Kidney Transplant Preemptive Therapy or Prophylaxis for CMV Prevention in D+R Recipients

Official title

Kidney Transplant Preemptive Therapy or Prophylaxis (KPoP) for CMV Prevention in D+R- Recipients

Overview

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

• Drug Valganciclovir (Pre-emptive CMV Therapy)
  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.
• Drug Valganciclovir CMV Prophylaxis
  Valganciclovir, 900 mg given orally once daily to all Prophylaxis group subjects for 200 days post transplantation as prophylaxis.

Primary outcome measures

• Incidence of endpoint committee (EC)-confirmed CMV disease (either syndrome or end-organ) by 1-year post-transplant. [Time frame: Within 1-year post-transplant]

Secondary outcome measures (6)

• 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. [Time frame: by 1-year post-transplant]
• Proportion of participants with investigator-determined CMV disease [Time frame: by 1-year post transplant]
• Time in days to biopsy-proven acute rejection (BIPAR) [Time frame: From date of randomization until the date of BIPAR from any cause, assessed up to 5.5 years]
• Time in days to graft loss [Time frame: From date of randomization until the date of graft loss from any cause, assessed up to 5.5 years]
• Time in days to death [Time frame: 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 [Time frame: 1, 2, 3, and 4-years post-transplant]

Eligibility criteria

Inclusion criteria

• Subject or legally authorized representative has provided written informed consent.
• Age ≥ 18 years of age at the time of informed consent.
• 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.
• Received a kidney transplant from a CMV seropositive (IgG positive) donor in the past 7 days prior to enrollment
• 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).

• 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

• In the opinion of the investigator, participants who are unable or unwilling to undergo preemptive therapy protocol (weekly CMV PCR, etc.)
• Patients who are breastfeeding or planning to breastfeed within 6 months post-transplant
• Allergy to valganciclovir/ganciclovir or Letermovir
• Receipt of immunoglobulin or CMV-specific immunoglobulin within the last 3 months (this includes COVID convalescent plasma)
• 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.
• Most recent platelet count post-transplant <25,000/uL
• Most recent ANC performed post-transplant <1000/uL
• Multi-organ transplant (except simultaneous kidney-pancreas) within the past 7 days
• Prior or planned receipt of a hematopoietic cell transplant
• Baseline immunodeficiency prior to transplant, including but not limited to:

• Known or suspected HIV infection
• Congenital or acquired immunodeficiency
• Unacceptable immunosuppression

• Receipt of desensitization therapy prior to kidney transplant, or
• Receipt of an ABO-incompatible kidney transplant except A2 to blood type B

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

Open label

Primary purpose

Prevention

Study locations

United States · 5 centers

• University of California, San Francisco School of Medicine — San Francisco
• University of Miami Miller School of Medicine — Miami
• Emory University School of Medicine — Atlanta
• Robert Wood Johnson Health Network Barnabas Health — Livingston
• Medical College of Virginia Commonwealth — Richmond

Publications

• Limaye AP, Budde K, Humar A, Vincenti F, Kuypers DRJ, Carroll RP, Stauffer N, Murata Y, Strizki JM, Teal VL, Gilbert CL, Haber BA. Letermovir vs Valganciclovir for Prophylaxis of Cytomegalovirus in High-Risk Kidney Transplant Recipients: A Randomized Clinical Trial. JAMA. 2023 Jul 3;330(1):33-42. doi: 10.1001/jama.2023.9106. PMID 37279999
• Kotton CN, Kumar D, Caliendo AM, Huprikar S, Chou S, Danziger-Isakov L, Humar A; The Transplantation Society International CMV Consensus Group. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation. 2018 Jun;102(6):900-931. doi: 10.1097/TP.0000000000002191. PMID 29596116

Identifiers

NCT: NCT06798909 · STUDY00020695 · 1R01AI184205-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