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Trial registered on ANZCTR
Registration number
ACTRN12618001763235
Ethics application status
Approved
Date submitted
24/10/2018
Date registered
25/10/2018
Date last updated
6/09/2019
Date data sharing statement initially provided
25/10/2018
Type of registration
Prospectively registered
Titles & IDs
Public title
Pharmacokinetics of ingested Ursolic Acid supplements in healthy men
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Scientific title
Pharmacokinetics of ingested Ursolic Acid supplements in healthy men
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Secondary ID [1]
296410
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none
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Universal Trial Number (UTN)
U1111-1222-7528
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
muscle wasting
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Condition category
Condition code
Musculoskeletal
308919
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0
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Other muscular and skeletal disorders
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
In a double-blind, randomised, cross-over design study to evaluate the bio-availability Ursolic Acid in three different forms.
Ursolic Acid will be ingested orally on 3 separate occasions with a minimum 7day wash-out period in between doses. The study personnel will directly observe the participant ingesting the dose.
The 3 single doses of ursolic acid will each contain 200mg ursolic acid within a capsule and will be indistinguishable from one-another, but with the following differences:
• UA-Pow; capsule containing 200mg Ursolic acid in powder form
• UA-Phy; capsule containing 200mg Ursolic Acid within Phytosomes
• UA-Oil; capsule containing 200mg Ursolic Acid within Phytosomes suspended in oil
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Intervention code [1]
312744
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Treatment: Drugs
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Comparator / control treatment
Comparator:
UA-Pow - this is the control - it is naturally derived ursolic acid.
The 2 other treatments (UA-Phy and UA-Oil) contain the same ursolic acid found in the control (UA-Pow) but with additional components thought to aid absorption and bioavailability)
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Control group
Active
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Outcomes
Primary outcome [1]
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To determine if the composition of orally ingested UA impacts its bio-availability in healthy men: This will be achieved through typical non-compartmental pharmacokinetic analysis of ursolic acid in blood, such as:
• Maximum plasma concentration (C-max) [ Time Frame: 6 hours]
• Time at C-max (T-max)
• Elimination half life (T-1/2)
• Elimination rate constant
• Area Under the Concentration Time-Curve – The integral of the concentration-time curve, from time zero to infinity (AUC 0–8) and from time zero to the last measurable time point (AUC0–t)
• Volume of distribution
• Clearance rate
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Assessment method [1]
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Timepoint [1]
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Blood sampled at: 10, 20, 30, 45, 60, 75, 90, 120, 180, 240, 300 and 360 mins post consumption will be used to determine the availability of ursolic acid
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Secondary outcome [1]
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The secondary aim of this study is to determine the safety and tolerability of UA, this will be achieved by:
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Assessment method [1]
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Timepoint [1]
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• The incidence of Treatment-Emergent Adverse Events (Time frame: 24hrs) collected through continuous observations of AEs during a dosing visit, monitoring vital signs and spontaneous reporting of AEs. AE’s will be summarized by dose and severity.
• The number of Serious Adverse Events
• The number of Grade 3-4 biochemical abnormalities (criteria defined by the U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute, Common Terminology Criteria for Adverse Events (CTCAE) Version 4.
Known adverse events: Possible hepatotoxicities. When 21 patients with advanced solid tumours were administered UA via IV infusion (doses of 56, 74, and 98mg/m2) 14% of patients experienced grade 2 GGT elevation. Two (10%) participants treated with 56 and 74mg/m2 UA had grade 1 abdominal distention. 1 (5%) had grade 2 ALT elevation. Grade 3 elevations in ALT at 130mg/m2.
Hepatotoxicities will be assessed via blood sample - using a liver function panel test.
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Eligibility
Key inclusion criteria
• Healthy men aged between 18-35 years
• A BMI >18 and <27.99 kg/m2
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Minimum age
18
Years
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Maximum age
35
Years
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Sex
Males
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Can healthy volunteers participate?
Yes
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Key exclusion criteria
• A BMI < 17.99 or > 28 kg/m2
• Active cardiovascular disease: uncontrolled hypertension (BP > 160/100), angina, heart failure (class III/IV), arrhythmia, right to left cardiac shunt or recent cardiac event
• Clinically significant (>2 × upper limit of normal [ULN]) abnormal blood test result at screening for any metabolite measured from: Full Blood Count, Urea & Electrolytes, Thyroid Function Tests, Coagulation Tests, Liver Function Tests, glucose, insulin, HbA1c, DBIL, TBIL, phosphate, calcium and Creatine Kinase.
• Taking beta-adrenergic blocking agents, statins or non-steroidal anti-inflammatory drugs
• Cerebrovascular disease: previous stroke, aneurysm (large vessel or intracranial)
• Epilepsy
• Respiratory disease including pulmonary hypertension, COPD, asthma or an FEV1 less than 1.5L
• Metabolic disease: hyper and hypo parathyroidism, untreated hyper and hypothyroidism, Cushing’s disease, types 1 or 2 diabetes
• Active inflammatory bowel or renal disease
• Malignancy
• Recent steroid treatment (within 6 months), or hormone replacement therapy
• Family history of early (<55y) death from cardiovascular disease
• Taking any prescription/ non-prescription medication / supplements that in the opinion of the CI or PI might interact with or impact UA absorption or metabolism
• Current or recent (last 30 days) smoker
• Known or possible sensitivity to Ursolic Acid (allergy to apples, rosemary plant, holy basil or bearberry).
