A Phase 2, Randomised, Placebo Controlled Study to Evaluate the Efficacy, Tolerability and Safety of Metabolic Cofactor Supplementation in Obese Subjects with Non-Alcoholic Fatty Liver Disease (NAFLD)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 32
- 试验地点
- 1
- 主要终点
- Magnetic Resonance Spectroscopy (MRS) Measurement
研究概览
简要总结
This short-term, randomized, placebo-controlled, investigator-initiated trial aims to establish metabolic improvements in NAFLD 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 three different pathways to enhance hepatic β-oxidation and this study's hypothesis is that this will result in decreased amount of fat in the liver.
详细描述
In this study, investigators aim to lower liver fat content in obese patients with NAFLD by increasing the hepatic 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 increase the amount of fat oxidization in liver: (1) First, the investigators will include L-carnitine 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). Carnitine also plays a role in stabilizing coenzyme A (CoA) and acetyl-CoA levels through the ability to receive or give an acetyl group. (2) Second, the investigators will include nicotinamide riboside, precursor of nicotinamide adenine dinucleotide (NAD+) 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. Furthermore, as L-carnitine, nicotinamide
riboside stimulate the transfer of fatty acids from cytosol to mitochondria.(3) Finally, they will include the two glutathione precursors serine and N-acetylcysteine 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 decrease liver fat amount 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 liver fat without significant side effect. Concomitant use of pivotal metabolic cofactors via simultaneous dietary supplementation will stimulate three different pathways to enhance hepatic β-oxidation. The novel design with this study is to give the L-carnitine, NR, serine and NAC as a cocktail. Based on investigators' hypothesis is that this will result in decreased amount of fat in the liver.
The study population will consist of 45 male and female adult overweight and obese subjects diagnosed with NAFLD. Eligible subjects must have signed an informed consent, meet all inclusion criteria and have none of the exclusion criteria. Patients will be randomized on a 2:1 basis to the cofactor mixture or placebo.
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
- Single (Participant)
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Men and women (18-70 years old)
- •Body mass index >27kg/m2
- •Triglyceride levels ≤354 mg/dl and LDL chol ≤175 mg/dl
- •No history of medication use for hepatic steatosis
- •Increased liver fat (>5.5%)
排除标准
- •Inability or unwillingness to give written informed consent
- •Systolic blood pressure >160 mm Hg and/or diastolic blood pressure > 105 mm Hg
- •Type 1 or type 2 diabetes
- •Chronic liver disease other than NAFLD (i.e. chronic infection with hepatitis C virus [HCV] or hepatitis B virus [HBV], autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson s disease, alpha-1 antitrypsin deficiency).
- •Previous gastric or small bowel surgery
- •Active gastric ulcer
- •Inflammatory bowel disease
- •ALT or AST >3× ULN (upper limit of normal)
- •Detection of cirrhosis by transient elastography or other imaging modalities
- •Diarrhea (defined as more than 2 stool per day) within 7 days before enrollment
- •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:
- •Lipid-lowering drugs within 3 months
- •Oral antidiabetics given for insulin resistance of obesity (metformin, liraglutide etc.) within 3 months
- •Thiazide diuretics with a dose >25 mg/d
- •Postmenopausal estrogen therapy
- •Any medication acting on nuclear hormone receptors or inducing Cytochromes P450 (CYPs)
- •Self-administration of dietary supplements such as any vitamins, omega-3 products, or plant stanol/sterol products within 1 month
- •Treatment with medications known to cause fatty liver disease such as atypical neuroleptics, tetracycline, methotrexate or tamoxifen
- •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.)
- •Subjects with Patatin-like phospholipase domain-containing protein 3( PNPLA3) I148M (homozygous for I148M)
- •Women who are pregnant, are planning pregnancy, or who are breast-feeding
- •Women of childbearing potential not protected by effective birth control method
- •Active participation in another clinical study
研究组 & 干预措施
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)
Placebo Arm
Subjects will take a mixture of placebo as powder dissolved in water by mouth.
干预措施: Sorbitol (Drug)
结局指标
主要结局
Magnetic Resonance Spectroscopy (MRS) Measurement
时间窗: 2 weeks, 6 weeks and 10 weeks
The change in liver fat content as well as subcutaneous abdominal and intra-abdominal fat content between the placebo and cofactor treatment arms in NAFLD patients from baseline to 2 weeks, 6 weeks and 10 weeks.
次要结局
- Changes in liver function tests [Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Gamma-glutamyl transferase (GGT), Alkaline phosphatase (ALP)] from baseline(10 weeks)
- Changes in liver function tests (Total Bilirubin, and Albumin) from baseline(10 weeks)
- Changes in creatinine kinase (CK) level from baseline(10 weeks)
- Change in blood insulin level from baseline(10 weeks)
- Change in thyroid-stimulating hormone (TSH) level from baseline(10 weeks)
- Microbiota analysis(2 weeks, 6 weeks and 10 weeks)
- Monitoring of adverse events(10 weeks)
- ECG Measurement(10 weeks)
- Changes in kidney function tests (creatinine, urea, uric acid) from baseline(10 weeks)
- Changes in kidney function tests (sodium, potassium) from baseline(10 weeks)
- Change in body weight from baseline(10 weeks)
- Change in Blood Pressure from baseline(10 weeks)
- Change in waist and hip circumference from baseline(10 weeks)
- Change of complete blood count (number of blood cells) from baseline(10 weeks)
- Changes in blood lipid levels (total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL-C), high density lipoprotein (HDL-C)) from baseline(2 weeks, 6 weeks and 10 weeks)
- Changes in blood glucose levels from baseline(10 weeks)
- Change of complete blood count (hemoglobin) from baseline(10 weeks)