Pathogenesis of Chronic Kidney Disease Associated With Metabolic Dysfunction- Associated Fatty Liver Disease (MAFLD) and Treatment Response of Oral Semaglutide - a Randomized Controlled Trial.
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 入组人数
- 90
- 试验地点
- 1
- 主要终点
- Time to first occurrence of a composite primary outcome event defined as persistent eGFR decline of greater than or equal to 50 percentage from trial start, reaching ESRD, death from kidney disease or death from cardiovascular disease.
研究概览
简要总结
This project aims to investigate how Chronic Kidney Disease (CKD) develops and progresses in patients who also have Non-Alcoholic Fatty Liver Disease (NAFLD) and to evaluate whether oral semaglutide (a GLP-1 receptor agonist) can slow or prevent this progression.
NAFLD and CKD frequently coexist due to shared mechanisms such as insulin resistance, inflammation, oxidative stress, dyslipidemia, and metabolic syndrome. Because of these overlapping pathways, a single therapy targeting both organs may offer major benefits.
Semaglutide is known to reduce liver fat, improve inflammation and fibrosis, promote weight loss, and provide renal protection. This project will test whether adding oral semaglutide to standard care leads to better kidney and liver outcomes than standard care alone.
The study is designed as a randomised controlled trial conducted at ILBS, enrolling adults having NAFLD with CKD (with specific eGFR and albuminuria criteria). Participants will be followed for 2 years, with regular assessment of kidney function (eGFR, ACR), liver health (FibroScan, ALT/AST), metabolic parameters, and cardiovascular outcomes.
A parallel animal study in mice with diet-induced fatty liver disease will validate mechanistic findings through liver and kidney histology, gene expression, metabolic tests, and biochemical markers after semaglutide treatment.
Expected outcome: To demonstrate that semaglutide slows CKD progression and improves NAFLD, supporting its use as a therapeutic option for patients with coexisting both conditions.
详细描述
NAFLD and metabolic syndrome have emerged as significant health concerns globally, with substantial implications for kidney health.The interplay between NAFLD, metabolic syndrome, and CKD necessitates a comprehensive understanding of the underlying mechanisms and shared pathogenic pathways. Their shared risk factors, molecular mechanisms, and genetic predisposition represent the basis for this relationship.
Accordingly, treatment approaches with combined efficacy in NAFLD and chronic renal impairment are expected to positively impact the natural history of this deleterious interaction.
GLP1-R agonists GLP1-R agonists (GLP1-RAs) are novel potent antidiabetic agents with proven efficacy in reducing major adverse cardiovascular events. Besides their glucose-lowering action, their beneficial hepatic effects may be related to the influence on the AMPK/mTOR pathway. Semaglutide was associated with significant decreases in body weight, alanine aminotransferase, liver steatosis, and stiffness.GLP1-RAs may also improve histologic features on NAFLD, such as liver fat deposition, steatohepatitis, and fibrosis. GLP1-RAs have shown benefits in preventing the development or halting the progression of CKD. It also promotes antioxidative and anti-inflammatory actions may be among the determining factors in this renoprotective effect, together with weight loss, blood pressure, and glucose-lowering.
Primary objective-To measure the progression of CKD and NAFLD in Semaglutide treated group versus non treated group.
Secondary objectives-1.To conduct animal model studies to confirm the primary objective by performing the liver and renal histology.
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
- Double (Participant, Investigator)
盲法说明
Double blind
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
- •1.Age above or equal to 18 years at the time of signing informed consent. 2.Diagnosed with type 2 diabetes mellitus 3.HbA1c less than or equal to 10% (less than or equal to 86 mmol/mol) 4.Renal impairment defined either by:
- •serum creatinine-based eGFR greater than or equal to 50 and less than or equal to 75 mL/min/1.73 m^2 (CKD-EPI) and UACR greater than 300 and less than 5000 mg/g or
- •serum creatinine-based eGFR greater than or equal to 25 and less than 50 mL/min/1.73 m^2 (CKD-EPI) and UACR greater than 100 and less than 5000 mg/g 5.Treatment with maximum labelled or tolerated dose of a reninangiotensin-aldosterone system (RAAS) blocking agent including an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB), unless such treatment is contraindicated or not tolerated. Treatment dose must be stable for at least 4 weeks prior to the date of the laboratory assessments used for determination of the inclusion criteria for renal impairment and kept stable until screening.
排除标准
- •Documented causes of chronic liver disease other than non-alcoholic fatty liver disease (NAFLD)
- •Positive HBsAg, positive anti-HIV, positive HCV RNA at screening (V2A) or any known presence of HCV RNA or HBsAg within 2 years of screening (V2A).
- •Presence or history of ascites, variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis or liver transplantation at randomisation.
- •Known or suspected excessive consumption of alcohol (greater than 20 g/day for women or greater than 30 g/day for men) or alcohol dependence (assessed by the Alcohol Use Disorders Identification Test (AUDIT questionnaire)).
- •Treatment with vitamin E (at doses greater than or equal to 800 IU/day) or pioglitazone or medications approved for treatment of NASH which has not been at a stable dose in the period from 90 days prior to the screening visit (V2A). In addition, for subjects with historical liver biopsies taken more than 90 days prior to screening, treatment should be at a stable dose from time of biopsy until screening.
