Cytomegalovirus (CMV) Vaccine in Orthotopic Liver Transplant Candidates

Official title

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

Overview

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.

Interventions

• 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
• Drug Placebo for CMV-MVA Triplex
  Arm 2 participants receive two doses of matching placebo CMV-MVA Triplex

Primary outcome measures

• Total days of Cytomegalovirus (CMV) active antiviral therapy (AVT) in CMV seropositive donor (D+) and seronegative (R-) and (D+R-) liver transplant recipients [Time frame: Within the first 100 days post-transplantation]
• Percent of participants with solicited adverse reactions [Time frame: Within 7 days of each dose]
• Percent of participants with pre-transplant treatment emergent serious adverse events (TESAE) [Time frame: Within 100 days after initial dose]
• Percent of participants with pre-transplant treatment emergent serious adverse events (TESAE) [Time frame: Within 28 days after each dose]
• Percent of participants with pre-transplant treatment emergent adverse events (TEAE) [Time frame: Within 28 days after each dose]
• Percent of participants with treatment emergent serious adverse events (TESAE) [Time frame: Throughout the study]

Secondary outcome measures (7)

• Percent of seropositive donor (D+) and seronegative (R-) liver transplant recipients (D+R- LTxRs) who develop Endpoint-Committee adjudicated Cytomegalovirus (CMV) disease [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: By 6 months post-transplant (Tx)]
• Time to onset of investigator-reported Cytomegalovirus (CMV) disease [Time frame: 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 [Time frame: 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 [Time frame: Within first 100 days post-transplant (Tx)]

Eligibility criteria

Inclusion criteria

• Subject must be able to understand and provide informed consent
• 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)
• Negative human immunodeficiency virus (HIV) testing and no clinical suspicion of HIV infection
• Planned for a first living donor liver transplant or listed/anticipated to be listed for a first deceased donor liver transplant.
• Anticipated to receive a liver transplant within 1-12 months
• 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)
• 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)
• 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:

• 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
• For women of reproductive potential as defined previously, a negative serum or urine pregnancy test (performed within 72 hours)

Exclusion criteria

• Women who are breastfeeding or planning to breastfeed
• Prior Cytomegalovirus (CMV) vaccination
• Receipt of immunoglobulin or CMV-specific immunoglobulin within the last 3 months (this includes coronavirus disease (COVID) convalescent plasma)
• Currently enrolled in another interventional study that, in the investigator's opinion, could affect the evaluation of safety and/or vaccine effect outcomes
• Prior (ever) receipt of a stem cell transplant (Peripheral blood stem cell (PBSC), marrow, cord blood, etc.)
• 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)
• Transplant status 1A or in the opinion of the investigator is likely to receive a transplant within the next month
• At the time of randomization, either listed for, or, in the opinion of the investigator, likely to receive any non-liver organ transplant
• Receipt of a clinical vaccine < 14 days before or planned to receive a clinical vaccine <14 days after the study agent
• Known allergy to any component of the study agent
• 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:

• Anaphylaxis or other severe reaction (Grade 4) considered definitely or probably attributable to dose 1
• Receipt of liver transplant prior to dose 2
• 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
• Receipt of a clinical vaccine < 14 days before or planned to receive a clinical vaccine <14 days after the study agent

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

United States · 18 centers

• University of Alabama at Birmingham, School of Medicine — Birmingham
• University of California, San Diego School of Medicine — La Jolla
• Stanford University — Redwood City
• University of California, San Francisco — San Francisco
• University of Miami, Jackson Memorial Hospital — Miami
• Emory University Hospital — Atlanta
• Northwestern University, Feinberg School of Medicine — Chicago
• Johns Hopkins University School of Medicine — Baltimore
• … and 10 more centers

Identifiers

NCT: NCT06075745 · DAIT CTOT-44

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