Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618001557224
Ethics application status
Approved
Date submitted
11/09/2018
Date registered
18/09/2018
Date last updated
29/04/2019
Date data sharing statement initially provided
19/11/2018
Date results information initially provided
29/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A study to evaluate the Absolute Bioavailability, Safety and Tolerability of Subcutaneous Formulation of RYI-018 Compared to Intravenous Formulation in Overweight and Obese Healthy Volunteers
Scientific title
A Phase 1, Open-Label, Single-Center Study Evaluating Absolute Bioavailability, Safety and Tolerability of Subcutaneous Formulation of RYI-018 Compared to Intravenous Formulation in Overweight and Obese Healthy Volunteers
Secondary ID [1] 296009 0
BRB-018-002
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Overweight 309545 0
Obesity 309666 0
Condition category
Condition code
Diet and Nutrition 308363 308363 0 0
Obesity

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study will be conducted in 20 healthy participants with a BMI of 25.0 to 40.0 kg/m2. Subjects will undergo screening procedures within 21 days of dosing day. Eligible subjects will be randomized in a 1:1 ratio to the following RYI-018 treatment arms (10 participants in each treatment arm):
- Treatment Arm 1: 100 mg of RYI-018 SC injection will be given in the abdomen in a 1 mL syringe
- Treatment Arm 2: 100 mg of RYI-018 IV in 100 mL of 0.9% normal saline infused over approximately 30 minutes
Randomization will be stratified according to baseline BMI; stratification groups will be defined as follows:
- Participants with BMI 25.0 to 32.5 kg/m2 (inclusive)
- Participants with BMI >32.5 to 40.0 kg/m2
Subjects will receive a single administration of study intervention (after an overnight fast of at least 10 hours) and will be confined to the Phase 1 unit for approximately 24 hours after RYI-018 administration (through Day 2) for PK, tolerability and safety assessments. Subsequently, all participants will be followed-up for PK and safety assessments through 90 days post-dose.
Intervention code [1] 312348 0
Treatment: Drugs
Comparator / control treatment
100 mg of RYI-018 IV in 100 mL of 0.9% normal saline infused over approximately 30 minutes
Control group
Active

Outcomes
Primary outcome [1] 307349 0
To assess the absolute bioavailability of RYI-018 administered by SC injection.
Timepoint [1] 307349 0
Absolute bioavailability is assessed by PK analyses
PK profile of RYI-018 is assessed on Day 1, PK blood samples will be collected at the following timepoints: predose (-15 minutes), 0.5 (immediately after the end of infusion), 1, 2, 4, 8 and 12 hours after the completion of dosing. Post-dose collection time-points are relative to the start of infusion time. Additional samples will be collected on Day 2 (24 hours postdose), 3 (48 hours post-dose), 4 (72 hours post-dose), 5 (96 hours post-dose). Allowable sampling time deviation windows are ± 5 minutes at 1, 2, and 4 hours and ± 10 minutes for all timepoints greater than 4 hours (in the domiciled periods). There is a ±2 hour collection window for PK blood samples collected on Day 4 and Day 5. Additional samples will be collected on Day, 8, 15, 22, 30, 45, 60, 75, and 90 at approximately the same time of day. Primary outcome is absolute bioavailability, calculated as (AUC0-8 ) SC / (AUC0-8) IV
Secondary outcome [1] 351557 0
To assess safety and tolerability of RYI-018 after SC injection and IV administration.
Timepoint [1] 351557 0
Safety and tolerability is assessed after administration of RYI-018. Injection site will be evaluated by the investigator after completion of study intervention administration for any local AEs (e.g. injection site reaction, swelling, erythema, edema).
Injection site reactions (including those which have developed after the 15 minute post administration assessment) will be assessed by the Investigator at each visit until resolved or considered stable by the Investigator and this assessment will include VAS administration.
Secondary outcome [2] 351558 0
To determine the PK profile of RYI-018 following a single SC or IV dose of RYI-018.
Timepoint [2] 351558 0
PK profile of RYI-018 is assessed on Day 1, PK blood samples will be collected at the following timepoints: predose (-15 minutes), 0.5 (immediately after the end of infusion), 1, 2, 4, 8 and 12 hours after the completion of dosing. Post-dose collection time-points are relative to the start of infusion time. Additional samples will be collected on Day 2 (24 hours postdose), 3 (48 hours post-dose), 4 (72 hours post-dose), 5 (96 hours post-dose). Allowable sampling time deviation windows are ± 5 minutes at 1, 2, and 4 hours and ± 10 minutes for all timepoints greater than 4 hours (in the domiciled periods). There is a ±2 hour collection window for PK blood samples collected on Day 4 and Day 5. Additional samples will be collected on Day, 8, 15, 22, 30, 45, 60, 75, and 90 at approximately the same time of day. The PK profile of RYI-018 following a single SC or IV dose of RYI-018 will be determined by:
• Area under the concentration-time curve (AUC) from time 0 to the time of the last sample collection (AUC0-t),
• Area under the serum concentration versus time curve extrapolated to infinity (AUC0-8)
• Percent extrapolation (AUC0-8-AUC0-t)/(AUC0-8)x100
• Serum maximum observed concentration (Cmax)
• Time to maximum observed concentration (tmax)
• Serum terminal elimination rate constant (IV) and apparent serum terminal elimination rate constant (SC) (?z)
• Elimination half-life (t½)
• Clearance (CL)
• Volume of distribution (Vd)
Secondary outcome [3] 351559 0
To determine levels of antidrug antibodies (ADA) after a single SC or IV dose of RYI-018.
Timepoint [3] 351559 0
Anti-RYI-018 antibody blood samples are collected at the following timepoints: predose, Day 22, Day 45 and Day 90(only if ADA is positive at Day 45).

