VITamine D Supplementation in RenAL Transplant Recipients - VITALE

Study Overview
=================
Brief Summary
-----------------
It has been proposed that the intake of high dose of cholecalciferol may have beneficial non classical effects (beside bone health). This could include the reduction of type 2 diabetes mellitus, cardiovascular diseases, cancers, autoimmune and infectious diseases. These pleiotropic effects are mostly documented by observational and experimental studies or small intervention trials. In renal transplant recipients, vitamin D insufficiency, defined as circulating 25(OH)vitamin D (25OHD) less than 30 ng/mL, is a frequent finding and this population is at risk of the previously cited complications.The primary purpose of this study is to compare the effects of high dose vs. low dose of cholecalciferol on a composite endpoint consisting in de novo diabetes mellitus, cardiovascular diseases, de novo cancer and patient death.Renal transplant recipients between 12 and 48 months after transplantation will be randomized to blindly receive either high or low dose of cholecalciferol with a follow-up of 2 years.

Detailed Description
-----------------
Rationale : Vitamin D cannot be considered any more as only necessary to prevent rickets or osteomalacia. Calcitriol produced in the kidney is known to have classical endocrine PHOSPHOCALCIC properties. More recently, vitamin D has been shown to play an important role in reducing the risk of many chronic diseases including type 2 diabetes mellitus, cardiovascular diseases, cancers, autoimmune and infectious diseases. These effects may be secondary to local production of calcitriol and to its autocrine and paracrine actions on cellular proliferation and differentiation, apoptosis, insulin and renin secretion, interleukin and bactericidal proteins production. These pleiotropic effects are mostly documented by observational and experimental studies or small intervention trials that most often evaluated intermediate parameters. In renal transplant recipients, vitamin D insufficiency (circulating 25OHD<30 ng/mL or 75 nmol/L) , is a frequent finding with more than 80% of patients displaying this profile. Objective: Primary objective: compare the effects of high dose vs. low dose of cholecalciferol on a composite endpoint including De novo diabetes mellitus (fasting glycemia > 7 MMOLES/l or glycemia > 11 MMOLES/l) Cardiovascular complications (acute coronary heart disease, acute heart failure, lower-extremity arterial disease, cerebrovascular disease). De novo cancer, Patient death. Secondary objectives : compare the effects of high dose vs. low dose of cholecalciferol on The occurrence of each event constituting the primary endpoint Blood pressure and blood pressure control (number and dosage of antihypertensive drugs) Echocardiography findings Infection including opportunistic (CMV, pneumocystis, nocardial infection, cryptococcal infection, aspergillosis) Acute rejection episode Renal allograft function including estimated glomerular filtration rate and proteinuria - Graft survival PHOSPHOCALCIC biological and clinical relevant parameters : Evolution of serum 25OHD, calcaemia, phosphataemia, serum PTH, bone mineral density and incidence of fractures Renal lithiasis Study protocol Number of patients: 320 patients in each group Inclusions : 2 years Follow-up after inclusion : 2 years Prospective, randomized, multicentre, double blind clinical study comparing high dose cholecalciferol [100 000 UI FORTHIGHTLY for 2 months then monthly for 22 months) vs. low dose cholecalciferol [12 000 UI FORTHIGHTLY for 2 months then monthly for 22 months).

Official Title
-----------------
Prospective Double Blind Multicentre Randomized Trial of Vitamine D Estimating the Profit of a Treatment by Vitamin D3 at the Dose of 100000 UI by Comparison With a Treatment in the Dose of 12 000 UI at Renal Transplanted Patients

Conditions
-----------------
Renal Transplant Candidate for Right Kidney

Intervention / Treatment
-----------------
* Drug: Cholecalciferol 100 000 UI
* Drug: Cholecalciferol 12 000 UI


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Renal transplant recipients between 12 and 48 months after transplantation with a stable renal function during the past 3 months. Vitamine D insufficiency defined as a concentration of 25OHD lower than 30 ng/ml. Patient between 18 and 75 years old Patient capable of understanding the advantages and the risks of the study. Affiliated with social security health insurance Written informed consent Exclusion Criteria: Calcaemia > 2,7 mmol/l Phosphataemia > 1,5 mmol/l Serum creatinine > 250 µmol/l Treatment by an active form of the vitamin D not being able to be interrupted Transplant of an organ other than the kidney Type I or type II diabetes mellitus Past medical history of granulomatosis or active granulomatosis Primary hyperoxaluria Malabsorption proved by the liposoluble vitamins Simultaneous participation in another therapeutic essay Patients presenting a drug addiction or a psychiatric disorder Pregnant or breast-feeding women Vitamin D hyper sensibility

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cholecalciferol 100 000 UI<br>Cholecalciferol 100 000 UI FORTHIGHTLY for 2 months then monthly for 22 months | Drug: Cholecalciferol 100 000 UI<br>* Cholecalciferol 100 000 UI FORTHIGHTLY for 2 months then monthly for 22 months<br>|
| Active Comparator: Cholecalciferol 12 000 UI (Control)<br>Cholecalciferol 12 000 UI FORTHIGHTLY for 2 months then monthly for 22 months. | Drug: Cholecalciferol 12 000 UI<br>* Cholecalciferol 12 000 UI FORTHIGHTLY for 2 months then monthly for 22 months.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| De novo diabetes mellitus | De novo diabetes mellitus (fasting glycemia > 7 mmoles/l or glycemia > 11 mmoles/l) | 2 years | 
| Cardiovascular complications | Cardiovascular complications (acute coronary heart disease, acute heart failure, lower-extremity arterial disease, cerebrovascular disease). | 2 years | 
| De novo cancer | Diagnosis of the incidence of any new cancer | 2 years | 
| Patient death |  | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood pressure control | Blood pressure and blood pressure control (number and dosage of antihypertensive drugs) | 2 years | 
| Echocardiography findings | Comparison of left ventricular ejection fraction | 2 years | 
| Infection including opportunistic | Infection including opportunistic (CMV, pneumocystis, nocardial infection, cryptococcal infection, aspergillosis) | 2 years | 
| Acute rejection episode |  | 2 years | 
| Renal allograft function | Renal allograft function including estimated glomerular filtration rate, proteinuria | 2 years | 
| Graft survival |  | 2 years | 
| Phosphocalcic biological and clinical relevant parameters | PHOSPHOCALCIC biological and clinical relevant parameters : Evolution of serum 25OHD, calcaemia, phosphataemia, serum PTH, bone mineral density and incidence of fractures | 2 years | 
| Renal lithiasis |  | 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Vitamine D, renal transplantation, diabetes mellitus, cancer, cardiovascular complications