Clinical trial NCT06075745: Cytomegalovirus (CMV) Vaccine in Orthotopic Liver Transplant Candidates
Official title: Cytomegalovirus (CMV) Vaccine in Orthotopic Liver Transplant Candidates (CTOT-44)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Liver Transplant
Keywords: Cytomegalovirus
Vaccine
Orthotopic Liver Transplant
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2023-10-10
Enrollment: 416
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

1. Subject must be able to understand and provide informed consent
2. Negative for antibody to Cytomegalovirus (CMV) as assessed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory within 6 months of enrollment, and no history of prior positive CMV serology (IgG antibody)
3. Negative screening test for human immunodeficiency virus (HIV) and no clinical suspicion of HIV infection
4. Listed for a first living or 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 within 3 months prior to enrollment by any laboratory with CLIA certification or equivalent of \>= 20,000 cells/mm\^3 prior to enrollment, and in the opinion of the investigator, has not decreased \< 20,000 cells/mm\^3 at time of IP administration.

Eligibility criteria required: Dose 2:

1. Most recent platelet count \>= 20,000 cells/mm\^3 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:

   1. 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)
   2. 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
7. Averaged daily corticosteroid therapy at a dose \>=20 mg of prednisone equivalent in the last 28 days prior to randomization
8. Receipt of T- or B-cell depleting agents (e.g., ATG, Alemtuzumab, Rituximab) within the last 6-months prior to randomization
9. Transplant status 1A or in the opinion of the investigator is likely to receive a transplant within the next 2 months
10. At the time of randomization, either listed for, or, in the opinion of the investigator, likely to receive any non-liver organ transplant
11. Receipt of or planned administration of:

    1. Live, attenuated vaccine within 14 days of study agent
    2. Subunit or inactivated vaccine within 14 days of study agent
12. Known allergy to any component of the study agent
13. 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

Primary outcomes:
measure: Total days of Cytomegalovirus (CMV) active antiviral therapy (AVT) in CMV seropositive donor (D+) and seronegative (R-) and (D+R-) liver transplant recipients
timeFrame: Within the first 100 days post-transplantation
measure: Percent of participants with solicited adverse reactions
timeFrame: Within 7 days of each dose
measure: Percent of participants with pre-transplant treatment emergent serious adverse events (TESAE)
timeFrame: Within 100 days after initial dose
measure: Percent of participants with pre-transplant treatment emergent serious adverse events (TESAE)
timeFrame: Within 28 days after each dose
measure: Percent of participants with pre-transplant treatment emergent adverse events (TEAE)
timeFrame: Within 28 days after each dose
measure: Percent of participants with treatment emergent serious adverse events (TESAE)
timeFrame: Throughout the study
Secondary outcomes:
measure: Percent of seropositive donor (D+) and seronegative (R-) liver transplant recipients (D+R- LTxRs) who develop Endpoint-Committee adjudicated Cytomegalovirus (CMV) disease
timeFrame: By 6 months post-transplant (Tx)
measure: Percent of seropositive donor (D+) and seronegative (R-) liver transplant recipients (D+R- LTxRs) who develop investigator-reported Cytomegalovirus (CMV) disease
timeFrame: By 6 months post-transplant (Tx)
measure: Time to onset of Endpoint-Committee adjudicated Cytomegalovirus (CMV) disease in seropositive donor (D+) and seronegative (R-) (D+R-) liver transplant recipients
timeFrame: By 6 months post-transplant (Tx)
measure: Time to onset of Endpoint-Committee adjudicated Cytomegalovirus (CMV) in seropositive donor (D+) and seronegative (R-) (D+R-) liver transplant recipients
timeFrame: By 6 months post-transplant (Tx)
measure: Time to onset of investigator-reported Cytomegalovirus (CMV) disease
timeFrame: By 6 months post-transplant (Tx)
measure: Percent of seropositive donor (D+) and seronegative (R-) liver transplant recipients (D+R- LTxRs) who develop CMV DNAemia >= 1000 IU/mL
timeFrame: Within first 100 days post-transplant (Tx)
measure: Percent of seropositive donor (D+) and seronegative (R-) liver transplant recipients (D+R- LTxRs) who develop Endpoint committee adjudicated CMV disease
timeFrame: Within first 100 days post-transplant (Tx)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham, School of Medicine
state: Alabama
city: La Jolla
country: United States
facility: University of California, San Diego School of Medicine
state: California
city: Redwood City
country: United States
facility: Stanford University
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Miami
country: United States
facility: University of Miami, Jackson Memorial Hospital
state: Florida
city: Atlanta
country: United States
facility: Emory University Hospital
state: Georgia
city: Chicago
country: United States
facility: Northwestern University, Feinberg School of Medicine
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins University School of Medicine
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan Medical Center
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic, Rochester - College of Medicine and Science
state: Minnesota
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Durham
country: United States
facility: Duke University School of Medicine
state: North Carolina
city: Portland
country: United States
facility: Oregon Health & Sciences University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania School of Medicine
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University School of Medicine
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Seattle
country: United States
facility: University of Washington Medical Center: Transplantation
state: Washington
Study officials:
affiliation: University of California, San Francisco: Transplantation
name: Ajit P Limaye, MD
role: STUDY_CHAIR
affiliation: University of Washington Medical Center: Transplantation
name: Cindy Fisher, M.D.
role: STUDY_CHAIR
References: