Oral Paricalcitol in Kidney Transplant Recipients

Study Overview
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Brief Summary
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This study is being done to find out whether patients who receive a kidney transplant can benefit from taking the medication paricalcitol (trade name Zemplar®) as compared to kidney transplant recipients not taking this medication. The main possible benefits being studied are: Lower risk for overactive parathyroid glands after kidney transplantation. Lower risk of low bone density in the spine and hip after kidney transplantation. By dividing patients in the study into a group receiving Zemplar® and a group not receiving Zemplar®, it will be possible to understand the good and bad effects of Zemplar® during the first year after a kidney transplant.

Detailed Description
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The most significant challenge in kidney transplantation at present is that of reducing the risk of long-term complications. This includes hyperparathyroidism, a common post kidney transplant complication that contributes to loss of bone density and fracture risk and necessitates surgical intervention in approximately 5% of kidney transplant patients. In order to take part in the study you will already have been accepted for kidney transplantation from a living donor or from a deceased donor at Mayo Clinic in Rochester, Minnesota. After you have agreed to take part in the study you will be put in one of two groups by chance (as in the flip of a coin): Group 1 (Standard Treatment or Control): Patients in this group will receive a combination of four anti-rejection medications that have been used at Mayo Clinic Rochester for many kidney transplant patients and does not include any research study medicines. These medications will include: Alemtuzumab (Campath®) - this medicine will be given intravenously (IV) on the day of the transplant during surgery. Methylprednisolone (Solumedrol®) - this medicine, which is part of a family of medicines often referred to as corticosteroids, will be given intravenously on the day of the transplant during surgery. This will be the only planned dose of corticosteroid medicine you will receive although this medicine and a tablet form called Prednisone may be given at a later time if you have an episode of transplant rejection. Mycophenolate Mofetil (Cellcept®) - this medicine will be given by mouth twice daily beginning the evening before the transplant (for living donor transplants) or the day of the transplant (for deceased donor transplants). It will be continued for as long as you have your transplant unless there is a medical reason to stop it. Tacrolimus (Prograf®) - this medicine will be given by mouth once daily beginning on the fourth day after the transplant. It will continue for as long as you have your transplant unless there is a medical reason to stop it. The dose will be adjusted based on a blood test that will be done between twice a week and once a month for as long as you take the medicine. Group 2 (Zemplar® + Standard Treatment): Patients in this group will receive the same combination of anti-rejection medications as the patients in Group 1 (a-d above) plus Zemplar®, which is the medicine being studied, will also be started on the day of the transplant. Zemplar® will be given as a capsule containing 1 microgram of Zemplar® once daily beginning the day after the transplant. It will be continued at the same dose for the first two weeks then, depending on the results of blood and urine testing, will be increased to 2 micrograms daily. The dose will remain at 2 micrograms daily until the end of the study unless there is a medical reason to reduce or stop it or unless the study is stopped early. Both groups of patients will be treated by the same team of doctors, nurses and nurse coordinators that care for all kidney transplant patients at Mayo Clinic. The procedures and treatments for your transplant will be the same as those recommended at Mayo Clinic for all patients receiving a kidney transplant. These include the surgical operation to carry out the transplant; the need to take anti-rejection medicines by mouth for the rest of your life; the need to have blood and urine testing at regular intervals for the rest of your life to monitor the progress of your transplant; and the recommendation to have a biopsy of your transplant carried out on three occasion during the first two years after the transplant surgery. These procedures and their potential complications will be described to you in detail by your transplant physician, transplant surgeon, and transplant coordinator. The study will not require extra hospital or outpatient visits compared to the usual care for all kidney transplant patients at Mayo Clinic Rochester.

Official Title
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Oral Paricalcitol in Kidney Transplant Recipients Receiving a Corticosteroid-free Immunosuppressive Regimen

Conditions
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Transplant; Failure, Kidney, Renal Disease, End Stage, Hyperparathyroidism, Secondary

Intervention / Treatment
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* Drug: Paricalcitol
* Other: Corticosteroid Avoidance Immune Suppression Protocol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years and older. First or second deceased donor or living donor renal transplant. Normocalcemia or hypocalcemia. Willing to give informed consent Exclusion Criteria: Third or subsequent renal transplant. Incompatible blood type or positive cross-match donor. Multiple organ transplant recipients. Diabetic with plans for future pancreas or islet transplant. Evidence of donor-specific sensitization (positive T-cell and/or B-cell flow cytometric cross-match). Documented hypercalcemia (total serum calcium 10.5 mg/dl on two separate occasions) prior to transplantation. Serum 25(OH)vitamin D concentration ≤ 10 ng/ml

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Other: Immunosuppression without paricalcitol (control)<br>Subjects will receive the standard immunosuppressive therapies consisting of induction therapy with Alemtuzumab (Campath®) and Methylprednisolone (Solumedrol®), then maintained with corticosteroid avoidance using Mycophenolate Mofetil (Cellcept®) and Tacrolimus (Prograf®). | Other: Corticosteroid Avoidance Immune Suppression Protocol<br>* Induction with Alemtuzumab and maintenance with Tacrolimus and Mycophenolate Mofetil. With standard antimicrobial prophylaxis and calcium supplementation.<br>* Other names: Standard Immune Suppression;|
| Active Comparator: Immunosuppression with paricalcitol<br>Subjects will receive the standard immunosuppressive therapy consisting of induction therapy with Alemtuzumab (Campath®) and Methylprednisolone (Solumedrol®), then maintained with corticosteroid avoidance using Mycophenolate Mofetil (Cellcept®) and Tacrolimus (Prograf®). In addition, subjects will receive the study medication paricalcitol (Zemplar®). | Drug: Paricalcitol<br>* Zemplar® - this medicine, which is the medicine being studied, will be given as a capsule containing 1 microgram of Zemplar® once daily beginning the day after the transplant. It will be continued at the same dose for the first two weeks then, depending on the results of blood and urine testing, will be increased to 2 micrograms daily. The dose will remain at 2 micrograms daily until the end of the study unless there is a medical reason to reduce or stop it or unless the study is stopped early.<br>* Other names: Brand name is Zemplar®;Other: Corticosteroid Avoidance Immune Suppression Protocol<br>* Induction with Alemtuzumab and maintenance with Tacrolimus and Mycophenolate Mofetil. With standard antimicrobial prophylaxis and calcium supplementation.<br>* Other names: Standard Immune Suppression;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Hyperparathyroidism at One Year | Parathyroid hormone (PTH) is a measure of how well the parathyroid gland is working and is measured by a blood test. Hyperparathyroidism (increased PTH) is defined as PTH blood value greater than 65 picograms/milliliter in the absence of hypocalcemia (low calcium) or if the subject had a parathyroidectomy (surgical removal of parathyroid glands) during the first year post-transplant. | 1 year post kidney transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Osteopenia/Osteoporosis of the Hip at One Year | Osteopenia/Osteoporosis are conditions where bone mineral density is lower than normal, reported by T-scores, measurements of the hip made using an Dual Energy X-ray Absorptiometry (DEXA) scan. The T-score is measured and compared to a normal healthy adult. A normal bone density results in a T-score between +1.0 and -1.0. A T-score of less than or equal to -1.5 was used for this study to define the presence of osteopenia/osteoporosis. Each participant will be categorized as having or not having osteopenia/osteoporosis of the hip at the end of the first post-transplant year based on bone mineral density results. | 1 year post kidney transplant | 
| Number of Subjects With Osteopenia/Osteoporosis of the Lumbar Spine at One Year | Osteopenia/Osteoporosis are conditions where bone mineral density is lower than normal, reported by T-scores, measurements of the lower spine made using an Dual Energy X-ray Absorptiometry (DEXA) scan. The T-score is measured and compared to a normal healthy adult. A normal bone density results in a T-score between +1.0 and -1.0. A T-score of less than or equal to -1.5 was used for this study to define the presence of osteopenia/osteoporosis. Each participant will be categorized as having or not having osteopenia/osteoporosis of the lumbar spine at the end of the first post-transplant year based on bone mineral density results. | 1 year post kidney transplant | 
| Serum Parathyroid Hormone (PTH) Level Over Time | Parathyroid hormone (PTH) is a hormone synthesized in the body's parathyroid glands that controls bone health. PTH controls calcium and phosphorus levels in the body. It is measured in the serum and reported in picograms per milliliter (pg/mL). | Baseline, 3 weeks, 3 months, 1 year post kidney transplant | 
| Serum Bone Alkaline Phosphatase (BAP) Level Over Time | BAP is a marker of bone turn-over, is measured in the serum and reported in micrograms per liter (mcg/L). | Baseline, 21 days, 90 days and 1 year post kidney transplant | 
| Change in Lumbar Spine Bone Mineral Density (BMD) | BMD was measured using a Dual Energy X-ray Absorptiometry (DEXA) scan and reported by T-scores, measurements of the lower spine made using the scan. The T-score reflects how your bone density measurement compares to normal healthy adults. A normal bone density results in a T-score between +1.0 and -1.0. A T-score of less than or equal to -1.5 was used for this study to define the presence of osteopenia/osteoporosis. Osteopenia is a condition of decreased bone mass or density but not thin enough to be diagnosed as osteoporosis. Osteoporosis is a condition where bone mass/density has diminished to a level causing higher risk of fracture. The average change in T-score from baseline to one year is reported. | Baseline, 1 year post kidney transplant | 
| Change in Hip Bone Mineral Density (BMD) | BMD was measured using a Dual Energy X-ray Absorptiometry (DEXA) scan and reported by T-scores, measurements made of the hip bones using the scan. The T-score reflects how your bone density measurement compares to normal healthy adults. A normal bone density results in a T-score between +1.0 and -1.0. A T-score of less than or equal to -1.5 was used for this study to define the presence of osteopenia/osteoporosis. Osteopenia is a condition of decreased bone mass or density but not thin enough to be diagnosed as osteoporosis. Osteoporosis is a condition where bone mass/density has diminished to a level causing higher risk of fracture. The average change in T-score from baseline to one year is reported. | Baseline, 1 year post kidney transplant | 
| Number of Subjects Who Died or Lost Their Renal Graft During First Year | The number of subject who died (or experienced failure of their kidney surgical graft) during the first year following kidney transplant are reported here. | Baseline to 1 year post kidney transplant | 
| Episodes of Acute Cellular Rejection (ACR) of the Renal Transplant | The number of episodes of ACR, as proven by renal biopsy, were recorded. | Baseline to 1 year post kidney transplant | 
| Mean Estimated Glomerular Filtration Rate (eGFR) at One Year | Glomerular filtration rate describes the amount that fluid is filtered through the kidney and can be estimated by using serum creatinine. eGFR is reported in milliliters per minute per 1.73 m^2 of body-surface area. | 1 year post kidney transplant | 
| Mean Change in Estimated Glomerular Filtration Rate (eGFR) Between 3 Weeks and 1 Year Post Transplant |  | 3 weeks, 1 year post kidney transplant | 
| 24-hour Total Protein in the Urine at 1 Year Post Transplant | A urine total protein test is conducted to detect excess protein in the urine. This test helps determine an individual's kidney functioning. Protein is not usually present in urine; therefore, presence of protein in the urine is a sign of abnormality. The quantity of protein in a sample of urine collected over 24-hour was measured and reported in milligrams per day. | 1 year post kidney transplant | 
| Degree of Interstitial Fibrosis on Graft Biopsy at One Year | Interstitial fibrosis refers to degree of scarring or fibrous tissue formed in the kidney. Renal pathologists reviewed biopsies of the subject's kidney grafts for fibrosis, with results expressed using the Banff schema; Quantitative criteria: ci0 = fibrosis observed in up to 5% of cortical area, ci1 = fibrosis in 6%-25% of cortical area (mild) , ci2 = fibrosis in 26%-50% of cortical area (moderate), ci3 = fibrosis in greater than 50% of cortical area (severe). The degree of interstital fibrosis for this study was defined and reported as follows: a Banff ci score of greater than 0 and less than 2 considered mild fibrosis and a ci score greater than or equal to 2 as moderate to severe fibrosis. | 1 year post kidney transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Paricalcitol, Parathyroid Hormone, Bone Alkaline Phosphatase, Chronic Kidney Disease, Glomerular Filtration Rate, Vitamin D Receptor, Interstitial Fibrosis and Tubular Atrophy, Zemplar®