A Double-blind, Randomized, Placebo-controlled, Combined Single and Multiple Ascending Dose Study to Investigate the Safety, Tolerability and Pharmacokinetic Profile of IFB-088, in Healthy Volunteers
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 72
- 试验地点
- 2
- 主要终点
- Number of Participants With Treatment Emergent Adverse Events Per Group
研究概览
简要总结
This is the first study of single and multiple doses of IFB-088 in human subjects. The current study is designed to assess in the first part, the safety, tolerability, plasma and urine pharmacokinetics (PK) of single oral doses of IFB-088 in healthy subjects (Single Ascending Doses - SAD) and in a second part safety, tolerability, plasma and urine pharmacokinetics (PK) of multiple oral doses of IFB-088 in healthy subjects (Multiple Ascending Doses - MAD)
详细描述
Randomized, double blind, placebo controlled study of single ascending doses (SAD) and multiple ascending doses (MAD).
The SAD part consists of 6 cohorts of 8 healthy young male subjects, each receiving a single oral dose of IFB-088 or placebo (6 verum and 2 placebo). In each cohort, 2 subjects (1 verum and 1 placebo) will be dosed first. If the safety and tolerability results are acceptable, the 6 remaining subjects will be dosed by 2 successive groups of 3 subjects, with an adequate period between the 2 groups to detect the occurrence of any reaction or adverse events, namely at least 48H for the first cohort and at least 36H for the following cohorts. Indeed, in the first cohort (2.5 mg IFB-088 base), dosing will be in the morning only. From the second cohort, the planned daily dose will be divided into 2 doses separated by an interval of 12 hours (1 dose in the morning fasting and 1 dose in the evening 2 hours before dinner).
The MAD part consists of 3 cohorts of 8 healthy young male subjects, each receiving an oral dose divided into two doses of IFB-088 or placebo (6 verum and 2 placebo) for 14 days. In each cohort, the 2 first subjects will be dosed on Day 1 (one on active treatment and one on placebo). The 6 remaining subjects will be dosed by 2 successive groups of maximum 3 subjects with an adequate period between the groups to observe for any reaction and adverse events. This period will be of at least 36H, corresponding to at least 5-fold the half-life of the drug (based on results obtained during the SAD part) when steady state will be achieved. In each MAD cohort, the total daily dose will be divided into 2 doses separated by an interval of 12 hours.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Capsules used for verum or placebo (Size 5 white opaque HPMC capsule) are identical and equally-weighted
入排标准
- 年龄范围
- 18 Years 至 40 Years（Adult）
- 性别
- Male
- 接受健康志愿者
- 是
入选标准
- •Healthy male 18 to 40 years of age inclusive, Caucasian.
- •Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests, vital signs and ECG.
- •AST, ALT, alkaline phosphatase and bilirubin < or = 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
- •ECG (12 leads) normal (120<PR<200ms; QRS<120ms; QTcF<450ms) and/or without clinically relevant impairments as judged by investigator.
- •Non-smoker, or user of not more than tobacco- or nicotine-containing products ≤ 5 cigarettes a day.
- •Negative screen for alcohol and drugs of abuse at screening and admission.
- •No history of psychiatric disorders assessed by a clinical psychological evaluation and the Mini International Neuropsychiatric Interview (MINI).
- •Body mass index (BMI) between 19 and 27 kg/m² inclusive.
- •Subject with female partners of child bearing potential must agree to use one of the contraception methods listed in Section 6.6.1 (Contraception requirements). This criterion must be followed from the time of the first dose of study medication until the follow up visit (for female partners) and with an additional period of 90 days (for subjects themselves).
- •Willing and able to understand and sign an approved Informed Consent Form.
- •Able to understand the protocol and to come to the visits.
- •Who is, in the judgement of the investigator likely to be compliant during the study.
- •Subject registered in the VRB file (volontaires se prêtant à des recherches impliquant la personne humaine).
- •Covered by Health Insurance System and / or in compliance with the recommendations of National Law in force relating to biomedical research.
排除标准
- •History of asthma, anaphylaxis or anaphylactoid reactions, severe allergic responses.
- •History of relevant atopy or drug hypersensitivity.
- •Known allergy to any component of IFB-088 oral capsule or its placebo (HPMC or cellulose microcrystalline).
- •History of major medical, psychiatric illness or surgery which, in the judgment of the investigator, puts them 'at risk' or is likely to modify their handling of the study drug.
- •Acute or chronic systemic disease or disorder (respiratory, gastrointestinal, renal, hepatic, haematological, lymphatic, neurological, cardiovascular, psychiatric, musculoskeletal, genitourinary, immunological, dermatological, endocrine).
- •Impaired renal function defined by a creatinine clearance < 90 mL/min calculated using the Cockcroft-Gault equation (according the FDA Guidance for Industry: Pharmacokinetics in patients with Impaired Renal Function, March 2010).
- •History of nephritic colic and/or renal calculi.
- •History of drug abuse and/or regular use of tobacco- or nicotine-containing products > 5/day within three months of the study.
- •History of alcohol consumption exceeding, (on average 21 drinks/week for men) within 6 months of the first dose of study medication.
- •Drinking excessive amounts of tea, coffee, chocolate and/or beverage containing caffeine (> 4 cups / day).
- •Vital signs with a clinically significant abnormality at screening.
- •ECG with a clinically significant abnormality at screening.
- •Laboratory test values outside the clinically acceptable 'normal range' for healthy volunteers at screening.
- •Positive HIV, Hepatitis B or Hepatitis C at screening.
- •Positive urine drug test or positive breath alcohol test at screening or at admission to the clinical unit.
- •Any medication (including St John's Wort) within 14 days before administration, or within 5 times the elimination half-life of that drug, whichever is the longest (except paracetamol).
- •Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) prior to screening.
- •Unable to refrain from consumption of grapefruit or grapefruit juice within 7 days prior to the first dose of study medication.
- •Unwillingness to abstain from sexual intercourse with pregnant or lactating women or to use a condom and spermicide and another form of contraception (e.g., IUD, birth control pills taken by female partner, diaphragm with spermicide) if engaging in sexual intercourse with a woman who could become pregnant until discharge from the study and during 90 additional days.
- •Subjects unlikely to co-operate in the study, and/or poor compliance anticipated by the investigator.
- •Subject being in the exclusion period of a previous trial.
- •Subject having exceeded the earnings for the last 12 months, including the indemnities for the present study.
- •Subject who could not be contacted in case of emergency.
- •Subject refusing to give written informed consent.
- •Subject who has received blood or plasma derivatives in the year preceding the study.
- •Subject who has given blood within the past 3 months or has planned to give blood or sperm within the 90 days following the study.
- •Subject who has forfeited their freedom by administrative or legal award, or who is under guardianship or under limited judicial protection.
研究组 & 干预措施
SAD IFB-088 2.5mg
Cohort 1: A single daily dose of 2.5mg IFB-088 in oral capsule, is administered with 250 ml of water at room temperature, in the morning around 8:00am, in one intake
干预措施: IFB-088 (2.5-60.0mg) oral capsule (Drug)
SAD Placebo 2.5mg
Cohort 1: A single daily dose of 2.5mg placebo in oral capsule, is administered with 250 ml of water at room temperature, in the morning around 8:00am, in one intake
干预措施: Placebo (2.5-60.mg) oral capsule (Drug)
SAD IFB-088 5.0mg
Cohort 2: A single daily dose of 5.0mg IFB-088 in oral capsule, divided in two doses of 2.5mg are administered with 250 ml of water at room temperature, seperated by an interval of 12h, in the morning around 8:00am, and in the evening around 8:00pm
干预措施: IFB-088 (2.5-60.0mg) oral capsule (Drug)
SAD Placebo 5.0mg
Cohort 2: A single daily dose of 5.0mg placebo in oral capsule, divided in two doses of 2.5mg are administered with 250 ml of water at room temperature, seperated by an interval of 12h, in the morning around 8:00am, and in the evening around 8:00pm
干预措施: Placebo (2.5-60.mg) oral capsule (Drug)
SAD IFB-088 10.0mg
Cohort 3: A single daily dose of 10.0mg IFB-088 in oral capsule, divided in two doses of 5.0mg are administered with 250 ml of water at room temperature, seperated by an interval of 12h, in the morning around 8:00am, and in the evening around 8:00pm
干预措施: IFB-088 (2.5-60.0mg) oral capsule (Drug)
SAD Placebo 10.0mg
Cohort 3: A single daily dose of 10.0mg Placebo in oral capsule, divided in two doses of 5.0mg are administered with 250 ml of water at room temperature, seperated by an interval of 12h, in the morning around 8:00am, and in the evening around 8:00pm
