An Adaptive, Randomized, Double-blind, Single-center, Placebo-controlled Phase I Study Evaluating ECG Effects, Safety and Pharmacokinetics of Single Ascending Doses of [6R]-5,10-Methylene Tetrahydrofolate (Modufolin® for Injection, 100mg) in Healthy Male Volunteers
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 33
- 试验地点
- 1
- 主要终点
- Change-from-baseline QTcF (ΔQTcF)
研究概览
简要总结
The purpose of this study is to evaluating ECG effects, safety, tolerability and pharmacokinetics of single ascending dose of Modufolin® in healthy male volunteers
详细描述
An adaptive randomised, double-blind, single-centre, placebo-controlled Phase I study evaluating ECG effects, safety, tolerability and PK of single ascending doses of Modufolin® for Injection, 100 mg in healthy male volunteers. Thirty-three (33) eligible and consenting subjects will be included in 3 cohorts, 11 subjects in each cohort. Within each cohort, subjects will be randomised to receive either placebo (3 subjects) or Modufolin® for Injection, 100 mg (8 subjects). There will be 3 pre-defined ascending dose-levels. Additional dose levels may be considered if recommended by the internal Safety Review cCommittee. There will be an interval between each dose level to allow time for safety data to be analyzed and evaluated by the iSRC. The iSRC will have the choice to decide to escalate the dose as planned, reduce or increase the dose escalation step, repeat the dose, reduce the dose or terminate the study. The total study duration for the subjects will be approximately 5 weeks and there will be in total 3 visits to the clinic. Subjects will be screened for eligibility according to study-specific inclusion/exclusion criteria within 4 weeks prior to start of stud treatment (Visit 1; Screening visit). The subjects will be confined to the research clinic from the evening before dosing (Day -1) until 24 hrs post dose (Days 1 and 2). The subjects should be fasting overnight (8 hrs) before IMP/placebo administration until 4 hrs post-dose. A Follow-up Visit will be performed 5 to 10 days after dose administration of for each cohort.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Single Group
- 主要目的
- Other
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
IMP (Modufolin® for Injection, 100 mg) and Placebo are not identical in appearance and all efforts will be made at the clinic in order to maintain the blind. Both the IMP and the placebo will be masked in such a way that study subjects and study staff will remain blinded during the study. An un-blinded study nurse will prepare the IMP/placebo for injection and will administer the IMP/placebo to the study subject. The un-blinded study nurse performing the dose administration will not be involved in any study-specific assessments or evaluations.
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- Male
- 接受健康志愿者
- 是
入选标准
- •Willing and able to provide a written informed consent for participation in the study.
- •Healthy male subject aged 18-60 years inclusive.
- •Body Mass Index (BMI) ≥ 18 and ≤ 30 kg/m2 and weight at least 50 kg and no more than 100 kg at screening and body surface area ≤ 2 m2
- •Clinically normal medical history, physical findings, vital signs, ECG and laboratory values at the time of screening, as judged by the Investigator.
- •Willing to use condom and highly effective contraceptive methods with a failure rate of < 1% to prevent pregnancy1 and drug exposure to a partner and refrain from donating sperm from the date of dosing until 3 months after dosing of the IMP/placebo.
排除标准
- •History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or subject´s ability to participate in the study.
- •Any clinically significant illness, medical/surgical procedure or trauma within four weeks of the first administration of IMP/placebo.
- •Any planned major surgery within the duration of the study.
- •Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody and Human Immunodeficiency Virus (HIV).
- •After 10 minutes (min) supine rest at the time of screening, any vital signs values outside the following ranges:
- •Systolic BP > 150 mm Hg
- •Diastolic BP > 90 mm Hg
- •Pulse < 40 or > 85 beats per min
- •Prolonged QTcF (>450 ms), cardiac arrhythmias or any clinically significant abnormalities in the resting ECG at the time of screening, as judged by the Investigator.
