A Study to Evaluate the Efficacy and Safety of Zenapax in Combination With CellCept, Cyclosporine, and Corticosteroids in Patients Undergoing Cardiac Transplantation

Study Overview
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Brief Summary
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The purpose of the study is to compare the number of randomized participants in each treatment group who experience an acute rejection episode in the first 6 months after undergoing cardiac transplantation.

Official Title
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A Double-Blind, Placebo -Controlled, Randomized Study to Assess the Efficacy and Safety of Zenapax in Combination With CellCept, Cyclosporine, and Corticosteroids in Patients Undergoing Cardiac Transplantation.

Conditions
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Heart Transplantation

Intervention / Treatment
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* Drug: Daclizumab
* Drug: Methylprednisolone
* Drug: Mycophenolate mofetil
* Drug: Placebo
* Drug: cyclosporine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must be undergoing their first cardiac allograft transplant Women of childbearing potential must have a negative serum pregnancy test within 48 hours prior to transplantation Women of childbearing potential must use two reliable forms of contraception simultaneously. Effective contraception must be used before beginning study drug therapy, and for 4 months following discontinuation of study drug therapy Participants and/or their guardians must be willing and be capable of understanding risks and comply with the purpose of the study Exclusion Criteria: Previous organ transplants Participants receiving multiple organs Participants requiring ventricular assist device (VAD) upon completion of transplantation surgery Women lactating, pregnant or of childbearing potential not using, or who are unwilling to use two reliable forms of contraception simultaneously during the study History of a psychological illness or condition which would interfere with the participant's ability to understand the requirements of the study White blood count =<2500/mm^3, platelets =<50,000/mm^3 or hemoglobin =<6 g/dL HIV-1, the presence of positive HBsAg, or chronic active hepatitis C Active peptic ulcer disease Severe diarrhea or other gastrointestinal disorders which might interfere with their ability to absorb oral medication Malignancies within the past 5 years, excluding skin carcinoma that have been adequately treated Participants who have received within the past 30 days or require concomitant treatment with other investigational drugs or immunosuppressive medications that are prohibited for this study Inability to start microemulsion form of cyclosporine within 72 hours

Ages Eligible for Study
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Minimum Age: 13 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Daclizumab<br>Daclizumab will be administered as a intravenous dose of 1 milligrams per kilogram [mg/kg] on Days 1, 8, 22, 36, and 50, along with mycophenolate mofetil (one dose of 1.5 mg twice daily [BID], cyclosporine 1-4 mg/kg IV or 2-6 mg/kg, and 500-1000 mg IV methylprednisolone peri operative switch to oral at 0.5-1 mg/kg/day followed by tapering. | Drug: Daclizumab<br>* Daclizumab will be administered as 1 mg/kg IV within 12 hours post-op (Day 1), and Days 8, 22, 36 and 50.<br>* Other names: Zenapax;Drug: Methylprednisolone<br>* Methylprednisolone will be administered as 500-1000 mg IV and peri-operative switch to oral at 0.5-1 mg/kg/day followed by tapering till 0.0-0.15 mg/kg/day (up to 365 days).<br>Drug: Mycophenolate mofetil<br>* Mycophenolate mofetil will be administered as 1.5 grams bid begun post-op, either IV or orally as required up to 365 days.<br>Drug: cyclosporine<br>* Cyclosporine will be administered as 1-4 mg/kg IV or 2-6 mg/kg orally up to 365 days.<br>|
| Placebo Comparator: Placebo<br>Matching placebo will be administered on Days 1, 8, 22, 36, and 50, along with mycophenolate mofetil (one dose of 1.5 mg twice daily [BID], cyclosporine 1-4 mg/kg IV or 2-6 mg/kg orally, and 500-1000 mg IV methylprednisolone peri-op switch to oral at 0.5-1 mg/kg/day followed by tapering. | Drug: Methylprednisolone<br>* Methylprednisolone will be administered as 500-1000 mg IV and peri-operative switch to oral at 0.5-1 mg/kg/day followed by tapering till 0.0-0.15 mg/kg/day (up to 365 days).<br>Drug: Mycophenolate mofetil<br>* Mycophenolate mofetil will be administered as 1.5 grams bid begun post-op, either IV or orally as required up to 365 days.<br>Drug: Placebo<br>* Matching placebo will be administered on Days 1, 8, 22, 36, and 50.<br>Drug: cyclosporine<br>* Cyclosporine will be administered as 1-4 mg/kg IV or 2-6 mg/kg orally up to 365 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Developed Acute Rejection Episode Within 6 Months Post-Transplant | The acute rejection episode was a composite end-point of acute rejection and treatment failure within 6 months post-transplant (PT). Participants with acute rejection included participants with a biopsy histology of International Society of Heart and Lung Transplant (ISHLT) Grade IIIA, IIIB, or IV and participants with hemodynamic compromise (HDC) who were treated for acute rejection (whether or not a biopsy was done and regardless of the grade of the biopsy). Participants who had treatment failure included participants who died within 6 months of transplantation before experiencing acute rejection or who were re-transplanted within 6 months of the primary transplantation and who did not experience an acute rejection or who were lost to follow-up. | Up to 6 months PT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Developed Acute Rejection Episode Within the 12 Months PT | The acute rejection episode was a composite end-point of acute rejection and treatment failure within 6 months. Participants with acute rejection included participants with a biopsy histology of ISHLT Grade IIIA, IIIB, or IV and participants with hemodynamic compromise (HDC) who were treated for acute rejection (whether or not a biopsy was done and regardless of the grade of the biopsy). Participants who had treatment failure included participants who died within 6 months of transplantation before experiencing acute rejection or who were re-transplanted within 6 months of the primary transplantation and who did not experience an acute rejection or who were lost to follow-up | Up to 12 months PT | 
| Number of Acute Rejection Episodes Per Participant Within the First 6 Months and 12 Months PT | The number of participants with 0,1, 2, 3 or 4 episodes at 6 and 12 months PT were reported. An episode of acute rejection was defined according to the date of positive biopsy of Grade IIIA or worse or the date of start of treatment for HDC, whichever came first. | Within 6 months and 12 months PT | 
| Number of Participant Who Died Within 6 Months 12 Months and 3 Years PT | The survival of the graft and participants at 6,12 months and 3 years PT was reported | At 6 months, 12 months , 3 years PT | 
| Number of Participants With Worst ISHLT Biopsy Grade Within First 6 Months and 12 Months PT | The number of participants with Worst International Society of Heart and Lung Transplant (ISHLT) grade within first 6 months and 12 months PT were reported. ISHLT is a standardized grading method to determine the acute cellular rejection on endomyocardial biopsy ; where 0= no rejection, IA= focal (perivascular or interstitial) infiltrate without necrosis, IB= diffuse but sparse infiltrate without necrosis, II=one focus only with aggressive infiltration and/or focal myocyte damage, IIIA=multifocal aggressive infiltrates and/or myocyte damage, IIIB= diffuse inflammatory process with necrosis, IV= diffuse aggressive polymorphous and/or infiltrate and/or edema and/or hemorrhage and/or vasculitis, with necrosis | Within 6 months and 12 months PT | 
| Median Time to First Acute Rejection Episode Within the First 6 Months and 12 Months PT | The median time to first acute rejection episode within first 6 months and 12 months PT was reported. | Within 6 months and 12 months PT | 
| Number of Participants Using Monomurab Cluster of Differentiation 3, Orthoclone Polyclonal Antithymocyte Globulin or Antilymphocyte Globulin in the First 6 Months and 12 Months PT | The number of participants who received monomurab Cluster of differentiation 3, orthoclone, polyclonal antithymocyte globulin or antilymphocyte globulin for treatment of biopsy proven rejection or HDC within 6 and 12 months PT were reported. | Within 6 months and 12 months PT | 
| Mean Maintenance Doses of Mycophenolate Mofetil, Cyclosporine, and Cumulative Dose of Corticosteroids at 6 and 12 Months PT | The maintenance doses of mycophenolate mofetil (1.5g twice a day daily), cyclosporine (1-4 mg/kg IV or 2-6 mg/kg oral [PO]/nasogastric [NG] within 72 hours post-operative]), and cumulative dose of corticosteroids (500-1000 mg IV methylprednisolone pre-operative switched to oral at 0.5-1 mg/kg/day. Tapered to 0.2 mg/kg/d by Day 28, 0.1-0.15 mg/kg/day from Days 36 to 90, and 0.1-0.15 mg/kg/day from Days 120 to 180)at 6 and 12 months PT were reported. Maintenance dose was calculated as total dose per day summed over all days that a participant was administered drug within the specified time interval, divided by number of days that a participant took drug within that time interval. | Within 6 months and 12 months PT | 
| Median Change From Baseline for Lipid Profile (Total Cholesterol, Low Density Lipoproteins, High Density Lipoproteins, and Triglycerides) | Lipid profile included total cholesterol, low density lipoproteins (LDL), high density lipoproteins (HDL), and triglycerides (all total cholesterol, LDL, HDL, and triglycerides with unit milligram per decilitre [mg/dL]), were reported. The median change from baseline (Day -2) in lipid profile values at 3 months and 6 months was reported. | From Baseline (Day -2) to 3 months and 6 months | 
| Median Change From Baseline for LDL/HDL Ratio |  | From Baseline (Day -2) to 3 months, and 6 months | 
| Number of Participants With Marked Laboratory Abnormalities: Hematology Parameters | A marked reference range was predefined by Roche. The marked reference range is broader than the standard reference range. Values falling outside the marked reference range (low or high) that also represent a defined change from Baseline were considered marked laboratory abnormalities (i.e. potentially clinically relevant). Hematology included hemoglobin, hematocrit, white blood cell count (WBC) with differential (including granulocytes or neutrophils, basophils, eosinophils, monocytes, lymphocytes), platelets, and erythrocyte count | Up to 12 months | 
| Number of Participants With Marked Laboratory Abnormalities: Biochemistry Parameters | A marked reference range was predefined by Roche. The marked reference range is broader than the standard reference range. Values falling outside the marked reference range (low or high) that also represent a defined change from Baseline were considered marked laboratory abnormalities (i.e. potentially clinically relevant). Biochemistry included blood urea nitrogen, creatinine, serum glutamic oxalacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), gamma-glutamyl transferase (GGT), phosphorous, total bilirubin, direct bilirubin, total protein, albumin, glucose, alkaline phosphatase, low density lipoprotein (LDH), uric acid, carbon dioxide, magnesium, sodium, potassium, chloride, calcium, LDL, HDL, total cholesterol, and triglycerides. | Up to 12 months | 
| Number of Participants With Any Adverse Events and Any Serious Adverse Event, and Adverse Events Leading to Premature Withdrawal | An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Pre-existing conditions which worsened during this study were reported as AEs. A serious adverse event (SAE) is any untoward medical occurrence that at any dose results in death, are life threatening, requires hospitalization or prolongation of hospitalization or results in disability/incapacity, and congenital anomaly/birth defect. | Up to 12 months | 
| Number of Participants With Malignancies and Opportunistic Infections | The opportunistic infections included infections with Cytomegalovirus, Aspergillus, Candida, Pneumocystis, Cryptococcus, Listeria, Herpes simplex, Herpes zoster. For malignancy, participants with any type of malignancy whose date of onset or diagnosis was after randomization was reported. | Up to 12 months |