Lipid Management in Renal Transplant Recipients Using Evolocumab.

Study Overview
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Brief Summary
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Cardiovascular disease is the leading cause of mortality after renal transplantation, accounting for more than 30% of deaths. Elevated lipid levels (hyperlipidemia) are a frequent finding following transplantation and the immunosuppressive medications play a central role in the development or worsening of hyperlipidemia. In the general population, the correlation between elevated serum cholesterol and increased risk of cardiovascular disease is well established and the reduction in serum LDL cholesterol has proved to significantly reduce both morbidity and mortality. Statin based drugs are the standard of care in the management of hyperlipidemia. Commonly used statin-based drugs include atorvastatin (Lipitor), fluvastatin (Lescol, Lescol XL), lovastatin (Mevacor, Altoprev), pravastatin (Pravachol), rosuvastatin (Crestor), simvastatin (Zocor), and pitavastatin (Livalo). These drugs have been proven to lower lipid levels as well as cardiovascular risk. However, statin-based drugs also cause a variety of side effects. While the most commonly encountered side effects are toxicity to the liver and muscles, a few others have also been known to cause increased excretion of protein in the urine and kidney failure. These side effects are also more common in a renal transplant recipient due to the simultaneous administration of drugs that prevent rejection. Therefore, there is an emergent need for newer drugs which are both efficient and safe especially in this population PCSK-9 inhibitors (Proprotein Convertase Subtilisin Kinase-9 inhibitors) are a new class of drugs that are highly efficient in lowering lipid levels in the general population. However, an exclusive trial involving kidney transplant recipients is yet to be done. Through this study, we would like to evaluate the safety and tolerability of Evolocumab (trade name: Repatha) which is a PCSK-9 inhibitor developed by Amgen, Inc in renal transplant recipients. The study would involve a total of 120 patients across 3 different hospitals in Boston, Massachusetts.

Detailed Description
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Cardiovascular disease is the leading cause of death in renal transplant recipients (RTR). 44% of RTR have LDL-C greater than 100mg/dL, six months after transplant. The correlation between the increase in serum LDL level and the increased risk of atherosclerotic cardiovascular disease (ASCVD) is well established. A reduction in LDL level is associated with a decreased risk of mortality and morbidity in patients with ASCVD. Statins have been the long-standing drug of choice in treating dyslipidemia. A single prospective randomized trial known as the ALERT trial compared the benefits of statins to placebo in transplant recipients. The original study consisted of 2000 RTR and an extension of this study evaluated 1652 patients and demonstrated a 21% reduction in major cardiac events (p=0.036) and a 29% reduction in cardiac death or definite non-fatal myocardial infarction (p=0.014). Even though statins decrease the probability of cardiovascular events there was no difference in graft survival or mortality benefit in RTR. Another concerning factor for the use of statins is the tolerability of these drugs. Statins have been associated with hepatotoxicity and myotoxicity, the incidence of which is higher in RTR. This effect is dose-related and may be precipitated by the administration of agents that inhibit cytochrome p450 isoenzymes such as Tacrolimus and Cyclosporine which are the most commonly used immunosuppressants. Another statin based drug (Fluvastatin) has been associated with proteinuria and renal failure. Hence there is a need to explore novel treatment options in the management of dyslipidemia, particularly in RTR. PCSK-9 inhibitors (Proprotein Convertase Subtilisin Kinase-9 inhibitors) have shown to decrease LDL levels by 60% in patients on statin therapy. However, these drugs have been studied sparingly in patients with Chronic Kidney Disease (CKD) and have not yet been analyzed in RTR. The study will involve 120 patients across 3 different hospitals. Two different but equivalent drug dosing strategies are available. A 420mg monthly subcutaneous injection using an on-body infusor (Repatha Pushtronex system) or a 140mg subcutaneous injection once every two weeks using a prefilled auto-injector (Repatha SureClick). The choice of dosing strategy will be based on patient preference. This study will be conducted over one year.

Official Title
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Lipid Management in Renal Transplant Recipients: A Pilot Study Evaluating the Use of PCSK-9 Inhibitor, Evolocumab.

Conditions
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Hyperlipidemias

Intervention / Treatment
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* Drug: Evolocumab
* Drug: Statins (Cardiovascular Agents)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult renal transplant recipients greater than 1-year post-transplantation, men and women between 18 and 85 years of age, inclusive. Any patient with documented ASCVD or diabetes and 1 or more risk factors for ASCVD, including, but not limited to obesity, inactive lifestyle, hypertension, smoking, and family history. and an LDL >70 mg/dl (Highest-Risk Patients) Any patient not classified as one of our highest-risk patients, that has an LDL >100 mg/dl Exclusion Criteria: Patients currently enrolled in another interventional clinical trial. Patients being actively treated for cellular or antibody-mediated rejection. Serious hypersensitivity to Evolocumab or any component of the formulation. Patients who are pregnant or planning a pregnancy in the next one year.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study model involves two groups. One group is for patients who are treated exclusively with Evolocumab while the second group involves patients who are treated using a combination of Evolocumab and a statin-based drug.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Evolocumab only<br>This arm includes subjects who are treated using Evolocumab. | Drug: Evolocumab<br>* Two different but equivalent drug dosing strategies are available. A 420mg monthly subcutaneous injection using an on-body infuser (Repatha Pushtronex system) or a 140mg subcutaneous injection once every two weeks using a prefilled auto-injector (Repatha SureClick). The choice of dosing strategy will be based on patient preference.<br>* Other names: Rapatha;|
| Experimental: Evolocumab plus statin<br>This arm includes subjects who are treated using a combination of Evolocumab and a statin-based drug. | Drug: Evolocumab<br>* Two different but equivalent drug dosing strategies are available. A 420mg monthly subcutaneous injection using an on-body infuser (Repatha Pushtronex system) or a 140mg subcutaneous injection once every two weeks using a prefilled auto-injector (Repatha SureClick). The choice of dosing strategy will be based on patient preference.<br>* Other names: Rapatha;Drug: Statins (Cardiovascular Agents)<br>* Previously prescribed statin therapy.<br>* Other names: HMG CoA reductase inhibitors;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent change from baseline in the LDL cholesterol level | The primary efficacy measure will be the percent change from baseline in the LDL cholesterol level at 12 months as compared to baseline. Serum LDL-cholesterol levels are measured in milligrams per deciliter. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| absolute change from baseline in the LDL cholesterol level | Secondary outcome measures will include the absolute change from baseline in the LDL cholesterol level, the number of patients who achieved LDL-cholesterol of <70 mg/dl, LDL/HDL ratio and evaluation of transplant-related outcomes, such as renal function, tacrolimus concentrations, and rejection episodes. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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renal transplant, high cholesterol, hyperlipidemia, cardiovascular disease, Evolocumab, PCSK-9 inhibitors, monoclonal antibody