A Phase 1, Single Ascending Dose Administration of MIB-725 to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics in Community Dwelling Healthy Adults
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 32
- 试验地点
- 1
- 主要终点
- Treatment-emergent adverse events
研究概览
简要总结
This is a single center, open label (i.e. participants and study staff will not be masked to the intervention) single ascending dose study to evaluate the safety, tolerability, pharmaokinetics and pharmacodynamics of MIB-725 in community dwelling, healthy adults. Up to 4 successive groups (cohorts) of 8 subjects each will be enrolled in this trial.
This study will determine the safety and tolerability of orally administered single ascending (increasing) doses (100, 200, 400, and 800 mg) of MIB-725 in healthy adults. The safety will be assessed by evaluating physical examination that includes an external eye examination, vital signs, adverse events, and changes in blood counts, EKG, urinalysis, coagulation measures, and blood chemistries, including but not limited to blood glucose, electrolytes, creatinine, liver function tests, uric acid, and creatine kinase.
详细描述
Nicotinamide adenine dinucleotide (NAD), a critically important cofactor for the functioning of all living cells, is required for the enzymatic processes that generate energy within the cell, through ATP production during glycolysis, the Krebs cycle, and oxidative phosphorylation (1-3). NAD+ also serves as a co- factor for enzymes, such as the sirtuin and PARP families of enzymes, that modify proteins regulating gene expression, and are involved in DNA repair, inflammation, and innate immune response. Reduced levels of NAD+ are associated with age-related diseases, including metabolic disorders, cancer, and neurodegenerative diseases. Therefore, there is enormous interest in developing therapeutic strategies to raise cellular NAD+ levels with the goal of preventing and treating age-related conditions and diseases in which NAD+ is depleted.
MIB-725 is a modified precursor in the NAD+ biosynthetic pathway. After its oral administration, MIB-725 undergoes biotransformation to produce NAD+. Metro International Biotech is developing this compound for the prevention and treatment of age-related diseases with specific initial focus on the prevention of acute kidney injury (AKI) in at-risk adults who are undergoing coronary artery bypass surgery. Towards this long- term goal, the proposed Phase 1 trial will determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple ascending doses of MIB-725.
This is Phase 1 study of a two part study that will have a separate submission. The first part is an SAD study in which 100, 200, 400, or 800 mg of MIB-725 will be administered as a single oral dose in ascending order starting with the lowest (100 mg) dose. The selection of these doses was informed by the toxicology and pharmacology studies in rats and Beagle dogs. Four groups of participants will be studied. The first group of 8 participants will receive a single dose of 100 mg of MIB-725 orally. If no dose limiting toxicity is observed at this dose, the second cohort (n=8) will receive a single dose of 200 mg MIB-725; the third cohort (n=8) will receive a single dose of 400 mg MIB-725; and the fourth cohort (n=8) will receive a single dose of 800 mg MIB-725. The dose escalation to the next level will be based on the review of the safety data at the lower dose and guided by the pre-specified dose escalation criteria.
The SAD Part 1 will enable the selection of the range of doses and dosing frequencies that can be administered safely in subsequent multiple ascending dose (MAD).
Specific Aims and Objectives Primary Objectives To determine the safety and tolerability of orally administered single ascending doses (100, 200, 400, and 800 mg) of MIB-725 in healthy adults. The safety will be assessed by evaluating physical examination that includes an external eye examination, vital signs, adverse events, and changes in blood counts, EKG, urinalysis, coagulation measures, and blood chemistries, including but not limited to blood glucose, electrolytes, creatinine, liver function tests (ALT, AST, bilirubin, alkaline phosphatase), uric acid, and creatine kinase.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
盲法说明
Because this is a phase one ascending dose study, masking is not possible.
入排标准
- 年龄范围
- 19 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Is a non-smoking healthy adult, 19 to 60 years of age, inclusive
- •Has a body mass index (BMI) between 19 and 37.5 kg/m2, inclusive
- •Is free from clinically significant medical problems as determined by the Investigator
- •Is able and willing to provide written informed consent.
- •Is able and willing to provide authorization for the use and disclosure of personal health information in accordance with the Health Insurance Portability and Accountability Act (HIPAA).
排除标准
- •Is a current cigarette smoker
- •AST or ALT > 1.5 times the upper limit of normal
- •Hematocrit < 37% or > 51%
- •Diagnosis of diabetes mellitus, as indicated by use of diabetes medication, hemoglobin A1C > 6.4% or fasting glucose ≥126 mg/dL
- •Serum creatinine > 2.0 mg/dL
- •Current use of barbiturates, benzodiazepines, opiates, amphetamine, cannabinoids and cocaine
- •Known allergy to niacin or nicotinamide mononucleotide
- •Unwilling to refrain from drinking alcohol during the duration of the study
- •Use of any other dietary supplement during the course of the trial
- •Use of anabolic steroids, rhGH, DHEA, androstenedione, or any other performance enhancing drug
- •In the judgment of the study physician, the participant is unlikely to comply with the study protocol for any reason or it may not be safe to administer the study medication
- •Has a history of myocardial infarction, stroke, or heart failure in the preceding 6 months.
- •Has a history of cancer other than nonmelanotic skin cancer requiring treatment in the previous 2 years.
- •Has other medical conditions which, in the opinion of the Principal Investigator, would jeopardize the safety of the study subject or impact the validity of the study results.
- •In addition, female participants must:
- •Be postmenopausal as indicated by cessation of menstruation at least one year before screening
- •Not be pregnant and not planning to become pregnant over the next 6 months
- •Prohibited medications and substances:
- •Current use of barbiturates, benzodiazepines, opiates, amphetamine, cannabinoids and cocaine
- •Use of any other dietary supplement during the course of the trial. Subjects who are using a supplement containing nicotinamide, niacin, nicotinamide mononucleotide, or nicotinamide riboside may be included if they agree to stop the supplement at least 2 weeks prior to day 0 and during the entire duration of the study.
- •Initiation of a new prescription drug during the preceding 4 weeks or during the course of the study
- •Use of anabolic steroids, rhGH, DHEA, androstenedione, or any other performance enhancing drug
研究组 & 干预措施
Safety and pharmacokinetic single dose ascending dose study
This is a single dose ascending study in which 100, 200, 400, or 800 mg of MIB-725 will be administered as a single oral dose in ascending order starting with the lowest (100 mg) dose
干预措施: MIB-725 (Drug)
结局指标
主要结局
Treatment-emergent adverse events
时间窗: Baseline to 28 days
Any treatment-emergent adverse events, including any ocular adverse events
Treatment-emergent serious adverse events
时间窗: Baseline to 28 days
Treatment-emergent serious adverse events, including any severe or serious ocular adverse events
次要结局
- Presence of conjunctival injection(Baseline to 28 days)
- Pharmacodynamics - blood concentrations of NAD+ levels over time(Baseline to 28 days)
- Pharmacodynamics - plasma concentrations of NAD+ metabolite,1-methylnicotinamide over time(Baseline to 28 days)
- Pharmacodynamics- plasma concentrations of NAD+ metabolites, 2PY, over time(Baseline to 28 days)
- Blood chemistry - Change in creatinine(Baseline to 28 days)
- Blood chemistry - Change in alanine aminotransferase (ALT)(Baseline to 28 days)
- Blood chemistry - Change in asparate aminotransferase (AST)(Baseline to 28 days)
- Change in heart rate(Baseline to 28 days)
- Change in blood pressure(Baseline to 28 days)
- Change in QTc interval(Baseline to 28 days)
- Pharmacokinetics(Baseline to 28 days)
- Change in blood concentration of nicotinic acid mononucleotide (NAMN)(Baseline to 28 days)
- Change in hemoglobin(Baseline to 28 days)
- Change in white blood cell count(Baseline to 28 days)
研究者
Shalender Bhasin
Principal Investigator
Brigham and Women's Hospital