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Trial registered on ANZCTR


Registration number
ACTRN12618001929291
Ethics application status
Approved
Date submitted
26/11/2018
Date registered
28/11/2018
Date last updated
23/07/2019
Date data sharing statement initially provided
28/11/2018
Date results information initially provided
23/07/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A human trial to evaluate the performance and safety of a new formulation containing a cholesterol-lowering drug to healthy male volunteers.
Scientific title
A Phase I, Proof-of-Concept, Randomised, Double-Blind, Cross-Over Clinical Trial to Assess the Safety, Tolerability and Pharmacokinetic Profile of LipoCeramic™ Simvastatin.
Secondary ID [1] 296657 0
LCS001
Secondary ID [2] 296662 0
RF001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hypercholesterolemia 310499 0
Condition category
Condition code
Cardiovascular 309208 309208 0 0
Coronary heart disease
Diet and Nutrition 309292 309292 0 0
Other diet and nutrition disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Simvastatin will be delivered in a new LipoCeramic formulation which contains soybean lecithin, Capmul MCM and silica nanoparticles. Two variations of silica nanoparticles will be trialled including Aerosil 300 and Syloid 224. These formulations will be referred to as LipoCeramic Formulation A and LipoCeramic Formulation B, respectively.

Volunteers will also be randomly assigned into Treatment Group 1 or Treatment Group 2 where they will be orally administered a simvastatin dose of 10 mg and 20 mg in LipoCeramic Formulation A or LipoCeramic Formulation B, respectively. Each dose will be administered with 240 mL of room temperature water following overnight fasting (at least 10 hours). Between each dose, there will be a 7 day wash-out period.

Prior to each dosing day, a reminder of the need to fast will be sent to the participant. During check-in on each dosing day, the participants will undergo a brief questionnaire to ensure they still adhere to the inclusion criteria and have not violated any exclusion criteria, including food intake.

All doses will be administered by a nurse and the oral cavity will be checked to ensure the capsule has been swallowed.
Intervention code [1] 312971 0
Treatment: Drugs
Comparator / control treatment
As a control, all subjects will receive one oral dose of a 20 mg commercial Simvastatin tablet (Sandoz Simvastatin). Simvastatin Sandoz, is manufactured by Sandoz Pty Ltd.

The dose will be administered by a nurse and the oral cavity will be checked to ensure the capsule has been swallowed.
Control group
Active

Outcomes
Primary outcome [1] 308190 0
Change in simvastatin plasma concentration
Timepoint [1] 308190 0
0.5, 0.75, 1, 1.5, 2, 3, 4, 6 and 8 hours post-dose administration
Primary outcome [2] 308191 0
Presence or absence of adverse events. The participants will be asked a non-leading question, such as, “how do you feel?"

Simvastatin is generally well-tolerated, however some patients may experience unwanted side effects with chronic use. The most common side effects of simvastatin which are mild and short-lived include: constipation, diarrhoea, wind, stomach upset or pain, nausea, headache and dizziness. If one of these were to occur, suitable medication will be administered to minimise discomfort for the patient. On rare occasions, patients have experienced the following side effects: aching muscles, muscle tenderness or weakness (not caused by exercise), brown/black coloured urine, tingling in the hand or feet, signs of anaemia (tiredness, shortness of breath, looking pale), fever, skin rash (hives), itchiness, painful or swollen joints, bruising more easily than normal and larger breasts than normal in men.
Timepoint [2] 308191 0
Within 1 hour pre-dose, and 2, 4 and 8 hours after a subject has received a dose of study medication
Secondary outcome [1] 354204 0
Nil
Timepoint [1] 354204 0
Nil

Eligibility
Key inclusion criteria
1. Gender: Male.

2. Age: 18 years and over.

3. General Health: Healthy. Health status will be determined by the subject’s medical history with specific attention to: (I) drug history identifying any known drug allergies or drug abuse, (II) any chronic use of medication, and (III) a thorough review of body systems. This will also be determined after a physical examination, including an electrocardiogram (ECG), revealing no abnormal findings, which in the opinion of the Principal Investigator, or medical nominee, would risk the safety of the subject of impact the validity of the study results.

4. Venous Access: Subjects require adequate venous access on their left or right arm to allow for collection of numerous blood samples.

