Diabetogenicity of Cyclosporine and Tacrolimus
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Insulin Sensitivity
研究概览
简要总结
Cyclosporine (CsA) and Tacrolimus (Tac) are immunosuppressive agents comprising the cornerstone of treatment among organ transplant recipients. Unfortunately diabetes is a known complication after transplantation, yet the underlying mechanisms of this type of diabetes are still unresolved. A direct comparison of the diabetogenic effects of CsA and Tac, without interference of corticosteroid treatment, has not yet been investigated using a hyperinsulinemic euglycemic glucose clamp technique, which is the best method for estimating insulin sensitivity.
Randomized, investigator-blinded cross-over studies will be carried out, studying 10 healthy subjects and 10 hemodialysis patients. Each participant will receive treatment with CsA, Tac and placebo respectively in a random order. The results will be of relevance to the choice and monitoring of immunosuppressive regimens in kidney transplant recipients as well as the development of better treatment modalities for diabetes.
详细描述
Background: Post-transplantation diabetes mellitus (PTDM) is a complication of the calcineurin inhibitors (CI) cyclosporine (CsA) and Tacrolimus (Tac), but much controversy still exists regarding the mechanism leading to this disorder. Several studies using intravenous (IVGTT) or oral glucose tolerance tests have shown that CsA and Tac tend to reduce insulin release, while corticosteroids increase insulin resistance. Decreased insulin secretion may be the result of beta-cell toxicity, apoptosis or inhibition of calcineurin signaling cessating insulin gene transcription. Comparing the drug using IVGTT has shown that long-term glucose metabolism is not significantly different between the two. Reviewing the literature brings forth that some of these data and the observed higher incidence of PTDM in Tac-treated recipients are conflicting.
To or knowledge, comparison of the diabetogenic effects of CsA and Tac, without concomitant corticosteroids, has never been investigated using the gold standard to estimate insulin sensitivity; a hyperinsulinemic euglycemic glucose clamp (HEGC).
Hypotheses: CsA and Tac are able to induce diabetes, by exerting acute and chronic effects on pancreas beta-cell performance and insulin sensitivity.
The hypothesized effects will be investigated during following studies:
- Acute effect in 10 healthy subjects undergoing HEGC
- Chronic effect in 10 pre-transplant uremic patients undergoing HEGC
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
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
- 是
入选标准
- •Healthy volunteers (Study 1):
- •Age between 18 years and 50 years. Upper limit can be +2 years if approved by main investigator.
- •Normal OGTT (0 and 120 min test).
- •Body mass index (BMI) 20 - 30 kg/m
- •Allowed variations are 5% from the upper and lower limit.
- •Normal serum creatinine and ionisized calcium. Allowed variations are 20% from the upper and lower limit of the normal value for creatinine and 5% for calcium.
- •Normal urine stix
- •Written consent to participate.
- •Hemodialysis Patients (study 2):
- •Age between 18 years and 70 years. Upper limit can be +2 years if approved by main investigator.
- •BMI < 30 kg/m
- •Allowed variations are 5% over the upper limit.
- •On the waiting-list for a kidney transplant.
- •Haemodialysis candidate.
- •Anti-conceptive treatment (contraceptive pill/intrauterine device/patch/ring/ implant/injectable contraceptive) if the patient is a fertile woman.
- •Written consent to participate. -
排除标准
- •Healthy volunteers (Study 1):
- •Anaemia with haemoglobin levels < 7 mmol/L
- •Participation in any other clinical trial.
- •Subjects who cannot adhere to test conditions.
- •Anamnesis of clinically significant disease, such as:
- •liver disease
- •kidney disease,
- •neurological disease
- •gastrointestinal disease
- •haematological disease
- •endocrine disease
- •lung disease
- •cardiac disease
- •Drug or alcohol abuse, which would render the subject unfit according to the main investigator.
- •Blood donation 1 month prior to the study day
- •Patients with established allergy against CI or other medical products, which might pose a risk if they participated in this study.
- •Use of prescription drugs within one month prior to the study days, unless they are clinically insignificant according to the main investigator.
- •Smoking 8 hours prior to the study day
- •Vigorous exercise 30 minutes prior to the study day.
- •Hemodialysis Patients (study 2):
- •Peritoneal dialysis.
- •Anaemia with haemoglobin levels < 6 mmol/L.
- •Participation in any other clinical trial.
- •Treatment with corticosteroids, CsA or Tac.
- •Patients who cannot adhere to test conditions.
- •Patients with established allergy against CI or other medical product, which might pose a risk if they participated in this study.
- •Drug or alcohol abuse, which would render the subject unfit according to the main investigator.
- •Anamnesis of current diabetes and/or intake of anti-diabetic medication.
- •Malignancy.
- •Uncontrolled infection.
- •Uncontrolled hypertension.
- •Smoking 8 hours prior to the study day.
- •Vigorous exercise 30 minutes prior to the study day
研究组 & 干预措施
CsA
Cyclosporine
干预措施: cyclosporine (Drug)
Tac
Tacrolimus
干预措施: tacrolimus (Drug)
Placebo
placebo/saline
干预措施: Capsules and isotonic saline (Other)
结局指标
主要结局
Insulin Sensitivity
时间窗: Serial measurements during 120 minute Hyperinsulinemic euglycemic clamp investigation. Performed 3 times on 3 individual days within 4 months after inclusion
次要结局
- insulin secretion(Serial measurements during IVGTT. Performed 3 times on 3 individual days within 4 months after inclusion.)
- serum free fatty acids(Serial measurements during 5-hour infusions of CsA, Tac or saline. Performed 3 times on 3 individual days within 4 months after inclusion.)
- serum C-peptide(erial measurements during 5-hour infusions of CsA, Tac or saline. Performed 3 times on 3 individual days within 4 months after inclusion.)
- blood cyclosporine(erial measurements during 5-hour infusions of CsA, Tac or saline. Performed 3 times on 3 individual days within 4 months after inclusion.)
- blood tacrolimus(Serial measurements during 5-hour infusions of CsA, Tac or saline. Performed 3 times on 3 individual days within 4 months after inclusion.)
- respiratory gas exchange, substrate metabolism(Indirect calorimetry performed 3 times on 3 individual days within 4 months after inclusion.)
- Pulsatile Insulin secretion(erial measurements during glucose entrainment. Performed 3 times on 3 individual days within 4 months after inclusion.)
- plasma Glucose(erial measurements during 5-hour infusions of CsA, Tac or saline. Performed 3 times on 3 individual days within 4 months after inclusion.)
- plasma glucagon(erial measurements during 5-hour infusions of CsA, Tac or saline. Performed 3 times on 3 individual days within 4 months after inclusion.)