A Phase 1 (First in Human) Randomized, Double-blind, Placebo-controlled SAD, MAD Study With an Adaptive Dose Design to Evaluate the Safety, Tolerability, and Pharmacokinetics of REM0046127 in Healthy Subjects
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- reMYND
- 入组人数
- 77
- 试验地点
- 1
- 主要终点
- Adverse Events
研究概览
简要总结
This is a phase 1 randomized double blind, first in human (FIH) study with the novel oral Alzheimer drug candidate REM0046127, which consists of two main parts, a single ascending dose (SAD) study with 7 cohorts followed by a multiple ascending dose (MAD) study with 2 cohorts.
详细描述
SAD
As a baseline, 5 cohorts of 8 young healthy males are foreseen, with a repeat to assess food impact and an additional elderly cohort. Depending on the early FIH findings, the number of cohorts could be more or less. FIH studies include initially only males due to the incomplete nature of preclinical reproductive toxicology studies
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Treatment duration: single day
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Each cohort:
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2 volunteers on placebos, of which 1 sentinel
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6 volunteers on study drug, of which 1 sentinel
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Timing for each cohort will be about 21 days
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Subjects will be screened for selection from day -21 to day -1 before starting the experimental phase of each cohort
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First the 2 sentinels will be dosed
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Following the review of sentinel safety and tolerability data through the Data Safety Monitoring Board (DSMB) after one day or 2 half-life times following the sentinel dosing, the remaining 1+5 subjects will be randomized and dosed approximately 7 days after the sentinels
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)
盲法说明
An independent statistician will provide the randomization list to an unblinded person at the site. The unblinded person prepares the medication for the subjects. The ready medication is handed over to the blinded investigator and the investigator will dose the blinded subjects.
Randomization numbers will be kept secret until data base lock. After data base lock the results will be unblinded for final analysis.
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •SAD/MAD: Young male subjects aged 18 to 45 years (limits included) willing and able to give their written consent to participate in the trial after having received information about the study design, the objectives of the project, the possible derivative risks, and their right to withdraw from the study at any time and for any reason
- •Elderly Cohorts: Elderly male and female (not of childbearing potential) subjects aged 55 to 80 (limits included) willing and able to give their written consent to participate in the trial after having received information about the study design, the objectives of the project, the possible derivative risks, and their right to withdraw from the study at any time and for any reason.
- •Women not of childbearing potential: Clinically significant abnormalities in screening laboratory tests, including:
- •Surgically sterile (bilateral tubal ligation, hysterectomy), or
- •Postmenopausal with last natural menses greater than 24 months
- •Electrocardiogram without clinically significant pathologic abnormalities and with corrected QT interval (cQT) values lesser than 450 ms
- •Normotensive as defined by Systolic Blood Pressure ≤ 150 mm Hg. Diastolic Blood Pressure ≤ 90 mm Hg without antihypertensive medication
- •Body Mass Index (BMI) between 18 and 30 kg/m
- •Body weight between 60 and 80 kg, inclusive
- •Only for the elderly cohort of the MAD:
- •Participants may be taking medication for non-serious chronic diseases, provided that the dose of these concomitant medications has been stable within the previous 2 months
- •No suicidal ideation, as demonstrated by a score of "0" on the Columbia Suicide Severity Rating Scale (C-SSRS)
排除标准
- •Women of childbearing potential (WOCBP)
- •Failure to perform screening or baseline examinations
- •Any chronic medical condition (such as type 1 diabetes) requiring chronic treatment that might increase the risk to the subject or confound the interpretation of safety observations according to the clinical assessment of the investigator (physician)
- •Evidence of active infection requiring antibiotic therapy within 14 days prior to screening
- •Medical history of vasculitis or any autoimmune disease excluding seasonal allergic rhinitis and childhood history of atopic dermatitis
- •History of any treatment for cancer within the past 2 years, other than basal cell or squamous cell carcinoma of the skin
- •Seropositive for human immunodeficiency virus (HIV)
- •History of acute/chronic hepatitis B or C and/or carriers of hepatitis B (seropositive for Hepatitis B surface antigen [HbsAg] or anti-Hepatitis C [Hepatitis C Virus (HCV)] antibody)
- •Clinically significant abnormalities in screening laboratory tests, including:
- •Absolute neutrophil count < 1.4 x109
- •Absolute lymphocyte count < 1.2 x 109
- •Alanine transaminase (ALT) or aspartate transaminase (AST) > 1.5 x the upper limit of normal (ULN)
- •Lactate Dehydrogenase (LDH) > 1.5 x ULN
- •Total bilirubin level: Out of normal range 0-1.5 mg/dL
- •Estimated glomerular filtration rate (eGFR) < 60 mL/min
- •Haemoglobin (Hgb): out of normal range (male: 13,5-18,0 g/dL).
