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Trial registered on ANZCTR


Registration number
ACTRN12619000417189
Ethics application status
Approved
Date submitted
5/03/2019
Date registered
14/03/2019
Date last updated
21/02/2020
Date data sharing statement initially provided
14/03/2019
Date results information initially provided
21/02/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase I Study to assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Oral Ascending Doses of BioE-1115 in Healthy Adult Volunteers
Scientific title
A Double-Blind, Randomised, Placebo Controlled Phase I Study to assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Oral Ascending Doses of BioE-1115 in Healthy Adult Volunteers
Secondary ID [1] 297572 0
BE-CT-001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Non-alcoholic fatty liver disease (NAFLD) 311826 0
Condition category
Condition code
Oral and Gastrointestinal 310432 310432 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This first in human (FIH) Phase 1 study to assess safety, tolerability, PK and PD of BioE-1115. The study is conducted in two parts a single ascending dose (SAD) where subjects receive only one dose of BioE-1115, and a multiple ascending dose (MAD) where subjects receive multiple daily dose of BioE-1115 for up to 7 days. Mode of administration of BioE-1115: Oral Capsules
A total of approximately up to 121 subjects from both parts are expected to be enrolled in this study. Each subject will be allowed to participate in either the SAD cohort or MAD cohort, but not both.
The SAD and MAD studies of BioE-1115 vs. placebo will be conducted in 2 parts of 5 × SAD and 4 × MAD dose cohorts.

Part A (SAD):
o Each cohort will consist of 8 subjects (2 receiving placebo and 6 receiving BioE-1115, in fasting state). One cohort may be called back to be redosed in a fed state after a washout period.
The dose of BioE-1115 administered in each cohort and/or the ascending schedule between cohorts of Part A (SAD): The study drug will be administered on Day 1. 5 dose levels in the range of 50 to 1000 mg/day are planned to be administered to the 5 cohorts. The starting dose will be 50 mg and subsequent higher dose levels will be determined by the Safety Review Committee (SRC) based on safety data and blinded PK data, evaluated up to and including Day 7, from the previous cohort(s). It is estimated that the dose levels will be approximately 50mg/day, 150mg/day, 450mg/day, 750mg/day and 1000mg/day.
All study doses will be administered an overnight fast of at least 10 hours. In the fed cohort, the IMP will be administered within 30 minutes after the start of a standardized meal.

Part B (MAD):
o Each MAD cohort will consist of 15 subjects, (3 receiving placebo and 12 receiving BioE-1115) in a fasted state.
The dose of BioE-1115 administered in each cohort and/or the ascending schedule between cohorts of Part B (MAD): The study drug will be administered daily, from Day 1 to Day 7 inclusive. 4 dose levels will be evaluated in Part B (MAD) and it is expected that the starting dose will be approximately 150mg/day. However, the starting dose will be determined by the SRC, following review of safety and PK data up to, and including SAD cohorts 1-3. Subsequent higher dose levels and frequency of dosing (once daily or twice daily) will be decided by the SRC based on safety and PK data, up to and including Day 14, evaluated from the previous cohort(s). Intermediate dose levels, a revised dosing regimen and/or an additional dose group may be considered if recommended by the SRC. The study drug will be administered after fasting period of at least 10 hours.

After an overnight fast of at least 10 hours, subjects will be administered investigational drug (BioE-1115/placebo) with 240 mL (8 fluid ounces) of water. No food will be allowed for at least 4 hours post-dose. Water will be allowed as desired except for 1 hour before and after drug administration. Subjects will receive standardized meals scheduled at the same time in each period of the study. Compliance with the fast will be ensured, with admission to the Phase I unit of all subjects 24 hours prior to dosing (Day -1).

Washout period' used for the fasted-then-fed cohort;
The predicted plasma half-life of BioE-1115 in humans based on animal studies is approximately 22 hours. We therefore anticipate that the washout period between fasting and fed dosing will be at least 5 half-lives, or approximately 1 week. However, if the Safety Review Committee decides to recall an SAD cohort back for repeat dosing in the fed state, it will also decide on the minimum wash-out period based on actual PK data from the SAD cohorts.

Intervention code [1] 313810 0
Treatment: Drugs
Comparator / control treatment
Matching Placebo
The composition of placebo treatment is Croscarmellose sodium 2.95% (13.6 mg/dose), Mannitol SD200 95.57% (440 mg/dose), Yellow Die 0.98% (4.5 mg/dose) and Magnesium stearate 0.52% (2.4 mg/dose
Control group
Placebo

Outcomes
Primary outcome [1] 319302 0
To assess safety and tolerability of BioE-1115 following escalating single and multiple doses of BioE-1115 in healthy volunteers.
Timepoint [1] 319302 0
The safety and tolerability will be evaluated by targeted physical examination including Adverse Events (AEs) reporting, Weight, Vital signs (blood pressure, heart rate, body temperature, respiration rate), 12-lead electrocardiogram (ECG) monitoring, Ambulatory arrhythmia monitoring (telemetry), Blood and urine sampling for haematology, clinical chemistry including Creatinine Phosphokinase (CPK) and cardiac troponins and coagulation
Secondary outcome [1] 367637 0
To determine pharmacokinetics (PK), including the effects on PK in fed vs. fasting states, of single ascending doses (SAD) of BioE-1115.

PK parameters- Area under the plasma concentration time curve (AUC), maximum concentration (Cmax), time to maximum concentration (Tmax). The PK concentrations by nominal time profile data will be presented graphically on linear and log-linear scales. Individual subject profiles (spaghetti or overlay plots) will be presented for each dosing group. The mean and median concentrations over time will also be presented. PK concentrations will be assessed using both plasma and urinalysis.
Timepoint [1] 367637 0
Part A (SAD):
PK analysis will be collected on Day 1 at pre-dose (within 5 minutes prior to IMP administration) and post-dose at 20 minutes, 40 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes, 4 hours, 6 hours, 9 hours, 12 hours and 18 hours; on Day 2 (24 hours post dosing on Day 1) and on Day 3 (48 hours post dosing on Day 1)


Secondary outcome [2] 368152 0
To assess the PK effects of BioE-1115 assessed as fructose-stimulated de-novo lipogenesis (FS-DNL) and resting metabolic rate (RMR) of multiple ascending doses (MAD) of BioE-1115.
Timepoint [2] 368152 0
Part B (MAD):
FS-DNL will be measured using sodium [1-13C1] acetate at approximately 1 week prior to the initiation of dosing and at the end of dosing. Subjects will undergo measurement of RMR along with the FS-DNL measurement.
Blood samples for PK analysis will be collected on Day 1 at pre-dose (within 5 minutes prior to IMP administration) and post-dose at 20 minutes, 40 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes, 4 hours, 6 hours, 9 hours, 12 hours and 18 hours; on Day 2 (24 hours post Day 1 dosing time) and on Day 3 (48 hours post Day 2 dosing time)
On Day 5, blood samples for PK analysis will be collected at pre-dose (within 5 minutes prior to IMP administration) only
Blood samples for PK analysis will again be collected on Day 7 at pre-dose (within 5 minutes prior to IMP administration) and post-dose at 20 minutes, 40 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes, 4 hours, 6 hours, 9 hours, 12 hours and 18 hours; on Day 8 (24 hours post Day 7 dosing time) and on Day 9 (48 hours post Day 7 dosing time).
Urine sampling for PK will be collected at 0 to 2 hours, 2 to 4 hours, 4 to 9 hours, 9 to 24 hours post Day 1 and Day 7 dosing time. Urine samples will also be collected at 24-36 and 36-48 hr time points post the last dose on Day 7.
Secondary outcome [3] 368154 0
To assess the Pharmacodynamic (PD) effects of
BioE-1115 assessed as fructose-stimulated de-novo lipogenesis (FS-DNL) and resting metabolic rate (RMR) of multiple ascending doses (MAD) of BioE-1115.
Timepoint [3] 368154 0
FS-DNL will be measured using sodium [1-13C1] acetate at approximately 1 week prior to the initiation of dosing and at the end of dosing. Subjects will undergo measurement of RMR along with the FS-DNL measurement. RMR will be measured by indirect calorimetry.