干预措施: Placebo (2.5-60.mg) oral capsule (Drug)
SAD IFB-088 20.0mg
Cohort 4: A single daily dose of 20.0mg IFB-088 in oral capsule, divided in two doses of 10.0mg are administered with 250 ml of water at room temperature, seperated by an interval of 12h, in the morning around 8:00am, and in the evening around 8:00pm
干预措施: IFB-088 (2.5-60.0mg) oral capsule (Drug)
SAD Placebo 20.0mg
Cohort 4: A single daily dose of 20.0mg Placebo in oral capsule, divided in two doses of 10.0mg are administered with 250 ml of water at room temperature, seperated by an interval of 12h, in the morning around 8:00am, and in the evening around 8:00pm
干预措施: Placebo (2.5-60.mg) oral capsule (Drug)
SAD IFB-088 40.0mg
Cohort 5: A single daily dose of 40.0mg IFB-088 in oral capsule, divided in two doses of 20.0mg are administered with 250 ml of water at room temperature, seperated by an interval of 12h, in the morning around 8:00am, and in the evening around 8:00pm
干预措施: IFB-088 (2.5-60.0mg) oral capsule (Drug)
SAD Placebo 40.0mg
Cohort 5: A single daily dose of 40.0mg Placebo in oral capsule, divided in two doses of 20.0mg are administered with 250 ml of water at room temperature, seperated by an interval of 12h, in the morning around 8:00am, and in the evening around 8:00pm
干预措施: Placebo (2.5-60.mg) oral capsule (Drug)
SAD IFB-088 60.0mg
Cohort 6: A single daily dose of 60.0mg IFB-088 in oral capsule, divided in two doses of 30.0mg are administered with 250 ml of water at room temperature, seperated by an interval of 12h, in the morning around 8:00am, and in the evening around 8:00pm
干预措施: IFB-088 (2.5-60.0mg) oral capsule (Drug)
SAD Placebo 60.0mg
Cohort 6: A single daily dose of 60.0mg Placebo in oral capsule, divided in two doses of 30.0mg are administered with 250 ml of water at room temperature, seperated by an interval of 12h, in the morning around 8:00am, and in the evening around 8:00pm
干预措施: Placebo (2.5-60.mg) oral capsule (Drug)
MAD IFB-088 15 mg
Cohort 7: subject taking 15.0mg of IFB-088 in oral capsule divided into 2 doses of 7.5mg administered with 250ml of water at room temperature, seperated by an interval of 12h, in the morning around 8:00am, an in the evening around 8:00pm, for 14 days.
干预措施: IFB-088 (15.0-50.0mg) oral capsule (Drug)
MAD Placebo 15 mg
Cohort 7: subject taking 15.0mg of placebo in oral capsule divided into 2 doses of 7.5mg administered with 250ml of water at room temperature, seperated by an interval of 12h, in the morning around 8:00am, an in the evening around 8:00pm, for 14 days.
干预措施: Placebo oral (15.0-50.0mg) capsule (Drug)
MAD IFB-088 30 mg
Cohort 8: subject taking 30.0mg of IFB-088 in oral capsule divided into 2 doses of 15.0mg administered with 250ml of water at room temperature, seperated by an interval of 12h, in the morning around 8:00am, an in the evening around 8:00pm, for 14 days.
干预措施: IFB-088 (15.0-50.0mg) oral capsule (Drug)
MAD Placebo 30 mg
Cohort 8: subject taking 30.0mg of Placebo in oral capsule divided into 2 doses of 15.0mg administered with 250ml of water at room temperature, seperated by an interval of 12h, in the morning around 8:00am, an in the evening around 8:00pm, for 14 days.
干预措施: Placebo oral (15.0-50.0mg) capsule (Drug)
MAD IFB-088 50 mg
Cohort 9: subject taking 50.0mg of IFB-088 in oral capsule divided into 2 doses of 25.0mg administered with 250ml of water at room temperature, seperated by an interval of 12h, in the morning around 8:00am, an in the evening around 8:00pm, for 14 days.
干预措施: IFB-088 (15.0-50.0mg) oral capsule (Drug)
MAD Placebo 50 mg
Cohort 9: subject taking 50.0mg of Placebo in oral capsule divided into 2 doses of 25.0mg administered with 250ml of water at room temperature, seperated by an interval of 12h, in the morning around 8:00am, an in the evening around 8:00pm, for 14 days.
干预措施: Placebo oral (15.0-50.0mg) capsule (Drug)
结局指标
主要结局
Number of Participants With Treatment Emergent Adverse Events Per Group
时间窗: SAD & MAD phases: Screening visit to End of study visit (7 to 14 days after last dosing) + 30 days
This safety outcome lists the number of subjects experiencing adverse events (AEs), whether not related, possibly or unlikely related to the study treatment. As all the parameters are developped in the pharmacovigilance section, please do refer to that section for further details.
次要结局
- Pharmacokinetic: Apparent Total Body Clearance (CL/F)(Starting 1 hour prior to dosing on Day 1 and until 72 hours after last dosing (Day 17))
- Number of Participants With With Clinically Significant Change in Hematology Parameters During the Study(SAD phase: Screening; Day -1; Day 2 (24 hours); end of study visit (7 to 14 days after last dosing) MAD phase: Screening; Day -1; predose, at Day 3, Day 6, Day 10, Day 13; Day 17; end of study visit (7 to 14 days after last dosing))
- Number of Participants With Change in Concomitant Medications(SAD & MAD phases: Continuous (Screening visit to End of study visit (7 to 14 days after last dosing) + 30 days))
- Pharmacokinetic: Maximum Observed Plasma Concentration (Cmax)(Starting 1 hour prior to dosing on Day 1 and until 72 hours after last dosing (Day 17))
- Pharmacokinetic: Time to Reach the Maximum Concentration in Plasma (Tmax)(Starting 1 hour prior to dosing on Day 1 and until 72 hours after last dosing (Day 17))
- Pharmacokinetic: Terminal Half-life (t1/2)(Starting 1 hour prior to dosing on Day 1 and until 72 hours after last dosing (Day 17))
- Pharmacokinetic: Area Under Plasma Concentration-time Curve From Hour 0 to Last Sample With Measurable Plasma Concentrations (AUClast)(Starting 1 hour prior to dosing on Day 1 and until 72 hours after last dosing (Day 17))
- Number of Participants With With Clinically Significant Change in Coagulation Parameters During the Study(SAD phase: Screening; Day -1; Day 2 (24 hours); end of study visit (7 to 14 days after last dosing) MAD phase: Screening; Day -1; predose at Day 3, Day 6, Day 10, Day ; Day 17; end of study visit (7 to 14 days after last dosing))
- Number of Participants With With Clinically Significant Change in Blood Biochemistry Parameters During the Study(SAD phase: Screening; Day -1; Day 2 (24 hours); end of study visit (7 to 14 days after last dosing) MAD phase: Screening; Day -1; predose at Day 3, Day 6, Day 10, Day 13; Day 17; end of study visit (7 to 14 days after last dosing))
- Pharmacokinetic: Apparent Volume of Distribution (Vd/F)(Starting 1 hour prior to dosing on Day 1 and until 72 hours after last dosing (Day 17))
- Pharmacokinetic: Renal Clearance (CLr)(Starting 1 hour prior to dosing on Day 1 and until 48 hours after last dosing (Day 16))
- Pharmacokinetic: Percent of Drug Recovered in Urine (Ae %Dose)(Starting 1 hour prior to dosing on Day 1 and until 48 hours after last dosing (Day 16))
- Number of Participants With Clinically Significant Change in Physical Evaluation During the Study(SAD & MAD phases: Screening; Day 2 (SAD) or Day 17 (MAD); and at End of study visit (7 to 14 days after last dosing))
- Number of Participants With Clinically Significant Change in Physiological Parameters During the Study(SAD & MAD phases: Screening; Day 2 (SAD) or Day 17 (MAD); and at End of study visit (7 to 14 days after last dosing))
- Number of Participants With With Clinically Significant Change in Cardiovascular Functions During the Study(From screening visit until end of study visit (7 to 14 days after last dosing))
- Number of Participants With With Clinically Significant Change in Tympanic Body Temperature During the Study(SAD phase (cohorts 1 to 6):Screening, Day -1;Day 1 ;end (7 to 14 days after last dosing) MAD phase: Screening;Day -1; Day 1 ;predose at Day 2, Day 4, Day 6, Day 8, Day 10, Day 12; Day 14 ; Day 17; end (7 to 14 days after last dosing))
- Number of Participants With Clinically Significant Change in Urinary Functions/Parameters During the Study(SAD phase: Screening; Day -1; Day 1 (predose, 12, 24, 32 hours); end of study visit (7 to 14 days after last dosing) MAD phase: Screening; Day -1; predose at Day 1, Day 3, Day 6, Day 10, Day 13; Day 17; end of study visit (7 to 14 days after last dosing))
- Number of Participants With Clinically Significant Change in Vigilance and Mood During the Study(SAD Phase: Screening; Day 1 (predose, 1.5, 12, 32 hours) MAD Phase: Screening; Day 1 (predose, 1.5, 12 hours); Day 14 (predose, 1.5, 12 hours))