5. Language: Fluent in English.

6. Informed Consent: Subject must voluntarily give written informed consent to participate in this study.
Minimum age
18 Years
Maximum age
No limit
Gender
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Hypersensitivity: History of hypersensitivity and/or allergy to simvastatin or any of the ingredients which are listed in the formulation, including soy. Hypersensitivity to lignocaine/lidocaine or any surgical dressings which may be used during the study.

2. Medical Conditions: (a) History of clinically significant gastrointestinal, hepatic, renal, cardiovascular, dermatological, immunological, respiratory, endocrine, oncological, neurological, metabolic, psychiatric disease or haematological disorders. (b) Any pre-existing condition which may interfere with the absorption, distribution, metabolism and/or excretion of drugs. (c) History of abnormal bleeding tendencies or thrombophlebitis unrelated to venous puncture or intravenous cannulation, or a history of Hepatitis B or C, or a positive test for Hepatitis antigen or antibodies, a history of HIV infection or presence of HIV antibodies.

3. Abnormal Laboratory Results: Any evidence of organ dysfunction or abnormality in clinical laboratory results which is deemed significant which would risk the safety of the subject of impact the validity of the study results.

4. Ethanol Use: Regular drinkers who consume more than four units of alcohol daily or those who may have difficulty abstaining from alcohol for 24 hours prior to dose administration and 8.5 hours following dose administration.

5. Drug and Alcohol Abuse: History or current evidence of alcohol or drug abuse, licit or illicit, or positive urine drug and breath alcohol screen.

6. Medication: Difficulty in refraining from the administration of potent CYP3A4 inhibitors for 14 days prior to the initial dose administration and until the exit evaluation. Subjects will be instructed not to take any prescription medication for 14 days prior to the first dose administration and for the duration of the study and to abstain from over- the-counter (OTC) medication within 7 days prior to initial dose administration and until the Exit Evaluation.

7. Xanthine Use: Difficulty in abstaining from food and/or beverages that contain caffeine or other xanthines (I.e. coffee, tea, cola and chocolate) during 24 hours prior to dose administration until the completion of blood sampling in each study period.

8. Psychiatric or Psychological Disorder: History or presence of any psychiatric ill ness or psychological disorder which may impair the subject’s ability to provide written consent or participate in the study.

9. Blood Donation: Standard blood donation (usually 550 mL) within the 12-week period before dose administration until the exit evaluation.

10. Dietary Habits: Unusual dietary habits including vegetarian diets, excessive or unusual vitamin intake. Difficulty in abstaining from grapefruit juice for 24 hours prior to dose administration until the exit evaluation.

11. Food Consumption: Difficulty in refraining from food consumption from 2300 hours the night before dosing (I.e. for 10 hours prior to dosing).

12. Tobacco: Tobacco users who smoke more than 10 cigarettes (or equivalent) per day and/or who are unable to refrain from smoking whilst confined in the Clinical Trial Facility each study period.

13. Contraception: Unwilling to use adequate contraception for the duration of the study (e.g. condoms), unless surgically sterile

14. Recent Study Participation: Consumption of any drug as part of a research study within 30 days of the initial dose administration in this study.

15. Protocol Compliance: Poor compliers or those who are unlikely to attend.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Once a volunteer gives consent to participate in the screening process, they will be identified by a randomisation number between R001 and R014 inclusive. On acceptance to the study, recruited subjects will then be assigned and identified by a study specific identification number.

The randomisation number does not dictate which treatment the subject will recieve and thus can be given by the person conducting the screening process. However, the study specific identification number will dictate the treatment group and will be allocated by someone who is 'off-site'.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
To determine which treatment group the volunteers will be enrolled, a simple randomisation schedule will be generated using computer software.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint(s)
Bio-availability
Statistical methods / analysis
A total of 12 subjects will be included in the study. As this is a proof of concept study, no formal sample size justification has been performed.

The concentration of simvastatin in the plasma samples of all subjects will be determined via liquid chromatography–mass spectrometry using a validated analytical method. The plasma concentrations of simvastatin at all time points will be tabulated and summarised per treatment. Pharmacokinetic variables will be calculated for all subjects who consumed at least one dose of the investigational product. Summaries of pharmacokinetic parameters will also be produced for each treatment group.

