Effects of Fenofibrate Administration in Patients With Diabetic Nephropathy
试验速览
- 阶段
- 3 期
- 入组人数
- 300
- 试验地点
- 1
- 主要终点
- Serum concentration of isoleucine following 30 days of fenofibrate treatment
研究概览
简要总结
Diabetic nephropathy (DN) is a common cause of end-stage renal disease (ESRD) and accounts for nearly half of all new patients starting dialysis in Singapore, the country with the highest rates of DN in the Asia-Pacific region. Despite the scale of the problem, little progress has been made in our understanding of the pathogenesis of the disorder and no new therapies have been offered.
The investigators have conducted a metabolomics study of human diabetic nephropathy that revealed evidence for alterations in mitochondrial fuel metabolism in patients with the disease, a finding also reported in other recent studies of human DN. Based on this finding the investigators believe that dysregulated mitochondrial fuel oxidation is a major driver of diabetic nephropathy.
Fenofibrate is an agonist of peroxisome-proliferator activating receptor (ppar)-alpha that is approved for the treatment of hypercholesterolaemia and hypertriglyceridemia alone or combined in patients unresponsive to dietary and other non-drug therapeutic measures. Fenofibrate is also indicated for the reduction in the progression of diabetic retinopathy in patients with type 2 diabetes and existing diabetic retinopathy. Presently fenofibrate is not indicated for the treatment of diabetic nephropathy.
The investigators hypothesize that treatment with fenofibrate, taken orally at 300mg per day or 100mg per day for 30 days will lead to significant changes in the circulating metabolomics patterns in patients with DN. The investigators propose to administer the drug for a period of 30 days and will perform a comprehensive analysis of the state of fuel metabolism in these patients before, and after the administration of fenofibrate using targeted metabolomics and other approaches. Fundal photography, Optical Coherence Tomography (OCT) and Optical Coherence Tomography Angiography (OCTA) will also be performed at baseline and post-treatment. A total of 300 subjects will be recruited from Singapore General Hospital (SGH) Diabetes and Metabolic Centre. Our goal is to discover key changes in fuel metabolism in DN patients receiving fenofibrate.
详细描述
In this single-centre, open label study, 300 adults with DN will be recruited over 3 years. Following screening and baseline metabolic evaluations, eligible subjects will be treated with fenofibrate for 30-days and re-assessed.
4.1 Study Visits and Procedures Subjects will have their written informed consent taken during Visit 1 at the SGH Clinical Trials Research Centre (CTRC) and undergo screening and baseline assessments. Eligible subjects will return within the next 14 days for the initiation of study drug (Visit 2). The post-treatment and final visit (Visit 3) will take place 30 ± 7 days after Visit 2. Details of study visits are described in Table 1 (Refer study protocol).
4.1.1 VISIT 1: Informed Consent and Screening Interested patients will be scheduled for their first study visit (Visit 1) at SGH CTRC. Written informed consent will be taken by the principal or co-investigators assigned by the PI. After consent has been taken, study procedures in Table 1 will be performed. Subject will be given a sample copy of the treatment diary to familiarize them with the method to record study drug intake.
At the end of Visit 1, subjects will head over to Singapore Eye Research Institution (SERI) or Singapore National Eye Centre (SNEC)) for eye tests as mentioned in the following paragraphs.
Fundus Photography, conventional OCT and Assessment and grading of diabetic retinopathy (DR). The presence and severity of Diabetic Retinopathy (DR) or Diabetic Macular Edema (DME) will be assessed from digital fundus photographs and OCT. Following pupillary dilation, 7-field ETDRS photography using a non-mydriatic 45º fundus cameras will be obtained for each eye. The modified Wisconsin protocol will be used for DR grading. DR will be considered present if any characteristic lesion as defined by the ETDRS severity scale is present: microaneurysms (MA), hemorrhages, cotton wool spots, intraretinal microvascular abnormalities (IRMA), hard exudates (HE), venous beading, and new vessels. For each eye, a retinopathy severity score will be assigned according to a scale modified from the Airlie House classification system. Macular edema is defined by hard exudates in the presence of MA and blot hemorrhage within 1 disc diameter from the foveal center or presence of focal photocoagulation scars in the macular area. Clinically significant macular edema (CSME) is considered present when the macular edema involved is within 500 mm of the foveal center or if focal photocoagulation scars are present in the macular area. DR is categorized as minimal non-proliferative DR (level 20), mild non-proliferative DR (level 35), moderate non-proliferative DR (level 43 through 47), severe Non-proliferative Diabetic Retinopathy (NPDR) (level 53), and proliferative retinopathy (>60). Vision-threatening retinopathy is defined as the presence of severe NPDR, Proliferative Diabetic Retinopathy (PDR), or CSME. Presence of DME (centre involving and non centre involving) and central retinal thickness will also be assessed on OCT.
