Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12607000157471
Ethics application status
Approved
Date submitted
2/03/2007
Date registered
6/03/2007
Date last updated
18/11/2015
Type of registration
Prospectively registered

Titles & IDs
Public title
Heparin in Severe Sepsis
Scientific title
Does Heparin improve survivial in severe sepsis? A pilot feasability study
Secondary ID [1] 287922 0
HISS Study
Secondary ID [2] 287923 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Severe sepsis 1659 0
Condition category
Condition code
Blood 1764 1764 0 0
Other blood disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Blinded study of low-dose intravenous unfractionated heparin (UFH) (control) compared to subcutaneous fondaparinux (intervention) in patients with severe sepsis.

Fondaparinux: an injection of fondaparinux 2.5mg in 0.5ml of saline for injection will be administered subcutaneously daily for 7 days commencing within 24 hours of onset of severe sepsis.
For blinding purposes, a continuous infusion of normal saline will also be required at the same time as the control arm.
Duration of the study is 7 days in both arms.
Intervention code [1] 1628 0
Treatment: Drugs
Comparator / control treatment
UFH: 500 international units per hour will run continuously for 7 days commencing within 24 hours of the onset of severe sepsis. For blinding purposes, a single daily dose of subcutaneous normal saline 0.5ml will also be required.
Control group
Active

Outcomes
Primary outcome [1] 2465 0
Survivial from severe sepsis.
Timepoint [1] 2465 0
At 28 days after randmisation
Primary outcome [2] 2466 0
All cause mortality
Timepoint [2] 2466 0
At 28 days after randmisation
Secondary outcome [1] 4228 0
Death from all causes
Timepoint [1] 4228 0
At 90 days after randomisation
Secondary outcome [2] 4229 0
Death in Intensive Care Unit (ICU)
Timepoint [2] 4229 0
28 days after randomisation and at hospital discharge
Secondary outcome [3] 4230 0
ICU and hospital length of stay
Timepoint [3] 4230 0
Whilst in ICU and hospital
Secondary outcome [4] 4231 0
The need for and duration of organ support(inotropic/vassopressor/mechanical ventilation) measured daily whilst in ICU.
Timepoint [4] 4231 0
Measured daily whilst an inpatient in ICU
Secondary outcome [5] 4232 0
Adverse events related to drug safety, particularly bleeding episodes, monitored daily.
Timepoint [5] 4232 0
Monitored daily till death or 90 days post randomisation

Eligibility
Key inclusion criteria
1. Diagnosis of severe sepsis 2. Patients able commence study treatment within 24 hours of fulfilling inclusion criteria. 3. Informed consent obtained from the patient or next of kin/legal surrogate.
Minimum age
18 Years
Maximum age
Not stated
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patient is receiving continued full anticoagulation treatment for any other reason with either unfractionated heparin (UFH) or coumarin agents2. Patients with contra-indication to low dose UFH or fondaparinux including intracranial haemorrhage, active bleeding or heparin induced thrombocytopaenia(HIT) in the past 3 months.3. Patients with prior adverse reaction to UFH or fondaparinux4. Patients with organ dysfunction due to sepsis present for more than 24 hours5. Patients not for full active treatment, except presence of DNR order.6. Patients not expected to survive 28 days due to underlying or comorbid condition.7. Patient is moribund with death or brain death expected within 24 hours.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation by phone via a computerised interactive voice response system.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by a computer software
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Allocation is concealed by blinding clinicians and patients (double-blind). Pharmacist outside the treatment team remains unblinded. The study drug will be administered by the ICU nurses according to the written protocol.The assessment of outcome is the application of objective numerical criteria to the clinical results in the daily clinical record maintained by the hospital staff.
Phase
Phase 2
Type of endpoint/s
Bio-equivalence
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Reason for early stopping/withdrawal
Date of first participant enrolment
Anticipated
9/06/2007
Actual
14/11/2007
Date of last participant enrolment
Anticipated
Actual
30/03/2008
Date of last data collection
Anticipated
Actual
Sample size
Target
40
Accrual to date
Final
7
Recruitment in Australia
Recruitment state(s)

Funding & Sponsors
Funding source category [1] 1916 0
Charities/Societies/Foundations
Name [1] 1916 0
Australian and New Zealand Intensive Care Foundation
Country [1] 1916 0
Australia
Primary sponsor type
Individual
Name
Dr Megan S Robertson
Address
Intensive Care Unit
The Royal Melbourne Hospital
Grattan Street Parville Victoria 3050
Country
Australia
Secondary sponsor category [1] 1728 0
Individual
Name [1] 1728 0
Prof J Cade
Address [1] 1728 0
Intensive Care Unit
The Royal Melbourne Hospital
Grattan Street Parville Victoria
Country [1] 1728 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 3563 0
The Alfred Hospital
Ethics committee address [1] 3563 0
Ethics committee country [1] 3563 0
Australia
Date submitted for ethics approval [1] 3563 0
Approval date [1] 3563 0
10/09/2007
Ethics approval number [1] 3563 0
Ethics committee name [2] 3564 0
The Royal Perth Hospital
Ethics committee address [2] 3564 0
Ethics committee country [2] 3564 0
Australia
Date submitted for ethics approval [2] 3564 0
Approval date [2] 3564 0
19/09/2007
Ethics approval number [2] 3564 0

Summary
Brief summary
In Australia and New Zealand, around 5000 patients are admitted to Intensive Care Units (ICU) annually with severe infection (sepsis). Despite aggressive treatment, around 35% of these patients will not survive, making severe sepsis the most common non-cardiac cause of death in ICU patients. Even surviving patients often suffer a period of multiple organ failure. Most patients admitted to ICU receive heparin injections to prevent the formation of blood clots in the leg veins which can travel to the lungs, causing major breathing difficulties. Traditionally, the agent most commonly given to prevent blood clots was unfractionated heparin, but over the last decade, more purified forms of heparin (low and ultra-low molecular weight heparins) have become available. These more modern agents are replacing the traditional heparin for blood clot prevention because of reported increased effectiveness. Recent studies in animals, healthy humans and critically ill patients with severe sepsis have suggested that unfractionated heparin may have beneficial therapeutic effects in infection, additional to its action to prevent blood clots. These immune-active effects are related to molecular size and thus may be lost with the current trend to use purified heparin forms. If this is true, then this additional benefit may be lost as we change to more purified heparin forms. We aim to perform a pilot study to assess the feasibility of conducting a large multi-centre study to investigate whether unfractionated heparin is beneficial for patients with severe sepsis. If unfractionated heparin is shown to be beneficial in these patients, this would be a simple, cheap and widely applicable additional treatment for severe infection that could save lives world-wide, and be accessible in first to third-world environments.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 27562 0
Dr Megan S Robertson
Address 27562 0
Principal Investigator no longer employed at this organisation. Contact details not available
Country 27562 0
Australia
Phone 27562 0
Not available
Fax 27562 0
Email 27562 0
not available
Contact person for public queries
Name 10817 0
Dr Megan S Robertson
Address 10817 0
Intensive Care Unit
The Royal melbourne Hospital
VIC 3050
Country 10817 0
Australia
Phone 10817 0
+61 3 93427441
Fax 10817 0
+61 3 93428812
Email 10817 0
[email protected]
Contact person for scientific queries
Name 1745 0
Dr Megan S Robertson
Address 1745 0
Intensive Care Unit
The Royal melbourne Hospital
VIC 3050
Country 1745 0
Australia
Phone 1745 0
+61 3 93427441
Fax 1745 0
+61 3 93428812
Email 1745 0
[email protected]

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