Condition category
Infections and Infestations
Date applied
Date assigned
Last edited
Retrospectively registered
Overall trial status
Recruitment status
No longer recruiting
Publication status

Plain English Summary

Not provided at time of registration

Trial website

Contact information



Primary contact

Mr Dale Rublee


Contact details

Aventis Behring LLC
1020 First Avenue
PO Box 61501
King of Prussia
PA 19406
United States of America
+1 610 878 4833

Additional identifiers

EudraCT number number

Protocol/serial number


Study information

Scientific title


Study hypothesis

To determine if high-dose antithrombin III (administered within 6 hours of onset) would provide a survival advantage in patients with severe sepsis and septic shock.

Ethics approval

Not provided at time of registration

Study design

Randomised controlled trial

Primary study design


Secondary study design

Randomised controlled trial

Trial setting


Trial type


Patient information sheet




Patients were randomly assigned to receive 30 000 IU antithrombin III (Aventis Behring, Marburg, Germany) with a loading dose of 6000 IU (given over 30 minutes), followed by a continuous IV infusion of 6000 IU per day for 4 days, or an equivalent volume of placebo solution (1% of human albumin).

Intervention type



Not Specified

Drug names

Antithrombin III

Primary outcome measure

28-day all-cause mortality in the primary efficacy population.

Secondary outcome measures

1. Survival time within 7 days
2. Length of intensive care unit stay within 7 days
3. Occurrence of new organ dysfunction (according to Logistic Organ Dysfunction score) within 7 days
4. Severity of sepsis was assessed via the Simplified Acute Physiology Score version II(SAPS II)
5. Surgical interventions and bleeding events, recorded for 28 days
6. Other serious adverse events, recorded for 14 days
7. Antithrombin III plasma concentrations (functional) at baseline and after 24 hours
8. Activated partial thromboplastin time and prothrombin time values, assessed at baseline and 3 times daily for days 1 through 5 and on day 7

Overall trial start date


Overall trial end date


Reason abandoned (if study stopped)


Participant inclusion criteria

1. Adult hospitalised men and women (greater than or equal to 18 years)
2. Gave informed consent
3. Met the following criteria within a 6-hour period:
3.1. Clinical evidence of sepsis with a suspected source of infection
3.2. Body temperature (rectal or core) higher than 38.5°C or lower than 35.5°C
3.3. Leukocyte count higher than 10 x 10^3/µL or lower than 3.5 x 10^3/µL
4. Three of the following 6 signs had to be met within the same 6-hour period:
4.1. Tachycardia (heart rate greater than 100/min)
4.2. Tachypnoea (greater than 24/min) or mechanical ventilation because of septic indication
4.3. Hypotension with systolic blood pressure lower than 90 mm Hg despite sufficient fluid replacement or the need of vasoactive agents to maintain systolic blood pressure of 90 mm Hg or greater
4.4. Thrombocytopenia with platelet counts of less than 100 x 103/µL
4.5. Elevated lactate levels (above upper limit of normal range) or metabolic acidosis (pH less than 7.3 or base excess -10 mmol/L) not secondary to respiratory alkalosis
4.6. Oliguria with urine output of less than 20 mL per hour despite sufficient fluid replacement

Participant type


Age group




Target number of participants


Participant exclusion criteria

1. Advanced directive to withhold life-sustaining treatment (except cardiopulmonary resuscitation)
2. Condition other than sepsis anticipated to be fatal within 28 days
3. Pregnancy or breastfeeding
4. History of hypersensitivity to study medication
5. Treatment with other investigational drugs within the last 30 days
6. Treatment with an antithrombin III concentrate within the last 48 hours
7. Treatment with heparin (except subcutaneous low dose or intravenous [IV] line flushing) or coumarin derivatives
8. Non-steroidal anti-inflammatory drug treatment within previous 2 days
9. Known bleeding disorder or ongoing massive surgical bleeding
10. Platelet count of less than 30 x 10^3/µL
11. Immunocompromised status
12. Acute myocardial infarction (within previous 7 days)
13. Third-degree burns (20% of total body area)
14. Incurable malignancy with documented metastases and life-expectancy of less than 3 months
15. Haematologic neoplasia during cytostatic treatment
16. Bone marrow aplasia
17. Preexisting dialysis-dependent renal failure
18. End-stage liver disease
19. Transplantation (postoperative state)
20. History of stroke within the last year
21. Severe cranial or spinal trauma within the last year
22. Planned cranial or spinal surgery (except nontraumatic lumbar puncture) within the next 48 hours

Recruitment start date


Recruitment end date



Countries of recruitment

Czech Republic, Denmark, Germany, South Africa, United Kingdom, United States of America

Trial participating centre

Aventis Behring LLC
King of Prussia
PA 19406
United States of America

Sponsor information


Aventis Behring LLC (USA)

Sponsor details

1020 First Avenue
PO Box 61501
King of Prussia
United States of America

Sponsor type




Funder type


Funder name

Aventis Behring LLC (USA)

Alternative name(s)

Funding Body Type

Funding Body Subtype


Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Basic results (scientific)

Publication list

1. 2001 Results in
2. 2002 Quality of life evaluation:
3. 2006 Results in

Publication citations

  1. Quality of life evaluation

    Rublee D, Opal SM, Schramm W, Keinecke HO, Knaub S, Quality of life effects of antithrombin III in sepsis survivors: results from the KyberSept trial [ISRCTN22931023]., Crit Care, 2002, 6, 4, 349-356.

  2. Results

    Gonano C, Sitzwohl C, Meitner E, Weinstabl C, Kettner SC, Four-day antithrombin therapy does not seem to attenuate hypercoagulability in patients suffering from sepsis., Crit Care, 2006, 10, 6, R160, doi: 10.1186/cc5098.

  3. Warren BL, Eid A, Singer P, Pillay SS, Carl P, Novak I, Chalupa P, Atherstone A, Pénzes I, Kübler A, Knaub S, Keinecke HO, Heinrichs H, Schindel F, Juers M, Bone RC, Opal SM, , Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial., JAMA, 2001, 286, 15, 1869-1878.

Additional files

Editorial Notes