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

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

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.

Study Overview

• Status: Completed
• Conditions: Cytomegalovirus Infection
• Intervention / Treatment: Drug: Valganciclovir

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).

• Study Type: Interventional
• Enrollment (Actual): 205
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095-8358
      • Ronald Reagan University of California Los Angeles Medical Center
  • Georgia
    • Atlanta, Georgia, United States, 30322-1013
      • Emory Clinic - Transplant Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905-0001
      • Mayo Clinic, Rochester - Infectious Diseases
  • New York
    • New York, New York, United States, 10029-6504
      • Mount Sinai School of Medicine - Medicine - Infectious Diseases
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213-3403
      • University of Pittsburgh - Medicine - Infectious Diseases
  • Washington
    • Seattle, Washington, United States, 98195-7110
      • University of Washington - Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Preemptive Therapy; 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; 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.
Active Comparator: Prophylaxis; 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; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): October 29, 2012
• Primary Completion (Actual): June 22, 2018
• Study Completion (Actual): June 22, 2018

Study Registration Dates

• First Submitted: March 2, 2012
• First Submitted That Met QC Criteria: March 8, 2012
• First Posted (Estimate): March 13, 2012

Study Record Updates

• Last Update Posted (Actual): August 26, 2021
• Last Update Submitted That Met QC Criteria: July 29, 2021
• Last Verified: March 22, 2018

More Information

Terms related to this study

• Keywords: valganciclovir; prophylaxis; CMV; liver transplant; ganciclovir; cytomegalovirus infections; preemptive therapy
• Additional Relevant MeSH Terms: Virus Diseases; Infections; DNA Virus Infections; Herpesviridae Infections; Cytomegalovirus Infections; Anti-Infective Agents; Antiviral Agents; Valganciclovir
• Other Study ID Numbers: 11-0073

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No