ValGanciclovir Versus ValAcyclovir for Viral Prophylaxis in Kidney Transplantation
|ClinicalTrials.gov Identifier: NCT01972035|
Recruitment Status : Active, not recruiting
First Posted : October 30, 2013
Last Update Posted : December 4, 2019
Our study will compare all kidney transplant recipients receiving valganciclovir vs. valacyclovir for one year following kidney transplant and compare:
- the incidence, magnitude and duration of CMV and EBV viremia in the first year after transplant.
- the side effects of the anti-viral drugs requiring dose reduction or cessation
In addition, we will test renal tissue obtained from any biopsies post-transplant (surveillance or clinically indicated biopsies) by both polymerase chain reaction (PCR) and fluorescence in situ hybridization to assess for latent CMV and/or EBV.
|Condition or disease||Intervention/treatment||Phase|
|Transplantation Infection Epstein-Barr Virus Infections Cytomegalovirus Infections||Drug: Valacyclovir Drug: Valganciclovir||Phase 2|
Herpes viruses such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV) cause considerable morbidity and mortality post-kidney transplant. Even subclinical CMV and/or EBV viremia have been associated with deterioration in kidney transplant function. Currently, valganciclovir (valG) is the primary prophylactic agent against CMV in kidney transplant recipients but CMV viremia has been noted in 22% of pediatric post-kidney transplant recipients, and the incidence at the University of Minnesota (UMMC) in all kidney transplant recipients is as high as 17% despite valG prophylaxis. CMV disease post-kidney transplant can manifest as fever, leucopenia, or mild to severe organ involvement. While an effective anti-CMV drug, valG has a number of adverse effects including leucopenia, also a side effect of mycophenolate mofetil (MMF), one of the cornerstones of current anti-rejection regimens. Combined therapy with MMF and valG frequently results in leucopenia associated infection or leucopenia necessitating reduction in MMF doses, increasing the risk of rejection. In addition, valG is prohibitively expensive forcing many centers adopt a pre-emptive therapeutic approach whereby post-Ktx patients are screened for CMV, and at new onset viremia, valG is initiated. This approach has been associated with increased CMV infections and resistant viral strains. Therefore, there is need for an alternate, more cost-effective drug with a more benign side effect profile and equal effectiveness against CMV.
To date, the anti-EBV effect of valG is poorly defined and prevention of EBV infection is by close monitoring and immunosuppression reduction at the discovery of EBV viremia. EBV can present post-kidney transplants as infectious mononucleosis syndrome, hepatitis and, most importantly, can initiate potentially fatal lymphoproliferative disorders (PTLD). Between October 2003 and December 2009, EBV viremia occurred in 20% of adults and 50% of pediatric kidney transplant recipients (60/120) at UMMC, and, PTLD occurred in 6% (7/120) of pediatric recipients. Effective anti-EBV prophylaxis could substantially improve kidney transplant outcomes.
UMMC conducts surveillance biopsies at transplant and 3 and 12 months post-kidney transplant on all adult transplant recipients, providing an ideal opportunity to assess kidney tissue for EBV and CMV via molecular and immunological assays. Isolating the virus from infected recipient would be a pivotal step in our understanding of the mechanisms of CMV and EBV infection post-kidney transplant.
In summary, if valacyclovir and valganciclovir have equivalent efficacy in CMV prophylaxis, and valacyclovir has the anticipated effect on EBV prevention, the use of valacyclovir will result in a reduced risk of leucopenia-associated infection, and a lower incidence of rejection by allowing the use of standard MMF doses. Since valacyclovir is cheaper, it is plausible that universal prophylaxis will be a plausible and affordable option for all transplant recipients.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||160 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||ValGanciclovir Versus ValAcyclovir for Viral Prophylaxis in Kidney Transplantation|
|Actual Study Start Date :||August 1, 2014|
|Estimated Primary Completion Date :||October 31, 2020|
|Estimated Study Completion Date :||October 31, 2020|
Kidney recipients who give informed consent will be randomly assigned to receive ValA or ValG in a 1:1 ratio. Duration of therapy is 3-12 months depending on risk and age of recipient. Dosing is based on glomerular filtration rate.
Active Comparator: ValGanciclovir
Kidney recipients who give informed consent will be randomly assigned to receive ValG or ValA in a 1:1 ratio. Duration of therapy is 3-12 months depending on risk and age of recipient. Dosing is based on glomerular filtration rate.
Standard of care
- Compare incidence, duration and magnitude of CMV and EBV viremia in kidney transplant recipients receiving valA vs. valG. [ Time Frame: First year post-kidney transplant ]In infectious mononucleosis intervention trials, two weeks of valA therapy resulted in a statistically significant reduction in oral EBV shedding, accompanied by a clinical benefit, and valA is currently used for the therapy of severe cases of infectious mononucleosis in the community. ValA has also been shown to reduce the incidence and delay the onset of CMV disease in both CMV seronegative patients (P<0.001) and CMV seropositive patients (P=0.03). Therefore we hypothesize that the anti-EBV and anti-CMV effects of valA will be equal to or more effective than valG in reducing post-kidney transplant EBV and CMV viremia.
- Compare dose-limiting side effects in kidney transplant recipients receiving valA vs. valG. [ Time Frame: First year post-kidney transplant ]ValG is associated with adverse events including diarrhea, fever, nausea, vomiting, tremor, leucopenia, neutropenia, anemia and thrombocytopenia in ≥20% of patients. ValG induced leucopenia often necessitates a reduction in immunosuppressive therapy, increasing the risk of allograft rejection. Fewer severe adverse events are related to valA, including rash (8%), abdominal pain (1% to 11%), nausea (5% to 15%), vomiting (less than 1% to 6%), headache (13% to 38%) and fatigue (8%). Very high doses of valA (8g/day) for post-kidney transplant CMV prophylaxis was shown to have no severe or treatment-limiting side effects compared to placebo. Therefore we anticipate that the proportion of patients requiring dose reduction or cessation of valA vs. valG due to adverse drug side effects will be less.
- To identify the presence and quantity of EBV and CMV in renal tissue biopsies from kidney transplant recipients. [ Time Frame: For first year post-kidney transplant ]It is postulated that latent virus in renal tissue is a major source of post-kidney transplant recipient infection, but this remains unproven. The ability in this research study to test renal tissue obtained from adult protocol biopsies at the time of kidney transplant and 3 and 12 months post-kidney transplant (corresponding with the timing of routine surveillance post-kidney transplant biopsies) by both polymerase chain reaction (PCR) and fluorescence in situ hybridization provides a unique opportunity to test this.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01972035
|United States, Minnesota|
|University of MN|
|Minneapolis, Minnesota, United States, 55455|
|Principal Investigator:||Hank Balfour, MD||University of Minnesota|