Eligibility
Key inclusion criteria
- Healthy males and females of 18 to 45 years of age inclusive, at the time of signing the informed consent.
- Participants who give voluntary consent and those who are medically healthy with clinically insignificant screening results (e.g., laboratory profiles, medical history, ECGs, physical exam) as judged by the Investigator.
- BMI equal to, or greater than 25.0, but less than or equal to 40.0 (kg/m2)
- Participants should use highly effective, double barrier contraception (both male and female partners) during the study and 90 days following last dose of RYI-018. Male partners of female patients and female partners of male
- patients must also use contraception, if they are of childbearing potential.
- Females of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test on Day -1. Females not of childbearing potential must be postmenopausal (defined as cessation of regular menstrual periods for at least 12 months), confirmed by follicle stimulating hormone (FSH) level >40 mIU/mL or surgically sterile.
Minimum age
18 Years
Maximum age
45 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions -
1. Positive testing for, human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C antibodies (HCV).
2. Have any known malignancy or history of malignancy, except for basal cell skin cancer that has been treated with no evidence of recurrence for at least 3 months before Baseline.
3. History of cerebrovascular disease, coronary artery disease, seizures, major depression, suicidality, or unexplained syncope.
4. Have any underlying physical or psychological medical condition that, in the opinion of the Investigator, would make it unlikely that the participant will comply with the study.
5. Have evidence of any chronic medical condition (e.g., hypertension, asthma, or diabetes). Participants with a history of childhood asthma which is not currently active are allowed.
6. Active clinically significant infection within 7 days of Baseline.
7. Any acute illness, deemed clinically significant by Investigator, within 30 days prior to Baseline
8. History or presence of alcoholism or drug abuse within the 2 years prior to Baseline.
9. Surgery within the past three months prior to the first study intervention administration determined by the Investigator to be clinically relevant.
Prior/Concomitant Therapy -
10. Use of any prescription or over-the counter medication (with the exception of oral
contraceptives or paracetamol) within 7 days of Baseline.
Prior/Concurrent Clinical Study Experience
11. Administration of investigational product in another study within 30 days prior to
Baseline.
Diagnostic assessments -
12. Any clinically significant laboratory abnormality.
13. Aspartate aminotransferase (AST) or alanine transaminase (ALT) > upper limit of normal (ULN). One repeat test may be allowed within 7 days at the discretion of the Investigator.
Other Exclusions -
14. Positive urine drug screen/alcohol breathalyzer test at Screening and Day -1.
15. Smokers who have smoked more than the equivalent of 2 cigarettes (by declaration, including tobacco or nicotine products) within 6 months prior to Screening. No current use of any nicotine containing product. Cotinine test positive at Screening and Day -1.
16. Blood donation or significant blood loss within 60 days prior to Baseline.
17. Plasma donation within 7 days prior to Baseline.
18. Failure to satisfy the Investigator of fitness to participate for any other reason.
19. Females who are pregnant or lactating. Females should not breast feed for 6 months after last dose of RYI-018.
20. Regular alcohol consumption in males >21 units per week and females >14 units per week (1 unit = 250 mL of beer, 25 mL of 40% spirit, or a 125-mL glass of wine) within 2 months prior to Screening.

