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Trial registered on ANZCTR


Registration number
ACTRN12608000573358
Ethics application status
Approved
Date submitted
21/07/2008
Date registered
12/11/2008
Date last updated
15/11/2019
Date data sharing statement initially provided
15/11/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Individualised versus conventional enoxaparin dosing: a randomised controlled trial
Scientific title
A randomised controlled trial to investigate whether an individualised dosage of enoxaparin reduces the incidence of minor and major bleeding when compared to conventional dosing in patients receiving treatment doses of enoxaparin for cardiovascular disease
Secondary ID [1] 299829 0
Nil known
Universal Trial Number (UTN)
Trial acronym
PK-Enox
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Coronary Syndrome 2560 0
Deep Vein Thrombosis 2561 0
Atrial Fibrillation 2562 0
Pulmonary Embolism 3431 0
Condition category
Condition code
Cardiovascular 3586 3586 0 0
Diseases of the vasculature and circulation including the lymphatic system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients will be randomly assigned to either a conventional dosing regimen or a pharmacokinetically-guided dosing regimen.
The amount of the first dose will be at the discretion of the prescribing doctor.
Patients will be enrolled by an investigator at the start of their enoxaparin treatment.

The pharmacokinetically-guided dosing regimen involves the following:
1. Initial dose as normal (please see below)
2. A blood sample will be collected 2-6 hours after the dose
3. enoxaparin concentration determined by measuring anti-factor Xa concentration in the sample
4. a pharmacokinetic (PK) analysis, based on enoxaparin concentration, will be carried out to estimate concentration-time profile
5. a subsequent dose will be recommended based on the PK analysis such that peak concentrations are over 500 IU/L and trough concentrations are below 500 IU/L.

Current criteria for initial dose are:
1. Venous thromboembolism (VTE) 1 mg/kg twice a day or 1.5 mg/kg daily based on total body weight (TBW)
2. Non-ST-elevation acute coronary syndrome 1 mg/kg twice a day based on TBW
3. Severe renal impairment CLCR < 30 ml/min* = 1 mg/kg daily based on TBW

The range of dosage for each regimen is:
In a conventional dosing regimen, enoxaparin dose is based on total body weight. That is, a 40 kg patient without severe renal impairment would receive 40 mg twice daily; a 40 kg patient with severe renal impairment would receive 40 mg once daily; a 140 kg patient without severe renal impairment would receive 140 mg twice daily; and a 140 kg patient with severe renal impairment would receive 140 mg once daily.

In a pharmacokinetically-guided dosing regimen, enoxaparin dose is based on patient demographics and enoxaparin concentration. The dose is unlikely to fall outside the range above (40-140 mg) but details are patient-specific and unavailable at this stage.

For both regimens enoxaparin is administered subcutaneously

Duration of intervention:
While on enoxaparin treatment (usually 2-8 days)

Duration of the overall intervention:
While on enoxaparin treatment (2-8 days). Patients will be followed up for up to 30 days after the commencement of treatment in order to monitor evidence of therapeutic outcomes and events such as revascularisation, re-thrombosis, or repeat emboli.
Intervention code [1] 2294 0
Treatment: Drugs
Comparator / control treatment
The conventional dosing regimen for all patients will be that determined by the prescribing doctor (and as recommended by the manufacture and approved by Medsafe).
Control group
Dose comparison

Outcomes
Primary outcome [1] 3572 0
The primary endpoint of this study will be the total number of patients with a bleeding event. A bleeding event incorporates any major or minor bleed. A major bleed is defined by a decrease in hemoglobin greater than 30 g/L or evidence of an internal anatomical bleed such as retroperitoneal, intracranial or intraocular (as used in the TIMI 11B trial, Antman et al. Circulation 1999; 100(15):1593-601).
Minor bleed is defined as a bleed other than a major bleed, e.g. epistaxis, haematuria, an injection or venepuncture site bleeding, and haematemesis.
Timepoint [1] 3572 0
All patients will be inspected daily for signs of bleeding by an investigator who is blinded to treatment.
This will take a few minutes each occasion and the investigator will be using a Clinical Report Form to record findings.
Each patient will be monitored for a period of 2-8 days of treatment and for as many days as the patient remains in hospital as per usual care (expected 24-48 hours). Each assessment will take approximately 10 minutes.
Secondary outcome [1] 5977 0
The secondary endpoint is defined as a composite of any primary endpoint and any single major bruise that has a surface area of greater than 20 cm2 and is distal to the site of injection and venipuncture sites for blood draws (as used in a post hoc analysis of the ESSENCE study, Berkowitz et al. Am J Cardiol. 2001; 88(11):1230-4)
Timepoint [1] 5977 0
All patients will be inspected daily for signs of bleeding by an investigator who is blinded to treatment.
This will take a few minutes each occasion and the investigator will be using a Clinical Report Form to record findings.
Each patient will be monitored for a period of 2-8 days of treatment and for as many days as the patient remains in hospital as per usual care (expected 24-48 hours). Each assessment will take approximately 10 minutes.

Eligibility
Key inclusion criteria
All patients admitted for treatment with enoxaparin who are likely to require treatment for at least 48 hours are eligible for inclusion into the study.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients who are pregnant; less than 18 years old; have received warfarin in the past 7 days or heparin therapy (unfractionated heparin 'UFH' or low-molecular weight heparin 'LMWH') in the last day; have an international normalised ratio 'INR' > 1.2 or an Activated Partial Thromboplastin Time 'APTT' > 60 seconds at the time of recruitment; or an estimated creatinine clearance less than 10 ml/min (using the Cockcroft and Gault equation calculated based on lean body weight).