- •Treatment with GLP-1 RAs in the period from 90 days prior to the screening visit (V2A). In addition, for subjects with historical liver biopsies taken more than 90 days prior to screening, any treatment with GLP-1 RAs from time of biopsy until screening (V2A).
- •Treatment with glucose-lowering agent(s) (other than GLP-1 RAs), lipid-lowering medication or weight loss medication not stable in the opinion of the investigator in the period from 90 days prior to the screening visit (V2A). In addition, for subjects with historical liver biopsies taken more than 90 days prior to screening, treatment should be at a stable dose in the opinion of the investigator from time of biopsy until screening.
- •Congenital or hereditary kidney diseases including polycystic kidney disease, autoimmune kidney diseases including glomerulonephritis or congenital urinary tract malformations
- •Myocardial infarction, stroke, hospitalisation for unstable angina pectoris or transient ischaemic attack within 60 days prior to the day of screening.
- •Presently classified as being in New York Heart Association (NYHA) Class IV heart failure
- •Planned coronary, carotid or peripheral artery revascularisation
- •Current (or within 90 days) chronic or intermittent haemodialysis or peritoneal dialysis 13 Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a fundus examination performed within the past 90 days prior to screening or in the period between screening and randomisation. Pharmacological pupildilation is a requirement unless using a digital fundus photography camera specified for non-dilated examination.
研究组 & 干预措施
Standard Medical Treatment (SMT)
Control arm : Participants in this arm will receive Placebo with Standard Medical Treatment (SMT).
干预措施: Placebo (Other)
Standard Medical Treatment (SMT)
Control arm : Participants in this arm will receive Placebo with Standard Medical Treatment (SMT).
干预措施: Standard medical treatment (Other)
Semaglutide with Standard Medical Treatment
Semaglutide with Standard Medical Treatment: Participants in this arm will receive Standard medical treatment and oral semaglutide starting from 3mg dose daily that gradually increases upto 14mg dose daily for 6 months.
干预措施: Semaglutide Oral Tablet (Drug)
Semaglutide with Standard Medical Treatment
Semaglutide with Standard Medical Treatment: Participants in this arm will receive Standard medical treatment and oral semaglutide starting from 3mg dose daily that gradually increases upto 14mg dose daily for 6 months.
干预措施: Standard medical treatment (Other)
结局指标
主要结局
Time to first occurrence of a composite primary outcome event defined as persistent eGFR decline of greater than or equal to 50 percentage from trial start, reaching ESRD, death from kidney disease or death from cardiovascular disease.
时间窗: 3 months, 6 months, 12 months,18 months and 24 months
次要结局
- Annual rate of change in eGFR (chronic kidney disease - epidemiology collaboration (CKD-EPI))(3 months, 6 months, 12 months,18 months and 24 months)
- ime to first occurrence of a composite cardiovascular major adverse cardiovascular event (MACE) endpoint consisting of: Non-fatal myocardial infarction, non-fatal stroke, and cardiovascular (CV) death(3 months, 6 months, 12 months,18 months and 24 months)
- Time to occurrence of all-cause death(3 months, 6 months, 12 months,18 months and 24 months)
- Change in eGFR and proteinuria.(3 months, 6 months, 12 months,18 months and 24 months)
- Annual rate of change in eGFR (CKD-EPI) (chronic eGFR slope)(3 months, 6 months, 12 months,18 months and 24 months)
- Change in eGFR (CKD-EPI) and cystatin C(3 months, 6 months, 12 months,18 months and 24 months)
- Change in albumin creatinine ratio(ACR)(3 months, 6 months, 12 months,18 months and 24 months)
- Change in bodyweight(3 months, 6 months, 12 months,18 months and 24 months)
- Change in HBA1c(3 months, 6 months, 12 months,18 months and 24 months)
- Change in Systolic and diastolic BP(3 months, 6 months, 12 months,18 months and 24 months)
- Number of hypoglycemic episodes(3 months, 6 months, 12 months,18 months and 24 months)
- Changes in the liver histology in the animal model as assessed by Alpha-SMA, Col-1.(4,8,16,24 weeks)
- Changes in the liver histology in the animal model as assessed by SGOT/SGPT.(4,8,16,24 weeks)
- Changes in the renal histology in the animal model as assessed by UPCR,GFR,Creatinine clearance.(4,8,16,24 weeks)
- Changes in the renal histology in the animal model as assessed by FITC-Sinistrin Clearance,cystatin-C.(4,8,16,24 weeks)
- Resolution of steatohepatitis and improvement in liver fibrosis (Yes/No)(3 months, 6 months, 12 months,18 months and 24 months)
- Changes in liver stiffness values assessed by transient elastography (FibroScan®)(3 months, 6 months, 12 months,18 months and 24 months)
- Change in ELF (Enhanced Liver Fibrosis) score(3 months, 6 months, 12 months,18 months and 24 months)
- Change in ALT/AST(3 months, 6 months, 12 months,18 months and 24 months)
- Change in CAP (Controlled Attenuation Parameter) values assessed by transient elastography (FibroScan)(3 months, 6 months, 12 months,18 months and 24 months)
- Change in FAST (FibroScan-AST) score(3 months, 6 months, 12 months,18 months and 24 months)
- Change in inflammation assessed by hsCRP (High Sensitive C-Reactive Protein)(3 months, 6 months, 12 months,18 months and 24 months)
- Change in triglyceride/LDL(3 months, 6 months, 12 months,18 months and 24 months)