Cytomegalovirus (CMV) Vaccine in Orthotopic Liver Transplant Candidates

Study Overview
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Brief Summary
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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 seronegative (R-) and seropositive donor (D+) (D+R-) liver transplant recipients (LTxRs). A protocol-mandated preemptive therapy (PET) strategy will be used for CMV disease prevention in D+R- LTxRs

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

Conditions
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Liver Transplant

Intervention / Treatment
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* Drug: CMV-MVA Triplex
* Drug: Placebo for CMV-MVA Triplex


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must be able to understand and provide informed consent; 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) Negative screening test for human immunodeficiency virus (HIV) and no clinical suspicion of HIV infection Listed for a first living or 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) In the absence of contraindications, must have received adult vaccinations or have documented immunity as outlined in current National Institute of Allergy and Infectious Diseases Division of Allergy, Immunology, and Transplantation (NIAID DAIT) Guidance for Patients in Transplant Trials 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: 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. 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: 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 Averaged daily corticosteroid therapy at a dose >=20 mg of prednisone equivalent in the last 28 days prior to randomization Receipt of T- or B-cell depleting agents (e.g., ATG, Alemtuzumab, Rituximab) within the last 6-months prior to randomization Transplant status 1A or in the opinion of the investigator is likely to receive a transplant within the next 2 months At the time of randomization, either listed for, or, in the opinion of the investigator, likely to receive any non-liver organ concurrent with liver transplant At the time of randomization listed for or, in the opinion of the investigator, likely to receive any non- liver organ concurrent with liver transplant Receipt of or planned administration of: Live, attenuated vaccine within 14 days of study agent Subunit or inactivated vaccine within 14 days of 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 subject 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vaccine Arm<br>Participants in this arm will receive two doses of Cytomegalovirus-Modified Vaccinia Ankara (CMV-MVA) Triplex CMV vaccine | Drug: CMV-MVA Triplex<br>* 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<br>|
| Placebo Comparator: Placebo Arm<br>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<br>* Arm 2 participants receive two doses of matching placebo CMV-MVA Triplex<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total days of Cytomegalovirus (CMV) antiviral therapy (AVT) in CMV seronegative (R-) and seropositive donor (D+) (D+R-) liver transplant recipients |  | Within the first 100 days post-transplantation | 
| 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 | 

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cytomegalovirus, Vaccine, Orthotopic Liver Transplant