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Trial registered on ANZCTR


Registration number
ACTRN12617000133336
Ethics application status
Approved
Date submitted
17/01/2017
Date registered
24/01/2017
Date last updated
10/02/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
An Adaptive Design Study for the Assessment of the Safety, Tolerability and Pharmacokinetics of RYI-018 after Single Dosing in Healthy Volunteers and Repeat Dosing in Subjects with Non-Alcoholic Fatty Liver Disease (NAFLD)
Scientific title
An Adaptive Design Study for the Assessment of the Safety, Tolerability and Pharmacokinetics of RYI-018 after Single Dosing in Healthy Volunteers and Repeat Dosing in Subjects with Non-Alcoholic Fatty Liver Disease (NAFLD)
Secondary ID [1] 290942 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Non-Alcoholic Fatty Liver Disease 301672 0
Condition category
Condition code
Oral and Gastrointestinal 301380 301380 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
An Adaptive Design Study for the Assessment of the Safety, Tolerability and Pharmacokinetics of RYI-018 after Single Dosing in Healthy Volunteers and Repeat Dosing in Subjects with Non-Alcoholic Fatty Liver Disease (NAFLD).

Part A: A total of 24 patients will be randomized into 3 cohorts. The anticipated dose levels of RYI-018 for Part A of the study will be 0.6 mg/kg (Cohort 1), 1.2 mg/kg (Cohort 2), and 2.5 mg/kg (Cohort 3), administered by intravenous (IV) infusion weekly as single ascending doses. Part A of the study will be conducted in healthy volunteer only
.
Part B: A total of 60 patients will be randomized into 3 cohorts that will receive three different dosages. The final doses of RYI-018 selected for Part B of the study will be based on the results from Part A. Subjects will be given a total of four (4) IV doses, administered by IV infusion at weekly intervals per the randomization plan. Part B of the study will be conducted in patients with NAFLD only..

The trial will be conducted in accordance with ICHGCP guidelines, and the National Statement. The Bird Rock Bio delegated monitor will contact and visit the site regularly and will be allowed on request to inspect the various records of the trial [case report forms (CRFs) and other pertinent data] provided that subject confidentiality is maintained. It will be the monitor's responsibility to inspect the CRFs at regular intervals throughout the study, to verify adherence to the protocol and the completeness, consistency and accuracy of the data being entered on them. The monitor must verify that the patient received the study drug assigned by the randomisation centre (by reviewing the written confirmation of the randomisation by IxRS). The monitor will have access to laboratory test reports and other subject records needed to verify the entries on the CRF. The investigator will cooperate with the monitor to ensure that any problems detected in the course of these monitoring visits are resolved. Bird Rock Bio delegated monitors and auditors will have direct access to appropriate parts of records relating to subjects participating in this study for the purpose of verifying the data provided to Bird Rock Bio. The site will permit monitoring, audits, Institutional Review Boards/Independent Ethics Committee (IRB/IEC) review and regulatory inspections by providing direct access to the source data and documents.
Intervention code [1] 296884 0
Treatment: Drugs
Comparator / control treatment
Placebo (saline) as comparator for infusion
Control group
Placebo

Outcomes
Primary outcome [1] 300778 0
Part A: To assess the safety and tolerability of single IV ascending doses of RYI-018 when administered to healthy adult volunteers by having blinded safety and tolerability data (including the assessment of physical examinations, ECGs, vital signs, clinical laboratory results, and AEs) from participants dosed in each cohort reviewed by the Safety Monitoring Committee.
Timepoint [1] 300778 0
Physical examination during Screening and 30 days after first dosing
ECGs during Screening, On the dosing day (predose, Hour 4, 8, 24, and 48), 7 days after Dosing, and 30 days after Dosing.
Vital signs during Screening, Day before the first dose, on the dosing day (predose, hour 1, 2, 4, 6, 8, 10, 12, 24, 48, 96), 7, 14, 21, and 30 days after Dosing
Clinical laboratory test during Screening, Day before the first dose, 48 hours after dosing, 7, 14, and 30 days after dosing
AEs over 30 days following dosing
Primary outcome [2] 300817 0
Part B: The primary objective of Part B of the study is to evaluate the safety and tolerability of multiple doses of RYI-018 after 4 weeks of dosing in subjects with NAFLD by having blinded safety and tolerability data (including the assessment of physical examinations, ECGs, vital signs, clinical laboratory results, and AEs) from participants dosed in each cohort reviewed by the Safety Monitoring Committee.
Timepoint [2] 300817 0
Physical examination during Screening, Day 2, 15, and 23
ECGs during Screening, Day 1, 2, 8, 15, 22, 23, and 36
Vital signs at every visit.
Clinical laboratory test during Screening, Day before the first dose, Day 2, 9, 16, 23, 29, and 36.
AEs over 30 days following dosing
Secondary outcome [1] 330830 0
Part A: The secondary objective of Part A of the study will be to assess the PK properties of single IV ascending doses of RYI-018 when administered to healthy adult volunteers.
The following PK parameters may be observed or estimated:Tmax, Cmax, AUC0-t, elimination rate constant (Kel), area under the plasma concentration versus time curve extrapolated to infinity (AUC0-inf), half-life (t1/2), clearance (CL), and volume of distribution (Vz) (where data are sufficient for parameter determination).
Timepoint [1] 330830 0
Pharmacokinetic blood samples will be collected predose (-15 minutes) at baseline and at 0.5, 1, 2, 4, 8, 24, 48, and 96 hours after dosing with additional sampling at 7, 14, 21, 30, and 45 days after dosing.
Secondary outcome [2] 330960 0
Part B: - To determine the PK profile of RYI-018 following single and multiple doses
The following PK parameters may be observed or estimated: Tmax, Cmax, AUC0-t, Kel, t1/2, CL, and Vz for the 1st and 4th dose; AUC0-inf and steady state concentration Cssave (if steady state is reached) after the 4th dose; accumulation index and trough (predose) concentration (Ctrough) from the repeat doses in each cohort.
Timepoint [2] 330960 0
Pharmacokinetic blood samples will be collected will be collected predose (-15 minutes) at Baseline and at 0.5, 1, 2, 4, 8, 24, 48, and 96 hours after the 1st and 4th dose. Pharmacokinetic blood samples will also be collected predose 2nd and 3rd dose and at Days 29, 36, and 67.
Secondary outcome [3] 331008 0
Part B: - To determine the appearance of antidrug antibodies (ADA) after dosing with RYI-018
Timepoint [3] 331008 0
Pharmacokinetic blood samples will be collected will be collected predose (-15 minutes) at Baseline and at 0.5, 1, 2, 4, 8, 24, 48, and 96 hours after the 1st and 4th dose. Pharmacokinetic blood samples will also be collected predose 2nd and 3rd dose and at Days 29, 36, and 67.

Eligibility
Key inclusion criteria
Inclusion
Part A
Volunteers must meet all of the following inclusion criteria to be enrolled in the study:
1. Adult male and females, 18 to 45 years of age
2. Medically healthy with clinically insignificant screening results as judged by the Principal Investigator (PI).
3. BMI greater than or equal to 18.0 and less than or equal to 29.9 (kg/m2).
4. No alcohol 48 hours before administration of study agent and during the inpatient period of the study.
5. Negative urine drug screen/alcohol breathalyzer test at screening and Day -1.
6. Non-smokers who have not smoked any cigarettes within 6 months prior to screening. No current use of any nicotine containing product.
7. Voluntary consent to participate in the study.
8. Use of highly effective, double barrier contraception (both male and female partners) during the study and 75 days following last dose of RYI-018.
9. Males must not donate sperm for at least 75 days postdose of the last study treatment. Male partners of female patients and female partners of male patients must also use contraception, if they are of childbearing potential.
10. Participant abstinence for the duration of the study and 75 days post last dose of RYI-018 is acceptable.