Recruitment
Recruitment status
Completed
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)
SA

Funding & Sponsors
Funding source category [1] 301237 0
Commercial sector/Industry
Name [1] 301237 0
Reform Pharm Pty Ltd
Address [1] 301237 0
c/o AK Accountant
Unit 4, 202-208 Glen Osmond Road
Fullarton SA 5063
Country [1] 301237 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Reform Pharm Pty Ltd
Address
c/o AK Accountant
Unit 4, 202-208 Glen Osmond Road
Fullarton SA 5063
Country
Australia
Secondary sponsor category [1] 300887 0
None
Name [1] 300887 0
Address [1] 300887 0
Country [1] 300887 0
Other collaborator category [1] 280441 0
University
Name [1] 280441 0
University of South Australia
Address [1] 280441 0
GPO Box 2471
Adelaide, South Australia 5001
Australia
Country [1] 280441 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301976 0
University of South Australia Human Research Ethics Committee
Ethics committee address [1] 301976 0
GPO Box 2471
Adelaide, South Australia 5001
Australia
Ethics committee country [1] 301976 0
Australia
Date submitted for ethics approval [1] 301976 0
20/09/2018
Approval date [1] 301976 0
16/11/2018
Ethics approval number [1] 301976 0
201719

Summary
Brief summary
The purpose of this study is to evaluate the safety and performance of LipoCeramic simvastatin when administered as an oral capsule. Simvastatin is a commonly prescribed lipid-regulating drug which is used to treat hypercholesterolemia, where there is high levels of cholesterol present in the blood. LipoCeramic technology combines simvastatin with numerous approved ingredients to improve the absorption of the drug in the body.

A total of twelve healthy male volunteers aged 18 or over, who meet all entry criteria will be accepted into the study. Participants will be randomly allocated to two groups which dictates which formulation they receive. The trial will be “double- blinded” which means neither the participants, nor the study staff, will know which formulations are being administered.

Volunteers will undergo a screening process to determine their eligibility for the study. Successfully recruited volunteers will be required to attend the Clinical Trial Facility on three occasions for a full-day (8:00 am to 5:30 pm) visit, where they will receive one oral dose of a commercial simvastatin tablet and two doses of simvastatin in a LipoCeramic Formulation. There will be a 7-day wash-out period between doses, meaning volunteers will return to the Clinical Trial Facility 7 days and 14 days after administration of their first dose to receive subsequent treatments.

Each dosing day will require blood sample collection prior to dosing and at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6 and 8 hours post dose administration. Numerous safety assessments will also be performed throughout the day.

The study will be held at the University of South Australia Clinical Trial Facility, located at the City East Campus, Bonython Jubilee Building, Frome Road. Volunteers will be financially reimbursed $600 for their time and inconvenience after completion of the study.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 88738 0
Prof Peter Clifton
Address 88738 0
University of South Australia
GPO Box 2471
Adelaide, South Australia 5001
Australia
Country 88738 0
Australia
Phone 88738 0
+61 (8) 8302 1357
Fax 88738 0
Email 88738 0
Peter.Clifton@unisa.edu.au
Contact person for public queries
Name 88739 0
Mrs Louise Massie
Address 88739 0
University of South Australia
Level 1, Bonython Jubilee Building
Frome Road, City East Campus
Adelaide, South Australia 5001
Australia
Country 88739 0
Australia
Phone 88739 0
+61 (8) 8302 2097
Fax 88739 0
Email 88739 0
Louise.Massie@unisa.edu.au
Contact person for scientific queries
Name 88740 0
Prof Clive Prestidge
Address 88740 0
University of South Australia
GPO Box 2471
Adelaide, South Australia 5001
Australia
Country 88740 0
Australia
Phone 88740 0
+61 (8) 8302 2438
Fax 88740 0
Email 88740 0
Clive.Prestidge@unisa.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
A study report containing IPD will be produced, however this will not be publicly available.

A journal article may be published containing the results of the work performed in relation to the study. The plasma concentrations of simvastatin at all time points will be tabulated and summarised per treatment. The concentration-time profiles for each subject and the mean concentration-time profiles per each treatment will be plotted with linear and logarithmic axes for concentration. However, it is undecided how the results will be graphed for publication for public viewing.
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary