A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Oral Single and Multiple Ascending Doses, Parallel Group Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of INS018_055 in Healthy Subjects
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 78
- 试验地点
- 1
- 主要终点
- Number of participants with treatment-related adverse events based on subjective and objective examination
研究概览
简要总结
The sponsor is planning to conduct a Phase 1, randomized, double-blind, placebo-controlled, oral single and multiple ascending-doses, parallel group study to evaluate the safety, tolerability and PK of INS018_055 in healthy subjects. The study will be conducted in 1 clinical site in the New Zealand, consisting of 2 parts: Part A (single ascending dose [SAD]) and Part B (multiple ascending dose [MAD]).
详细描述
This is a Phase 1, randomized, 2-part (Part A and B), double-blind, placebo controlled single and multiple ascending doses study designed to assess the safety, tolerability, and PK of INS018_055 when administered as oral doses to healthy subjects. Additionally, this study will investigate the impact of food on the PK of INS018_055.
Part A (Single Ascending Dose [SAD]):
Eight healthy subjects will be assigned to each of up to 5 sequential dose cohorts and will be randomly assigned within each dose cohort to receive INS018_055 or a matched placebo in a ratio of 3:1 (6 active, 2 placebo) on Day 1 for a total of up to approximately 40 subjects. Subjects in Part A will be admitted to the study site on Day -1 and dosed on Day 1 after fasting (nothing to eat or drink, except water) for at least 10 hours. Water is not allowed 1 hour prior to and 1 hour after dosing. Water can be consumed ad libitum at other times. Subjects will remain fasted on Day 1 for 4 hours after dosing. Subjects will be discharged from the study site on Day 4, after the scheduled procedures and review of the Day 4 safety data by the investigator (or designee). Subjects will come back for an end of study (EOS) visit on Day 8 (± 1 day).
A sentinel cohort of 2 subjects will be used to mitigate the risk of unexpected adverse events (AEs) not predicted by preclinical pharmacology and toxicology studies for each dosing cohort, starting with Cohort 1 (the initial dose cohort). The sentinel subjects will be dosed in a blinded fashion (1 active, 1 placebo) and monitored for at least 1 day before the remaining 6 subjects in that cohort are dosed. Initiation of dosing of the remaining 6 subjects will depend on an initial safety review by the investigator indicating that administration of the study treatment was safe and well tolerated in the sentinel subjects.
Dose escalation will occur only after the real time PK, safety, and tolerability data (including reported AEs, physical examinations, vital signs, electrocardiograms (ECGs), and clinical laboratory results up to 48 hours after dosing) of the preceding dose cohort for at least 6 subjects are assessed and the study treatment is deemed safe and well tolerated by the safety review committee (SRC). As new safety and/or PK data become available, the anticipated dose escalation scheme may change following a review of the data by the SRC. Preliminary PK data from subjects in this study will help guide dose escalation to higher doses. Dose escalation in Cohorts 4 and 5 will only occur after the PK data from at least the first 2 cohorts have been assessed and deemed sufficient to model exposures for Cohorts 4 and 5.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •The subject is a male or female 18 to 55 years of age, inclusive.
- •The subject has a body mass index 18 to 32 kg/m2, inclusive, and a total body weight ≥50 kg, inclusive, at screening.
- •The subject is considered by the investigator to be in good general health as determined by medical history, clinical laboratory test results, vital sign measurements, 12-lead ECG results, and physical examination findings at screening.
- •Female subjects of childbearing potential must be non-pregnant and non-lactating and must use one of the methods of contraception listed below for the duration of the treatment until at least 28 days after the last dose of the study drug, or be surgically sterile (ie, hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), or postmenopausal (defined as amenorrhea 12 consecutive months and documented plasma follicle stimulating hormone level >40 IU/mL). Female subjects must have a negative pregnancy test at screening and before the first dose of study drug.
- •Highly effective methods of contraception are those that result in a failure rate of less than 1% per year when used consistently. Examples are provided below:
- •Implant contraceptive (eg, Jadelle®)
- •Intrauterine device containing either copper or levonorgestrel (eg, Mirena®)
- •Male sterilization with absence of sperm in the post-vasectomy ejaculate
- •OR an effective method that result in a failure rate of less than 5% to 10% per year. Examples are provided below:
- •Injectable contraceptive (eg, Depo Provera)
- •Oral contraceptive pill (combined hormonal contraceptive pill or progestogen-only 'mini-pill')
- •Vaginal contraceptive ring (eg, NuvaRing®)
- •Female subjects must also agree not to donate eggs, from dosing until at least 28 days after the last dose of study drug.
- •A male subject and his female partner who is of childbearing potential must agree to use one of the methods of contraception listed above for the duration of the treatment until at least 28 days after the last dose of the study drug. A male subject must also agree not to donate sperm, for the duration of the treatment until at least 28 days after the last dose of the study drug.
- •The subject agrees to comply with all protocol requirements.
- •The subject is able to provide written informed consent.
排除标准
- •The subject has current evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing).
- •The subject has any condition possibly affecting drug absorption (eg, gastrectomy).
- •The subject has a history of cancer with the exception of adequately treated basal cell or squamous cell carcinoma of the skin.
- •The subject has supine blood pressure (BP) >140 mm Hg (systolic) or >90 mm Hg (diastolic), following at least 5 minutes of supine rest. If BP is >140 mm Hg (systolic) or >90 mm Hg (diastolic), the BP should be repeated 2 more times and the average of the 3 BP values should be used to determine the subject's eligibility at screening.
- •The subject has 12-lead ECG demonstrating corrected QT interval by Fridericia (QTcF) >450 msec, or a QRS interval >120 msec at screening. If QTcF exceeds 450 msec, or QRS interval exceeds 120 msec, the ECG should be repeated 2 more times and the average of the 3 QTcF (or QRS interval) values should be used to determine the subject's eligibility.
- •The subject has ANY of the following abnormalities in clinical laboratory tests at screening, as assessed by the study-specific laboratory and confirmed by a single repeat, if deemed necessary:
- •Serum creatinine level above the upper limit of normal (ULN) or an estimated glomerular filtration rate value <80 mL/min/1.73 m2 calculated with the Chronic Kidney Disease Epidemiology Collaboration formula and the absence of protein in urine, at screening.
- •Aspartate aminotransferase or alanine aminotransferase values more than >1.5 × ULN.
- •Fasting glucose >110 mg/dL (6.1 mmol/L).
- •Total bilirubin >1.5 × ULN.
- •Hematological values outside the normal reference range for local laboratory results.
- •Positive fecal occult blood test at screening or at check-in (Day -1).
- •The subject has any medical history of disease that has the potential to cause a rise in total bilirubin over the ULN. Subjects with borderline clinical laboratory values outside the reference range may be included in the study if the investigator deems that the values are not clinically significant.
- •Note: Subjects with a history of Gilbert's syndrome may have a direct bilirubin measured and would be eligible for this study provided the direct bilirubin is <ULN.
- •The subject has a history of any lymphoproliferative disorder (such as Epstein Barr Virus related lymphoproliferative disorder, as reported in some subjects on immunosuppressive drugs), history of lymphoma, leukemia, myeloproliferative disorders, multiple myeloma, or signs and symptoms suggestive of current lymphatic disease.
- •The subject has a history of relevant drug and/or food allergies (ie, allergy to any study drug or excipients, or any significant food allergy that could preclude a standard diet in the clinical unit).
- •The subject has a clinically significant infection currently or within 6 months of first dose of study drug (eg, those requiring hospitalization or parenteral antimicrobial therapy or opportunistic infections within the last 6 months), or a history of chronic or recurrent infectious disease.
- •The subject has other severe acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
- •The subject has or has had symptomatic herpes zoster or herpes simplex within 12 weeks, more than one episode of local herpes zoster, or a history (single episode) of disseminated zoster.
- •The subject has a positive test result for hepatitis B surface antigen, hepatitis C virus antibody, or human immunodeficiency virus types 1 or 2 antibodies at screening.
- •The subject is a female who is pregnant or lactating.
- •The subject is a fertile male who is unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 28 days after the last dose of investigational product.
- •The subject is unwilling or unable to comply with the lifestyle restrictions described in this protocol.
- •The subject is a smoker or has used nicotine or nicotine-containing products (eg, snuff, nicotine patch, nicotine chewing gum, mock cigarettes, or inhalers) within 6 months before the first dose of study drug.
- •The subject has a positive test result for drugs of abuse, or cotinine (indicating active current smoking) at screening or before the first dose of study drug.
- •The subject has used any prescription or over the counter medications (except paracetamol [up to 2 g per day]), including herbal supplements, within 14 days before the first dose of study drug. Nutritional supplements are allowed if unlikely to interfere with the study results and agreed by medical monitor and investigator.
- •The subject has consumed grapefruit or grapefruit juice, Seville orange or Seville orange containing products (eg, marmalade), or alcohol-, caffeine-, or xanthine containing products within 48 hours before the first dose of study drug.
- •The subject will have vaccination with live virus, attenuated live virus, or any live viral components within 2 weeks prior to the first dose of study drug or is to receive these vaccines at any time during treatment or within 8 weeks following completion of study treatment.
- •The subject has a positive test result for severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). The subject has received the Coronavirus disease 2019 (COVID-19) vaccine within 2 weeks prior to the first dose of study drug or plans to receive a COVID-19 vaccine within 12 weeks after study drug dosing or has positive test for SARS CoV 2 during screening or presence of COVID 19 symptoms within 4 weeks prior to Day -
- •The subject has undergone significant trauma or major surgery within 4 weeks of screening.
- •The subject has bleeding risk: genetic predisposition to bleeding, a hemorrhagic event in the 12 months before the start of screening, or abnormal laboratory coagulation parameters.
- •The subject has a first-degree relative with a hereditary immunodeficiency.
- •The subject has investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or subjects who are sponsor employees including their family members are directly involved in the conduct of the study.
- •The subject has a history of alcohol abuse or drug addiction within the last year or excessive alcohol consumption (regular alcohol intake >21 units per week for male subjects and >14 units of alcohol per week for female subjects) (1 unit is equal to approximately ½ pint [200 mL] of beer, 1 small glass [100 mL] of wine, or 1 measure [25 mL] of spirits) or use of alcohol 48 hours before the first dose of study drug.
- •The subject is involved in strenuous activity or contact sports within 24 hours before dosing and during the study.
- •The subject has donated blood or blood products >450 mL within 30 days before the first dose of study drug.
- •The subject has received study drug in another investigational study within 30 days of dosing.
- •The subject received cytochrome P450 (CYP)/ multidrug and toxin extrusion (MATE) classes of medications within 4 weeks of first dose of INS018_055 or was likely to receive CYP/MATE classes of medications during the study.
- •In the opinion of the investigator, the subject is not suitable for entry into the study.
研究组 & 干预措施
INS018_055
oral doses of INS018_055_single dose; oral doses of INS018_055_multiple ascending dose over 10days.
干预措施: INS018_055 (Drug)
Placebo
No active ingredient. Frequency similar to the 2 arms above.
干预措施: Placebo (Drug)
结局指标
主要结局
Number of participants with treatment-related adverse events based on subjective and objective examination
时间窗: 12 months
Subjective examination refers to the participant response to standard question to elicit any medically related changes in their well-being. Descriptive examination refers to laboratory values as reviewed by the investigator, physical examination findings and ECG Changes, or other documents that are relevant to participant safety. AEs will be classified as: Mild: These events require minimal or no treatment and do not interfere with the subject's daily activities. Moderate: These events result in a low level of inconvenience or require minor therapeutic measures. Moderate events may cause some interference with normal functioning. Severe: These events interrupt a subject's usual daily activity and may require systemic drug therapy or other treatment. Severe events are usually incapacitating.
次要结局
- Accumulation ratio (AR), calculated as AUC0-To (Day 10)/AUC0-To (Day 1)(12 months)
- AUC from time 0 extrapolated to infinity (AUC0-inf)(12 months)
- AUC from time 0 to the time of the dosing interval (To; AUC0-To)(12 months)
- Apparent volume of distribution (Vd/F)(12 months)
- Total amount of drug excreted unchanged in urine from 0 to 24 hours after dosing (XU0-24)(12 months)
- Area under the plasma concentration versus time curve (AUC) from time 0 to the last quantifiable concentration (AUC0-t)(12 months)
- Pre-dose concentrations on Days 1 through 10 (C trough)(12 months)
- Apparent total body clearance (CL/F)(12 months)
- Metabolite-to parent ratio based on AUC calculated as AUCmetabolite/AUCparent(12 months)
- Metabolite-to parent ratio based on Cmax calculated as Cmax, metabolite/Cmax, parent(12 months)
- Maximum Plasma Concentration [Cmax](12 months)
- AR calculated as Cmax (Day 10)/Cmax (Day 1)(12 months)
- Average concentration on Day 1 and Day 10 (Cav)(12 months)
- Terminal elimination rate constant (Kel)(12 months)
- Terminal elimination half-life (t1/2)(12 months)
- Time to reach Cmax (Tmax)(12 months)
- Renal clearance (CLr)(12 months)
- Peak to trough ratio calculated as Cmax/Ctrough(12 months)