Not listed
KIDNEY TRANSPLANT PREEMPTIVE THERAPY OR PROPHYLAXIS (KPOP) FOR CMV PREVENTIONIN D+R- RECIPIENTS - IN KIDNEY TRANSPLANT RECIPIENTS (KTR), CYTOMEGALOVIRUS (CMV) INCREASES SHORT- AND LONG-TERM MORBIDITY, MORTALITY, AND ALLOGRAFT FAILURE, MAINLY DUE TO LIMITATIONS IN CURRENT PREVENTIVE STRATEGIES. ~90% OF CMV DISEASE OCCURS IN THE ~20% OF RECIPIENTS WHO ARE CMV SERONEGATIVE (R-) AND RECEIVE OF AN ORGAN FROM A CMV SEROPOSITIVE DONOR (D+) [D+R-], AND RESULTS FROM IMMUNE-SUPPRESSION-IMPAIRED DEVELOPMENT OF PROTECTIVE CMV-SPECIFIC IMMUNE RESPONSES. THE STRATEGIES FOR CMV PREVENTION IN D+R- KTR ARE ANTIVIRAL PROPHYLAXIS [AP] (SUPPRESSIVE ANTIVIRAL DRUG [VALGANCICLOVIR [VALGAN] OR LETERMOVIR [LET] GIVEN FOR 200D), AND PREEMPTIVE THERAPY [PET] (CMV DNAEMIA IS MONITORED BY SENSITIVE QUANTITATIVE PCR (QPCR) FOR 100D AND VALGAN IS GIVEN ONLY TO THOSE WITH CMV DNAEMIA. AP IS USED BY >90% OF CENTERS DUE TO A SMALLER EVIDENCE BASE FOR PET (ESPECIALLY WITH ATG USE) AND UNCERTAINTY ABOUT OTHER LONG-TERM OUTCOMES WITH PET VS AP. IN CMV D+R- LIVER TXP, A RANDOMIZED CLINICAL TRIAL (RCT) SHOWED THAT PET WAS FEASIBLE (>90% ADHERENCE), REDUCED ANTIVIRAL DRUG DAYS BY ~40% (62D VS. 100D), INCREASED PROTECTIVE CMV-SPECIFIC IMMUNITY (MULTIFUNCTIONAL CD4/CD8 T- CELLS, NK CELLS, AND NEUTRALIZING ANTIBODY [NAB]) AND DECREASED CMV DISEASE BY >50% VS. AP. THESE RESULTS CANNOT BE DIRECTLY EXTRAPOLATED TO KTR DUE TO IMPORTANT DIFFERENCES BETWEEN LIVER AND KIDNEY TXP, INCLUDING THE INTENSITY OF IMMUNOSUPPRESSION AND DIFFERENT ESTABLISHED/APPROVED PROPHYLAXIS REGIMENS. AS A RESULT, DESPITE POTENTIAL ADVANTAGES, USE OF PET IN D+R- KTR REMAINS MINIMAL. THE LONG-TERM GOALS ARE TO REDUCE THE NEGATIVE IMPACT OF CMV IN D+R- SOT BY HARNESSING CMV-SPECIFIC IMMUNITY, TO DEFINE CMV IMMUNE CORRELATES FOR FUTURE IMMUNE-BASED PREVENTIVE STRATEGIES, AND TO PROVIDE HIGH-QUALITY EVIDENCE TO CHANGE CLINICAL PRACTICE. THE CENTRAL HYPOTHESIS IS THAT PET, COMPARED TO AP, THROUGH PERMISSIVE VIRAL REPLICATION AND ASSOCIATED ANTIGEN EXPOSURE-MEDIATED IMMUNE PRIMING, LEADS TO INCREASED CMV-SPECIFIC HUMORAL AND CELLULAR IMMUNE RESPONSES THAT RESULT IN LOWER CMV DISEASE INCIDENCE IN HIGH-RISK D+R- KTR. THE SPECIFIC AIMS ARE 1) TO COMPARE PET AND AP IN D+R- KTR FOR THE PREVENTION OF ENDPOINT COMMITTEE CONFIRMED CMV DISEASE BY 1-YEAR POST-TXP (PRIMARY ENDPOINT) AND LONGER-TERM OUTCOMES (GRAFT AND PATIENT SURVIVAL, BIOPSY-PROVEN ACUTE ALLOGRAFT