Eligibility
Key inclusion criteria
1. Healthy males and females aged 18-55 years, inclusive, at the time of signing the informed consent
2. Body Mass Index (BMI) greater than or equal to 18 kg/m2 and lesser than or equal to 30 kg/m2 and body weight greater than or equal to 50 kg and lesser than or equal to 100 kg at screening
3. Subjects have not used any nicotine product from 12 weeks prior to screening
4. No significant medical condition, and normal physical findings, vital signs (systolic blood pressure [BP]: 90- 140 mm Hg, diastolic BP: 40-90 mm Hg, pulse:40-100
beats per minute, respiratory rate: 10-22 breaths per minute, body temperature: 35.5-37.5 degree Celsius) and laboratory values at the time of screening, as judged by
the Investigator
5. Normal 12-lead electrocardiogram (ECG) or 1 with abnormalities that are considered clinically insignificant by the Investigator
6. Normal renal function (estimated glomerular filtration rate calculated using the Cockcroft-Gault equation greater than or equal to 90 mL/min)
7. Haemoglobin (Hb)A1C less than 5.7% and no history of fasting hyperglycaemia (glucose greater than or equal to 100 mg/dL and/or HbA1C greater than or equal to 5.7%), sustained hypertension ( greater than 95th percentile) or abnormal lipids (LDL cholesterol lesser than 130 mg/dL, TAG lesser than 130 mg/dL, HDL-C greater than 40 mg/dL).
8. Weight stable for at least 3 months prior to screening ( lesser than 5% change)
9. Subjects must be willing to not undertake any strenuous exercise within 7 days of the dosing periods, during inpatient period, and 48 hours before each follow-up visits
10. Female subjects must be either post-menopausal or, if pre-menopausal, must have a negative pregnancy test and agree to use 2 forms of contraception (as below) from
screening until 30 days after the last dose of IMP.
Male subjects must be surgically sterile, or if sexually active and having a pre-menopausal female partner must agree to use 2 forms of contraception (as below) for 3 months after the last dose of the IMP. They must also refrain from donating sperm from the date of dosing until 3 months after dosing of the IMP.
Adequate contraception allowed in this trial is defined as follows:
a. A condom for the male partner;
AND
b. A highly effective method of birth control for the female partner, including one of the following:
i. Hormonal contraceptives (oral, injected or implanted) associated with suppression of
ovulation
ii. Intrauterine devices or the implantation of intrauterine system
iii. Sterilization surgery such as tubal ligation in females and vasectomy in males at least 6
months prior to screening.
In addition, sexual abstinence for the entire duration of risk is acceptable if this is consistent with the usual and preferred lifestyle of the participant.
11. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal subjects. Women will be considered post-menopausal if
they have been amenorrhoeic for 12 months without an alternative medical cause. The following age-specific requirements apply:
a. Women lesser than 50 years of age will be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy)
b. Women greater than or equal to 50 years of age will be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatments, had radiationinduced menopause with last menses greater than 1 year
ago, had chemotherapy-induced menopause with last menses greater than 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)
12. Willing and able to give written informed consent for participation in the study.
Minimum age
18 Years
Maximum age
55 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Any clinically significant medical, psychiatric or endocrine disorder including pharmacologically treated thyroid conditions or other disorder which, in the opinion of the Investigator, might adversely affect the safety of the subject and/or the ability of the subject to comply with study procedures
2. Major surgery anticipated during the study participation
3. Intolerance to fructose
4. Positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody and/or human immunodeficiency virus (HIV)
5. Prolonged QTcF (greater than 450 ms), cardiac arrhythmia, or any clinically significant abnormality in the resting ECG, as judged by the Investigator
6. Regular use of any prescribed or non-prescribed medications, including herbal remedies, which, in the opinion of the Investigator, might adversely affect the safety of the subject or the interpretability of study results
7. Regular use of agents that affect lipid metabolism, including but not limited to 5-hydroxy-3-methylglutarylcoenzyme A [HMG-CoA] reductase inhibitors (statins), orlistat, fibrates, silymarin, N acetylcysteine
8. Blood or plasma donation (or corresponding blood loss) within 1 month prior to screening
9. Inability to undergo venepuncture and/or tolerate venous access
10. Inability to swallow the required number of IMP tablets at the applicable dose level
11. History of or present alcohol abuse, or excessive intake of alcohol, as judged by the Investigator
12. Positive screen for drugs of abuse, nicotine use, or alcohol at screening or on admission to the clinic prior to administration of the IMP. In the event of a positive screen for drugs of abuse, the investigator may repeat the test at their discretion (i.e. if false positive result
suspected)
13. History of severe allergy/hypersensitivity to drugs with a similar chemical structure or class to BioE-1115.
14. Administration of another investigational medicinal product (IMP, defined as a compound that has not been approved for marketing) or has participated in any other
clinical study that included IMP treatment within 3 months prior to administration of IMP in this study.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Safety concerns
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)
VIC
Recruitment hospital [1] 13297 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 25871 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 302122 0
Commercial sector/Industry
Name [1] 302122 0
Synergenics LLC
Address [1] 302122 0
1700 Owens Street; Suite 515
San Francisco, CA 94158
USA
Country [1] 302122 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Synergenics LLC
Address
1700 Owens Street; Suite 515
San Francisco, CA 94158
USA
Country
United States of America
Secondary sponsor category [1] 301958 0
Commercial sector/Industry
Name [1] 301958 0
Synergenics Australia Pty Ltd
Address [1] 301958 0
58 Gipps St,
Collingwood VIC 3066
Australia
Country [1] 301958 0
Australia
Other collaborator category [1] 280579 0
Commercial sector/Industry
Name [1] 280579 0
Novotech (Australia) Pty Limited
Address [1] 280579 0
Level 3, 235 Pyrmont Street, Pyrmont NSW 2009
Country [1] 280579 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302802 0
Alfred HREC
Ethics committee address [1] 302802 0
55 Commercial Rd, Melbourne VIC 3004
Ethics committee country [1] 302802 0
Australia
Date submitted for ethics approval [1] 302802 0
06/03/2019
Approval date [1] 302802 0
01/05/2019
Ethics approval number [1] 302802 0

