CMV Antiviral Prevention Strategies in D+R-Liver Transplants (CAPSIL)

Study Overview
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Brief Summary
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This is a trial of preemptive therapy vs. prophylaxis for prevention of Cytomegalovirus (CMV) disease in R-D+ liver transplant patients. Subjects will be randomized within 10 days of transplant to receive in an open label design, either antiviral prophylaxis with valganciclovir, 900 mg orally once daily or preemptive therapy (weekly monitoring for CMV viremia by plasma PCR) for 100 days post-randomization with initiation of oral valganciclovir 900mg orally twice daily at onset of CMV viremia and continued until plasma PCR is negative on two consecutive weekly PCR tests). A minimum of 176 subjects will be enrolled in the study. The study duration is 7 years. The primary objective of this study is to compare prophylaxis versus preemptive therapy using valganciclovir for the prevention of CMV disease in R-/D+ liver transplant recipients.

Detailed Description
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This is a prospective, randomized, multicenter trial of preemptive therapy vs. prophylaxis for prevention of Cytomegalovirus (CMV) disease in seronegative recipient- seropositive donor (R-D+) liver transplant patients.Subjects will be randomized within 10 days of transplant to receive in an open label design, either antiviral prophylaxis with valganciclovir 900 mg orally once daily or preemptive therapy for 100 days post-randomization with initiation of oral valganciclovir 900mg orally twice daily at onset of CMV viremia (monitored weekly) and continued until plasma PCR is negative on two consecutive weekly PCR tests. Study participants will be followed during the intervention period (100 days post randomization) and until 12 months post-transplant for CMV disease, toxicity, and clinical outcomes (opportunistic infections, rejection, graft loss and mortality). Drug safety labs will be assessed and recorded for the entire treatment period in both the prophylaxis and preemptive group. Re-transplantation and all-cause mortality will also be assessed at study closure and no longer than 5 years after enrollment. Additionally, the impact of the two CMV prevention strategies on CMV-specific cellular and humoral immune responses will be evaluated at 100 days after randomization, and 6 and 12 months post-transplant. A minimum of 176 subjects will be enrolled in the study. Allowing for over-enrollment to replace dropouts, up to 205 subjects may be enrolled to achieve the target enrollment of 176. Subjects will be randomized into one of the two groups in 1:1 ratio. The study duration is 7 years. The primary objective of this study is to compare prophylaxis versus preemptive therapy using valganciclovir for the prevention of CMV disease in R-/D+ liver transplant recipients. The secondary objectives are:1) to assess the two preventive strategies for clinical outcomes (major bacterial, fungal and non-CMV viral infections, rejection, graft loss and mortality) at one year post transplantation; 2) to assess the two preventive strategies for hematologic toxicity (assessment of neutropenia and receipt of hematopoietic growth factor during study days 1-107).

Official Title
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Prophylaxis Versus Preemptive Therapy for the Prevention of CMV in High-Risk R-D+ Liver Transplant Recipients

Conditions
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Cytomegalovirus Infection

Intervention / Treatment
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* Drug: Valganciclovir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be > / = 18 years of age. Have negative Cytomegalovirus (CMV) serology (confirmed within 6 months of transplant) and receive a liver from a donor with positive CMV serology (R-/D+). Have received their first orthotopic liver transplant (the transplanted liver may be deceased donor or live donor graft) within 10 days prior. Have absolute neutrophil count > 1000/µL at randomization. - If female, and not postmenopausal or surgically sterile, must have negative pregnancy test (serum or urine) within 48 hours prior to randomization and must also agree to use medically approved method of contraception. Acceptable methods include: barrier method, intrauterine device (hormonal or non-hormonal), oral hormonal contraceptives, abstinence for 100 days after randomization and 3 months after valganciclovir cessation. -- If male, and has not had a vasectomy, he must agree to practice barrier method of contraception for 100 days after randomization and 3 months after valganciclovir cessation. Subject or legally authorized representative has provided written informed consent. Exclusion Criteria: Currently enrolled in any interventional trial of an investigational therapeutic agent unless co-enrollment has been approved by study Principal Investigators (PIs) and the DMID prior to enrollment. Have hypersensitivity to acyclovir, ganciclovir or valganciclovir. Be breast-feeding mother. Have known Human immunodeficiency virus (HIV) infection (based on testing performed during the transplant evaluation process). Be undergoing multi organ transplant or have undergone prior organ transplant. Have expected life expectancy of less than 72 hours.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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 |
| --- | --- |
| Experimental: Preemptive Therapy<br>900 mg of Valganciclovir given orally twice daily to Preemptive Therapy subjects upon detection of CMV viremia until plasma PCR is negative on two consecutive weekly PCR test. All dosages adjusted for renal dysfunction. n=88 | Drug: Valganciclovir<br>* Valganciclovir, 900 mg given orally once daily to all Prophylaxis group subjects for 100 days post transplantation as prophylaxis. Valganciclovir, 900 mg given orally twice daily to Preemptive Therapy group subjects as a PET only after a positive CMV PCR test and stopped after PCR is negative for 2 consecutive weeks.<br>|
| Active Comparator: Prophylaxis<br>900 mg of Valganciclovir given orally once daily to subjects for 100 days post transplantation. All dosages adjusted for renal dysfunction. n=88 | Drug: Valganciclovir<br>* Valganciclovir, 900 mg given orally once daily to all Prophylaxis group subjects for 100 days post transplantation as prophylaxis. Valganciclovir, 900 mg given orally twice daily to Preemptive Therapy group subjects as a PET only after a positive CMV PCR test and stopped after PCR is negative for 2 consecutive weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Cytomegalovirus (CMV) Disease. | CMV disease as verified by an independent end point committee | 365 days post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause Mortality | Survival probability at 1 year | Up to 365 days post-transplant | 
| Incidence of Allograft Rejection | Number of subjects with allograft rejection | Up to 365 days post-transplant | 
| Graft Loss | Incidence of graft loss (re-transplantation) | Up to 365 days post-transplant | 
| Late-onset CMV Disease | Incidence of late-onset CMV disease (occurring after 100 days post-randomization) as adjudicated by end point committee | Up to 365 days post-transplant | 
| Bacterial Infections | Incidence of bacterial opportunistic infections | Up to 365 days post-transplant | 
| Major Fungal Infections | Opportunistic fungal infections | Up to 365 days post-transplant | 
| Major Non-CMV Viral Infections | Incidence of non-CMV viral infections | Up to 365 days post-transplant | 
| Neutropenia | Incidence of neutropenia less than 1000/µL while on valganciclovir treatment | Day 1 through Day 107 | 
| Neutropenia Less Than 500 | ANC less than 500 while on valganciclovir | prior to day 107 | 
| Hematopoietic Growth Factors | Hematopoietic growth factor receipt for ANC less than 500 during valganciclovir treatment. | Day 1 through Day 107 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CMV, cytomegalovirus infections, ganciclovir, liver transplant, preemptive therapy, prophylaxis, valganciclovir