Part B
Subjects must meet all of the following inclusion criteria to be enrolled in the study:
1. Adult male or females, 18 to 65 years of age
2. BMI greater than or equal to 25.0 and less than or equal to 40.0 (kg/m2).
3. Weight stable (no more than 2.5 kg weight loss or gain within 3 months prior to screening and no more than 2.5 kg weight gain or loss from screening to randomization).
4. Liver ultrasound which qualitatively shows fatty liver or known history of NAFLD.
5. Liver fat percentage by MRI of at least 10%.
6. Diabetes or prediabetes by glycosylated hemoglobin (HbA1c) or by fasting plasma glucose or oral glucose tolerance test results.
7. Subjects on anti-hypertensive medications must be controlled by stable dose of anti-hypertensive medication for at least 4 weeks prior to screening (and the stable dose must be maintained throughout the study).
8. Subjects on lipid lowering medications must be on a stable dose for at least 4 weeks prior to screening (and the stable dose must be maintained throughout the study).
9. Subjects previously treated with vitamin E, polyunsaturated fatty acid or ursodeoxycholic acid or fish oil can be included if stopped at least 3 months prior to screening.
10. For Subjects with Type 2 Diabetes, who are treated with glucose lowering medications, glycaemia must be controlled on a stable dose of medications for at least 12 weeks prior to screening. A stable dose must be maintained throughout the study. Subjects treated with thiazolidinediones within the past 90 days will be excluded from the study.
11. No alcohol 48 hours before administration of study agent and during the in-subject period of the study.
12. Negative urine drug screen/alcohol breath test at screening and Day-1.
13. Non-smokers who have not smoked any cigarettes within 6 months prior to screening. No current use of any nicotine containing product.
14. Voluntary consent to participate in the study.
15. Use of highly effective, double barrier contraception (both male and female partners) during the study and for 75 days following the last dose of RYI-018.
16. Males must not donate sperm for at least 75 days post last dose of the last study treatment. Male partners of female subjects and female partners of male subjects must also use contraception, if they are of childbearing potential.
17. Subject abstinence for the duration of the study and 75 days after the dose of RYI-018 is acceptable.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Exclusion
Part A
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Positive testing forHIV, HBsAg, or 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 Day 1.
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 would make it unlikely that the participant will comply with the study.
5. Have evidence of any chronic medical condition.
6. Use of any prescription or over-the counter medication (with the exception of oral contraceptives or paracetamol) within 7 days of randomization.
7. Any clinically significant laboratory abnormality.
8. Aspartate aminotransferase (AST) or alanine transaminase (ALT) >upper limit of normal (ULN).
9. History or presence of alcoholism or drug abuse within the 2 years prior to the first study drug administration.
10. Blood donation or significant blood loss within 60 days prior to the first study drug administration.
11. Plasma donation within 7 days prior to the first study drug administration.
12. Administration of investigational product (IP) in another trial within 30 days prior to the first study drug administration.
13. Females who are pregnant or lactating. 14. Surgery within the past three months prior to the first study drug administration determined by the PI to be clinically relevant.
15. Regular alcohol consumption in males >21 units per week and females >14 units per week.
16. Failure to satisfy the PI of fitness to participate for any other reason.
17. Active infection.
18. Any acute illness within 30 days prior to Day 1.

