None listed
Conditions
Brief summary
This is a randomized, double-blind, placebo-controlled dose-escalation study to evaluate the safety, tolerability and PK of ACT004 after administration of single (Part A) and multiple (Part B) oral doses in healthy adult subjects. Approximately five sequential dose cohorts (single oral doses of 100, 200, 400, 600 and 800 mg ACT004) will be evaluated as single ascending doses (SAD) in Part A. Select appropriate dose cohort(s) (seven consecutive days for respectively daily oral) based on the Part A and safety review committee (SRC), which will be evaluated as multiple ascending doses (MAD) in Part B. For each dose cohort in this study, ten healthy subjects will be randomized in an 8:2 ratio to receive either ACT004 or placebo in SAD and MAD. Based on the safety, tolerability, and PK data of the previous dose cohort, the SRC will make decisions on whether to proceed with dose escalations, dosage adjustments, use of sentinel subjects or termination of the study, etc. Higher dose cohort(s) may be attempted additionally if judged necessary by the SRC. Safety data up to Day 7 in SAD study and up to Day 14 in MAD study will be reviewed prior to dose escalation by the SRC. Dosing will be escalated in a sequential fashion if approved by the SRC. Dose escalations will be terminated when there are 1/2 or more subjects with grade 2 adverse events (AEs), or 1/3 or more subjects with grade 3 AEs, or 1 or more subjects with serious adverse events (SAEs) related to the study drug in the current dose cohort. Each subject will receive only one dosing regimen in this study. The proposed doses/dosing frequency of ACT004 may be adjusted over the course of the whole study, and cohorts may be added or removed depending on the exposure of ACT004 in humans. For the safety of subjects, two sentinel subjects will be randomly dosed (ACT004: placebo=1:1) at least 24 hours prior to the remaining subjects in each cohort. Once safety is confirmed, the remaining 8 subjects will be dosed in 7:1 to receive ACT004 or placebo.
Interventions
This is a randomized, double-blind, placebo-controlled dose-escalation study to evaluate the safety, tolerability and Pharmacokinetics (PK) of ACT004 after administration of single (Part A) and multiple (Part B) oral doses in healthy adult subjects. Approximately five sequential dose cohorts (single oral doses of 100, 200, 400, 600 and 800 mg ACT004) will be evaluated as single ascending doses (SAD) in Part A. Select appropriate dose cohort(s) (seven consecutive days for respectively daily oral)
This is a randomized, double-blind, placebo-controlled dose-escalation study to evaluate the safety, tolerability and Pharmacokinetics (PK) of ACT004 after administration of single (Part A) and multiple (Part B) oral doses in healthy adult subjects. Approximately five sequential dose cohorts (single oral doses of 100, 200, 400, 600 and 800 mg ACT004) will be evaluated as single ascending doses (SAD) in Part A. Select appropriate dose cohort(s) (seven consecutive days for respectively daily oral) based on the Part A and safety review committee (SRC), which will be evaluated as multiple ascending doses (MAD) in Part B. For each dose cohort in this study, ten healthy subjects will be randomized in an 8:2 ratio to receive either ACT004 or a placebo in SAD and MAD. Based on the safety, tolerability, and PK data of the previous dose cohort, the SRC will make decisions on whether to proceed with dose escalations, dosage adjustments, use of sentinel subjects or termination of the study, etc. Higher dose cohort(s) may be attempted additionally if judged necessary by the SRC. Each subject will receive only one dosing regimen in this study. The proposed doses/dosing frequency of ACT004 may be adjusted over the course of the whole study, and cohorts may be added or removed depending on the exposure of ACT004 in humans. * Part A - SAD study (Cohort A1-A5) Approximately 35 days: Healthy subjects will be screened within 28 days prior to dosing. Subjects will be admitted to the clinical site on Day -1 and dosed orally on Day 1 under fasting conditions (fasting for at least 10 hours) with approximately 240 mL of warm water . Following completion of all safety assessments and sampling for Pharmacokinetic analysis, subjects will be monitored at clinical site and discharged on Day 4 and return for an end of study (EOS) visit on Day 7. EOS visit will also be the early termination (ET) visit if required (to be completed within 3 days of ET wherever possible). ACT004 capsule will be administered to subjects orally at a starting dose of 100 mg and increased to 200, 400, 600 and 800 mg in sequential dosing cohorts. Dose escalation will be based on the SRC review of blinded safety data including Adverse Event (AE) data, clinical laboratory results, ECGs, vital signs and physical examinations findings, and PK data up to and including Day 7. Once a minimum of 10 subjects randomized in a given cohort complete the Day 7 study visit, all safety and PK data will be reviewed by the SRC prior to dose escalation to the next dose cohort. For the safety of subjects, two sentinel subjects will be randomly dosed (ACT004: placebo = 1:1) at least 24 hours prior to the remaining subjects in each cohort. Once safety is confirmed, the remaining 8 subjects