REJECTION, AND EGFR BY END OF FOLLOW-UP (SECONDARY ENDPOINTS), AND 2) TO CHARACTERIZE LONGITUDINAL CMV-SPECIFIC HUMORAL (NAB) AND CELLULAR (T-CELL, NK CELL) IMMUNE RESPONSES AND THEIR ASSOCIATION WITH PREVENTION STRATEGY, CMV INFECTION (DNAEMIA) IN THE PET ARM, AND ENDPOINT COMMITTEE CONFIRMED CMV DISEASE. THE AIMS WILL BE ACCOMPLISHED WITH A 5-CENTER TRIAL OF 360 ADULT CMV D+R- KTR WHO WILL BE RANDOMIZED 1:1 TO A STANDARDIZED PET PROTOCOL FOR 100D (DESCRIBED ABOVE) OR TO AP (200D OF VALGAN OR LETERMOVIR). CMV-SPECIFIC IMMUNITY ASSESSMENTS AT 3, 6, 12, 24, AND 36 MONTHS WILL INCLUDE NAB, NK CELLS, AND MULTIFUNCTIONAL T-CELLS WITH MULTI-COLOR FLOW CYTOMETRY THAT INCORPORATES A NOVEL COMPUTATIONAL APPROACH (COMBINATORIAL POLYFUNCTIONALITY ANALYSIS OF ANTIGEN-SPECIFIC T CELL SUBSETS [COMPASS]).
$148.7k 9/4/24 Not listed
KIDNEY TRANSPLANT PREEMPTIVE THERAPY OR PROPHYLAXIS (KPOP) FOR CMV PREVENTIONIN D+R- RECIPIENTS - IN KIDNEY TRANSPLANT RECIPIENTS (KTR), CYTOMEGALOVIRUS (CMV) INCREASES SHORT- AND LONG-TERM MORBIDITY, MORTALITY, AND ALLOGRAFT FAILURE, MAINLY DUE TO LIMITATIONS IN CURRENT PREVENTIVE STRATEGIES. ~90% OF CMV DISEASE OCCURS IN THE ~20% OF RECIPIENTS WHO ARE CMV SERONEGATIVE (R-) AND RECEIVE OF AN ORGAN FROM A CMV SEROPOSITIVE DONOR (D+) [D+R-], AND RESULTS FROM IMMUNE-SUPPRESSION-IMPAIRED DEVELOPMENT OF PROTECTIVE CMV-SPECIFIC IMMUNE RESPONSES. THE STRATEGIES FOR CMV PREVENTION IN D+R- KTR ARE ANTIVIRAL PROPHYLAXIS [AP] (SUPPRESSIVE ANTIVIRAL DRUG [VALGANCICLOVIR [VALGAN] OR LETERMOVIR [LET] GIVEN FOR 200D), AND PREEMPTIVE THERAPY [PET] (CMV DNAEMIA IS MONITORED BY SENSITIVE QUANTITATIVE PCR (QPCR) FOR 100D AND VALGAN IS GIVEN ONLY TO THOSE WITH CMV DNAEMIA. AP IS USED BY >90% OF CENTERS DUE TO A SMALLER EVIDENCE BASE FOR PET (ESPECIALLY WITH ATG USE) AND UNCERTAINTY ABOUT OTHER LONG-TERM OUTCOMES WITH PET VS AP. IN CMV D+R- LIVER TXP, A RANDOMIZED CLINICAL TRIAL (RCT) SHOWED THAT PET WAS FEASIBLE (>90% ADHERENCE), REDUCED ANTIVIRAL DRUG DAYS BY ~40% (62D VS. 100D), INCREASED PROTECTIVE CMV-SPECIFIC IMMUNITY (MULTIFUNCTIONAL CD4/CD8 T- CELLS, NK CELLS, AND NEUTRALIZING ANTIBODY [NAB]) AND DECREASED CMV DISEASE BY >50% VS. AP. THESE RESULTS CANNOT BE DIRECTLY EXTRAPOLATED TO KTR DUE TO IMPORTANT DIFFERENCES BETWEEN LIVER AND KIDNEY TXP, INCLUDING THE INTENSITY OF IMMUNOSUPPRESSION AND DIFFERENT ESTABLISHED/APPROVED PROPHYLAXIS REGIMENS. AS A RESULT, DESPITE POTENTIAL ADVANTAGES, USE OF PET