Corticosteroid Therapy of Septic Shock - Corticus

Phase 3

Completed

• Conditions: Shock, Septic
• Interventions: Drug: Placebo; Drug: hydrocortisone sodium succinate

• Registration Number: NCT00147004
• Lead Sponsor: Hadassah Medical Organization

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.

Study Timeline

• Study Start: 2002-03
• Study First Submitted: 2005-09-06
• Study First Submitted QC: 2005-09-06
• Study First Posted: 2005-09-07
• Primary Completion: 2005-11
• Study Completion: 2005-11
• Status Verified: 2008-04
• Last Update Submitted: 2008-04-23
• Last Update Posted: 2008-04-24

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 500

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).

6. Informed Consent

7. 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

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
2	Placebo	Placebo
1	hydrocortisone sodium succinate	hydrocortisone sodium succinate

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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

Trial Locations

Locations (57)

Universitaetsklinik fuer Innere Medizin II; 🇦🇹 Wien, Austria

Hopital St. Joseph; 🇧🇪 Arlon, Belgium

Cliniques Universitaires St. Luc, UCL; 🇧🇪 Brussels, Belgium

Hospital de St. Antonio do Capuchos; 🇵🇹 Lisboa, Portugal

University Hospital Erasme; 🇧🇪 Brussels, Belgium

Policlinico di Tor Vergata; 🇮🇹 Roma, Italy

Renier de Graaf Hospital; 🇳🇱 Delft, Netherlands

Vivantes-Klinikum Spandau; 🇩🇪 Berlin, Germany

Hopital Raymond Poincare; 🇫🇷 Paris, Garches, France

Charité Campus Virchow-Klinikum; 🇩🇪 Berlin, Germany

KH-BHS Linz; 🇦🇹 Linz, Austria

Charité - Campus Charité Mitte; 🇩🇪 Berlin, Germany

Vivantes-Klinikum Neukoelln; 🇩🇪 Berlin, Germany

Southend Hospital; 🇬🇧 Essex, United Kingdom

Hadassah Medical Organisation; 🇮🇱 Jerusalem, Israel

Krankenhaus Hennigsdort; 🇩🇪 Hennigsdorf, Germany

LKH Feldkirch; 🇦🇹 Feldkirch, Austria

Hopital Caremeau; 🇫🇷 Nimes, France

Vivantes-Klinikum im Friedrichshain; 🇩🇪 Berlin, Germany

Charité Campus Mitte; 🇩🇪 Berlin, Germany

Klinikum Kemptern-Oberallegaeu; 🇩🇪 Kempten, Germany

Univesitaet Erlangen-Namberg; 🇩🇪 Nurenberg, Germany

Hopital Huriez; 🇫🇷 Lille, France

Zentralklinikum Augsburg; 🇩🇪 Augsburg, Germany

Klinikum Landshut; 🇩🇪 Landshut, Germany

Ichilov Hospital; 🇮🇱 Tel Aviv, Israel

Evangelisches Waldkrankenhaus Spandau; 🇩🇪 Berlin, Germany

St. Joseph Krankenhaus; 🇩🇪 Berlin, Germany

Aberdeen Royal Infirmary; 🇬🇧 Aberdeen, United Kingdom

Erasmus University Medical Centre; 🇳🇱 Rotterdam, Netherlands

Ipswich Hospital; 🇬🇧 Ipswich, United Kingdom

Beilinson Medical Centre; 🇮🇱 Petach Tikva, Israel

Staedtisches Krankenhaus Muenchen-Harlaching; 🇩🇪 Muenchen, Germany

University Hospital Dresden; 🇩🇪 Dresden, Germany

UCIP, Hospital de Desterro; 🇵🇹 Lisbon, Portugal

Hopital de Caen; 🇫🇷 Caen, France

Southampton General Hospital; 🇬🇧 Southampton, United Kingdom

Charité Campus Virchow -Klinikum; 🇩🇪 Berlin, Germany

Institute for Anaesthesia and Operative Intensive Care; 🇩🇪 Darmstadt, Germany

Friedrich-Schiller Universitaet; 🇩🇪 Jena, Germany

Klinikum Mannheim, University of Heidelberg; 🇩🇪 Mannheim, Germany

Ludwig-Maximilian-Universitaet Muenchen; 🇩🇪 Muenchen, Germany

Klinikum Ernst von Bergman; 🇩🇪 Potsdam, Germany

Charité- Campus Virchow- Klinikum; 🇩🇪 Berlin, Germany

Centro di Rianimazione Ospedale S.Eugenio; 🇮🇹 Roma, Italy

Charité - Campus Benjamin Franklin; 🇩🇪 Berlin, Germany

Klinikum Grosshadern, LMU Munich; 🇩🇪 Munich, Germany

Hopital Lariboisiere; 🇫🇷 Paris, Oarus, France

Krankenhaus der Barmherzigen Schwestern Ges. mbH; 🇦🇹 Linz, Austria

Hopital Saint-Antoine; 🇫🇷 Paris, France

Haemek Hospital; 🇮🇱 Afula, Israel

Hospital de Egas Moniz; 🇵🇹 Lisbon, Portugal

Bloomsbury Institute of Intensive Care Medicine; 🇬🇧 London, United Kingdom

Royal Lancaster Infirmary; 🇬🇧 Lancaster, United Kingdom

The General Infirmary at Leeds; 🇬🇧 Leeds, United Kingdom

University of Manchester, Hope Hospital; 🇬🇧 Salford, United Kingdom

CHU Charleroi; 🇧🇪 Charleroi, Belgium