- •History of severe allergy/hypersensitivity or on-going allergy/hypersensitivity, as judged by the Investigator, or history of hypersensitivity to drugs with a similar chemical structure or class to Modufolin® (i.e., folate derivatives).
- •Regular use of any prescribed or non-prescribed medication including antacids, analgesics, herbal remedies, vitamins and minerals within two weeks prior to the administration of IMP/placebo, except occasional intake of paracetamol (maximum 2000 mg/day; and not exceeding 3 000 mg/week), at the discretion of the Investigator and nasal decongestants without cortisone or antihistamine for a maximum of 10 days, at the discretion of the Investigator.
- •Regular use of any prescribed or non-prescribed medication which could influence folate and vitamin B12 status within 30 days prior to the administration of IMP/placebo.
- •Administration of another new chemical entity (defined as a compound which has not been approved for marketing) or has participated in any other clinical study that included drug treatment with less than three months between administration of last dose and first dose of IMP/placebo in this study. Subjects consented and screened but not dosed in previous phase I studies are not excluded.
- •Current smokers or users of nicotine products. Irregular use of nicotine (e.g., smoking, snuffing, chewing tobacco) less than three times per week is allowed before screening visit.
- •Positive screen for drugs of abuse or alcohol at screening or on admission to the unit prior to administration of the IMP/placebo.
- •Current or history of alcohol abuse and/or use of anabolic steroids or drugs of abuse.
- •Intake of xanthine and/or taurine containing energy drinks within two days prior to screening.
- •Plasma donation within one month of screening or blood donation (or corresponding blood loss) during the three months prior to dosing.
- •Investigator considers the subject unlikely to comply with study procedures, restrictions and requirements.
研究组 & 干预措施
Modufolin® for injection, 200, 350 and 500 mg/m2
Three cohorts, 8 subjects will be randomised to Modufolin ® for injection 100 mg
干预措施: Modufolin (arfolitixorin) (Drug)
0.9% NaCl sterile solution
Three cohorts, 3 subjects will be randomised to placebo
干预措施: Modufolin (arfolitixorin) (Drug)
结局指标
主要结局
Change-from-baseline QTcF (ΔQTcF)
时间窗: Pre-dose at following timepoints -2 h, -45 min, -30 min, -15 min. Then at following timepoints; 0, 5 min, 15 min, 30 min, 1 h, 2h, 3h, 4h, 5h, 6h, 8h, 12h and 24h post-dose.
At each nominal time point specified in the CSP, up to 10 ECG replicates were extracted with TQT Plus methods. TQT Plus ECG extraction technique: Twelve-lead ECGs were extracted from continuous recordings (Holter recordings) prior to and serially after IMP administration at time points as shown in the Schedule of events. Subjects were supinely resting for at least 10 min prior to time points for ECG recordings. The 12-lead Holter and ECG equipment were supplied and supported by iCardiac Technologies, Inc. For all ECG parameters, baseline is defined as the average of the measured ECG intervals from the three pre-dose time points (45, 30, and 15 min pre-dose) on Day 1.
次要结局
- Relationship Between ΔΔQTc and Modufolin® (and Metabolites) Plasma Concentrations(5 minute post-dose time point)
- Number of Participants With Categorical QTcF Outliers(Pre-dose at following timepoints -2 h, -45 min, -30 min, -15 min. Then at following timepoints; 0, 5 min, 15 min, 30 min, 1 h, 2h, 3h, 4h, 5h, 6h, 8h, 12h and 24h post-dose.)
- Change-from-baseline Heart Rate (ΔHR)(Pre-dose at following timepoints -2 h, -45 min, -30 min, -15 min. Then at following timepoints; 0, 5 min, 15 min, 30 min, 1 h, 2h, 3h, 4h, 5h, 6h, 8h, 12h and 24h post-dose.)
- Physical Examination(At visit 1 (screening) and follow-up)
- Systolic Blood Pressure(Predose at following timepoints: At screening (visit 1) and at -15 min (visit 2). Postdose at following timepoints: 3h, 5h, 8 h and 24h (visit 2) and at visit 3 (follow-up visit).)
