Nicotinamide Adenine Dinucleotide Augmentation to Prevent or Reverse the Progression of Alzheimer's Disease in People With Down Syndrome
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 24
- 试验地点
- 4
- 主要终点
- Treatment emergent adverse events
研究概览
简要总结
The aim of the study is to determine the safety and tolerability of different increasing doses of MIB-626 (a microcrystalline form of β nicotinamide mononucleotide; NMN) given daily for 28 consecutive days to adults with Down syndrome (DS). The study will also explore how the drug moves through the body over time (pharmacokinetics or PK) and how the drug affects the body in different ways (pharmacodynamics or PD). The study participants will be monitored for adverse events and measurements to detect safety events will take place including laboratory tests of blood counts, chemistries and coagulation profile, and electrocardiogram (ECG). The trial will enroll a total of 24 adults with DS who are 18 years or older and are medically stable. People enrolled in the study will be randomly assigned to receive either the active intervention (MIB-626) tablets, or placebo tablets for 28 days. Study participants will be followed for an additional 28 days (total 56 days of follow-up). This study will also explore the effect of MIB-626 on different measures associated with aging and risk of Alzheimer's Disease (AD).
详细描述
Specific Aims / Objectives Primary Aim To determine the safety and tolerability of multiple ascending doses of MIB-626 administered daily for 28 consecutive days in adults with DS by structured monitoring of adverse events and the measurement of safety laboratory tests including blood counts and chemistries, coagulation profile, and ECG.
Secondary Aims
- To study the PK of oral, multiple ascending doses of MIB-626 in adults with DS starting with the 500 mg daily dose and escalating the dose in ascending order to the maximum dose of 1000 mg twice daily or a maximal tolerated dose if that is lower than 1000 mg twice daily dose. PK parameters (Caverage 0-24 h, Cmax, Tmax, AUClast, AUC24hr, AUCinf, and T1/2) will be computed using nonparametric methods.
- To characterize the pharmacodynamics (PD) of MIB-626 by analyzing the blood concentrations of NAD+ and plasma concentrations of NAD+ metabolites (nicotinamide, 1-methylnicotinamide, N-Methyl-2-pyridone-5-carboxamide [2-PY], N-Methyl-4-pyridone-3-carboxamide [4-PY], nicotinic acid, and nicotinuric acid). The concentrations in urine of NAD+ metabolites will also be measured. The investigators will determine whether oral MIB-626 increases the abundance of NAD+ in the brain, measured by ultra-high field 7T magnetic resonance spectroscopy (MRS).
Exploratory Aims This trial is neither long enough nor large enough to determine the effects of MIB-626 on Alzheimer's Disease (AD) imaging or plasma biomarkers, or neuropsychological outcomes. However, the investigators have included some clinically important exploratory outcomes: (1) blood pressure and lipids that were improved in earlier human studies with MIB-626, and which may independently affect morbidity, and mortality; (2) muscle performance and physical function because people with DS often experience physical limitations, and MIB-626 improves mitochondrial function and running distance in mice, and improves muscle fatigability in humans.
The trial will provide important information on the safety, PK, PD, and engagement of target mechanisms that is necessary for guiding the stepwise progression of this promising molecule towards larger efficacy trials.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •A diagnosis of full trisomy for chromosome 21 or complete unbalanced translocation of chromosome 21, confirmed by karyotype analysis or clinical documentation.
- •18 years or older
- •Participant has a caregiver/ informant who has direct contact with the participant >10 hours/ week and who can provide information about participant's health
- •Participant or Legal Authorized Representative is able to understand and willing to provide written informed consent and capable of completing study assessments.
- •In addition, female participants must Not be pregnant and not planning to become pregnant over the next 6 months.
排除标准
- •Fasting morning UACR > 5,000 mg/ g creatinine
- •Other laboratory abnormalities:
- •Has AST or ALT > 3 times the upper limit of normal
- •eGFR < 30 mL/ min / 1.73 m2
- •Hematocrit < 0.34 or > 0.50 L/L
- •A major adverse cardiovascular event in preceding 3 months
- •Participation in an investigational trial to evaluate pharmaceuticals or biologics within the past 3 months or 5 half-lives, whichever is shorter
- •Current alcohol or substance use disorder or dependence (DSM 5 criteria).
- •Major depressive disorder, bipolar disorder, schizophrenia, or current psychotic symptoms or behavioral problems that could interfere with study procedures.
- •An acute illness, including COVID-19, requiring hospitalization within the past 3 months or any acute illness, including COVID-19, within the past month.
- •Has a history of anaphylaxis from vitamin B3 derivatives
- •BMI > 42.5 kg/ m2
- •Non-ambulatory
研究组 & 干预措施
Safety and pharmacokinetic ascending dose intervention group
MIB-626 tablets will be provided at dose strength of 500mg. Three doses will be studied in ascending order: 500 mg (one tablet) once daily; 1000 mg (two 500 mg tablets once daily) or 1000 mg (two 500 mg tablets) twice daily.
干预措施: MIB-626 (Drug)
Placebo tablets
Matching placebo tablets (number and frequency of tablets will match the active intervention group at each of the three doses)
干预措施: Placebo (Drug)
结局指标
主要结局
Treatment emergent adverse events
时间窗: Baseline to 56 days after drug administration
All treatment emergent adverse events
Treatment emergent serious adverse events
时间窗: Baseline to 56 days after drug administration
All treatment emergent serious adverse events
次要结局
- Pharmacokinetics of NMN(Baseline to 56 days)
- Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)(Change from baseline to 28 days)
- Change in biomarkers of aging: Insulin Growth Factor 1 (IGF-1)(Baseline to 28 days)
- Pharmacodynamics - steady state concentration of NAD+ in the brain(Baseline and Day 28)
- Pharmacodynamics - Blood NAD+ level(Baseline to Day 56)
- Pharmacodynamics - Plasma concentrations of NAD+ metabolites(Pre-dose up to Day 28)
- Urine concentration of NAD+(Day 1 and Day 28)
- Blood pressure(Baseline to Day 56)
- Hemoglobin A1c (HbA1c)(Change from baseline to 28 days)
- Fasting glucose and insulin(Baseline to 28 days)
- Change in biomarkers of aging: Tumor necrosis factor-alpha (TNF-alpha)(Baseline to 28 days)
- Change in biomarkers of aging: F2-isoprostanes (F2-IsoPs)(Baseline to 28 days)
- Change in biomarkers of aging: Triiodothyronine (T3)(Baseline to 28 days)
研究者
Shalendar Bhasin, MD
Principal Investigator
Brigham and Women's Hospital