Summary
Brief summary
This first in human (FIH) Phase 1 study is a prospective, randomized, double-blind, placebo-controlled study designed to assess the safety, tolerability and PK, including the effect on PK of fed vs. fasting, of single oral ascending doses of BioE-1115 in healthy adult subjects followed by the safety, tolerability, PK and PD effects assessed as FS-DNL and RMR of multiple oral doses of BioE-1115 in healthy adult subjects.
A total of up to approximately 121 subjects from both parts is expected to be enrolled in this study. Subjects will be recruited to participate in either a SAD cohort or MAD cohort but not both. Safety data for each cohort will be reviewed by a Safety Review Committee. The study will be conducted in 2 parts of 5 SAD and 4 MAD dose cohorts:

Part A (SAD):
Part A of the study will include a double-blind assessment of the safety, tolerability and PK, including the effect on PK of fed vs. fasting, of SAD of BioE-1115.
Each SAD cohort will consist of 8 subjects, including 2 receiving placebo and 6 receiving BioE-1115, in fasting state. One of the cohorts may be called back to be redosed in a fed state.

Part B (MAD):
Part B of the study will include a double-blind assessment of the safety, tolerability, PK and PD assessed as FS-DNL and RMR of MAD of BioE-1115/placebo.
Each MAD cohort consists of 15 subjects, including 3 receiving placebo and 12 receiving BioE-1115. MAD subjects will be dosed in a fasted state
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 91450 0
Dr Jason Lickliter
Address 91450 0
Nucleus Network
Level 1, 484 St. Kilda Road
Melbourne VIC 3004
Country 91450 0
Australia
Phone 91450 0
+61390898214
Fax 91450 0
Email 91450 0
j.lickliter@nucleusnetwork.com.au
Contact person for public queries
Name 91451 0
Dr Jason Lickliter
Address 91451 0
Nucleus Network
Level 1, 484 St. Kilda Road
Melbourne VIC 3004
Country 91451 0
Australia
Phone 91451 0
+61390898214
Fax 91451 0
Email 91451 0
j.lickliter@nucleusnetwork.com.au
Contact person for scientific queries
Name 91452 0
Dr Bruce F. Scharschmidt
Address 91452 0
BioEnergenix, LLC,
1700 Owens Street; Suite 515
San Francisco, CA 94158
USA
Country 91452 0
United States of America
Phone 91452 0
001-415-407-8212
Fax 91452 0
Email 91452 0
bruce@synergenics.net

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary