A Study of Valcyte (Valganciclovir) CMV Prophylaxis After Renal Transplantation

Study Overview
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Brief Summary
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This 2 arm study will compare the efficacy of 100 days of Valcyte (900mg po daily) prophylaxis with that of no prophylaxis, under the condition of pre-emptive therapy of active CMV infection, in CMV positive renal transplant recipients. The influence of the two prevention concepts on the occurrence of direct and indirect effects of active CMV infections will be compared. The anticipated time on study treatment is 3 months-1 year, and the target sample size is 100-500 individuals.

Official Title
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A Randomized Trial Comparing Valcyte CMV Prophylaxis Versus Pre-emptive Therapy After Renal Transplantation Using Proteomics for Monitoring of Graft Alteration

Conditions
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Cytomegalovirus Infections

Intervention / Treatment
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* Drug: Valganciclovir CMV Prophylaxis
* Drug: Valganciclovir (Pre-emptive CMV Therapy)
* Drug: Ganciclovir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: primary or secondary renal allograft within preceding 14 days; IgG seropositive for CMV; receiving immunosuppressive therapy. Exclusion Criteria: active CMV infection; current/history of malignancy; acute steroid resistant rejection episode since transplantation.

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Valganciclovir Cytomegalovirus (CMV) Prophylaxis<br> | Drug: Valganciclovir CMV Prophylaxis<br>* 900 mg valganciclovir, taken orally once daily, adjusted to renal function starting within 14 days of transplantation until Day 100 after transplantation.<br>* Other names: Valcyte;|
| Active Comparator: Pre-emptive CMV Therapy<br> | Drug: Valganciclovir (Pre-emptive CMV Therapy)<br>* If plasma polymerase chain reaction (PCR) ≥ 400 CMV copies/millilitre, then 1800 mg valganciclovir per day adjusted to renal function for at least 14 days until the second negative PCR (below 400 copies/ml) followed by secondary prophylaxis for 28 days with 900 mg valganciclovir adjusted to renal function. If CMV disease or no response to valganciclovir treatment after 14 days (not falling viral load), then intravenous (IV) ganciclovir or additional appropriate therapy could have been administered according to the local site's standard, instead of valganciclovir.<br>* Other names: Valcyte;Drug: Ganciclovir<br>* If CMV disease or no response to valganciclovir treatment after 14 days (not falling viral load), then intravenous (IV) ganciclovir or additional appropriate therapy could have been administered according to the local site's standard, instead of valganciclovir.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Active Cytomegalovirus (CMV) Infection Within 12 Months | Active CMV infection was defined as plasma polymerase chain reaction (PCR) ≥ 400 copies/millilitre (ml). | Up to 12 months | 
| Percentage of Participants With CMV Disease Within 12 Months Including CMV Syndrome and Tissue Invasive Disease | CMV disease comprises the two components of CMV syndrome as well as CMV tissue invasive disease. CMV syndrome was defined as viremia according to plasma PCR ≥ 400 copies/ml and at least one of the following signs: fever of ≥38 °C; new or increased malaise (malaise defined as normal activity reduced >50%; cannot work or unable to care for self; leukopenia on 2 successive measurements separated by at least 24 hours thrombocytopenia; elevation of hepatic transaminases (alanine aminotransferase (ALT) or aspartate aminotransferase (AST) to at least 2 x upper limit of normal (ULN). CMV tissue invasive disease was defined as viremia according plasma PCR ≥ 400 copies/ml and clinical evidence of localized CMV infection (CMV inclusion cells or in situ detection of CMV antigen or deoxyribonucleic acid [DNA] by immunostaining or hybridization, respectively), cerebral spinal fluid [CSF]) and/or relevant symptoms or signs of organ dysfunction. | Up to 12 months | 
| Urine Proteomic Pattern at Month 12 | Proteomics is the complete set of proteins expressed by an organism, tissue, or cell. Urine proteomic pattern was measured on a scale between -1, indicating no graft alteration, and +1, indicating graft alteration. | Up to 12 months | 
| Percentage of Participants With Graft Loss at Month 84 |  | Up to 84 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With CMV Syndrome Within 12 Months | CMV syndrome was defined as viremia according to plasma PCR ≥ 400 copies/ml and at least one of the following signs: fever of ≥38 °C; new or increased malaise (malaise defined as normal activity reduced >50%; cannot work or unable to care for self; leukopenia on 2 successive measurements separated by at least 24 hours thrombocytopenia; elevation of hepatic transaminases (alanine aminotransferase (ALT) or aspartate aminotransferase (AST) to at least 2 x upper limit of normal (ULN). | Up to 12 months | 
| Percentage of Participants With CMV Tissue Invasive Disease Within 12 Months | CMV tissue invasive disease was defined as viremia: PCR ≥ 400 copies/ml and clinical evidence of localized CMV infection (CMV inclusion cells or in situ detection of CMV antigen or deoxyribonucleic acid [DNA] by immunostaining or hybridization, respectively), cerebral spinal fluid [CSF]) and/or relevant symptoms or signs of organ dysfunction. | Up to 12 months | 
| Time to Occurrence of First Viremia Within 12 Months | Viremia was defined as plasma PCR ≥ 400 copies/ml. | Up to 12 months | 
| Viral Burden at Viremia | Time-weighted area under the curve (AUC) of the polymerase chain reaction (PCR). Viremia was defined as plasma PCR ≥ 400 copies/ml. | Up to 12 months | 
| Creatinine Clearance at Month 12 | Creatinine clearance was estimated using the Cockcroft-Gault formula. | Up to 12 months | 
| Percentage of Participants With at Least One Treated and Biopsy-Proven Acute Rejection Episode Within 12 Months |  | Up to 12 months | 
| Days of Hospitalization |  | Up to 12 months | 
| Relationship Between Proteomics Pattern and Graft Survival | Proteomics is the complete set of proteins expressed by an organism, tissue, or cell. The proteomics of CKD273, CMV, and nephropathy was measured on a scale between -1, indicating no graft alteration, and +1, indicating graft alteration. | Up to 12 months | 
| Relationship Between Proteomics Pattern and Participant Survival | Proteomics is the complete set of proteins expressed by an organism, tissue, or cell. The proteomics of CKD273, CMV, and nephropathy was measured on a scale between -1, indicating no graft alteration, and +1, indicating graft alteration. | Up to 12 months | 
| Proteomics Parameter: CKD273 | Proteomics is the complete set of proteins expressed by an organism, tissue, or cell. The proteomics of CKD273 was measured on a scale between -1, indicating no graft alteration, and +1, indicating graft alteration. | Up to 12 months | 
| Proteomics Parameter: CMV | Proteomics is the complete set of proteins expressed by an organism, tissue, or cell. The proteomics of CMV was measured on a scale between -1, indicating no graft alteration, and +1, indicating graft alteration. | Up to 12 months | 
| Proteomics Parameter: Nephropathy | Proteomics is the complete set of proteins expressed by an organism, tissue, or cell. The proteomics of nephropathy was measured on a scale between -1, indicating no graft alteration, and +1, indicating graft alteration. | Up to 12 months | 
| Percentage of Participants Surviving at Month 12 |  | Up to 12 months | 
| Percentage of Participants With Graft Survival at Month 12 |  | Up to 12 months | 
| Percentage of Participants With Leukopenia Within 12 Months | Leukopenia: white blood cell (WBC) of < 3,500/microlitre (μL) and < 1,000/μL | Up to 12 months | 
| Percentage of Participants With Neutropenia Within 12 Months | Neutropenia: absolute neutrophil count (ANC) < 750/μL within 12 months. | Up to 12 months | 
| Percentage of Participants With Any Opportunistic Infection Within 12 Months |  | Up to 12 months | 
| Percentage of Participants With Post-Transplant Diabetes Mellitus |  | Up to 12 months | 
| Percentage of Participants With Active CMV Infections Not Responding to Valganciclovir or IV Ganciclovir Treatment | Active CMV infection was defined as plasma polymerase chain reaction (PCR) ≥ 400 copies/millilitre (ml). | Up to 12 months | 
| Number of Participants With CMV Viremia (Active CMV Infection) From Baseline to Month 24 and Every 12 Months up to Month 84 | Viremia (active CMV Infection) was defined as PCR ≥ 400 copies/ml. | From Month 24 to Month 84 | 
| Number of Participants With CMV Disease From Baseline to Month 24 and Every 12 Months up to Month 84 | CMV disease comprises the two components of CMV syndrome as well as CMV tissue invasive disease. CMV syndrome was defined as viremia according to plasma PCR ≥ 400 copies/ml and at least one of the following signs: fever of ≥38 °C; new or increased malaise (malaise defined as normal activity reduced >50%; cannot work or unable to care for self; leukopenia on 2 successive measurements separated by at least 24 hours thrombocytopenia; elevation of hepatic transaminases (alanine aminotransferase (ALT) or aspartate aminotransferase (AST) to at least 2 x upper limit of normal (ULN). CMV tissue invasive disease was defined as viremia according plasma PCR ≥ 400 copies/ml and clinical evidence of localized CMV infection (CMV inclusion cells or in situ detection of CMV antigen or deoxyribonucleic acid [DNA] by immunostaining or hybridization, respectively), cerebral spinal fluid [CSF]) and/or relevant symptoms or signs of organ dysfunction. | From Month 24 to Month 84 | 
| Number of Participants With CMV Syndrome From Baseline to Month 24 and Every 12 Months up to Month 84 | CMV syndrome was defined as viremia according to plasma PCR ≥ 400 copies/ml and at least one of the following signs: fever of ≥38 °C; new or increased malaise (malaise defined as normal activity reduced >50%; cannot work or unable to care for self; leukopenia on 2 successive measurements separated by at least 24 hours thrombocytopenia; elevation of hepatic transaminases (alanine aminotransferase (ALT) or aspartate aminotransferase (AST) to at least 2 x upper limit of normal (ULN). | From Month 24 to Month 84 | 
| Number of Participants With CMV Tissue Invasive Disease From Baseline to Month 24 and Every 12 Months up to Month 84 | CMV tissue invasive disease was defined as viremia according plasma PCR ≥ 400 copies/ml and clinical evidence of localized CMV infection (CMV inclusion cells or in situ detection of CMV antigen or deoxyribonucleic acid [DNA] by immunostaining or hybridization, respectively), cerebral spinal fluid [CSF]) and/or relevant symptoms or signs of organ dysfunction. | From Month 24 to Month 84 | 
| Number of Participants With Active CMV Infection After Month 24 and Every 12 Months up to Month 84 | Active CMV infection was defined as plasma polymerase chain reaction (PCR) ≥ 400 copies/millilitre (ml). | From Month 24 to Month 84 | 
| Number of Participants With CMV Disease After Month 24 and Every 12 Months up to Month 84 | CMV disease comprises the two components of CMV syndrome as well as CMV tissue invasive disease. CMV syndrome was defined as viremia according to plasma PCR ≥ 400 copies/ml and at least one of the following signs: fever of ≥38 °C; new or increased malaise (malaise defined as normal activity reduced >50%; cannot work or unable to care for self; leukopenia on 2 successive measurements separated by at least 24 hours thrombocytopenia; elevation of hepatic transaminases (alanine aminotransferase (ALT) or aspartate aminotransferase (AST) to at least 2 x upper limit of normal (ULN). CMV tissue invasive disease was defined as viremia according plasma PCR ≥ 400 copies/ml and clinical evidence of localized CMV infection (CMV inclusion cells or in situ detection of CMV antigen or deoxyribonucleic acid [DNA] by immunostaining or hybridization, respectively), cerebral spinal fluid [CSF]) and/or relevant symptoms or signs of organ dysfunction. | From Month 24 to Month 84 | 
| Percentage of Participants Surviving at Month 24 and Every 12 Months up to Month 84 |  | From Month 24 to Month 84 | 
| Number of Participants Who Died From Months 24 to Month 84 |  | From Month 24 to Month 84 | 
| Percentage of Participants With Graft Survival at Month 24 and Every 12 Months up to Month 84 |  | From Month 24 to Month 84 | 
| Number of Participants Who Had Lost Their Transplant up to Month 84 |  | From Month 24 to Month 84 | 
| Number of Participants With Active CMV Infection Who Had Lost Their Transplant up to Month 84 |  | From Month 24 to Month 84 | 
| Number of Participants Without Active CMV Infection Who Had Lost Their Transplant up to Month 84 |  | From Month 24 to Month 84 | 
| Kaplan-Meier Estimate of the Percentage of Participants (With Versus Without Active CMV Infection) on Valganciclovir CMV Prophylaxis With First Occurrence of Graft Loss at Month 84 | An analysis for the time to first occurrence of graft loss within month 84 (by means of Kaplan-Meier analysis) was done for all patients who suffered at least once from acute CMV infection (CMV viremia) during this study versus all patients who did not suffer from acute CMV infection (CMV viremia) during the study. Active CMV infection was defined as plasma polymerase chain reaction (PCR) ≥ 400 copies/millilitre (ml). | Up to 84 months | 
| Kaplan-Meier Estimate of the Percentage of Participants (With Versus Without Active CMV Infection) on Pre-emptive CMV Therapy With First Occurrence of Graft Loss at Month 84 | An analysis for the time to first occurrence of graft loss within month 84 (by means of Kaplan-Meier analysis) was done for all patients who suffered at least once from acute CMV infection (CMV viremia) during this study versus all patients who did not suffer from acute CMV infection (CMV viremia) during the study. Active CMV infection was defined as plasma polymerase chain reaction (PCR) ≥ 400 copies/millilitre (ml). | Up to 84 months | 
| Number of Participants Who Had Lost Their Transplant or Died up to Month 84 |  | From Month 24 to Month 84 | 
| Percentage of Participants With Graft Survival or Participant Survival at Month 24 and Every 12 Months up to Month 84 |  | From Month 24 to Month 84 | 
| Number of Participants With Graft Rejections by CMV Status (Positive or Negative) of the Donor at Month 24 and Every 12 Months up to Month 84 |  | From Month 24 to Month 84 | 
| Number of Graft Rejections by CMV Status (Positive or Negative) of the Donor at Month 24 and Every 12 Months up to Month 84 |  | From Month 24 to Month 84 | 
| Creatinine Clearance at Month 24 and Every 12 Months up to Month 84 | Creatinine Clearance estimated by Cockcroft-Gault formula. | From Month 24 to Month 84 |