• Planned surgery during the course of the trial;
• History of or current diagnosis of any cancer (except successfully treated basal cell carcinoma or cancer in full remission >5 years after diagnosis);
• History of blood/bleeding disorders;
• Participation in another clinical research trial within 30 days before randomization
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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)
central randomisation by computer
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
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Intervention assignment
Crossover
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Other design features
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Phase
Phase 1
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Type of endpoint/s
Pharmacokinetics
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Statistical methods / analysis
UA availability in humans has yet to be fully determined, thus a relevant power calculation is difficult to perform. Power calculations based on data from dose-response studies using different nutritional compounds are not applicable, as the bio-availability of each nutrient is inherently different to each other. However, we anticipate that with 8 participants (providing a total of 24 datasets), this will be adequate to achieve statistical significance in our results. Any increases seen in blood UA concentrations are likely to be significant, even with very low participant numbers.
Repeated measures ANOVAs, with significance accepted at P < 0.05 will be employed to explore differences between the 3 types of UA for the following: UA plasma time concentration data (Pharmacokinetic variables described above), metabolite plasma time concentration data, vital signs, temperature, blood pressure, heart rate, gastro-intestinal health, oxygen saturation, blood biochemistry.
For the metabolomics analysis, univariate (e.g. FDR-corrected t-test) and multivariate (e.g. Partial Least Squares-Discriminant Analysis) data analysis techniques will be applied to identify metabolic differences between the different types of UA.
Missing data points will be accounted for by imputation, using linear interpolation from the individual participant’s data. If insufficient data points are available for an individual to construct a reliable imputation value, then this participant’s dataset will be excluded from analysis.
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Recruitment
Recruitment status
Not yet recruiting
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Date of first participant enrolment
Anticipated
1/11/2019
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Actual
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Date of last participant enrolment
Anticipated
1/06/2020
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Actual
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Date of last data collection
Anticipated
3/08/2020
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Actual
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Sample size
Target
8
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Accrual to date
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Final
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Recruitment in Australia
Recruitment state(s)
NSW
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Recruitment hospital [1]
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St Vincent's Hospital (Darlinghurst) - Darlinghurst
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Recruitment postcode(s) [1]
24443
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2010 - Darlinghurst
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Recruitment postcode(s) [2]
24444
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2035 - Maroubra
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Recruitment postcode(s) [3]
24445
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2000 - Barangaroo
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Recruitment postcode(s) [4]
24446
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2001 - Sydney
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Recruitment postcode(s) [5]
24447
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2002 - World Square
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Funding & Sponsors
Funding source category [1]
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Commercial sector/Industry
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Name [1]
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Elysium Health, INC
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Address [1]
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434 Broadway
2nd Floor
New York
NY10013
USA
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Country [1]
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Australia
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Primary sponsor type
Other Collaborative groups
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Name
Garvan Institute of Medical Research
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Address
384 Victoria Street, Darlinghurst, NSW, 2010, Australia
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Country
Australia
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Secondary sponsor category [1]
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None
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Name [1]
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Address [1]
300605
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Country [1]
300605
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
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St Vincent's hospital human research ethics commitee
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Ethics committee address [1]
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St Vincent's hospital human research ethics commitee
Research Office
St Vincent's hospital translational research centre
97-105 Boundary Street
Darlinghurst
NSW, 2010
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Ethics committee country [1]
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Australia
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Date submitted for ethics approval [1]
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19/11/2018
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Approval date [1]
301773
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14/02/2019
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Ethics approval number [1]
301773
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Summary
Brief summary
Muscle wasting, or atrophy, is a widespread problem in elderly human populations, and greatly increases the chances of falls and metabolic diseases such as type 2 diabetes. Ursolic acid (UA) is a natural food-derived nutrient (found in many herbs such as Rosmarinus officinalis (rosemary), Origanum vulgare (oregano), and the peel of fruits such as apples) has been shown in rodents to prevent muscle atrophy and promote muscle growth. However, the bioavailability, safety and tolerability of orally ingested ursolic acid in humans is not fully known.
Therefore, our aims for this study are:
To determine the bio-availability, safety and tolerability of 3 different forms of orally ingested Ursolic Acid in healthy men.
We hypothesise that UA will be adequately absorbed to elicit a measurable appearance in the blood and expect to see the greatest bioavailability of UA from the UA-Oil > UA-Phy > UA-Pow, with no severe adverse events, safety or tolerability complications with any of the UA supplements taken.
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Trial website
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Dr Andy Philp
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Address
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Garvan Institute of Medical Research
384 Victoria Street, Darlinghurst NSW 2010
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Country
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Australia
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Phone
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+61 029295 8249
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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 Gareth Fletcher
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Address
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Garvan Institute of Medical Research
384 Victoria Street, Darlinghurst NSW 2010
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Country
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Australia
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Phone
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+61 029295 8313
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Fax
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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 Gareth Fletcher
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Address
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Garvan Institute of Medical Research
384 Victoria Street, Darlinghurst NSW 2010
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Country
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Australia
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Phone
88056
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+61 029295 8313
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Fax
88056
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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)?
Yes
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What data in particular will be shared?
All non-identifiable data will be made available.
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When will data be available (start and end dates)?
01.12.2020 - 01.12.2035
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Available to whom?
Accessible to anyone with internet connection
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Available for what types of analyses?
not specified
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How or where can data be obtained?
unrestricted access via repository in LabArchives
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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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