Part B
1. Positive testing for HIV, HBsAg, or 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 prior to Screening.
3. Have any underlying physical or psychological medical condition that would make it unlikely that the subject will complete the study.
4. ALT >5 x ULN at screening.
5. Subject with clinical evidence of hepatic decompensation at screening.
6. Subject uses drugs historically associated with NAFLD for more than 4 weeks in the previous year.
7. History or presence of alcoholism or drug abuse within the 2 years prior to the first study drug administration.
8. Blood donation or significant blood loss within 60 days prior to the first study drug administration.
9. Administration of IP in another trial within 30 Days or 5 times the investigational drug half-life, whichever is longer, prior to the first study drug administration.
10. Surgery within the past three months prior to the first study drug administration determined by the Investigator to be clinically relevant.
11. History of cerebrovascular event acute coronary syndrome within 6 months of screening.
12. Any history of seizures, major depression, suicidality, or unexplained syncope.
13. Any acute illness within 30 days prior to screening.
14. Subjects with other active liver disease other than NASH.
15. Subjects who have a known history of liver cirrhosis and/or hepatic decompensation.
16. Subjects with familial hypertriglyceridemia and familial hypercholesterolemia.
17. Use of prescription weight loss medications, thiazolidinediones, investigational or approved medications for NASH, or antidepressant medications within 90 days of screening.
18. History of bariatric surgery or plans for bariatric surgery or an attempt to lose weight during study.
19. Diabetes Mellitus other than Type 2.
20. Daily alcohol intake >20 g/day for women and >30 g/day for men.
21. Uncontrolled hypothyroidism defined as thyroid stimulating hormone above the ULN.
22. Subjects with renal dysfunction estimated glomerular filtration rate <40 mL/min/1.73 m2.
23. Systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg at screening.
24. HbA1c >9.5% at 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
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
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
Safety information after administration of single dose of RYI-018 in healthy subjects for Part A and after administration of multiple doses of RYI-018 in patients with NAFLD for Part B will be evaluated by tabulating adverse experiences and clinical assessment of clinical laboratory data.
Part A:
The primary objective regarding safety will be evaluated based on the following calculations:
If a particular adverse experience is not observed in any of the 6 subjects at each dose level, the true incidence rate is less than 0.24 with 80% confidence (0.32 with 90% confidence).
Part B:
The primary objective regarding safety will be evaluated based on the following calculations:
If a particular adverse experience is not observed in any of the 15 subjects at each dose level, the true incidence rate is less than 0.10 with 80% confidence (0.14 with 90% confidence).

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
14/02/2017
Actual
Date of last participant enrolment
Anticipated
31/07/2017
Actual
Date of last data collection
Anticipated
31/08/2017
Actual
Sample size
Target
84
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 7330 0
Linear Clinical Research - Nedlands
Recruitment postcode(s) [1] 15111 0
6009 - Nedlands
Recruitment outside Australia
Country [1] 8583 0
New Zealand
State/province [1] 8583 0
Country [2] 8584 0
United States of America
State/province [2] 8584 0

Funding & Sponsors
Funding source category [1] 295361 0
Commercial sector/Industry
Name [1] 295361 0
Bird Rock Bio Inc
Country [1] 295361 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Bird Rock Bio Inc
Address
Bird Rock Bio
505 Coast Blvd S, Suite 300
La Jolla, California 92037
Country
United States of America
Secondary sponsor category [1] 294186 0
None
Name [1] 294186 0
Address [1] 294186 0
Country [1] 294186 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296692 0
Bellberry HREC Committee D
Ethics committee address [1] 296692 0
Ethics committee country [1] 296692 0
Australia
Date submitted for ethics approval [1] 296692 0
26/10/2016
Approval date [1] 296692 0
16/12/2016
Ethics approval number [1] 296692 0
2016-10-764

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

Contacts
Principal investigator
Name 71758 0
Dr Andrew Redfern
Address 71758 0
Linear Clinical Research
QEII Medical Centre
First Floor, B Block Hospital Avenue
Nedlands WA 6009
Country 71758 0
Australia
Phone 71758 0
+61863825100
Fax 71758 0
Email 71758 0
contactus@linear.org.au
Contact person for public queries
Name 71759 0
Alan Glicklich
Address 71759 0
Bird Rock Bio
505 Coast Blvd S, Suite 300
La Jolla, California 92037
Country 71759 0
United States of America
Phone 71759 0
+1 858-587-4815
Fax 71759 0
Email 71759 0
alan@birdrockbio.com
Contact person for scientific queries
Name 71760 0
Alan Glicklich
Address 71760 0
Bird Rock Bio
505 Coast Blvd S, Suite 300
La Jolla, California 92037
Country 71760 0
United States of America
Phone 71760 0
+1 858-587-4815
Fax 71760 0
Email 71760 0
alan@birdrockbio.com

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