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Trial registered on ANZCTR


Registration number
ACTRN12618001629224p
Ethics application status
Not yet submitted
Date submitted
28/09/2018
Date registered
3/10/2018
Date last updated
3/10/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Optimal supplementation dosing strategy for Ursolic Acid in healthy men
Scientific title
Optimal supplementation dosing strategy for Ursolic Acid in healthy men
Secondary ID [1] 296071 0
None
Universal Trial Number (UTN)
U1111-1220-3787
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
muscle wasting
309630 0
Condition category
Condition code
Musculoskeletal 308442 308442 0 0
Other muscular and skeletal disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
In a randomised, cross-over design study to evaluate the bio-availability of Ursolic Acid.
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.
3 single doses of ursolic acid will be ingested;
1. 500mg,
2. 1000mg
3. 1500mg
Intervention code [1] 312524 0
Treatment: Drugs
Comparator / control treatment
no control group
Control group
Active

Outcomes
Primary outcome [1] 307584 0
Determine the bio-availability of Ursolic Acid in the blood following oral ingestion.
This will be achieved by analysing the blood (plasma/serum) and urine UA concentration over the complete time-course after dosing. Typical non-compartmental pharmacokinetic analysis will be explored for the 3 different doses of UA from both blood and urine for concentrations of Ursolic Acid such as:
1. Maximum plasma concentration (C-max) [ Time Frame: 6 hours]
2. Time at C-max (T-max)
3. Elimination half life (T-1/2)
4. Elimination rate constant
5. 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)
6. Volume of distribution
7. Clearance rate
8. Metabolomic analysis will be conducted from urine samples to explore potential insights into UA induced changes in the metabolome
Timepoint [1] 307584 0
Blood will be sampled at 10, 20, 30, 45, 60, 75, 90, 120, 180, 240, 300 and 360mins post consumption for the determination of ursolic acid.
Secondary outcome [1] 352370 0
To determine the safety and tolerability of Ursolic Acid following oral ingestion. This will be achieved through:
1. 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 frequency and severity.
2. The number of Serious Adverse Events
3. 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.
Timepoint [1] 352370 0
AEs will be monitored continuously whilst under observation for 6hrs post ingestion and recorded for 24hrs post consumption.
Blood will be sampled 360mins + 24hrs post consumption for the determination of biochemical abnormalities.

Eligibility
Key inclusion criteria
Healthy men
age between 18-35 years
A BMI >18 and <27.99 kg/m2
Minimum age
18 Years
Maximum age
35 Years
Gender
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
Ursolic Acid 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. It should be stressed that the primary aim of this study is to measure the appearance of Ursolic Acid in the blood following oral ingestion. As such, any increases in blood Ursolic Acid concentrations are likely to be significant, even with very low participant numbers. As we anticipate a 20% drop-out rate we will aim to recruit 10 healthy men. However, once 8 participants have completed all trials no further volunteers will be recruited. Data will be analysed via ANOVA.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment postcode(s) [1] 24181 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 24182 0
2035 - Maroubra
Recruitment postcode(s) [3] 24183 0
2000 - Barangaroo
Recruitment postcode(s) [4] 24184 0
2001 - Sydney

Funding & Sponsors
Funding source category [1] 300660 0
Commercial sector/Industry
Name [1] 300660 0
Elysium Health, Inc
Address [1] 300660 0
434 Broadway
2nd Floor
New York
NY10013
USA
Country [1] 300660 0
United States of America
Primary sponsor type
Other Collaborative groups
Name
Garvan Institute of Medical Research
Address
384 Victoria St
Darlinghurst
NSW 2010
Australia
Country
Australia
Secondary sponsor category [1] 300176 0
None
Name [1] 300176 0
Address [1] 300176 0
Country [1] 300176 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 301445 0
St Vincent’s Hospital Human Research Ethics Committee
Ethics committee address [1] 301445 0
St Vincent’s Hospital Human Research Ethics Committee
Research Office
St Vincent’s Hospital Translational Research Centre (Map)
97-105 Boundary Street
Darlinghurst NSW 2010
Ethics committee country [1] 301445 0
Australia
Date submitted for ethics approval [1] 301445 0
22/10/2018
Approval date [1] 301445 0
Ethics approval number [1] 301445 0

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 orally ingested Ursolic Acid in healthy men.
We hypothesise that Ursolic Acid will be adequately absorbed to elicit a measurable appearance in the blood in a dose response fashion. We expect to see the greatest bioavailability in the blood from the 1500mg dose with no substantial increase in Adverse Events at this dose.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 87026 0
Dr Andy Philp
Address 87026 0
Garvan Institute of Medical Research
Mitochondrial Metabolism and Ageing
Diabetes and Metabolism Division
384 Victoria St, Darlinghurst, NSW 2010, Australia
Country 87026 0
Australia
Phone 87026 0
+61 02 9295 8249 |
Fax 87026 0
Email 87026 0
a.philp@garvan.org.au
Contact person for public queries
Name 87027 0
Dr Gareth Fletcher
Address 87027 0
Garvan Institute of Medical Research
Mitochondrial Metabolism and Ageing
Diabetes and Metabolism Division
384 Victoria St, Darlinghurst, NSW 2010, Australia
Country 87027 0
Australia
Phone 87027 0
+61 02 9355 8313
Fax 87027 0
Email 87027 0
g.fletcher@garvan.org.au
Contact person for scientific queries
Name 87028 0
Dr Gareth Fletcher
Address 87028 0
Garvan Institute of Medical Research
Mitochondrial Metabolism and Ageing
Diabetes and Metabolism Division
384 Victoria St, Darlinghurst, NSW 2010, Australia
Country 87028 0
Australia
Phone 87028 0
+61 02 9355 8313
Fax 87028 0
Email 87028 0
g.fletcher@garvan.org.au

No data has been provided for results reporting
Summary results
Not applicable