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

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

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.

Study Overview

• Status: Completed
• Conditions: Cytomegalovirus Infections
• Intervention / Treatment: Drug: Valganciclovir CMV Prophylaxis; Drug: Valganciclovir (Pre-emptive CMV Therapy); Drug: Ganciclovir

• Study Type: Interventional
• Enrollment (Actual): 299
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Innsbruck, Austria, 6020
  • Wien, Austria, 1090
• Germany
  • Aachen, Germany, 52057
  • Berlin, Germany, 13353
  • Berlin, Germany, 12203
  • Bremen, Germany, 28205
  • Düsseldorf, Germany, 40225
  • Erlangen, Germany, 91054
  • Essen, Germany, 45122
  • Frankfurt, Germany, 60596
  • Freiburg, Germany, 79106
  • Hamburg, Germany, 20246
  • Hann. Münden, Germany, 34346
  • Hannover, Germany, 30625
  • Jena, Germany, 07747
  • Köln, Germany, 50937
  • Leipzig, Germany, 04103
  • Lübeck, Germany, 23562
  • Muenchen, Germany, 81377
  • München, Germany, 81675
  • Münster, Germany, 48149
  • Regensburg, Germany, 93053
  • Tübingen, Germany, 72076
  • Wuerzburg, Germany, 97080

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Valganciclovir Cytomegalovirus (CMV) Prophylaxis	Drug: Valganciclovir CMV Prophylaxis; 900 mg valganciclovir, taken orally once daily, adjusted to renal function starting within 14 days of transplantation until Day 100 after transplantation.; Other Names: Valcyte
Active Comparator: Pre-emptive CMV Therapy	Drug: Valganciclovir (Pre-emptive CMV Therapy); 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.; Other Names: Valcyte; Drug: Ganciclovir; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Mazzola P, Schaeffeler E, Witzke O, Nitschke M, Kliem V, Zortel M, Wagner EM, Schwab M, Hauser IA. No association of genetic variants in TLR4, TNF-alpha, IL10, IFN-gamma, and IL37 in cytomegalovirus-positive renal allograft recipients with active CMV infection-Subanalysis of the prospective randomised VIPP study. PLoS One. 2021 Apr 16;16(4):e0246118. doi: 10.1371/journal.pone.0246118. eCollection 2021.
• Witzke O, Nitschke M, Bartels M, Wolters H, Wolf G, Reinke P, Hauser IA, Alshuth U, Kliem V. Valganciclovir Prophylaxis Versus Preemptive Therapy in Cytomegalovirus-Positive Renal Allograft Recipients: Long-term Results After 7 Years of a Randomized Clinical Trial. Transplantation. 2018 May;102(5):876-882. doi: 10.1097/TP.0000000000002024.

Study record dates

Study Major Dates

• Study Start: May 1, 2006
• Primary Completion (Actual): October 1, 2015
• Study Completion (Actual): October 1, 2015

Study Registration Dates

• First Submitted: September 5, 2006
• First Submitted That Met QC Criteria: September 5, 2006
• First Posted (Estimate): September 6, 2006

Study Record Updates

• Last Update Posted (Actual): March 11, 2020
• Last Update Submitted That Met QC Criteria: February 26, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Virus Diseases; Infections; DNA Virus Infections; Herpesviridae Infections; Cytomegalovirus Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Valganciclovir; Ganciclovir; Ganciclovir triphosphate
• Other Study ID Numbers: ML19313