Mycophenolate Mofetil for Reducing Cardiovascular Risk in Renal Transplant Recipients (MMCR)
The purpose of this research study is to determine if adding or increasing the dose of CellCept while lowering the dose of tacrolimus (Prograf or Advagraf) or cyclosporine (Neoral), and/or steroids can reduce the likelihood of developing coronary heart disease in the next 10 years.
The investigators will calculate the change in risk of developing coronary heart disease using the Framingham score. The Framingham score is a mathematical equation that includes the following information: Age, Gender, Diabetes status, Smoking status, Lipids, Blood Pressure. The Framingham score estimates how likely it is that someone will develop coronary heart disease over the next 10 years.
Drug: mycophenolate mofetil
Other: standard immunosuppression
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Prevention
|Official Title:||A 6-month, Prospective, Open-label, Randomized, Controlled, Pilot Study Evaluating the Efficacy, Safety and Toxicity of an Optimized Immunosuppressive Regimen of CellCept (Mycophenolate Mofetil, MMF) and Reduced Doses of Both Calcineurin-inhibitors and Prednisone in Renal Transplant Recipients With an Increased 10-year Coronary Heart Disease Risk|
- The change in the Framingham 10-yr age and gender adjusted score for coronary heart disease from baseline to Month 6 [ Time Frame: Baseline to Month 6 ] [ Designated as safety issue: No ]
- The incidence of a composite of acute rejection (clinically suspected and biopsy-proven), graft loss or patient death. [ Time Frame: Month 6 ] [ Designated as safety issue: Yes ]
- Framingham point total [ Time Frame: Baseline to Month 6 ] [ Designated as safety issue: No ]Change in Framingham point total from baseline to month 6
- Day and night blood pressure [ Time Frame: Baseline to Month 6 ] [ Designated as safety issue: No ]Change in day and night blood pressure (defined by awake and sleep times) measured by 24-hour ambulatory blood pressure monitoring (ABPM) from baseline to month 6
- Glucose metabolism [ Time Frame: Baseline to Month 6 ] [ Designated as safety issue: No ]Change in glucose metabolism, based on HbA1C levels in patients with and without diabetes, and the prevalence of impaired fasting glucose (IFG) and impaired glucose intolerance (IGT) in patients without overt diabetes from baseline/randomization to month 6.
- Lipid metabolism [ Time Frame: Baseline to Month 6 ] [ Designated as safety issue: No ]Change in lipid metabolism, measured by the fasting levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG)and ratio of TC to HDL-C from baseline/randomization to month 6
- Change in renal function [ Time Frame: Baseline to Month 6 ] [ Designated as safety issue: No ]Change in renal function from baseline/randomization to month 6 as measured by serum creatinine, estimated glomerular filtration rate, (MDRD 4-variable equation), change in eGFR slope, change in chronic kidney disease (CKD), 24-hr urine creatinine clearance and protein/albumin excretion
- Adverse cardiovascular events [ Time Frame: Month 6 ] [ Designated as safety issue: No ]Proportion of patients who experience any adverse cardiovascular event such as myocardial infarction (MI), percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), fatal and non-fatal cerebrovascular events (including fatal or non-fatal stroke, transient ischemic attack, reversible ischemic neurological deficit and subarachnoid hemorrhage). Cardiovascular events will be adjudicated by a cardiologist blinded to treatment assignment.
- Highly-sensitive C-reactive protein (CRP) level [ Time Frame: Randomization to Month 6 ] [ Designated as safety issue: No ]Change in highly-sensitive CRP level between randomization and month 6.
- Change in other biomarkers of cardiovascular risk [ Time Frame: Randomization to Month 6 ] [ Designated as safety issue: No ]Change in other biomarkers of cardiovascular risk between randomization and month 6: human adiponectin (including its high molecular weight isoform), uric acid, early morning urine albumin-to-creatinine ratio, B-type (brain) natriuretic peptide (BNP), fibrinogen, D-dimer (fibrin degradation fragment), advanced glycosylation endproduct (AGE), paraoxonase B, cystatin C, insulin, proinsulin, malondialdehyde (MDA), protein carbonyl, glutathione reductase/total and apolipoprotein A1, B and Lp(a).
- Incidence of MMF-attributable adverse events [ Time Frame: Month 6 ] [ Designated as safety issue: Yes ]Incidence of MMF-attributable adverse events including gastrointestinal toxicities, thrombocytopenia, leucopenia and anemia.
- Additional treatment with cardiovascular co-interventions [ Time Frame: Month 6 ] [ Designated as safety issue: Yes ]Requirements for additional treatment with cardiovascular co-interventions - as per guideline documents.
- Opportunistic infections [ Time Frame: Month 6 ] [ Designated as safety issue: Yes ]Incidence of opportunistic infections
- Malignancies [ Time Frame: Month 6 ] [ Designated as safety issue: Yes ]Incidence of malignancies
- Adverse events [ Time Frame: Month 6 ] [ Designated as safety issue: Yes ]All adverse events (AEs), including clinically significant abnormalities of clinical and laboratory parameters will be captured. Summary statistics will be created for all adverse events and will be summarized by treatment group, by relation to study treatment and seriousness of the event.
|Study Start Date:||October 2010|
|Study Completion Date:||December 2011|
|Primary Completion Date:||October 2011 (Final data collection date for primary outcome measure)|
|Experimental: CellCept optimization||
Drug: mycophenolate mofetil
Introduction of CellCept or increase in the dose of CellCept to a maximum of 2 g/day. In patients not already receiving CellCept, azathioprine (AZA), enteric-coated mycophenolate sodium (EC-MPS) or sirolimus (SRL) will be discontinued and replaced by CellCept in divided doses to a maximum of 2 g/day. CNI doses will be reduced to conform to the target trough levels in the low-dose CNI arms of the ELITE-Symphony study +/- steroid dose reduction. Any CNI dose change will require measurement of CNI trough levels at 7 days post dose change +/- 3 days.
Target CNI trough levels in the Symphony study:
Other Name: CellCept, MMF
|Active Comparator: Control||
Other: standard immunosuppression
Current immunosuppressive therapy will be maintained throughout the study unless a change is required for safety reasons.
Kidney transplant recipients are required to take medications called immunosuppressants to lower their immune systems to help protect the donated kidney. The medications have improved over the years and as a result the donated kidneys are generally working longer. This allows the Transplant Team to focus more on the long term complications of kidney transplantation such as cardiovascular disease.
There have been few prospective (looking forward) research studies looking at kidney transplant recipient cardiovascular risk factors after transplant.
We know that immunosuppressive medications have a number of serious side effects that can increase cardiovascular disease risk factors such as high blood pressure, high lipids (fats in the blood), and high blood sugar. Medications such as tacrolimus, cyclosporine and prednisone work well to protect the donated kidney but are also known to increase the risk of developing or worsening cardiovascular disease.
CellCept is another type of immunosuppressive agent. CellCept is not associated as much with the risk of developing cardiovascular disease.
This is a pilot study being done to collect information about cardiovascular risk factors in kidney transplant recipients and to see if adjusting the immunosuppressive medications can help to lower the overall risk for developing heart disease in the future.
This research study plans to enroll 45 participants from 2 different transplant centres in Canada: St. Michael's Hospital in Toronto and St. Paul's Hospital in Saskatoon. The study duration is approximately 7 months per participant. The study will be looking for participants who are 30 years of age or older and who are at least 6 months after the transplant operation.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01213394
|St. Michael's Hospital|
|Toronto, Ontario, Canada, M5C 2T2|
|Principal Investigator:||Dr. Ramesh Prasad, MBBS MSc||St. Michael's Hospital, Toronto|