Safety and Efficacy of Oral Semaglutide in Hyperglycaemic Patients After Renal Transplantation
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 入组人数
- 104
- 试验地点
- 1
- 主要终点
- Mean sensor glucose (mmol/L)
研究概览
简要总结
Background: Post-transplant hyperglycaemia occurs frequently in renal transplant recipients within the first two weeks after transplantation. Standard-of-care is primarily based on insulin treatment with the adherent risk of hypoglycaemia and weight gain. Semaglutide produces an effective lowering of plasma glucose in diabetes patients with chronic kidney disease (CKD) and leads to a reduction in weight and the incidence of hypoglycaemia. The efficacy of semaglutide is untested in renal transplant recipients, and safety concerns remain, primarily on renal graft function.
Objectives: The primary objective is to establish whether tablet semaglutide (Rybelsus) compared with placebo, both as add-on to standard-of-care, is non-inferior in regulating plasma glucose in patients with hyperglycaemia after renal transplantation. Secondary objectives aim to evaluate the effect of tablet semaglutide on renal graft function, weight, use of insulin, cardiovascular parameters and safety parameters (plasma semaglutide concentration, gastrointestinal side effects, dose of immunosuppressants).
Design: An investigator-initiated, placebo-controlled, double-blinded, parallel-group, randomised trial.
Population: Patients (n = 104) with post-transplant hyperglycaemia or type 2 diabetes and an estimated glomerular filtration rate (eGFR) > 15 ml/min/1.73 m2.
Methods: Participants diagnosed with post-transplant hyperglycaemia or type 2 diabetes, 10 to 40 days post-transplant, will be randomised 1:1 to either 14 weeks of tablet semaglutide once daily or placebo both as add-on to standard glucose-lowering therapy. Participants will maintain weekly contact with the clinic during the first five weeks and at two to four weeks intervals during the remaining study period. During the trial, each patient will be monitored according to blood laboratory values with safety assessed at every visit by a nephrologist. Pre-prandial plasma glucose will be measured in the morning and evening to adjust glucose-lowering therapy after consultation with an endocrinologist. Double blinded continuous glucose monitoring (CGM) will be performed for 10-14 days from baseline and at weeks 5, 9, and 13.
Primary endpoint:
- Mean sensor glucose (mmol/L) evaluated by CGM
Key secondary endpoints:
- Incidence of hypoglycaemia
- Body weight (kg)
- Creatinine (μmol/L)
- Daily insulin dose (IE per day)
- Plasma concentration of semaglutide (nmol/L)
- Blood concentrations of cyclosporine and tacrolimus (μg/L)
详细描述
Introduction:
In renal transplant recipients, hyperglycaemia develops frequently in the immediate period after renal transplantation. Insulin is the primary choice of treatment but carries the adherent risk of hypoglycaemia and weight gain. Tablet semaglutide is a potent glucose-lowering agent that can reduce weight and the incidence of hypoglycaemia. It also has the ability to delay progression of chronic kidney disease (CKD). However, semaglutide is not recommended for renal transplant recipients, as safety and efficacy has yet to be established. The aim of this study is to prove that semaglutide is safe in renal transplant recipients and potentially just as effective as insulin-treatment. We expect that semaglutide can reduce daily insulin-usage and, for a large number of patients, even completely replace insulin as treatment, thereby avoiding the harmful side-effects of this drug.
Objectives:
The primary aim is to establish if tablet semaglutide (Rybelsus) compared with placebo, both as add-on to standard-of-care, is non-inferior in regulating plasma glucose in patients with hyperglycaemia in the immediate weeks after renal transplantation.
Secondary objectives aim to evaluate the effect of tablet semaglutide on renal allograft function, weight, daily use of insulin and safety parameters (plasma semaglutide concentration, gastrointestinal side effects, dose of immunosuppressants).
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)
盲法说明
double-blinded
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written informed consent obtained before any trial-related procedures are performed
- •Male or female; age: 18-80 years
- •Diagnosis of post-transplant hyperglycaemia 10 to 40 days after transplantation: Fasting plasma glucose ≥ 7.0 mmol/L or an oral glucose tolerance test with at plasma glucose ≥ 11.1 mmol/L or Pre-transplant type 2 diabetes: Receiving glucose-lowring treatment prior to kidney transplantation
- •An eGFR > 15 ml/min/1.73 m2 10 to 40 days after renal transplantation
- •Subject must be willing and able to comply with trial protocol
排除标准
- •Type 1 diabetes
- •High risk immunological transplantation (not including ABO-incompatible or re-transplantation)
- •Early graft rejection (all rejections verified by biopsy, except borderline rejections. Study initiations can begin 5 days after last dose of rejection treatment with methylprednisolone)
- •Chronic pancreatitis/previous acute pancreatitis
- •Known or suspected hypersensitivity to trial or related products
- •Use of DPP-4 inhibitors within five days prior to screening
- •Use of GLP-1RA within 10 days prior to screening
- •Malignancy (except basal cell carcinoma)
- •Inflammatory bowel disease
- •Previous bowel resection
- •Cardiac disease defined as decompensated heart failure (New York Heart Association class III-IV) and/or diagnosis of unstable angina pectoris and/or myocardial infarction within the last six months
- •Any acute condition or exacerbation of chronic condition that would in the investigator's opinion interfere with the initial trial visit schedule and procedures.
- •Females of childbearing potential who are pregnant, breast-feeding, intend to become pregnant, or are not using adequate contraceptive methods
- •Impaired liver function (plasma ALAT > two times upper reference levels)
- •Elevated amylase (plasma amylase > two times upper reference levels)
- •Untreated proliferative diabetic retinopathy, untreated diabetic macular edema or active conditions of this type that are not under therapeutic control according
- •Any condition that clinically significantly impairs the observation of the fundus or anterior chamber
研究组 & 干预措施
Semaglutide treated group
Oral semaglutide once-daily as add-on to standard-of-care for post-transplant hyperglycaemia
干预措施: Semaglutide 14 MG [Rybelsus] (Drug)
Placebo treated group
Oral placebo once-daily as add-on to standard-of-care for post-transplant hyperglycaemia
干预措施: Placebo (Drug)
结局指标
主要结局
Mean sensor glucose (mmol/L)
时间窗: 14 weeks
Mean sensor glucose evaluated by 10 days of CGM obtained at baseline, week 5, week 9 and week 13.
次要结局
- Percentage time in target range (3.9-10.0 mmol/L)(14 weeks)
- Percentage time in hypoglycaemia (level 1 [3.0-3.8 mmol/L] and level 2 [below 3.0 mmol/L])(14 weeks)
- Percentage time in hyperglycaemia (level 1 (10.1-13.9 mmol/L) and level 2 (above 13.9 mmol/L)(14 weeks)
- Glucose variability (standard deviation [mmol/L] and coefficient of variation [%])(14 weeks)
- Glucose management indicator (mmol/mol and %)(14 weeks)
- HbA1c (mmol/mol)(14 weeks)
- HbA1c (%)(14 weeks)
- Body weight (kg)(14 weeks)
- Body mass index (kg/m2)(14 weeks)
- Creatinine (μmol/L)(14 weeks)
- eGFR (ml/min/1.73m2)(14 weeks)
- Systolic and diastolic blood pressure (mmHg)(14 weeks)
- Urinary albumin-to-creatinine ratio (mg/g)(14 weeks)
- Plasma concentrations of cholesterol(14 weeks)
- Plasma concentrations of low-density lipoproteins(14 weeks)
- PPlasma concentrations of high-density lipoproteins(14 weeks)
- Plasma concentrations of triglycerides(14 weeks)
- Daily insulin dose (IE per day)(14 weeks)
- Daily dose of immunosuppressant (prednisone, cyclosporine, tacrolimus, mycophenolate mofetile)(14 weeks)
- Plasma concentration of semaglutide (nmol/L)(14 weeks)
- Dose-corrected plasma concentration of semaglutide (nmol/L)(14 weeks)
- Plasma insulin (pmol/L)(14 weeks)
- C-peptide (nmol/L)(14 weeks)
- Homeostatic model assessment (HOMA) for assessing beta-cell function and insulin 192 resistance(14 weeks)
- Plasma alanine transaminase (ALAT) (U/L)(14 weeks)
- Plasma amylase (U/L)(14 weeks)
- Gastrointestinal side effects evaluated using the Gastrointestinal symptom rating scale (GSRS)(14 weeks)
- Incidence of adverse events and serious adverse events(14 weeks)
- Incidence of self-reported hypoglycaemic episodes(14 weeks)
研究者
Bo Feldt-Rasmussen
MD, Professor
Rigshospitalet, Denmark