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
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Bio-availability
Statistical methods / analysis
As the primary objective of this study is to assess the absolute bioavailability of RYI-018 administered by SC injection, no formal hypothesis testing will be done. 20 Healthy Participants will be evaluated in this study.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/10/2018
Actual
21/10/2018
Date of last participant enrolment
Anticipated
22/11/2018
Actual
3/12/2018
Date of last data collection
Anticipated
24/01/2019
Actual
2/03/2019
Sample size
Target
20
Accrual to date
Final
20
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 11801 0
Linear Clinical Research - Nedlands
Recruitment postcode(s) [1] 23928 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 300604 0
Commercial sector/Industry
Name [1] 300604 0
Bird Rock Bio, Inc.
Country [1] 300604 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Bird Rock Bio, Inc.
Address
2223 Avenida de la Playa, Suite 205,
La Jolla, CA 92037 USA
Country
United States of America
Secondary sponsor category [1] 300115 0
None
Name [1] 300115 0
Address [1] 300115 0
Country [1] 300115 0
Other collaborator category [1] 280338 0
Commercial sector/Industry
Name [1] 280338 0
Novotech (Australia) Pty Limited
Address [1] 280338 0
Level 3,235 Pyrmont Street, Pyrmont NSW 2009
Country [1] 280338 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301391 0
Bellberry Limited
Ethics committee address [1] 301391 0
129 Glen Osmond Road, Eastwood, SA, 5063
Ethics committee country [1] 301391 0
Australia
Date submitted for ethics approval [1] 301391 0
21/08/2018
Approval date [1] 301391 0
25/09/2018
Ethics approval number [1] 301391 0

Summary
Brief summary
This study of RYI-018 will be conducted in 20 healthy participants with a BMI between 25.0 and 40.0 kg/m2. The participants will be randomized in to one of two treatment arms, each arm having 10 participants. The study will estimate the absolute bioavailability of a sub-cutaneous formulation versus an IV formulation, as well as assess the safety and tolerability of RYI-018. Participants will receive a single dose of RYI-018 (after an overnight fast of at least 10 hours) and will be confined for approximately 24 hours after RYI-018 administration. All participants will be followed-up through 90 days post-dose. It is hypothesised that the subcutaneous formulation will work in the same way as the intravenous formulation, allowing for easier administration of RYI-018 and subsequently higher treatment compliance.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 86846 0
Dr Lara Hatchuel
Address 86846 0
Level 1, B Block, QEII Medical Centre, Hospital Avenue, Nedlands WA 6009
Country 86846 0
Australia
Phone 86846 0
+61 8 6382 5100
Fax 86846 0
Email 86846 0
lhatchuel@linear.org.au
Contact person for public queries
Name 86847 0
Dr Lara Hatchuel
Address 86847 0
Level 1, B Block, QEII Medical Centre, Hospital Avenue, Nedlands WA 6009
Country 86847 0
Australia
Phone 86847 0
+61 8 6382 5100
Fax 86847 0
Email 86847 0
lhatchuel@linear.org.au
Contact person for scientific queries
Name 86848 0
Dr Alan Glicklich
Address 86848 0
Bird Rock Bio, 2223 Avenida de la Playa, Suite 205, La Jolla, CA 92037 USA
Country 86848 0
United States of America
Phone 86848 0
+1 203 241 3418
Fax 86848 0
Email 86848 0
alan@birdrockbio.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Undecided
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?
No
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary