Clinical trial NCT01552369: CMV Antiviral Prevention Strategies in D+R-Liver Transplants ("CAPSIL")
Official title: Prophylaxis Versus Preemptive Therapy for the Prevention of CMV in High-Risk R-D+ Liver Transplant Recipients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Cytomegalovirus Infection
Keywords: CMV
cytomegalovirus infections
ganciclovir
liver transplant
preemptive therapy
prophylaxis
valganciclovir
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2012-03-13
Enrollment: 205
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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).

Eligibility criteria: Inclusion Criteria:

1. Be \> / = 18 years of age.
2. Have negative Cytomegalovirus (CMV) serology (confirmed within 6 months of transplant) and receive a liver from a donor with positive CMV serology (R-/D+).
3. Have received their first orthotopic liver transplant (the transplanted liver may be deceased donor or live donor graft) within 10 days prior.
4. Have absolute neutrophil count \> 1000/µL at randomization.
5. - 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.
6. Subject or legally authorized representative has provided written informed consent.

Exclusion Criteria:

1. 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.
2. Have hypersensitivity to acyclovir, ganciclovir or valganciclovir.
3. Be breast-feeding mother.
4. Have known Human immunodeficiency virus (HIV) infection (based on testing performed during the transplant evaluation process).
5. Be undergoing multi organ transplant or have undergone prior organ transplant.
6. Have expected life expectancy of less than 72 hours.

Primary outcomes:
measure: Incidence of Cytomegalovirus (CMV) Disease.
timeFrame: 365 days post-transplant
Secondary outcomes:
measure: All-cause Mortality
timeFrame: Up to 365 days post-transplant
measure: Incidence of Allograft Rejection
timeFrame: Up to 365 days post-transplant
measure: Graft Loss
timeFrame: Up to 365 days post-transplant
measure: Late-onset CMV Disease
timeFrame: Up to 365 days post-transplant
measure: Bacterial Infections
timeFrame: Up to 365 days post-transplant
measure: Major Fungal Infections
timeFrame: Up to 365 days post-transplant
measure: Major Non-CMV Viral Infections
timeFrame: Up to 365 days post-transplant
measure: Neutropenia
timeFrame: Day 1 through Day 107
measure: Neutropenia Less Than 500
timeFrame: prior to day 107
measure: Hematopoietic Growth Factors
timeFrame: Day 1 through Day 107
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Ronald Reagan University of California Los Angeles Medical Center
state: California
city: Atlanta
country: United States
facility: Emory Clinic - Transplant Center
state: Georgia
city: Rochester
country: United States
facility: Mayo Clinic, Rochester - Infectious Diseases
state: Minnesota
city: New York
country: United States
facility: Mount Sinai School of Medicine - Medicine - Infectious Diseases
state: New York
city: Pittsburgh
country: United States
facility: University of Pittsburgh - Medicine - Infectious Diseases
state: Pennsylvania
city: Seattle
country: United States
facility: University of Washington - Medicine
state: Washington
Study officials:
References:
citation: Singh N, Winston DJ, Razonable RR, Lyon GM, Silveira FP, Wagener MM, Limaye AP. Risk Factors for Cytomegalovirus Viremia following Liver Transplantation With a Seropositive Donor and Seronegative Recipient Receiving Antiviral Therapy. J Infect Dis. 2021 Mar 29;223(6):1073-1077. doi: 10.1093/infdis/jiaa470.
citation: Singh N, Winston DJ, Razonable RR, Lyon GM, Silveira FP, Wagener MM, Stevens-Ayers T, Edmison B, Boeckh M, Limaye AP. Effect of Preemptive Therapy vs Antiviral Prophylaxis on Cytomegalovirus Disease in Seronegative Liver Transplant Recipients With Seropositive Donors: A Randomized Clinical Trial. JAMA. 2020 Apr 14;323(14):1378-1387. doi: 10.1001/jama.2020.3138.