- •Haemoglobin (Hgb): out of normal range (female: 12,0-16,0 g/dL)
- •Use of an investigational drug within 2 months prior to dosing in this study
- •Any disorder that could interfere with the absorption, distribution, metabolism or excretion of drugs (e.g. small bowel disease, Crohn's disease, celiac disease, or liver disease)
- •Chronic kidney disease (defined as the presence of any degree of proteinuria on urine analysis and/or an eGFR of <60 ml/min using the (Modification of Diet in Renal Disease (MDRD) formula)
- •Psychiatric history of current or past psychosis, bi-polar disorder, major depression, or anxiety disorder requiring chronic medication within the past 5 years
- •History of substance abuse, including alcohol and nicotine or positive urine drug screen at screening visit
- •Any reason or opinion of the investigator that would prevent the subject from participation in the study
- •Inability to follow the instructions or an unwillingness to collaborate during the study
- •Male subjects with female partner of child-bearing potential who are unwilling or unable to adhere to contraception requirements
- •Only for the elderly cohort of the MAD:
- •Chronic daily drug intake during the study period:
- •Benzodiazepines, neuroleptics or major sedatives
- •Antiepileptics
- •Centrally active anti-hypertensive drugs (clonidine, l-methyl-DOPA, guanidine, guanfacine, etc.)
- •Opioid containing analgesics
- •History of cancer within the last 5 years, except basal cell carcinoma, non-squamous skin carcinoma, prostate cancer or carcinoma in situ with no significant progression over the past 2 years
- •Clinically significant, advanced or unstable disease that may interfere with primary or secondary variable evaluations, and which may bias the assessment of the clinical or mental status of the volunteer or put the volunteer at special risk, such as:
- •Chronic liver disease, liver function test abnormalities or other signs of hepatic insufficiency (Alanine-Aminotransferase (ALT), Aspartate-Aminotransferase (AST), Gamma Glutamyl-Transferase (GT), alkaline phosphatase > 2.0 ULN)
- •Respiratory insufficiency
- •Heart disease (myocardial infarction, unstable angina, heart failure, cardiomyopathy within six months before screening)
- •Bradycardia (heartbeat <50/min) or tachycardia (heartbeat >95/min)
- •Hypertension (<180/95) or hypotension requiring treatment with more than 2 drugs
- •Atrioventricular (AV) block (type II / Mobitz II and type III), congenital long QT syndrome, sinus node dysfunction or prolonged QTcF-interval (males >450 and females >470 ms)
- •Uncontrolled diabetes defined by HbA1c >8.5
- •Renal insufficiency (serum creatinine > 2mg/dL) or creatinine clearance ≤ 30 mL/min according to Cockcroft-Gault formula).
研究组 & 干预措施
Placebo
Each subject receives either a single (SAD) or multiple (MAD) dose of REM0046127 as oral solution with a concentration of 0 mg/mL REM0046127. The dose for each cohort is corresponding the amount of solution needed in the verum group.
干预措施: Placebo (Drug)
Study Drug
Each subject receives either a single dose (SAD) or a multiple dose (MAD) of REM0046127 as oral solution with a concentration of 100 mg/mL REM0046127. The starting dose for the first cohort in the SAD is 35mg up to a maximum of 2000mg at cohort 5. The starting dose for the MAD study is 0,75 of the Maximum Tolerated Dose (MTD) from the SAD.
干预措施: REM0046127 (Drug)
结局指标
主要结局
Adverse Events
时间窗: SAD: from dosing to 72 hours after dosing. MAD: from the first dosing until 48 hours after the last dosing on day 7.
Number of Adverse Events either related or not related to treatment in the verum group in comparison to the placebo group
MAD: Plasma Concentration
时间窗: Plasma samples will be taken pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24 hours post-dose, pre-dose on Day 5 and on Day 7: 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24 hours (Day 8) and 48 hours (Day 9).
Peak Plasma Concentration (Cmax) between Baseline and 48 hours after the last dosing.
SAD: Plasma Concentration including Half-Life(t1/2)
时间窗: Plasma samples will be taken during SAD at baseline and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours post-dose.
The plasma concentration during 48 hours after the dosing.
MAD: Half-Life(t1/2) between Baseline and 48 hours after the last dosing.
时间窗: Plasma samples will be taken pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24 hours post-dose, pre-dose on Day 5 and on Day 7: 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24 hours (Day 8) and 48 hours (Day 9).
Half-Life(t1/2) between Baseline and 48 hours after the last dosing.
SAD: Area under the Curve (AUC)
时间窗: Plasma samples will be taken during SAD at baseline and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours post-dose.
The AUC between baseline and 48 hour safter dosing.
MAD: Area under the Curve (AUC)
时间窗: Plasma samples will be taken pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24 hours post-dose, pre-dose on Day 5 and on Day 7: 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24 hours (Day 8) and 48 hours (Day 9).
The AUC and steady-state volume of distribution(Vss) during the time interval from the first dose and 48 hour safterlast dose
Cerebrospinal Fluid (CSF) PK (MAD)
时间窗: CSF samples will be collected on the last day of dosing (Day 7) at approximately Tmax determined during SAD
In CSF the unbound brain/plasma partition coefficient (Kp,u) will be determined.
SAD: Plasma Concentration including Peak Plasma Concentration (Cmax)
时间窗: Plasma samples will be taken during SAD at baseline and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours post-dose.
The plasma concentration during 48 hours after the dosing.
次要结局
未报告次要终点