Cytomegalovirus (CMV) Vaccine in Orthotopic Liver Transplant Candidates (COLT)

Cytomegalovirus (CMV) Vaccine in Orthotopic Liver Transplant Candidates (CTOT-44)

This is a multi-center clinical trial in Cytomegalovirus (CMV) seronegative prospective liver transplant recipients to determine the efficacy of two doses of Cytomegalovirus-Modified Vaccinia Ankara (CMV-MVA) Triplex CMV vaccine pre-transplant. The primary objective is to assess the effect of pre-transplant (Tx) Triplex vaccination on duration of CMV antiviral therapy (AVT) within the first 100 days post-Tx in CMV seropositive donor (D+) and seronegative (R-) (D+R-) liver transplant recipients (LTxRs). A protocol-mandated preemptive therapy (PET) will be used for CMV disease prevention in D+R- LTxRs.

Study Overview

• Status: Recruiting
• Conditions: Liver Transplant
• Intervention / Treatment: Drug: CMV-MVA Triplex; Drug: Placebo for CMV-MVA Triplex

• Study Type: Interventional
• Enrollment (Estimated): 416
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Withdrawn
      • University of Alabama at Birmingham, School of Medicine
  • California
    • La Jolla, California, United States, 92093
      • Recruiting
      • University of California, San Diego School of Medicine
      • Contact: Saima Aslam, MD; Phone Number: 619-543-6146; Email: saslam@health.ucsd.edu
    • Redwood City, California, United States, 94063-3126
      • Recruiting
      • Stanford University
      • Contact: Dora Yuk-Wai Ho, MD, PhD; Phone Number: 650-736-2442; Email: jsbach@stanford.edu
    • San Francisco, California, United States, 94143-0000
      • Recruiting
      • University of California, San Francisco
      • Contact: Monica Fung, MD, MPH; Phone Number: 415-353-1275; Email: monica.fung@ucsf.edu
  • Florida
    • Miami, Florida, United States, 33136-1003
      • Recruiting
      • University of Miami, Jackson Memorial Hospital
      • Contact: Yoichiro Natori, MD, MPH; Phone Number: Please email; Email: yxn138@med.miami.edu
  • Georgia
    • Atlanta, Georgia, United States, 30322-0000
      • Recruiting
      • Emory University Hospital
      • Contact: Aneesh Mehta; Phone Number: Please email; Email: aneesh.mehta@emory.edu
  • Illinois
    • Chicago, Illinois, United States, 60611-0000
      • Recruiting
      • Northwestern University, Feinberg School of Medicine
      • Contact: Michael Angarone, DO; Phone Number: 312-695-6601; Email: m-angarone@northwestern.edu
  • Maryland
    • Baltimore, Maryland, United States, 21205-0000
      • Recruiting
      • Johns Hopkins University School of Medicine
      • Contact: Robin Avery, MD; Phone Number: 410-614-6702; Email: ravery4@jhmi.edu
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-1274
      • Recruiting
      • University of Michigan Medical Center
      • Contact: Kevin Gregg, MD; Phone Number: 734-232-1486; Email: kvngregg@med.umich.edu
  • Minnesota
    • Rochester, Minnesota, United States, 55905-0001
      • Recruiting
      • Mayo Clinic, Rochester - College of Medicine and Science
      • Contact: Raymund Razonable, MD; Phone Number: 507-255-7761; Email: Razonable.Raymund@mayo.edu
  • Nebraska
    • Omaha, Nebraska, United States, 68198-7835
      • Recruiting
      • University of Nebraska Medical Center
      • Contact: Sias Scherger, MD; Phone Number: 402-559-8650; Email: sscherger@unmc.edu
  • North Carolina
    • Durham, North Carolina, United States, 27710-1000
      • Recruiting
      • Duke University School of Medicine
      • Contact: Matthew Kappus, MD; Phone Number: 919-385-5487; Email: matthew.kappus@duke.edu
  • Oregon
    • Portland, Oregon, United States, 97239-3098
      • Active, not recruiting
      • Oregon Health & Sciences University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104-5127
      • Recruiting
      • University of Pennsylvania School of medicine
      • Contact: Emily Blumberg, MD; Phone Number: Please email; Email: eblumber@pennmedicine.upenn.edu
    • Pittsburgh, Pennsylvania, United States, 15213-0000
      • Recruiting
      • University of Pittsburgh Medical Center
      • Contact: Fernanda Silveira, MD, MS; Phone Number: 412-648-6512; Email: silvfd@upmc.edu
  • Tennessee
    • Nashville, Tennessee, United States, 37232-0011
      • Recruiting
      • Vanderbilt University School of Medicine
      • Contact: Suzanne Sharpton, MD; Phone Number: Please email; Email: suzanne.sharpton@vumc.org
  • Texas
    • Dallas, Texas, United States, 75390-0000
      • Recruiting
      • University of Texas Southwestern Medical Center
      • Contact: Ricardo La Hoz, MD; Phone Number: 205-306-5037; Email: ricardo.lahoz@utsouthwestern.edu
  • Washington
    • Seattle, Washington, United States, 98195
      • Recruiting
      • University of Washington Medical Center: Transplantation
      • Contact: Cindy P. Fisher, MD; Phone Number: 206-598-9149; Email: celaine@uw.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Subject must be able to understand and provide informed consent
2. Negative for Cytomegalovirus (CMV) IgG antibody as assessed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory within 12 months of enrollment, and no history of prior positive CMV serology (IgG antibody)
3. Negative human immunodeficiency virus (HIV) testing and no clinical suspicion of HIV infection
4. Planned for a first living donor liver transplant or listed/anticipated to be listed for a first deceased donor liver transplant.
5. Anticipated to receive a liver transplant within 1-12 months
6. For individuals of reproductive potential, a negative serum or urine pregnancy test within 72 hours prior to enrollment. NOTE: Individuals of reproductive potential are defined as individuals who have reached menarche and who have not been post-menopausal for at least 12 consecutive months with follicle-stimulating hormone (FSH) >=40 IU/mL or 24 consecutive months if an FSH is not available, i.e., who have had menses within the preceding 24 months, and have not undergone a sterilization procedure (e.g., hysterectomy, bilateral oophorectomy, or salpingectomy)
7. Participants who are able to impregnate or become pregnant (i.e., of reproductive potential) and are participating in sexual activity that could lead to pregnancy must agree to practice contraception/birth control (hormonal or barrier method) or agree to not participate in a conception process (e.g., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization) for at least 1 month following the last vaccine/placebo dose. For acceptable contraception methods that are more than 80 percent effective, see Food and Drug Administration (FDA) Office of Women's Health (http://www.fda.gov/birthcontrol)
8. The most recent platelet count is >= 20,000 cells/mm^3 within 3 months prior to enrollment and in the opinion of the investigator, has not decreased < 20,000 cells/mm^3 at time of study IP administration.

Eligibility criteria required: Dose 2:

1. Most recent platelet count >= 20,000 cells/mm^3 within 3 months prior to enrollment and in the opinion of the investigator, has not decreased < 20,000 cells/mm^3 since last result
2. For women of reproductive potential as defined previously, a negative serum or urine pregnancy test (performed within 72 hours)

Exclusion Criteria:

1. Women who are breastfeeding or planning to breastfeed
2. Prior Cytomegalovirus (CMV) vaccination
3. Receipt of immunoglobulin or CMV-specific immunoglobulin within the last 3 months (this includes coronavirus disease (COVID) convalescent plasma)
4. Currently enrolled in another interventional study that, in the investigator's opinion, could affect the evaluation of safety and/or vaccine effect outcomes
5. Prior (ever) receipt of a stem cell transplant (Peripheral blood stem cell (PBSC), marrow, cord blood, etc.)

6. Receipt of immunosuppression:

   • Within the last 3 months prior to randomization:

     • Systemic Chemotherapy or immunotherapy for cancer in the last 3 months (localized therapy for hepatocellular carcinoma [HCC] such as chemoembolization, Y-90 are not considered "systemic chemotherapy" and are not excluded)
     • Systemic immunosuppressive agents (e.g., cyclophosphamide, methotrexate, mycophenolate, azathioprine, calcineurin inhibitors, mTOR inhibitors, TNF-alpha inhibitors) and/or combination immunosuppressive drugs for any autoimmune or other conditions in the last 3 months except corticosteroids as below
   • Within the last 28 days prior to randomization: averaged daily corticosteroid therapy dose ≥20 mg of prednisone equivalent
   • Within the last 6 months prior to randomization: receipt of T- or Bcell depleting agents (e.g. ATG, Alemtuzumab, Rituximab)
7. Transplant status 1A or in the opinion of the investigator is likely to receive a transplant within the next month
8. At the time of randomization, either listed for, or, in the opinion of the investigator, likely to receive any non-liver organ transplant
9. Receipt of a clinical vaccine < 14 days before or planned to receive a clinical vaccine <14 days after the study agent
10. Known allergy to any component of the study agent
11. Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study

Exclusion criteria required: Dose 2:

1. Anaphylaxis or other severe reaction (Grade 4) considered definitely or probably attributable to dose 1
2. Receipt of liver transplant prior to dose 2
3. The participant must not have any severe acute illness or other factor, that, in the opinion of the investigator, requires postponement of dose 2 because of safety concerns. The participant can be re-evaluated for eligibility throughout the window of eligibility for the dose 2, once the illness or other factor has improved or resolved
4. Receipt of a clinical vaccine < 14 days before or planned to receive a clinical vaccine <14 days after the study agent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Vaccine Arm; Participants in this arm will receive two doses of Cytomegalovirus-Modified Vaccinia Ankara (CMV-MVA) Triplex CMV vaccine	Drug: CMV-MVA Triplex; The dosage used will be 5.0 x 10^8 pfu, administered under sterile conditions intramuscularly. The CMV-MVA Triplex vaccine lots range in titre from 5.0 to 9.0 x 10^8 pfu/mL in a supplied volume of 1.0 mL
Placebo Comparator: Placebo Arm; Participants will receive two doses of matching placebo of the Cytomegalovirus-Modified Vaccinia Ankara (CMV-MVA) Triplex CMV vaccine	Drug: Placebo for CMV-MVA Triplex; Arm 2 participants receive two doses of matching placebo CMV-MVA Triplex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent of participants with solicited adverse reactions	Consisting of local reactions including: injection site pain, swelling, erythema (redness); systemic reactions: fever, headache, muscle ache, fatigue)	Within 7 days of each dose
Percent of participants with pre-transplant treatment emergent serious adverse events (TESAE)		Within 100 days after initial dose
Percent of participants with pre-transplant treatment emergent serious adverse events (TESAE)		Within 28 days after each dose
Percent of participants with pre-transplant treatment emergent adverse events (TEAE)	Grade >=3 severity or increase of severity of baseline abnormality that results in grade >= 3 severity	Within 28 days after each dose
Percent of participants with treatment emergent serious adverse events (TESAE)	Grade >= 4 severity	Throughout the study
Total days of Cytomegalovirus (CMV) active antiviral therapy (AVT) in CMV seropositive donor (D+) and seronegative (R-) and (D+R-) liver transplant recipients		Within the first 100 days post-transplantation

Secondary Outcome Measures

Outcome Measure	Time Frame
Time to onset of investigator-reported Cytomegalovirus (CMV) disease	By 6 months post-transplant (Tx)
Percent of seropositive donor (D+) and seronegative (R-) liver transplant recipients (D+R- LTxRs) who develop Endpoint-Committee adjudicated Cytomegalovirus (CMV) disease	By 6 months post-transplant (Tx)
Percent of seropositive donor (D+) and seronegative (R-) liver transplant recipients (D+R- LTxRs) who develop investigator-reported Cytomegalovirus (CMV) disease	By 6 months post-transplant (Tx)
Time to onset of Endpoint-Committee adjudicated Cytomegalovirus (CMV) disease in seropositive donor (D+) and seronegative (R-) (D+R-) liver transplant recipients	By 6 months post-transplant (Tx)
Time to onset of Endpoint-Committee adjudicated Cytomegalovirus (CMV) in seropositive donor (D+) and seronegative (R-) (D+R-) liver transplant recipients	By 6 months post-transplant (Tx)
Percent of seropositive donor (D+) and seronegative (R-) liver transplant recipients (D+R- LTxRs) who develop CMV DNAemia >= 1000 IU/mL	Within first 100 days post-transplant (Tx)
Percent of seropositive donor (D+) and seronegative (R-) liver transplant recipients (D+R- LTxRs) who develop Endpoint committee adjudicated CMV disease	Within first 100 days post-transplant (Tx)

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Study Chair: Cindy Fisher, M.D., University of Washington Medical Center: Transplantation; Study Chair: Ajit P Limaye, MD, University of California, San Francisco: Transplantation

Publications and helpful links

Helpful Links

• Division of Allergy, Immunology, and Transplantation
• National Institute of Allergy and Infectious Diseases
• Clinical Trials in Organ Transplantation

Study record dates

Study Major Dates

• Study Start (Actual): March 5, 2024
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): February 28, 2028

Study Registration Dates

• First Submitted: October 4, 2023
• First Submitted That Met QC Criteria: October 4, 2023
• First Posted (Actual): October 10, 2023

Study Record Updates

• Last Update Posted (Actual): April 2, 2026
• Last Update Submitted That Met QC Criteria: March 27, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Vaccine; Cytomegalovirus; Orthotopic Liver Transplant
• Additional Relevant MeSH Terms: Infections; Virus Diseases; DNA Virus Infections; Herpesviridae Infections; Cytomegalovirus Infections
• Other Study ID Numbers: DAIT CTOT-44

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The plan is to share data upon completion of the study in: Immunology Database and Analysis Portal (ImmPort), a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts.
• IPD Sharing Time Frame: On average, within 24 months after database lock for the trial
• IPD Sharing Access Criteria: Open access

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