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
入排标准
- 年龄范围
- 21 Years 至 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Man or woman between 21 and 100 years of age
- •Type 2 diabetes mellitus Increased urine protein excretion as defined as:
- •More than one measurement in the past 1-year with urine microalbumin/creatinine ratio (ACR) > 3.3 mg/mmol creatinine, or urine total protein/creatinine ratio (PCR) > 0.2 g/urine creatinine, or creatinine clearance between 30-60 ml/min
- •More than one measurement in the past 1-year with urine microalbumin/creatinine ratio (ACR) > 3.3 mg/mmol creatinine or urine total protein/creatinine ratio (PCR) > 0.2 g/urine creatinine
- •Known diabetes duration > 3 months
- •HbA1c < 9%(within 3 months prior to enrolment)
- •No change in dose of diabetes medications by more than two-fold or new agents added within the previous 3 months
- •No change in dose of lipid-lowering medications by more than two-fold or new agents added within the previous 3 months
- •Capable of providing informed consent
- •Exclusion Criteria
- •Type 1 diabetes mellitus
- •Known intolerance or allergic to statins
- •Known intolerance or allergic to fenofibrate
- •Known intolerance or allergic to peanut oil or soybean lecithin or related products
- •Concurrent use of fibrates
- •Concurrent use Colchicine
- •Concurrent use Nicotinic Acid
- •Concurrent use Cyclosporine
- •Concurrent use Tacrolimus
- •Concurrent use Amodiaquine
- •Concurrent use Bile acid sequestrants
- •Concurrent use Chenodiol
- •Concurrent use Ciprofibrate
- •Oral anticoagulants: vitamin K antagonist (e.g. warfarin), factor Xa inhibitors (eg. rivaroxaban, apixaban and dabigatran)
- •Concurrent use Anti-obesity medications (e.g. phentermine, orlistat)
- •Concurrent use Systemic steroids (e.g. prednisolone, hydrocortisone, dexamethasone)
- •Hepatitis B
- •Hepatitis C
- •Autoimmune hepatitis
- •Hemochromatosis
- •Previous pancreatitis
- •Serum alanine aminotransferase or aspartate aminotransferase above 2x upper limit of normal
- •Serum creatinine kinase above upper limit of normal
- •Creatinine clearance < 30 ml/min
- •Renal replacement therapy
- •Presence of any non-DN renal glomerular disease
- •Any previous organ transplantation
- •Previous bariatric surgery
- •Gallbladder disease
- •Untreated hypothyroidism
- •Untreated thyrotoxicosis
- •Hemoglobin < 10 g/L
- •Any leukopenia
- •Any thrombocytopenia)
- •Cancer within the last 5 years (except basal cell carcinoma)
- •Medical condition likely to limit survival to less than 3 years
- •Currently participation in another clinical trial
- •Pregnancy, or currently trying to become pregnant
- •Nursing mothers
- •Hospitalization within 1 month prior to enrolment
- 另有 4 项未显示
排除标准
- 未提供
研究组 & 干预措施
Fenofibrate
(Refer to intervention)
干预措施: Fenofibrate (Drug)
结局指标
主要结局
Serum concentration of isoleucine following 30 days of fenofibrate treatment
时间窗: Baseline and after 30 days of treatment
Percentage change in serum concentration of isoleucine following 30 days of fenofibrate treatment compared with baseline
Serum concentration of acetylcarnitine following 30 days of fenofibrate treatment
时间窗: Baseline and after 30 days of treatment
Percentage change in serum concentration of acetylcarnitine following 30 days of fenofibrate treatment compared to baseline
Triglyceride concentration following 30 days of fenofibrate treatment
时间窗: Baseline and after 30 days of treatment
Absolute change in serum triglyceride (mmol/L) concentration following 30 days of fenofibrate treatment with baseline
Serum concentration of palmitoylcarnitine following 30 days of fenofibrate treatment
时间窗: Baseline and after 30 days of treatment
Percentage change in serum concentration of palmitoylcarnitine following 30 days of fenofibrate treatment compared to baseline
Serum concentration of leucine following 30 days of fenofibrate treatment
时间窗: Baseline and after 30 days of treatment
Percentage change in serum concentration of leucine following 30 days of fenofibrate treatment compared with baseline
Serum concentration of valine following 30 days of fenofibrate treatment
时间窗: Baseline and after 30 days of treatment
Percentage change in serum concentration of valine following 30 days of fenofibrate treatment compared with baseline
次要结局
- Change in ETDRS scale following 30 days of fenofibrate treatment(Baseline and after 30 days of treatment)