Condition category
Infections and Infestations
Date applied
05/06/2002
Date assigned
05/06/2002
Last edited
15/11/2013
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Not provided at time of registration

Trial website

Contact information

Type

Scientific

Primary contact

Mr Dale Rublee

ORCID ID

Contact details

Aventis Behring LLC
1020 First Avenue
PO Box 61501
King of Prussia
PA 19406
United States of America
+1 610 878 4833
dale.rublee@aventis.com

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

N/A

Study information

Scientific title

Acronym

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

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Condition

Sepsis

Intervention

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

Drug

Phase

Not Specified

Drug names

Antithrombin III

Primary outcome measures

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

01/03/1997

Overall trial end date

01/01/2000

Reason abandoned

Eligibility

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

Patient

Age group

Adult

Gender

Both

Target number of participants

2,314

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

01/03/1997

Recruitment end date

01/01/2000

Locations

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

Organisation

Aventis Behring LLC (USA)

Sponsor details

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

Sponsor type

Industry

Website

http://www.cslbehring.com/

Funders

Funder type

Industry

Funder name

Aventis Behring LLC (USA)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

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

Results - basic reporting

Publication summary

1. 2001 Results in http://www.ncbi.nlm.nih.gov/pubmed/11597289
2. 2002 Quality of life evaluation: http://www.ncbi.nlm.nih.gov/pubmed/12225612
3. 2006 Results in http://www.ncbi.nlm.nih.gov/pubmed/17107615

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