A Phase 2, Randomized, Placebo Controlled Study to Evaluate the Efficacy, Tolerability and Safety of Metabolic Cofactor Supplementation in Alzheimer's Disease (AD) And Parkinson's Disease (PD) Patients
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 120
- 试验地点
- 2
- 主要终点
- Mini Mental State Examination (MMSE)
研究概览
简要总结
This double-blind, randomized, placebo-controlled, investigator-initiated, multi-centre trial aims to establish metabolic improvements in AD and PD subjects by dietary supplementation with cofactors N-acetylcysteine, L-carnitine tartrate, nicotinamide riboside and serine. Concomitant use of pivotal metabolic cofactors via simultaneous dietary supplementation will stimulate to enhance hepatic β-oxidation and this study's hypothesis is that this will result in increased mitochondrial activity in human brain cell-types.
详细描述
In this study, investigators aim to activate mitochondria of brain cell-types in AD and PD patients by increasing the hepatic, plasma and brain levels of pivotal metabolic cofactors via simultaneous dietary supplementation of serine, L-carnitine, N-acetylcysteine (NAC) and nicotinamide riboside (NR).
The study is based on a three-step strategy to activate the mitochondria in human brain cells: (1) The investigators will use L-carnitine tartrate to enhance the transport of fatty acids across the mitochondrial membrane (by forming a long chain acetylcarnitine ester and being transported by carnitine palmitoyltransferase [CPT] I and CPT II) and to stabilize acetyl-CoA and coenzyme A levels. (2) Nicotinamide riboside, precursor of NAD+ will be included to boost the level of hepatic β-oxidation of fatty acids in mitochondria. Decreased electron transport chain function combined with impaired rates of fatty acid β-oxidation leads to the accumulation of incomplete products of β-oxidation, which combined with increased levels of reactive oxygen species (ROS), contribute to insulin resistance. Nicotinamide riboside stimulates the transfer of fatty acids from cytosol to mitochondria, similar to L-carnitine tartrate. (3) Two glutathione precursors, serine and N-acetylcysteine, will be included to increase glutathione levels in the hepatocytes. Increased glutathione levels will also protect against free radical-mediated oxidative stress generated by the increased β-oxidation of fatty acids in mitochondria.
Previous studies showed that each agent is able to activate mitochondria separately and a proof-of-concept study using serine supplementation, and a phase I study using this three-step approach resulted in a significant decrease in plasma metabolites associated with mitochondrial dysfunction without significant side effect. The novel design with this study is to give the L-carnitine, NR, serine and NAC as a cocktail. Based on investigators' earlier results, that this will improve the efficacy of the intervention.
The study population will consist of 60 Alzheimer's and 60 Parkinson's disease patients. Eligible subjects must have signed an informed consent, meet all inclusion criteria and have none of the exclusion criteria listed below. Patients will be randomized on a 2:1 basis to the cofactor mixture or placebo in two different centres.
The subjects will take a mixture of cofactors or matching placebo as powder dissolved in water by mouth. Subjects in active treatment will receive dietary supplementation with N-acetylcysteine, L-carnitine tartrate, nicotinamide riboside, and serine, administered as a mixture. Half dosage of the co-factors will be given for two weeks (one dose taken just after dinner), and full dosage for 8 weeks (two equal doses taken just after breakfast and dinner). Patients who cannot tolerate taking full dose may continue the study with half dose (i.e. one dose taken just after dinner). Patients who cannot tolerate the study agents will be withdrawn from the study.
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
- •Men and women diagnosed with Parkinson's Disease (Hoehn Yahr 2-4, age >18 years) or men and women diagnosed with Alzheimer's Disease. Include patients older than 50 years with mild to moderate Alzheimer's disease according to ADAS-cog (Alzheimer's Disease Assessment Scale-cognitive subscale; ADAS≥12) and the Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB; CDR≤2).
- •Patients with stable treatments and clinical course
排除标准
- •Inability or unwillingness to give written informed consent
- •History of stroke, severe brain trauma, toxic drug exposure
- •Neurological examination which indicate to Parkinson-Plus syndrome (i.e., pyramidal, cerebellar and autonomic dysfunction findings and gaze paralysis) for PD
- •Uncontrolled Type 1 or type 2 diabetes
- •Diarrhea (defined as more than 2 stool per day) within 7 days before enrolment
- •Chronic kidney disease with an estimated glomerular filtration rate <60 ml/min/1.73m2
- •Significant cardiovascular co-morbidity (i.e. heart failure, documented coronary artery disease, valvular heart disease)
- •Patients with active bronchial asthma
- •Patients with phenylketonuria (contraindicated for NAC)
- •Patients with histamine intolerance
- •Clinically significant TSH level outside the normal range (0.04-6 mU/L)
- •Known allergy for substances used in the study
- •Concomitant medication use: Self-administration of dietary supplements such as any vitamins, omega-3 products, or plant stanol/sterol products within 1 month; Use of an antimicrobial agent in the 4 weeks preceding randomization
- •Active smokers consuming >10 cigarettes/day
- •Alcohol consumption over 192 grams for men and 128 grams for women per week
- •Patients considered as inappropriate for this study for any reason (patients unable to undergo MRI study, noncompliance etc.)