IN D+R- KTR REMAINS MINIMAL. THE LONG-TERM GOALS ARE TO REDUCE THE NEGATIVE IMPACT OF CMV IN D+R- SOT BY HARNESSING CMV-SPECIFIC IMMUNITY, TO DEFINE CMV IMMUNE CORRELATES FOR FUTURE IMMUNE-BASED PREVENTIVE STRATEGIES, AND TO PROVIDE HIGH-QUALITY EVIDENCE TO CHANGE CLINICAL PRACTICE. THE CENTRAL HYPOTHESIS IS THAT PET, COMPARED TO AP, THROUGH PERMISSIVE VIRAL REPLICATION AND ASSOCIATED ANTIGEN EXPOSURE-MEDIATED IMMUNE PRIMING, LEADS TO INCREASED CMV-SPECIFIC HUMORAL AND CELLULAR IMMUNE RESPONSES THAT RESULT IN LOWER CMV DISEASE INCIDENCE IN HIGH-RISK D+R- KTR. THE SPECIFIC AIMS ARE 1) TO COMPARE PET AND AP IN D+R- KTR FOR THE PREVENTION OF ENDPOINT COMMITTEE CONFIRMED CMV DISEASE BY 1-YEAR POST-TXP (PRIMARY ENDPOINT) AND LONGER-TERM OUTCOMES (GRAFT AND PATIENT SURVIVAL, BIOPSY-PROVEN ACUTE ALLOGRAFT REJECTION, AND EGFR BY END OF FOLLOW-UP (SECONDARY ENDPOINTS), AND 2) TO CHARACTERIZE LONGITUDINAL CMV-SPECIFIC HUMORAL (NAB) AND CELLULAR (T-CELL, NK CELL) IMMUNE RESPONSES AND THEIR ASSOCIATION WITH PREVENTION STRATEGY, CMV INFECTION (DNAEMIA) IN THE PET ARM, AND ENDPOINT COMMITTEE CONFIRMED CMV DISEASE. THE AIMS WILL BE ACCOMPLISHED WITH A 5-CENTER TRIAL OF 360 ADULT CMV D+R- KTR WHO WILL BE RANDOMIZED 1:1 TO A STANDARDIZED PET PROTOCOL FOR 100D (DESCRIBED ABOVE) OR TO AP (200D OF VALGAN OR LETERMOVIR). CMV-SPECIFIC IMMUNITY ASSESSMENTS AT 3, 6, 12, 24, AND 36 MONTHS WILL INCLUDE NAB, NK CELLS, AND MULTIFUNCTIONAL T-CELLS WITH MULTI-COLOR FLOW CYTOMETRY THAT INCORPORATES A NOVEL COMPUTATIONAL APPROACH (COMBINATORIAL POLYFUNCTIONALITY ANALYSIS OF ANTIGEN-SPECIFIC T CELL SUBSETS [COMPASS]).
$1.4m 7/12/24 Not listed
KIDNEY TRANSPLANT PREEMPTIVE THERAPY OR PROPHYLAXIS (KPOP) FOR CMV PREVENTIONIN D+R- RECIPIENTS - IN KIDNEY TRANSPLANT RECIPIENTS (KTR), CYTOMEGALOVIRUS (CMV) INCREASES SHORT- AND LONG-TERM MORBIDITY, MORTALITY, AND ALLOGRAFT FAILURE, MAINLY DUE TO LIMITATIONS IN CURRENT PREVENTIVE STRATEGIES. ~90% OF CMV DISEASE OCCURS IN THE ~20% OF RECIPIENTS WHO ARE CMV SERONEGATIVE (R-) AND RECEIVE OF AN ORGAN FROM A CMV SEROPOSITIVE DONOR (D+) [D+R-], AND RESULTS FROM IMMUNE-SUPPRESSION-IMPAIRED DEVELOPMENT OF PROTECTIVE CMV-SPECIFIC IMMUNE RESPONSES. THE STRATEGIES FOR CMV PREVENTION IN D+R- KTR ARE ANTIVIRAL PROPHYLAXIS [AP] (SUPPRESSIVE ANTIVIRAL DRUG [VALGANCICLOVIR [VALGAN] OR LETERMOVIR [LET] GIVEN FOR 200D), AND PREEMPTIVE THERAPY [PET] (CMV DNAEMIA IS MONITORED BY SENSITIVE QUANTITATIVE PCR (QPCR) FOR 100D AND VALGAN IS GIVEN ONLY TO THOSE WITH CMV DNAEMIA. AP IS USED BY >90% OF CENTERS DUE TO A SMALLER EVIDENCE BASE FOR PET (ESPECIALLY WITH ATG USE) AND UNCERTAINTY ABOUT OTHER LONG-TERM OUTCOMES WITH PET VS AP. IN CMV D+R- LIVER TXP, A RANDOMIZED CLINICAL TRIAL (RCT) SHOWED THAT PET WAS FEASIBLE (>90% ADHERENCE), REDUCED ANTIVIRAL DRUG DAYS BY ~40% (62D VS. 100D), INCREASED PROTECTIVE CMV-SPECIFIC IMMUNITY (MULTIFUNCTIONAL CD4/CD8 T- CELLS, NK CELLS, AND NEUTRALIZING ANTIBODY [NAB]) AND DECREASED CMV DISEASE BY >50% VS. AP. THESE RESULTS CANNOT BE DIRECTLY EXTRAPOLATED TO KTR DUE TO IMPORTANT DIFFERENCES BETWEEN LIVER AND KIDNEY TXP, INCLUDING THE INTENSITY OF IMMUNOSUPPRESSION AND DIFFERENT ESTABLISHED/APPROVED PROPHYLAXIS REGIMENS. AS A RESULT, DESPITE POTENTIAL ADVANTAGES, USE OF PET IN D+R- KTR REMAINS MINIMAL. THE LONG-TERM GOALS ARE TO REDUCE THE NEGATIVE IMPACT OF CMV IN D+R- SOT BY HARNESSING CMV-SPECIFIC IMMUNITY, TO DEFINE CMV IMMUNE CORRELATES FOR FUTURE IMMUNE-BASED PREVENTIVE STRATEGIES, AND TO PROVIDE HIGH-QUALITY EVIDENCE TO CHANGE CLINICAL PRACTICE. THE CENTRAL HYPOTHESIS IS THAT PET, COMPARED TO AP, THROUGH PERMISSIVE VIRAL REPLICATION AND ASSOCIATED ANTIGEN EXPOSURE-MEDIATED IMMUNE PRIMING, LEADS TO INCREASED CMV-SPECIFIC HUMORAL AND CELLULAR IMMUNE RESPONSES THAT RESULT IN LOWER CMV DISEASE INCIDENCE IN HIGH-RISK D+R- KTR. THE SPECIFIC AIMS ARE 1) TO COMPARE PET AND AP IN D+R- KTR FOR THE PREVENTION OF ENDPOINT COMMITTEE CONFIRMED CMV DISEASE BY 1-YEAR POST-TXP (PRIMARY ENDPOINT) AND LONGER-TERM OUTCOMES (GRAFT AND PATIENT SURVIVAL, BIOPSY-PROVEN ACUTE ALLOGRAFT REJECTION, AND EGFR BY END OF FOLLOW-UP (SECONDARY ENDPOINTS), AND 2) TO CHARACTERIZE LONGITUDINAL CMV-SPECIFIC HUMORAL (NAB) AND CELLULAR (T-CELL, NK CELL) IMMUNE RESPONSES AND THEIR ASSOCIATION WITH PREVENTION STRATEGY, CMV INFECTION (DNAEMIA) IN THE PET ARM, AND ENDPOINT COMMITTEE CONFIRMED CMV DISEASE. THE AIMS WILL BE ACCOMPLISHED WITH A 5-CENTER TRIAL OF 360 ADULT CMV D+R- KTR WHO WILL BE RANDOMIZED 1:1 TO A STANDARDIZED PET PROTOCOL FOR 100D (DESCRIBED ABOVE) OR TO AP (200D OF VALGAN OR LETERMOVIR). CMV-SPECIFIC IMMUNITY ASSESSMENTS AT 3, 6, 12, 24, AND 36 MONTHS WILL INCLUDE NAB, NK CELLS, AND MULTIFUNCTIONAL T-CELLS WITH MULTI-COLOR FLOW CYTOMETRY THAT INCORPORATES A NOVEL COMPUTATIONAL APPROACH (COMBINATORIAL POLYFUNCTIONALITY ANALYSIS OF ANTIGEN-SPECIFIC T CELL SUBSETS [COMPASS]).
$1.4m 7/12/24