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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
Scientific title
Pharmacokinetics of ingested Ursolic Acid supplements in healthy men
Secondary ID [1] 296410 0
none
Universal Trial Number (UTN)
U1111-1222-7528
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
muscle wasting 310166 0
Condition category
Condition code
Musculoskeletal 308919 308919 0 0
Other muscular and skeletal disorders

Intervention/exposure
Study type
Interventional
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
Intervention code [1] 312744 0
Treatment: Drugs
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)
Control group
Active

Outcomes
Primary outcome [1] 307885 0
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
Timepoint [1] 307885 0
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
Secondary outcome [1] 353223 0
The secondary aim of this study is to determine the safety and tolerability of UA, this will be achieved by:
Timepoint [1] 353223 0
• 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.

Eligibility
Key inclusion criteria
• Healthy men aged between 18-35 years
• A BMI >18 and <27.99 kg/m2
Minimum age
18 Years
Maximum age
35 Years
Sex
Males
Can healthy volunteers participate?
Yes
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

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)
central randomisation by computer
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)
Masking / blinding
Blinded (masking used)
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
Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
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.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/11/2019
Actual
Date of last participant enrolment
Anticipated
1/06/2020
Actual
Date of last data collection
Anticipated
3/08/2020
Actual
Sample size
Target
8
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 12257 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment postcode(s) [1] 24443 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 24444 0
2035 - Maroubra
Recruitment postcode(s) [3] 24445 0
2000 - Barangaroo
Recruitment postcode(s) [4] 24446 0
2001 - Sydney
Recruitment postcode(s) [5] 24447 0
2002 - World Square

Funding & Sponsors
Funding source category [1] 301018 0
Commercial sector/Industry
Name [1] 301018 0
Elysium Health, INC
Country [1] 301018 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Garvan Institute of Medical Research
Address
384 Victoria Street, Darlinghurst, NSW, 2010, Australia
Country
Australia
Secondary sponsor category [1] 300605 0
None
Name [1] 300605 0
Address [1] 300605 0
Country [1] 300605 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301773 0
St Vincent's hospital human research ethics commitee
Ethics committee address [1] 301773 0
Ethics committee country [1] 301773 0
Australia
Date submitted for ethics approval [1] 301773 0
19/11/2018
Approval date [1] 301773 0
14/02/2019
Ethics approval number [1] 301773 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 88054 0
Dr Andy Philp
Address 88054 0
Garvan Institute of Medical Research
384 Victoria Street, Darlinghurst NSW 2010
Country 88054 0
Australia
Phone 88054 0
+61 029295 8249
Fax 88054 0
Email 88054 0
[email protected]
Contact person for public queries
Name 88055 0
Gareth Fletcher
Address 88055 0
Garvan Institute of Medical Research
384 Victoria Street, Darlinghurst NSW 2010
Country 88055 0
Australia
Phone 88055 0
+61 029295 8313
Fax 88055 0
Email 88055 0
[email protected]
Contact person for scientific queries
Name 88056 0
Gareth Fletcher
Address 88056 0
Garvan Institute of Medical Research
384 Victoria Street, Darlinghurst NSW 2010
Country 88056 0
Australia
Phone 88056 0
+61 029295 8313
Fax 88056 0
Email 88056 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All non-identifiable data will be made available.
When will data be available (start and end dates)?
01.12.2020 - 01.12.2035
Available to whom?
Accessible to anyone with internet connection
Available for what types of analyses?
not specified
How or where can data be obtained?
unrestricted access via repository in LabArchives


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.