will be dosed at 7:1 to receive ACT004 or a placebo. *Part B - MAD study (Cohort B1) Approximately 45 days : MAD cohorts may commence at the discretion of the SRC, after the safety data from a SAD cohort at a higher dose (and hence higher exposure) have been evaluated. Dosing will commence with the lowest dose cohort (B1). subjects will receive either ACT004 capsule or placebo once daily with approximately 240 mL of warm water for 7 consecutive days from Day 1 to Day 7. Subjects should receive ACT004 or placebo once daily at the same time whenever possible. Subjects will be required to take the study drug on an empty stomach (fasting for at least 10 h) in the morning of Day 1 and Day 7, and have breakfast 2 hour after dosing, lunch and dinner 4 and 10 hours after dose. The planned dose regimen for Part B (MAD study) may be adjusted by the SRC according to safety, tolerability, and PK results of Part A. Healthy subjects will be screened within 28 days prior to dosing and admitted to the clinical site on Day -1. Eligible subjects will be randomized into appropriate dose cohort(s) in an 8:2 ratio to receive ACT004 or placebo on Day 1 to Day 7. Following completion of all PK sample collection and safety assessments, subjects will be discharged on Day 10 and followed up on Day 14. Dose escalation will be based on SRC review of blinded safety data including AE data, clinical laboratory results, ECGs, vital signs and physical examinations findings up to and including Day 14 along with PK data up to and including Day 10. Once a minimum of 10 subjects randomized in a given cohort complete the Day 14 study visit, all safety and PK data will be reviewed by the SRC prior to dose escalation to the next dose cohort. Telemetry monitoring will be performed continuously from pre-dose to 6 hour post dose in both Part A and Part B. Telemetry monitoring includes blood pressure, heart rate, and respiratory rate. During telemetry monitoring items as vital signs or 12 Lead- ECG can be monitored once. Adherence to the intervention will be done via Drug Accountability.
Sponsors
Accendatech AU Pty Ltd.
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
All
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy male and female subjects, 18-55 years of age (both inclusive) at the time of screening. 2. Subjects able to provide a signed and dated informed consent and/or assent document indicating that the subject has been informed of all pertinent aspects of the study before any assessment is performed. 3. Subjects who agree to comply with protocol restrictions, including refraining from consuming alcohol, caffeinated beverages (e.g., tea, coffee, etc.), and tobacco or nicotine containing products from 24 hours before Day 1 until the last PK blood sample collection is finished; able to remain in house for the confinement period of the study without interruption. 4. Body mass index (BMI, weight [kg]/height2 [m2]) within 18.0-28.0 kg/m2 (both inclusive). 5. A female participant is eligible to participate if she is not pregnant and intending to become pregnant or breastfeeding, and at least one of the following conditions applies: - surgically sterile (by means of hysterectomy and/or bilateral oophorectomy) or post-menopausal for at least one year, defined as amenorrhea for 12 consecutive months without another cause and with a follicle stimulating hormone (FSH) level greater than or equal to 40 mIU/mL at screening. - a woman of childbearing potential and using a contraceptive method that is highly effective, with a failure rate of less than 1%, during the treatment period and for at least 1 month after the last dose of study treatment. 6. Male subjects must be willing to remain abstinent (when this is in line with their preferred and usual lifestyle), or, if engaging in sexual intercourse with a female partner of childbearing potential, willing to use a condom in addition to having the female partner use a highly effective method of female contraception from the time of the first study drug administration until 30 days following the last dose of study drug. This requirement does not apply to subjects in a same-sex relationship, subjects with female partners of non-childbearing potentials, or vasectomized subjects who have not undergone any reversal procedure. Male subjects must also be willing to not donate sperms from the time of the first study drug administration until 30 days after the last dose of study drug. 7. No clinically significant abnormal values on vital signs, B-ultrasound and 12-lead ECG. QT interval corrected for heart rate according to Fridericia's formula (QTcF) must be within the following ranges: QTcF less than or equal to 450 msec for male subjects, and QTcF less than or equal to 470 msec for female subject. Assessment may be repeated once if deemed appropriate by the Investigator. 8. No clinically significant abnormal findings noted during screening for medical history and physical examination, or clinically significant abnormal results during screening clinical laboratory tests, including white blood cells (WBCs), liver function and kidney function. Assessment may be repeated once if deemed appropriate by the Investigator. 9. Negative urine drug screen and alcohol breath testing at screening and on Day -1. 10. Ability to swallow all study drugs.
Exclusion criteria
1. Subjects who have a clinically relevant intolerance or allergy to drugs, or are known or suspected to have hypersensitivity to any ingredient in the study drugs; 2. History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered drugs; 3. History or clinical manifestations of any clinically significant gastrointestinal, renal, urologic, bronchopulmonary, neurological, psychiatric, cardiovascular, endocrinological, hematological or allergic disease, metabolic disorder or cancer, at the discretion of the Investigator; 4. Current or chronic history of liver disease or known hepatic or biliary abnormalities, including ALT, aspartate aminotransferase (AST), alkaline phosphatase and bilirubin greater than upper limit of normal (ULN); 5. Current or history of clinically significant cardiac arrhythmias (symptomatic or asymptomatic); 6. Subjects who have had any significant acute infection, e.g., influenza, local infection, acute gastrointestinal symptoms or any other clinically significant illness within two weeks of dose administration. Subjects with a mild upper respiratory infection may be enrolled at the discretion of the Investigator; 7. Creatinine clearance less than 90 mL/min (using the Cockcroft-Gault method based on serum creatine and actual body weight) at screening; 8. Major illness or surgery (except for minor outpatient surgery) within past 3 months of study Day 1, or planned surgery during the study period; 9. Intolerance to direct venepuncture; 10. Participation in any clinical study with an investigational drug, biologic or device within 4 weeks or 5 times the half-life of the specific product if applicable (whichever is longer) since the last dosing or the last use of the investigation drug, biologic or device, prior to the first dosing of ACT004; 11. Donated blood greater than 400 mL or significant blood loss equivalent to 400 mL, or received blood transfusion within 1 months of screening, or have plans to donate blood during the study; 12. History of malignancy within 5 years of screening visit (excluding non-melanoma skin cancer that has been resected); 13. Positive test at screening of any of the following: serum hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV RNA or HCV Ab) or human immunodeficiency virus 1 and 2 (HIV Ab); 14. Recent administration or plans to receive administration of any live vaccine within 12 weeks before Day 1; 15. Use of any other drug, including prescription and over-the-counter medications, within one week of first dosing or within 5 times the elimination half-life of the medication (whichever is longer) prior to first dosing. Exceptions may be made on a case-by-case basis following discussion and agreement between the Investigator and the sponsor. - Paracetamol at a dose of less than 2 g in 24 hours but no more than 1 g in 4 hours is permitted; - Dietary vitamins may be allowed at the discretion of the Investigator (e.g., vitamin D taken at a standard replacement dose and at a time remote from IP administration); - Herbal supplements are not permitted; 16. Unwilling to refrain from caffeinated beverages (i.e., tea, coffee, etc.) from 24 hours before Day -1 until completion of the confinement period; 17. Use of food or beverages likely to influence liver metabolism or inhibit CYP2C9, within 14 days prior to the first dose of the study drug (e.g., star fruit, pomelos, grapefruit & Seville oranges); 18. 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 for female subjects and 21 units of alcohol per week for male subjects (1 Unit = 360 mL of beer or 45 mL of alcohol 40% or 150 mL of wine) and, unwilling to refrain from consumption of alcohol from 24 hours before Day -1 until completion of the confinement period; 19. Use of tobacco or nicotine products or smoking within 30 days (more than 5 cigarettes per day) prior to screening, and, unwilling to refrain from 24 hours before Day -1 until completion of the confinement period; 20. Known or suspected history of drug abuse (e.g., amphetamines [AMP], Methamphetamines [MET], methadone [MTD], barbiturates [BAR], benzodiazepines [BZO], cocaine [COC], opiates [OPI], methyl enedioxy, methamphetamine [MDMA], phencyclidine [PCP], tetrahydrocannabinol [THC]) within the past 2 years or presence of drug abuse within 3 months before screening, or evidence of such abuse on laboratory assays at screening unless explained by a therapeutic dose of a prescribed medication that was ceased at least 14 days prior to Day 1. Drug screening may be repeated once at the discretion of the Investigator; 21. Pregnant (positive pregnancy test) or lactating women; 22. Any factor, which in the opinion of the Investigator would jeopardize the evaluation or safety or be associated with poor adherence to the protocol, rendering the subject unsuitable for participating in the study.
Outcome results
None listed