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)
Bird Rock Bio Inc
84 participants
Feb 14, 2017
Interventional
Conditions
Summary
This study will be conducted as an adaptive design, randomized, parallel group study to evaluate the pharmacokinetics (PK) and safety of single IV doses of RYI-018 in healthy volunteers and repeat IV doses of RYI-018 in subjects with NAFLD. Part A of the study will be conducted as a double-blind, placebo controlled, randomized, single ascending dose study to determine the safety, tolerability, and PK of RYI-018 in healthy volunteers. During Part B of the study, subjects in each cohort shall be randomized to either RYI-018 or placebo. Three (3) cohorts which will include 20 subjects per cohort with 15 subjects randomized to receive active drug administered at weekly intervals and 5 subjects randomized to receive placebo in each cohort at weekly intervals, per the randomization plan. The primary objective of Part A of the study will be to assess the safety and tolerability of single IV ascending doses of RYI-018 when administered to healthy adult volunteers 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.
Eligibility
Inclusion Criteria29
- Part A
- Adult male and females, 18 to 45 years of age
- Medically healthy with clinically insignificant screening results as judged by the Principal Investigator (PI).
- BMI greater than or equal to 18.0 and less than or equal to 29.9 (kg/m2).
- No alcohol 48 hours before administration of study agent and during the inpatient period of the study.
- Negative urine drug screen/alcohol breathalyzer test at screening and Day -1.
- Non-smokers who have not smoked any cigarettes within 6 months prior to screening. No current use of any nicotine containing product.
- Voluntary consent to participate in the study.
- Use of highly effective, double barrier contraception (both male and female partners) during the study and 75 days following last dose of RYI-018.
- 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.
- Participant abstinence for the duration of the study and 75 days post last dose of RYI-018 is acceptable.
- Part B
- Adult male or females, 18 to 65 years of age
- BMI greater than or equal to 25.0 and less than or equal to 40.0 (kg/m2).
- 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).
- Liver ultrasound which qualitatively shows fatty liver or known history of NAFLD.
- Liver fat percentage by MRI of at least 10%.
- Diabetes or prediabetes by glycosylated hemoglobin (HbA1c) or by fasting plasma glucose or oral glucose tolerance test results.
- 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).
- 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).
- 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.
- 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.
- No alcohol 48 hours before administration of study agent and during the in-subject period of the study.
- Negative urine drug screen/alcohol breath test at screening and Day-1.
- Non-smokers who have not smoked any cigarettes within 6 months prior to screening. No current use of any nicotine containing product.
- Voluntary consent to participate in the study.
- 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.
- 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.
- Subject abstinence for the duration of the study and 75 days after the dose of RYI-018 is acceptable.
Exclusion Criteria43
- Part A
- Positive testing forHIV, HBsAg, or HCV.
- 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.
- History of cerebrovascular disease, coronary artery disease, seizures, major depression, suicidality, or unexplained syncope.
- Have any underlying physical or psychological medical condition that would make it unlikely that the participant will comply with the study.
- Have evidence of any chronic medical condition.
- Use of any prescription or over-the counter medication (with the exception of oral contraceptives or paracetamol) within 7 days of randomization.
- Any clinically significant laboratory abnormality.
- Aspartate aminotransferase (AST) or alanine transaminase (ALT) >upper limit of normal (ULN).
- History or presence of alcoholism or drug abuse within the 2 years prior to the first study drug administration.
- Blood donation or significant blood loss within 60 days prior to the first study drug administration.
- Plasma donation within 7 days prior to the first study drug administration.
- Administration of investigational product (IP) in another trial within 30 days prior to the first study drug administration.
- 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.
- Regular alcohol consumption in males >21 units per week and females >14 units per week.
- Failure to satisfy the PI of fitness to participate for any other reason.
- Active infection.
- Any acute illness within 30 days prior to Day 1.
- Part B
- Positive testing for HIV, HBsAg, or HCV.
- 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.
- Have any underlying physical or psychological medical condition that would make it unlikely that the subject will complete the study.
- ALT >5 x ULN at screening.
- Subject with clinical evidence of hepatic decompensation at screening.
- Subject uses drugs historically associated with NAFLD for more than 4 weeks in the previous year.
- History or presence of alcoholism or drug abuse within the 2 years prior to the first study drug administration.
- Blood donation or significant blood loss within 60 days prior to the first study drug administration.
- 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.
- Surgery within the past three months prior to the first study drug administration determined by the Investigator to be clinically relevant.
- History of cerebrovascular event acute coronary syndrome within 6 months of screening.
- Any history of seizures, major depression, suicidality, or unexplained syncope.
- Any acute illness within 30 days prior to screening.
- Subjects with other active liver disease other than NASH.
- Subjects who have a known history of liver cirrhosis and/or hepatic decompensation.
- Subjects with familial hypertriglyceridemia and familial hypercholesterolemia.
- Use of prescription weight loss medications, thiazolidinediones, investigational or approved medications for NASH, or antidepressant medications within 90 days of screening.
- History of bariatric surgery or plans for bariatric surgery or an attempt to lose weight during study.
- Diabetes Mellitus other than Type 2.
- Daily alcohol intake >20 g/day for women and >30 g/day for men.
- Uncontrolled hypothyroidism defined as thyroid stimulating hormone above the ULN.
- Subjects with renal dysfunction estimated glomerular filtration rate <40 mL/min/1.73 m2.
- Systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg at screening.
- HbA1c >9.5% at screening.
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Interventions
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.
Locations(3)
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ACTRN12617000133336