- Change-from-baseline QRS (ΔQRS)(Pre-dose at following timepoints -2 h, -45 min, -30 min, -15 min. Then at following timepoints; 0, 5 min, 15 min, 30 min, 1 h, 2h, 3h, 4h, 5h, 6h, 8h, 12h and 24h post-dose.)
- Vital Signs: Pulse(Predose at following timepoints: At screening (visit 1) and at -15 min (visit 2). Postdose at following timepoints: 3h, 5h, 8 h and 24h (visit 2) and at visit 3 (follow-up visit).)
- Change-from-baseline PR (ΔPR)(Pre-dose at following timepoints -2 h, -45 min, -30 min, -15 min. Then at following timepoints; 0, 5 min, 15 min, 30 min, 1 h, 2h, 3h, 4h, 5h, 6h, 8h, 12h and 24h post-dose.)
- Categorical Outliers for HR, PR Interval, QRS Interval(Pre-dose at following timepoints -2 h, -45 min, -30 min, -15 min. Then at following timepoints; 0, 5 min, 15 min, 30 min, 1 h, 2h, 3h, 4h, 5h, 6h, 8h, 12h and 24h post-dose.)
- Categorical Analysis for T Wave Morphology(Pre-dose at following timepoints -2 h, -45 min, -30 min, -15 min. Then at following timepoints; 0, 5 min, 15 min, 30 min, 1 h, 2h, 3h, 4h, 5h, 6h, 8h, 12h and 24h post-dose.)
- Diastolic Blood Pressure(Predose at following timepoints: At screening (visit 1) and at -15 min (visit 2). Postdose at following timepoints: 3h, 5h, 8 h and 24h (visit 2) and at visit 3 (follow-up visit).)
- Plasma PK Characteristics: AUClast/Dose(Pre-dose at -15 min and post-dose at following timepoints: 5 min, 15 min, 30 min, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h.)
- Plasma PK Characteristics: t1/2(Pre-dose at -15 min and post-dose at following timepoints: 5 min, 15 min, 30 min, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h.)
- Plasma PK Characteristics: CL(Pre-dose at -15 min and post-dose at following timepoints: 5 min, 15 min, 30 min, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h.)
- Safety Laboratory Measurements(Pre-dose at screening (visit 1) and -2h (visit 2). Post-dose at following timepoints: 24 h (visit 2) and at follow-up (visit 3))
- Frequency, Seriousness and Intensity of AEs(From start of IMP administration to follow-up visit)
- Plasma PK Characteristics: C0(Pre-dose at -15 min and post-dose at following timepoints: 5 min, 15 min, 30 min, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h. pre-dose to 24 h post-dose)
- Plasma PK Characteristics: C5min(Pre-dose at -15 min and post-dose at following timepoints: 5 min, 15 min, 30 min, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h)
- Plasma PK Characteristics: AUClast(Pre-dose at -15 min and post-dose at following timepoints: 5 min, 15 min, 30 min, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h.)
- Plasma PK Characteristics: Timepoint for Last Measured Plasma Concentration (Tlast)(Pre-dose at -15 min and post-dose at following timepoints: 5 min, 15 min, 30 min, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h.)
- Plasma PK Characteristics: Tmax(Pre-dose at -15 min and post-dose at following timepoints: 5 min, 15 min, 30 min, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h.)
- Plasma PK Characteristics: Cmax/Dose for Metabolite 5-Formyl-THF(Pre-dose at -15 min and post-dose at following timepoints: 5 min, 15 min, 30 min, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h)
- Number of Subjects With AEs(From start of IMP administration to follow-up visit)
- Plasma PK Characteristics: Vss(Pre-dose at -15 min and post-dose at following timepoints: 5 min, 15 min, 30 min, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h)
- Plasma PK Characteristics: Cmax(Pre-dose at -15 min and post-dose at following timepoints: 5 min, 15 min, 30 min, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h.)