Cytomegalovirus (CMV), Kidney Diseases, Kidney Transplant; Complications
Conditions
Brief summary
This is a prospective, randomized multicenter trial of preemptive therapy (PET) vs. antiviral prophylaxis (AP) for prevention of cytomegalovirus (CMV) disease in adult D+R- kidney transplant recipients (KTR). Patients meeting study eligibility criteria and who have provided informed consent will be randomized (1:1) within 7 days of transplant to receive, in an open label design, either AP with valganciclovir 900 mg orally once daily or letermovir 480 mg orally once daily \[both dose adjusted per Food and Drug Administration (FDA) label\] for 200 days post-transplant), or PET (central lab weekly plasma polymerase chain reaction (PCR) monitoring for CMV deoxyribonucleic acidemia (DNAemia)) for 100 days post-transplant, with oral valganciclovir 900mg orally twice daily (or renally dosed per FDA label) at onset of CMV DNAemia at any level and continued until plasma CMV DNAemia is negative or below the level of quantitation in two consecutive weekly plasma samples. Study participants will be followed for pre-specified outcomes (clinical, laboratory, immunologic, safety) until withdrawal, death, or study closure, up to a maximum of 5.5 years post-transplant. Approximately 360 participants (180 participants in each group) will be randomized into the study. Estimated Time to Complete Enrollment: 4 years
Interventions
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.
Valganciclovir, 900 mg given orally once daily to all Prophylaxis group subjects for 200 days post transplantation as prophylaxis.
Sponsors
University of California, San Francisco
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Subject or legally authorized representative has provided written informed consent. 2. Age ≥ 18 years of age at the time of informed consent. 3. Negative for IgG antibody to CMV as assessed in a CLIA-certified laboratory between 28 days prior to transplant and up to 7 days post-transplant but prior to randomization. 4. Received a kidney transplant from a CMV seropositive (IgG positive) donor in the past 7 days prior to enrollment 5. Individuals of reproductive (childbearing) potential must have a negative pregnancy test (serum or urine) collected prior to randomization (SOC results within 7 days prior to transplant may be used), and must also agree to use a medically approved method of contraception. Acceptable methods include: barrier method, intrauterine device (hormonal or non-hormonal), oral hormonal contraceptives, abstinence from the time of enrollment through until discontinuation of ganciclovir or valganciclovir in either arm during the intervention period. 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). 6. If male, must agree to practice a barrier method of contraception or abstinence from the time of enrollment through 3 months after discontinuation of ganciclovir or valganciclovir in either arm during the intervention period.
Exclusion criteria
1. In the opinion of the investigator, participants who are unable or unwilling to undergo preemptive therapy protocol (weekly CMV PCR, etc.) 2. Patients who are breastfeeding or planning to breastfeed within 6 months post-transplant 3. Allergy to valganciclovir/ganciclovir or Letermovir 4. Receipt of immunoglobulin or CMV-specific immunoglobulin within the last 3 months (this includes COVID convalescent plasma) 5. Currently enrolled or anticipated enrollment in another interventional study that, in the opinion of scientific leadership team, could affect evaluation of the primary safety and/or efficacy outcomes. 6. Most recent platelet count post-transplant \<25,000/uL 7. Most recent ANC performed post-transplant \<1000/uL 8. Multi-organ transplant (except simultaneous kidney-pancreas) within the past 7 days 9. Prior or planned receipt of a hematopoietic cell transplant 10. Baseline immunodeficiency prior to transplant, including but not limited to: 1. Known or suspected HIV infection 2. Congenital or acquired immunodeficiency 11. Unacceptable immunosuppression 1. Receipt of desensitization therapy prior to kidney transplant, or 2. Receipt of an ABO-incompatible kidney transplant except A2 to blood type B
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Incidence of endpoint committee (EC)-confirmed CMV disease (either syndrome or end-organ) by 1-year post-transplant. | Within 1-year post-transplant |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Non-inferiority of PET (within a 10% margin) vs AP for EC-confirmed CMV disease by 1-year post-transplant, contingent on failure to meet the primary superiority endpoint. | by 1-year post-transplant | Although the study sample size is powered to detect the superiority of one preventive strategy compared to the other, it is possible that the two approaches may have similar efficacy with respect to prevention of CMV disease. Therefore, should there be insufficient evidence to conclude superiority of one of the approaches, a key Secondary Outcome is a non-inferiority assessment of preemptive therapy to prophylaxis, assuming a non-inferiority margin of 10%. This margin is based on what is known about the effectiveness of the two approaches as published in literature and the potential that the two strategies could be similarly efficacious in preventing CMV disease. The success rate for the prophylaxis group is estimated to be \~80% based on a systematic review and meta-analysis with hypothesized success rates for the preemptive group expected to be higher. |
| Proportion of participants with investigator-determined CMV disease | by 1-year post transplant | — |
| Time in days to biopsy-proven acute rejection (BIPAR) | From date of randomization until the date of BIPAR from any cause, assessed up to 5.5 years | — |
| Time in days to graft loss | From date of randomization until the date of graft loss from any cause, assessed up to 5.5 years | — |
| Time in days to death | From date of randomization until the date of death from any cause, assessed up to 5.5 years | — |
| Mean estimated glomerular filtration rate (eGFR) in mL/min/1.73m2 at 1, 2, 3, and 4-years post-transplant | 1, 2, 3, and 4-years post-transplant | — |
Countries
United States
Contacts
CONTACTMegan Gish
PRINCIPAL_INVESTIGATORAbhijit P. Limaye, MD
University of California, San Francisco
Outcome results
None listed