: Berlin
country: Germany
facility: Charité Campus Virchow-Klinikum
city: Berlin
country: Germany
facility: Charité- Campus Virchow- Klinikum
city: Darmstadt
country: Germany
facility: Institute for Anaesthesia and Operative Intensive Care
city: Dresden
country: Germany
facility: University Hospital Dresden
city: Hennigsdorf
country: Germany
facility: Krankenhaus Hennigsdort
city: Jena
country: Germany
facility: Friedrich-Schiller Universitaet
city: Kempten
country: Germany
facility: Klinikum Kemptern-Oberallegaeu
city: Landshut
country: Germany
facility: Klinikum Landshut
city: Mannheim
country: Germany
facility: Klinikum Mannheim, University of Heidelberg
city: Muenchen
country: Germany
facility: Staedtisches Krankenhaus Muenchen-Harlaching
city: Muenchen
country: Germany
facility: Ludwig-Maximilian-Universitaet Muenchen
city: Munich
country: Germany
facility: Klinikum Grosshadern, LMU Munich
city: Nurenberg
country: Germany
facility: Univesitaet Erlangen-Namberg
city: Potsdam
country: Germany
facility: Klinikum Ernst von Bergman
city: Afula
country: Israel
facility: Haemek Hospital
city: Jerusalem
country: Israel
facility: Hadassah Medical Organisation
city: Petach Tikva
country: Israel
facility: Beilinson Medical Centre
city: Tel Aviv
country: Israel
facility: Ichilov Hospital
city: Roma
country: Italy
facility: Policlinico di Tor Vergata
city: Roma
country: Italy
facility: Centro di Rianimazione Ospedale S.Eugenio
city: Delft
country: Netherlands
facility: Renier de Graaf Hospital
city: Rotterdam
country: Netherlands
facility: Erasmus University Medical Centre
city: Lisboa
country: Portugal
facility: Hospital de St. Antonio do Capuchos
city: Lisbon
country: Portugal
facility: UCIP, Hospital de Desterro
city: Lisbon
country: Portugal
facility: Hospital de Egas Moniz
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
city: Essex
country: United Kingdom
facility: Southend Hospital
city: Ipswich
country: United Kingdom
facility: Ipswich Hospital
city: Lancaster
country: United Kingdom
facility: Royal Lancaster Infirmary
city: Leeds
country: United Kingdom
facility: The General Infirmary at Leeds
city: London
country: United Kingdom
facility: Bloomsbury Institute of Intensive Care Medicine
city: Salford
country: United Kingdom
facility: University of Manchester, Hope Hospital
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
Study officials:
affiliation: Hadasah Medical Organization
name: Charles L Sprung, MD
role: STUDY_CHAIR
affiliation: Hopital Raymond Poincare
name: Djillali Annane, MD
role: STUDY_DIRECTOR
affiliation: Ludwig-Maximilian-Universitaet Muenchen
name: Josef Briegel, MD
role: STUDY_DIRECTOR
affiliation: Charite Campus Virchow-Klinikum
name: Didier Keh, MD
role: STUDY_DIRECTOR
affiliation: Hospital de St. António dos Capuchos
name: Rui Moreno, MD
role: STUDY_DIRECTOR
affiliation: University Hospital, Geneva
name: Didier Pittet, MD
role: STUDY_DIRECTOR
affiliation: University College, London
name: Mervyn Singer, MD
role: STUDY_DIRECTOR
References:
citation: 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.
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. 2008 Jan 10;358(2):111-24. doi: 10.1056/NEJMoa071366.
citation: 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.