Study Comparing Effect On Carotid Atherosclerosis Following Conversion From Tacrolimus To Sirolimus Post-Transplant In Kidney Transplant Patients

Study Overview
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Brief Summary
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The purpose of this study is to determine whether immunosuppression by tacrolimus, mycophenolate mofetil, and prednisone compared to conversion to sirolimus, mycophenolate mofetil, and prednisone affect the progression of atherosclerosis in renal transplant recipients.

Detailed Description
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A decision to terminate the study was taken in November 2011 and a communication to that effect sent to all participating sites on November 18. All sites were asked to have patients returned to the sites and have all end of study procedures performed by Dec 31, 2011. The decision to terminate this study was made following the conduct of an interim analysis which demonstrated that the study did not reach its primary endpoint. The termination of this study was not driven by any safety concerns and had no impact on subject safety and well-being.

Official Title
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A Prospective, Randomized, Open-Label, Pilot Study To Compare The Effect On Carotid Atherosclerosis Of A Tacrolimus-Based Regimen With Conversion From A Tacrolimus- To A Sirolimus-Based Regimen At 3-4 Months Post-Transplant In De Novo Renal Transplant Recipients

Conditions
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Atherosclerosis, Kidney Failure

Intervention / Treatment
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* Drug: tacrolimus
* Drug: mycophenolate mofetil
* Drug: prednisone
* Drug: sirolimus
* Drug: tacrolimus
* Drug: mycophenolate mofetil
* Drug: prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At least one of the following characteristics: History of dialysis for at least 3 years. History of diabetes for at least 5 years. Hypertension or ischemic nephropathy as a cause of the end stage renal disease or loss of the first transplant. History of coronary artery disease, stroke, myocardial infarction, or amputation for vascular disease. Exclusion Criteria: History of malignancy within the last 5 years (except adequately treated skin cancer). Recipients of non-renal organ transplant. Active gastrointestinal disease that may interfere with drug absorption. Active HIV, hepatitis B or C infection. Women who are pregnant or breastfeeding.

Ages Eligible for Study
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Minimum Age: 35 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>Tacrolimus + MMF + Steroids | Drug: tacrolimus<br>* The daily dosage and formulation for each study treatment will be chosen by the investigator as medically appropriate for each individual subject, in order to achieve the target levels specified in the protocol TAC should be initiated within 24 hours before or after transplantation or within 14 days of transplantation as per local standard of care and tapered to a target trough level of 3-10 ng/mL by the Pre-Conversion visit at month 3-4 post-transplantation. The target trough level of TAC will be maintained at 3-10 ng/mL through to the end of the study.<br>* Other names: CNI;Drug: mycophenolate mofetil<br>* The daily dosage and formulation for each study treatment will be chosen by the investigator as medically appropriate for each individual subject, in order to achieve the target levels specified in the protocol MMF or MPS should be initiated within 24 hours before or after transplantation or within 14 days of transplantation per local standard of care and tapered to a minimum oral dose of MMF ≥ 500 mg/day or MPS ≥ 360 mg/day by the Pre-Conversion visit at month 3-4 post-transplantation. At the discretion of the investigator, MMF may be changed to MPS, or MPS may be changed to MMF. MMF is to be continued at ≥ 500 mg/day dose or MPS is to be continued at ≥ 360 mg/day dose through to the end of study.<br>* Other names: MMF, MPS;Drug: prednisone<br>* The daily dosage and formulation for each study treatment will be chosen by the investigator as medically appropriate for each individual subject, in order to achieve the target levels specified in the protocol CCS should be initiated within 24 hours before or after transplantation or within 14 days of transplantation per local standard of care and tapered to a minimum of 5 mg/day of prednisone orally or the alternate day equivalent by the Pre-Conversion visit at month 3-4 post-transplant. Continue administration of prednisone as per local standard of care to a minimum dose of 2.5 mg/day or alternate day equivalent dose to the end of the study. Withdrawal of CCS is prohibited.<br>* Other names: CCS;|
| Experimental: 2<br>Tacrolimus + MMF + Steroids with conversion from Tacrolimus to Sirolimus at 3-4 months post-transplant | Drug: sirolimus<br>* The daily dosage and formulation for each study treatment will be chosen by the investigator as medically appropriate for each individual subject, in order to achieve the target levels specified in the protocol. On study Day 1 Conversion, the daily dose of TAC will not be taken, and SRL is initiated as a single 5-10 mg loading dose, followed by 3 mg/day on subsequent days, adjusted to maintain a SRL target trough level of 8-15 ng/mL through to month 24 post-transplant, then 5-12 ng/mL to the end of month 36 post-transplant.<br>Drug: tacrolimus<br>* The daily dosage and formulation for each study treatment will be chosen by the investigator as medically appropriate for each individual subject, in order to achieve the target levels specified in the protocol TAC should be initiated within 24 hours before or after transplantation or within 14 days of transplantation as per local standard of care and tapered to a target trough level of 3-10 ng/mL by the Pre-Conversion visit at month 3-4 post-transplantation. Reintroduction of TAC or introduction of CsA is not permitted in the SRL Therapy group.<br>* Other names: CNI;Drug: mycophenolate mofetil<br>* The daily dosage and formulation for each study treatment will be chosen by the investigator as medically appropriate for each individual subject, in order to achieve the target levels specified in the protocol MMF or MPS should be initiated within 24 hours before or after transplantation or within 14 days of transplantation per local standard of care and tapered to a minimum oral dose of MMF ≥ 500 mg/day or MPS ≥ 360 mg/day by the Pre-Conversion visit at month 3-4 post-transplantation. At the discretion of the investigator, MMF may be changed to MPS, or MPS may be changed to MMF. MMF is to be continued at ≥ 500 mg/day dose or MPS is to be continued at ≥ 360 mg/day dose through to the end of study.<br>* Other names: MMF, MPS;Drug: prednisone<br>* The daily dosage and formulation for each study treatment will be chosen by the investigator as medically appropriate for each individual subject, in order to achieve the target levels specified in the protocol CCS should be initiated within 24 hours before or after transplantation or within 14 days of transplantation per local standard of care and tapered to a minimum of 5 mg/day of prednisone orally or the alternate day equivalent by the Pre-Conversion visit at month 3-4 post-transplant. Continue administration of prednisone as per local standard of care to a minimum dose of 2.5 mg/day or alternate day equivalent dose to the end of the study. Withdrawal of CCS is prohibited.<br>* Other names: CCS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annual Change Rate in Total Plaque Volume (TPV) From Pre-conversion Baseline to 12 Months Post-transplant | Within-subject annual change rate in TPV in the left and right distal common carotid arteries from the pre-conversion baseline to 12 months post kidney transplant as determined by ultrasound. Annual change rate equals (=) (TPV at month 12 post-transplant minus [-] TPV at pre-conversion baseline) divided (/) by imaging interval in years. TPV is the sum of assessment in left and right distal common carotid arteries. | Pre-conversion baseline and 12 months post-transplant | 
| TPV at Pre-conversion Baseline | TPV is the sum of the assessment in left and right distal common carotid arteries. | Pre-conversion baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annual Change Rate in Carotid Intima Media Thickness (CIMT) From Pre-conversion Baseline at 12, 18, 24 and 36 Months Post-transplant | Within-subject annual change rate in CIMT as determined by ultrasound. Mean CIMT=average of left CIMT and right CIMT. Annual CIMT Change Rate (mm/year) = (CIMT at Month x Post-transplant Visit - CIMT at Conversion Baseline) / Imaging interval in years. | Pre-conversion baseline, and 12, 18, 24 and 36 months post-transplant | 
| CIMT at Pre-conversion Baseline | Mean CIMT=average of left CIMT and right CIMT. | Pre-conversion baseline | 
| Change From Pre-conversion Baseline in Carotid Plaque Roughness at 12 and 24 Months Post-transplant | Carotid plaque roughness as determined by ultrasound. Change equals (=) value at post-transplant month x minus (-) pre-conversion baseline. | Pre-conversion baseline, 12, and 24 months post-transplant | 
| Change From Pre-conversion Baseline in Fasting Lipid Parameters at 12, 18, 24 and 36 Months Post-transplant | Total Cholesterol (TC), Low Density Lipoprotein (LDL), High Density Lipoprotein (HDL) and Triglyceride (Tg) blood concentrations. Higher levels of TC, LDL and Tg are less desirable. Lower levels of HDL are less desirable. Change for each parameter = value at 12, 18, 24 and 36 months post-transplant - value at pre-conversion baseline. | Pre-conversion baseline, and 12, 18, 24 and 36 months post-transplant | 
| Change From Pre-conversion Baseline in Glucose at Months 12, 24 and 36 Post-transplant | Fasting plasma glucose. Change = value at month x post-transplant - pre-conversion baseline values. | Pre-conversion baseline, 12, 24 and 36 months post-transplant | 
| Change From Pre-conversion Baseline in Insulin at Months 12, 24, and 36 Post-transplant | Fasting insulin. Change = value at month x post-transplant - pre-conversion baseline. | Pre-conversion baseline, 12, 24 and 36 months post-transplant | 
| Change From Pre-conversion Baseline in Glycosylated Hemoglobin(HbA1C) at Months 12, 24, and 36 Post-transplant | HbA1C, change = value at month x post-transplant - pre-conversion baseline. | Pre-conversion baseline, 12, 24 and 36 months post-transplant | 
| Change From Pre-conversion Baseline in Adiponectin at Months 12, 24 and 36 Post-transplant | Adiponectin is a biomarker for cardiovascular disease and atherosclerosis risk. A higher level indicates less risk. Change = month x post-transplant values - pre-conversion baseline values. | Pre-conversion baseline, 12, 24 and 36 months post-transplant | 
| Change From Pre-conversion Baseline in High Sensitivity C-Reactive Protein (hsCRP) at Months 12, 24 and 36 Post-transplant. | hsCRP is a biomarker of cardiovascular disease and atherosclerosis risk. A higher level indicates a greater risk. Change = month x post-transplant values - pre-conversion baseline values. | Pre-conversion baseline, 12, 24 and 36 months post-transplant | 
| Change From Pre-conversion Baseline in Tumor Necrosis Factor Alpha (TNF-alpha) at Months 12, 24 and 36 Post-transplant | TNF-alpha is a biomarker for cardiovascular disease and atherosclerosis risk. A higher level indicates a greater risk. Change = month x post-transplant values - pre-conversion baseline values. | Pre-conversion baseline, 12, 24 and 36 months post-transplant | 
| Change From Pre-conversion Baseline in Endothelin-1 at Months 12, 24 and 36 Post-transplant | Endothelin-1 is a biomarker for cardiovascular disease and atherosclerosis risk. A higher level indicates greater risk. Change = month x post-transplant values - pre-conversion baseline values. | Pre-conversion baseline, 12, 24 and 36 months post-transplant | 
| Change From Pre-conversion Baseline in Interleukin-6 (IL-6) at Months 12, 24 and 36 Post-transplant | IL-6 is a biomarker for cardiovascular disease and atherosclerosis risk. A higher level indicates a greater risk. Change = month x post-transplant values - pre-conversion values. | Pre-conversion baseline, 12, 24 and 36 months post-transplant | 
| Change From Pre-conversion Baseline in Homocysteine at Months 12, 24 and 36 Post-transplant | Homocysteine is a biomarker for cardiovascular disease and atherosclerosis risk. A higher level indicates a greater risk. Change = month x post-transplant values - pre-conversion baseline values. | Pre-conversion baseline, 12, 24 and 36 months post-transplant | 
| Change From Pre-conversion Baseline in Lipoprotein(a) at Months 12, 24 and 36 Post-transplant | Lipoprotein(a) is a biomarker for cardiovascular disease and atherosclerosis risk. A higher level indicates a greater risk. Change = month x post-transplant values - pre-conversion baseline values. | Pre-conversion baseline, 12, 24 and 36 months post-transplant | 
| Change From Pre-conversion Baseline in Fibrinogen at Months 12, 24 and 36 Post-transplant | Fibrinogen is a biomarker for cardiovascular disease and atherosclerosis risk. A higher level indicates a greater risk. Change = month x post-transplant values - pre-conversion baseline values. | Pre-conversion baseline, 12, 24 and 36 months post-transplant | 
| Change From Pre-conversion Baseline in Vitamin B12 at Months 12, 24 and 36 Post-transplant | Vitamin B12 is a biomarker for cardiovascular disease and atherosclerosis risk. A lower level indicates a greater risk. Change = month x post-transplant values - pre-conversion values. | Pre-conversion baseline, 12, 24 and 36 months post-transplant | 
| Change From Pre-conversion Baseline in Uric Acid at Months 12, 24 and 36 Post-transplant | Uric Acid is a biomarker for cardiovascular disease and atherosclerosis risk. A higher level indicates a greater risk. Change = month x post-transplant values - pre-conversion baseline values. | Pre-conversion baseline, 12, 24 and 36 months post-transplant | 
| Change From Pre-conversion Baseline in Folate at 12, 24 and 36 Months Post-transplant | Folate is a biomarker for cardiovascular disease and atherosclerosis risk. A lower level indicates a greater risk. Change = month x post-transplant values - pre-conversion baseline values. | Pre-conversion baseline, 12, 24 and 36 months post-transplant | 
| Number of Participants Who Used Lipid Lowering Therapies | Participants who reported yes for taking lipid lowering therapies as concomitant medication. | From consent to conversion, from conversion to Month 12, from Months 12 to 24, and from Months 24 to 36 post-transplant | 
| Number of Participants Who Used Anti-hypertensive Medications | Participants who reported yes for taking anti-hypertensive medications as concomitant medication. | From consent to conversion, from conversion to Month 12, from Months 12 to 24, and from Months 24 to 36 post-transplant | 
| Annual Rate of Change in TPV From Pre-conversion Baseline to 18, 24 and 36 Months Post Transplant | Within-subject annual change rate in TPV in the left and right distal common carotid arteries from the pre-conversion baseline to 18, 24 and 36 months post kidney transplant as determined by ultrasound. Annual change rate equals (=) (TPV at month 18, 24 and 36 post-transplant minus [-] TPV at pre-conversion baseline) divided (/) by imaging interval in years. TPV is the sum of assessment in left and right distal common carotid arteries. | Pre-conversion baseline, and 18, 24 and 36 months post-transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Kidney transplant, Renal transplant, Immunosuppression, Atherosclerosis, Graft Rejection