A randomized, double-blind, placebo-controlled dose-escalation study of AND017 capsules in healthy subjects following oral single and multiple dose administration
A randomized, double-blind, placebo-controlled dose-escalation study in healthy subjects to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of AND017 following oral single and multiple dose administration
BalanceBio Pty Ltd
78 participants
Jan 15, 2019
Interventional
Conditions
Summary
This is a phase I, randomized, double-blind, placebo-controlled, dose-escalation study to investigate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD)of AND017 in healthy subjects. The study will involve two sequential parts: a single dose phase (SAD cohorts, Part A) followed by a multiple dose phase (MAD cohorts, Part B). Single doses of 1, 4, 10, 20, 30, and 50 mg AND017(n=6/dose) or placebo (n=2/dose) will be assessed in six consecutive cohorts of 8 subjects each in SAD cohorts (Part A) except Cohort 1 (4 subjects randomized at 1:1 to receive AND017 or placebo). Multiple doses of 4, 10, 20, and 30 mg AND017 (n=6/dose) or placebo (n=2/dose) will be administered daily for 10 days and assessed in four consecutive cohorts of 8 subjects each in MAD cohorts (Part B). Subjects will be fasted for at least 10 hours before administrating the investigational medicine with 240 mL water on dosing days. Subjects in SAD cohorts (Part A) will be inpatient for approximately 4 days with study drug administered on Day 1, and subjects in MAD cohorts (Part B) will be inpatient for approximately 14 days with study drug administered on Days 1-10. Subjects will be enrolled only in one study part and randomized to one cohort per the randomization schedule. For safety purpose, a sentinel dosing design will be applied in Cohort 1 (SAD cohort, Part A). The first 2 subjects will be dosed with one subject receiving AND017 and the other receiving placebo. After an interval of 48 h and review of all safety data of sentinel subjects, the remaining 4 subjects will be randomized at 3:1 to receive AND017 or placebo. There will be also a safety review (4 and 10 days in SAD (Part A) and MAD cohorts (Part B), respectively) before dose escalation for each cohort. Dose escalation will be stopped when predefined safety or pharmacodynamic criteria are met. This study allows some alteration from the currently outlined dosing schedule to reduce risk of subjects. Additional dosing cohorts may also be added to further evaluate the safety, PK and/or PD of AND017.
Eligibility
Inclusion Criteria13
- Each subject must meet the following criteria to be enrolled in this
- study:
- Healthy male or female, 18-45 years of age (both inclusive);
- Able to give signed written informed consent form;
- Able to remain in house for the duration of the study without interruption;
- Body mass index (BMI, weight [kg]/height2 [m]2) within 18.0-30.0 kg/m2 (both inclusive);
- Blood Pressure (BP) and 12-lead electrocardiogram (ECG) showing
- no clinically significant abnormalities during screening;
- Subjects have no clinically significant abnormal values on physical examination, clinical laboratory test, liver function or kidney function;
- Agree to completely refrain from consuming alcohol, caffeinated beverages (i.e. tea, coffee, etc.), and tobacco from 24 h pre the 1st dose until the last PK blood sample collection is finished;
- If male, a willingness not to donate sperm and if engaging in sexual intercourse with a female partner who could become pregnant, a willingness to use a condom in addition to having the female partner use a highly effective method of birth control (such as an intrauterine device, diaphragm, oral contraceptives, injectable progesterone, subdermal implants, or a tubal ligation). This criterion applies to males (and/or female partners) who are surgically sterile and must be followed from the time of first study drug administration until 90 days after the final administration of study drug.
- If female, be of non-childbearing potential (e.g. post-menopausal as demonstrated by follicle stimulating hormone (FSH) or surgical sterilization i.e., tubal ligation or hysterectomy). Provision of documentation is not required for female sterilization, verbal confirmation is adequate; If of childbearing potential females must use a highly effective method of birth control (such as an intrauterine device, diaphragm, oral contraceptives, injectable progesterone, subdermal implants, or a tubal ligation).
- Negative urine drug screen at screening and Day-1.
Exclusion Criteria25
- Subjects who meet any of the following criteria will be excluded from
- the study:
- History of severe drug (e.g. or asthma induced by aspirin) or excipient allergy, or hypersensitivity to AND017 capsules or other HIF-PHD inhibitors;
- Current or chronic history of liver disease or known hepatic or biliary abnormalities (except Gilbert’s syndrome or asymptomatic gallstones), including but not limited to ALT, alkaline phosphatase and bilirubin greater than 1.5xULN (isolated bilirubin greater than 1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin greater than 35%);
- Subjects with Hb: male (less than 120 g/L or greater than 160 g/L), female (less than 110 g/L or greater than 150 g/L);
- Subjects with any abnormalities of hematology during screening: Mean corpuscular volume (MCV), platelet count, serum iron, ferritin;
- Subjects with the history of medicine or disease to increase the risk of bleeding or disturbance of blood coagulation;
- History of deep vein thrombosis, stoke, transient ischemic attack, pulmonary embolism or other thrombosis related condition within the last five years;
- History of myocardial infarction, heart failure or acute coronary syndrome;
- History of pulmonary artery hypertension;
- Evidence of active peptic, duodenal or esophageal ulcer disease at screening;
- Subjects with major illness or surgery (except for minor outpatient surgery) within past 3 months prior to screening, or planned surgery during study;
- History of sensitivity to heparin or heparin-induced thrombocytopenia (if the clinical research unit uses heparin to maintain intravenous cannula patency);
- Subjects with intolerance to direct venipuncture;
- Known or suspected history of drug abuse within the past 5 years or presence of drug abuse within 3 months before study;
- Participation in any clinical study with an investigational drug, biologic or device within 4 weeks or 5 times the half-life of the specific drug/biologics (whichever is longer), prior to dosing;
- Donated blood greater than 400 mL or significant blood loss equivalent to 400 mL or received blood transfusion within 3months of screening; or donated blood greater than 200 mL or significant blood loss equivalent to 200 mL within 1 month prior to screening
- Use of any other drug, including over-the-counter medications, herbs, within 14 days prior to the first dose of study medication (except for contraceptive medication in WOCBP);
- Take in food or drink beverages which can influence metabolism of liver 7 days prior to the first dose of the study drug (e.g. grapefruit & Seville oranges );
- Habitual use of nicotine products or smoking within 3 months (more than 5 cigarettes per day) prior to screening;
- History of significant alcohol abuse within 6 months of screening or any indication of regular use of more than 14 units of alcohol per week (1 Unit equal to 360 mL of beer or 45 mL of alcohol 40% or 150 mL of wine) or taking the product containing alcohol 2 days prior to dosing;
- Positive screening test for any one or more: serum hepatitis B surface antigen (HBsAg), hepatitis C antibody, or HIV;
- Malignancy within 5 years within screening visit (except basal cell skin carcinoma);
- Subject who is considered unsuitable for participating in the study in the opinion of investigator;
- Nursing mothers, pregnancy women
Interested in this trial?
Get notified about updates and connect with the research team.
Interventions
This is a phase I, randomized, double-blind, placebo-controlled, dose-escalation study to investigate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of AND017 in healthy subjects. The study will involve two sequential parts: a single ascending dose (SAD) phase (Part A) followed by a multiple ascending dose (MAD) phase (Part B). In the SAD doses of 1, 4, 10, 20, 30, and 50 mg AND017 (n=6/dose) or placebo (n=2/dose) will be assessed in six consecutive cohorts of 8 subjects except Cohort 1 (6 subjects randomized at 4:2 to receive AND017 or placebo). In the MAD doses of 4, 10, 20, and 30 mg AND017 (n=6/dose) or placebo (n=2/dose) will be administered daily for 10 days and assessed in four consecutive cohorts of 8 subjects. Subjects will be fasted for at least 10 hours before oral administrating the investigational product AND017 or placebo capsules with 240 mL water on dosing days. Subjects in the SAD will be inpatients for approximately 4 days with study drug administered on Day 1, and subjects in the MAD will be inpatients for approximately 14 days with study drug administered on Days 1-10. Subjects will be enrolled only in one study part and randomized to one cohort per the randomization schedule. SAD. Healthy subjects will be screened within 21 days prior to dosing. Subjects will be admitted to the clinical facility on Day -1 for up to 4 days. Oral administration of a single dose of AND017 or placebo capsules will occur on Day 1. Following completion of all safety assessments and sampling for PK analyses, subjects will be discharged on Day 4. Double-blind dosing will occur in cohorts 1 through 6. In all cohorts except cohort 1, 6 participants will receive oral administrating AND017 capsules and 2 participants will receive matching placebo. Doses will escalate in the dose range of 1 mg to 50 mg. The dose escalation steps may be altered following review of the safety data upon completion of each cohort. In Cohort 1, (4 AND017, 2 placebo) 2 participants (sentinels) will be dosed at least 24 hours prior to the remaining participants. One sentinel will be orally dosed with AND017 and the other with matching placebo. The remaining 4 participants will only be dosed if no safety are identified in the sentinel participants. The non-sentinel participants in Cohort 1 will be admitted to the clinical research facility at least 24 hours later than the sentinels. There will be no sentinels in Cohorts 2-6. In the SAD part of the study, all participants will be admitted to the clinical research unit on Day 1. Oral dosing will take place on the morning of Day 1. After each SAD dose cohort has completed oral administration of study drug and evaluation, the Safety Review Committee (SRC) will review blinded cumulative safety data (including the follow-up visit data) to determine the safety and tolerability of study drug. If the dose level is determined to be safe and tolerated, the next dose cohort will be enrolled and randomized to receive the next dose level of active AND017 or placebo. The SRC will review the data, discuss the findings, and decide to: 1) enroll the next dose cohort at the protocol-defined dose level; 2) enroll the next dose cohort at an intermediate dose level; or 3) terminate enrollment in the SAD part of the study. If the dose level is determined not to be safe and tolerated, the study drug assignment for those participants with a safety concern may be un-blinded. MAD. The MAD part of the study will commence following the establishment of safety and tolerability of Cohort 6 in the SAD. The SRC will evaluate the safety and tolerability data obtained for the participants in Cohorts 1-6 to determine if appropriate the dose levels planned to be utilized in the MAD cohorts (Cohort 7-10). 4 dose levels are anticipated to be evaluated in the MAD. Up to 2 additional cohorts may be added for the purposes of cohort expansion or to explore a dose level intermediate to previously evaluated doses. In the MAD part of the study, all subjects will be screened within 21 days prior to dosing and will be admitted to the clinical facility on Day 1. Oral dosing will commence on the morning of Day 1. Daily oral dosing will continue for 10 consecutive days. The last dose will be administered on the morning of Day 10. Subjects will be discharged on Day 17 following completion of all PK sample collection and safety assessments. After each MAD dose cohort has completed oral administration of study drug and evaluation, the SRC will review blinded cumulative safety data (including the follow-up visit data) to determine the safety and tolerability of study drug. If the dose level is determined to be safe and tolerated, the next dose cohort will be enrolled and randomized to receive the next dose level of active AND017 or placebo. The SRC will review the data, discuss the findings, and decide to: 1) enroll the next dose cohort at the protocol-defined dose level; 2) enroll the next dose cohort at an intermediate dose level; or 3) terminate enrollment in the MAD part of the study. If the dose level is determined not to be safe and tolerated, the study drug assignment for those participants with a safety concern may be un-blinded. After the final MAD cohort has been completed, the Sponsor may, after consulting with the SRC, initiate up to two optional cohorts for the following purposes: to expand a previous dose level cohort; to explore a dose level that is intermediate between two doses that have already been evaluated as part of the MAD, or if the final dose level is determined to be safe and tolerated, explore a higher dose level. Dose levels anticipated to be evaluated in the MAD will be in the range of 4 –30 mg.
Locations(1)
View Full Details on ANZCTR
For the most up-to-date information, visit the official listing.
ACTRN12620000725965