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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
Date results information initially provided
15/11/2019
Type of registration
Prospectively registered
Titles & IDs
Public title
Individualised versus conventional enoxaparin dosing: a randomised controlled trial
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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
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Secondary ID [1]
299829
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Nil known
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Universal Trial Number (UTN)
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Trial acronym
PK-Enox
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Acute Coronary Syndrome
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Deep Vein Thrombosis
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Atrial Fibrillation
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Pulmonary Embolism
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Condition category
Condition code
Cardiovascular
3586
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0
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Diseases of the vasculature and circulation including the lymphatic system
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Intervention/exposure
Study type
Interventional
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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.
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Intervention code [1]
2294
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Treatment: Drugs
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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).
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Control group
Dose comparison
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Outcomes
Primary outcome [1]
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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.
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Assessment method [1]
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Timepoint [1]
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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.
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Secondary outcome [1]
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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)
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Assessment method [1]
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Timepoint [1]
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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.
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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.
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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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).
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Study design
Purpose of the study
Prevention
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Allocation to intervention
Randomised controlled trial
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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
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer-generated randomisation table.
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 4
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Type of endpoint/s
Safety/efficacy
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Date of first participant enrolment
Anticipated
24/11/2008
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Actual
1/12/2009
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Date of last participant enrolment
Anticipated
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Actual
1/02/2012
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Date of last data collection
Anticipated
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Actual
1/02/2012
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Sample size
Target
140
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Accrual to date
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Final
22
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Recruitment outside Australia
Country [1]
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New Zealand
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State/province [1]
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Dunedin
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Country [2]
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New Zealand
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State/province [2]
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Otago
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Funding & Sponsors
Funding source category [1]
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Charities/Societies/Foundations
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Name [1]
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Otago Medical Research Foundation
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Address [1]
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Otago Medical Research Foundation
PO BOx 1245
Dunedin 9054
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Country [1]
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New Zealand
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Primary sponsor type
University
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Name
School of Pharmacy
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Address
School of Pharmacy
University of Otago
PO Box 913
Dunedin 9054
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Country
New Zealand
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Secondary sponsor category [1]
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Individual
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Name [1]
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Dr John Schollum
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Address [1]
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Department of Nephrology
Dunedin Hospital
Private Bag 1921
Dunedin 9054
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Country [1]
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New Zealand
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
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Lower South Regional Ethics Committee
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Ethics committee address [1]
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Administrator: Riria Tautau-Grant
Postal address:
229 Moray Place
PO Box 5849
Dunedin 9054
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Ethics committee country [1]
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New Zealand
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Date submitted for ethics approval [1]
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Approval date [1]
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30/01/2008
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Ethics approval number [1]
5666
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Project Key: LRS/07/11/041 Lower South Regional Ethics Committee
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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.
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Trial website
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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.
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Public notes
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Contacts
Principal investigator
Name
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Dr Hesham Al-Sallami
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Address
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School of Pharmacy
18 Frederick Street
Dunedin
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Country
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New Zealand
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Phone
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+6434797295
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Fax
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Email
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[email protected]
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Contact person for public queries
Name
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Dr Hesham Al-Sallami
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Address
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School of Pharmacy
University of Otago
PO Box 913
Dunedin 9054, New Zealand
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Country
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New Zealand
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Phone
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+6434797295
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Fax
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+6434797034
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Email
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[email protected]
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Contact person for scientific queries
Name
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Dr Hesham Al-Sallami
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Address
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School of Pharmacy
University of Otago
PO Box 913
Dunedin 9054, New Zealand
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Country
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New Zealand
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Phone
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+6434797295
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Fax
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+6434797034
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Email
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[email protected]
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Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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No/undecided IPD sharing reason/comment
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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.
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