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
1. block randomisation (block of 10) to be undertaken by HA who is blinded
2. consenting patients to be undertaken by HA or JS
3. randomisation of patient to be undertaken by HA. Allocation is concealed and allocation schedule is off-site to be held by SD
4. collecting blood samples from all patients to be undertaken by HA, L, JS, or FV
5. assaying blood samples from all patients to be undertaken by HA
6. analysing blood sample and using TCIWorks to estimate a dose for every patient to be undertaken by HA. HA will then print out a pharmacokinetic profile (including time for next sample) and hand this to JS or RW
7. JS or RW will check with SD (who has possession of the allocation schedule) whether the patient is in individualised or controlled group (unconcealment) and heed dose recommendation only if patient is in the individualised group
8. bleeding and bruising assessment to be undertaken by L (by using lab results recorded in the programme iSOFT, by performing a physical assessment, and by checking the clinical notes) or by HA (by using lab results recorded in the programme iSOFT and by performing a physical assessment).
9. the 30-day follow up to be undertaken by HA by accessing the programme ORACARE.
10. the final analysis to be undertake by HA
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer-generated randomisation table.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
24/11/2008
Actual
1/12/2009
Date of last participant enrolment
Anticipated
Actual
1/02/2012
Date of last data collection
Anticipated
Actual
1/02/2012
Sample size
Target
140
Accrual to date
Final
22
Recruitment outside Australia
Country [1] 665 0
New Zealand
State/province [1] 665 0
Dunedin
Country [2] 666 0
New Zealand
State/province [2] 666 0
Otago

Funding & Sponsors
Funding source category [1] 2805 0
Charities/Societies/Foundations
Name [1] 2805 0
Otago Medical Research Foundation
Country [1] 2805 0
New Zealand
Primary sponsor type
University
Name
School of Pharmacy
Address
School of Pharmacy
University of Otago
PO Box 913
Dunedin 9054
Country
New Zealand
Secondary sponsor category [1] 3252 0
Individual
Name [1] 3252 0
Dr John Schollum
Address [1] 3252 0
Department of Nephrology
Dunedin Hospital
Private Bag 1921
Dunedin 9054
Country [1] 3252 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 5666 0
Lower South Regional Ethics Committee
Ethics committee address [1] 5666 0
Administrator: Riria Tautau-Grant

Postal address:
229 Moray Place
PO Box 5849
Dunedin 9054
Ethics committee country [1] 5666 0
New Zealand
Date submitted for ethics approval [1] 5666 0
Approval date [1] 5666 0
30/01/2008
Ethics approval number [1] 5666 0
Project Key: LRS/07/11/041 Lower South Regional Ethics Committee

Summary
Brief summary
Enoxaparin is a low molecular weight heparin (LMWH) widely used in clinical practice (e.g. heart attacks, and clots in the lungs. It has been proven to be a safe and effective alternative to the traditional unfractionated heparin (UFH). Unlike UFH where dose is monitored, enoxaparin is given on a weight-based regime, without any monitoring. The safety of this dosing regimen of enoxaparin is not well established particularly in patients who are obese or have kidney disease. The effect of enoxaparin can be monitored by measuring a serum protein (anti-Xa). It is known that there is an increased rate of bleeding complications if the anti-Xa concentration is higher than 1000 IU/L.

We wish to undertake a randomised controlled trial of patients admitted to Dunedin Hospital who are treated with enoxaparin. Patients will be randomly assigned to either a conventional dosing regimen or a pharmacokinetically-guided dosing regimen. The main endpoints are minor and major bleeding events as defined in the literature (Antman et al. Circulation 1999; 100(15):1593-601).

The conventional dosing regimen for all patients will be that determined by the prescribing doctor (as per the product’s license). For the pharmacokinetically-guided dosing regimen, the initial dosing regimen is one chosen by the prescribing doctor. Subsequent doses will be calculated using the anti-Xa concentration obtained from blood samples.
Trial website
Trial related presentations / publications
Al-Sallami, H. (2015). Optimising Patient Care by Individualising Drug Dosage (Thesis, Doctor of Philosophy). University of Otago. Retrieved from http://hdl.handle.net/10523/5787

Al-Sallami HS, Schollum J, Barras M, Duffull SB. The use of a Bayesian dosing tool to optimise enoxaparin treatment: a pilot clinical study. In proc. of The Population Approach Group in Europe (PAGE), 28 (2019), [www.page-meeting.org/?abstract=9011], Stockholm, Sweden.
Public notes

Contacts
Principal investigator
Name 28194 0
Dr Hesham Al-Sallami
Address 28194 0
School of Pharmacy
18 Frederick Street
Dunedin
Country 28194 0
New Zealand
Phone 28194 0
+6434797295
Fax 28194 0
Email 28194 0
[email protected]
Contact person for public queries
Name 11351 0
Hesham Al-Sallami
Address 11351 0
School of Pharmacy
University of Otago
PO Box 913
Dunedin 9054, New Zealand
Country 11351 0
New Zealand
Phone 11351 0
+6434797295
Fax 11351 0
+6434797034
Email 11351 0
[email protected]
Contact person for scientific queries
Name 2279 0
Hesham Al-Sallami
Address 2279 0
School of Pharmacy
University of Otago
PO Box 913
Dunedin 9054, New Zealand
Country 2279 0
New Zealand
Phone 2279 0
+6434797295
Fax 2279 0
+6434797034
Email 2279 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.