- •Active participation in another clinical study
研究组 & 干预措施
Placebo Arm
Subjects will take a mixture of placebo as powder dissolved in water by mouth.
干预措施: Sorbitol (Drug)
Treatment Arm
Subjects in active treatment will receive dietary supplementation with N-acetylcysteine, L-carnitine tartrate, nicotinamide riboside, and serine, administered as a mixture.
干预措施: Metabolic Cofactor Supplementation (Drug)
结局指标
主要结局
Mini Mental State Examination (MMSE)
时间窗: 4 weeks and 12 weeks
The change in Mini Mental State Examination (MMSE) scores between the placebo and the treatment arms in AD patient from baseline to 4 weeks and 12 weeks. MMSE is global cognitive evaluation scale for AD patients. It consists of eleven questions and is evaluated over 30 points. It is normal between 24-30 points.
Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog)
时间窗: 4 weeks and 12 weeks
The change in Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) scores between the placebo and the treatment arms in AD patients from baseline to 4 weeks and 12 weeks. ADAS-cog is cognitive evaluation scale for AD patients. ADAS-Cog includes 11 tasks that include both subject-completed tests and observer-based assessments. Together these tasks assess the cognitive domains of memory, language, and praxis. The ADAS-cog is scored between 0-70 and high scores indicate poor status.
Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL)
时间窗: 4 weeks and 12 weeks
The change in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scores between the placebo and the treatment arms in AD patients from baseline to 4 weeks and 12 weeks. ADCS-ADL is daily life activity evaluation scale for AD patients. This is a questionnaire structured to evaluate functional capacity in AD patients. It is scored between 0-78 and low scores indicate addiction. It is applied to the patient's relatives.
Unified Parkinson's Disease Rating Scale (UPDRS)
时间窗: 4 weeks and 12 weeks
The change in Unified Parkinson's Disease Rating Scale (UPDRS) scores between the placebo and the treatment arms in PD patients from baseline to 4 weeks and 12 weeks. UPDRS is motor evaluation scale for PD patients. The UPDRS is used to follow the longitudinal course of Parkinson's disease. UPDRS has four parts: Part I (non-motor experiences of daily living), Part II (motor experiences of daily living, Part III (motor examination) and Part IV (motor complications). The first part 4, the second part 13, the third part 14 and the fourth part consists of 11 items. Each item scored between 0 (none) and 4 (heaviest). A score of 147 on the UPDRS scale represents the worst (total disability) with a score of zero representing (no disability).
次要结局
- Monitoring of adverse events(1 week, 4 weeks and 12 weeks)
- Change in heart rate from baseline(1 week, 4 weeks and 12 weeks)
- Change in waist and hip circumference from baseline(1 week, 4 weeks and 12 weeks)
- Volumetric Magnetic resonance Imaging (MRI) and resting state functional magnetic resonance imaging (rest-fMRI)(12 weeks)
- Neuropsychiatric Inventory (NPI)(4 weeks and 12 weeks)
- Changes in serum omic profile from baseline(4 weeks and 12 weeks)
- Montreal Cognitive Assessment (MoCA)(4 weeks and 12 weeks)
- Microbiota analysis(4 weeks and 12 weeks)
- Change in blood pressure from baseline(1 week, 4 weeks and 12 weeks)
- Change in body weight from baseline(1 week, 4 weeks and 12 weeks)
- Change of complete blood count from baseline(4 weeks and 12 weeks)
- Changes in liver function tests (alkaline phosphatase (ALP), alanine aminotransferase (ALT), Aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), total and direct Bilirubin, Albumin) from baseline(4 weeks and 12 weeks)
- Changes in blood lipid levels (total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL-C), high density lipoprotein (HDL-C)) from baseline(4 weeks and 12 weeks)
- Changes in kidney function tests (creatinine, urea, urate, sodium, potassium) from baseline(4 weeks and 12 weeks)
- Changes in creatinine kinase (CK) level from baseline(4 weeks and 12 weeks)
- Change in thyroid-stimulating hormone (TSH) level from baseline(4 weeks and 12 weeks)
- Change in blood insulin level from baseline(4 weeks and 12 weeks)
- Change in glycated haemoglobin (HbA1c) level from baseline(4 weeks and 12 weeks)
- Changes in blood glucose levels from baseline(4 weeks and 12 weeks)
研究者
Prof. Lutfu Hanoglu, MD
Professor
Istanbul Medipol University Hospital