Ignite Creation Date:
2024-05-06 @ 8:19 PM
Last Modification Date:
2024-10-26 @ 3:25 PM
Study NCT ID:
NCT06339892
Status:
RECRUITING
Last Update Posted:
2024-04-01
First Post:
2024-03-25
Brief Title:
HCMV Breakthrough Infections During Letermovir Prophylaxis
Sponsor:
Fondazione IRCCS Policlinico San Matteo di Pavia
Organization:
Fondazione IRCCS Policlinico San Matteo di Pavia
Study Overview
Official Title:
Comparison of Two Strategies for Monitoring HCMV Breakthrough Infections During Letermovir Prophylaxis A Multicenter Randomized Open-label Trial
Status:
RECRUITING
Status Verified Date:
2024-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
CMVbreak
Brief Summary:
The goal of this clinical trial is to compare two strategies to monitor human cytomegalovirus HCMV infections in transplanted patients receiving letermovir LTV as anti-HCMV prophylaxis
HCMV infection after transplantation is diagnosed by detection of HCMV DNA in blood However due to the peculiar mechanism of action of LTV most episodes of HCMV DNA detection are caused by release in the blood stream of non-infectious HCMV DNA
In true episodes of productive infection HCMV DNA in blood is present inside the virion and therefore is resistant to DNAse digestion Conversely when non-infectious free-floating HCMV DNA is released in the bloodstream it will be degraded after treatment of plasma with DNAse and will not be detectable by real-time PCR assays
Researchers will compare determination of HCMV DNA in blood with or without previous digestion of non-infectious free-floating DNA with DNAse
In patients of the Control group HCMV DNA will be tested without DNAse digestion If HCMV DNA is positive patients will stop LTV prophylaxis and receive antiviral therapy with another drug
In patients of the Study group HCMV DNA will be tested after DNAse digestion Only if HCMV DNA is positive after DNAse digestion patients will stop LTV prophylaxis and receive antiviral therapy with another drug
The main aim of the study is to demonstrate that by avoiding inappropriate antiviral therapy during LTV prophylaxis transplant patients will suffer of lower antiviral-drug-related toxicity A monitoring strategy able to identify true episodes of HCMV productive infection during LTV prophylaxis will lead to a lower rate of inappropriate antiviral therapy and drug-related toxicity without an increased risk of HCMV disease
HCMV infection after transplantation is diagnosed by detection of HCMV DNA in blood However due to the peculiar mechanism of action of LTV most episodes of HCMV DNA detection are caused by release in the blood stream of non-infectious HCMV DNA
In true episodes of productive infection HCMV DNA in blood is present inside the virion and therefore is resistant to DNAse digestion Conversely when non-infectious free-floating HCMV DNA is released in the bloodstream it will be degraded after treatment of plasma with DNAse and will not be detectable by real-time PCR assays
Researchers will compare determination of HCMV DNA in blood with or without previous digestion of non-infectious free-floating DNA with DNAse
In patients of the Control group HCMV DNA will be tested without DNAse digestion If HCMV DNA is positive patients will stop LTV prophylaxis and receive antiviral therapy with another drug
In patients of the Study group HCMV DNA will be tested after DNAse digestion Only if HCMV DNA is positive after DNAse digestion patients will stop LTV prophylaxis and receive antiviral therapy with another drug
The main aim of the study is to demonstrate that by avoiding inappropriate antiviral therapy during LTV prophylaxis transplant patients will suffer of lower antiviral-drug-related toxicity A monitoring strategy able to identify true episodes of HCMV productive infection during LTV prophylaxis will lead to a lower rate of inappropriate antiviral therapy and drug-related toxicity without an increased risk of HCMV disease
Detailed Description:
Patients will be enrolled at the start of conditioning regimen and all patients of both arms will receive LTV prophylaxis after transplantation until day 100 according to standard procedures Patients will be randomized 11 in two arms in case of positive HCMV DNAemia and will follow two different diagnostic strategies to assess HCMV refractivity to LTV prophylaxis
In the Control arm patients will stop LTV shifting to GCVVGCVFOS pre-emptive therapy in case of positive HCMV DNAemia confirmed in two consecutive samples
In the Study arm patients will stop LTV shifting to GCVVGCVFOS pre-emptive therapy in case of positive HCMV DNA and subsequent confirmation of productive infection by detection of DNAse-resistant HCMV plasma DNAemia However for safety reasons patients of the Study arm will stop LTV and shift to pre-emptive therapy in case of HCMV DNAemia 10000 copiesml whole blood in two consecutive samples even if DNAse-resistant HCMV plasma DNAemia is negative
GCVVGCVFOS pre-emptive therapy will be stopped in all cases after detection of a negative HCMV DNAemia ie below detection level of the assay adopted in two consecutive samples
After the end of LTV prophylaxis HCMV infection will be treated with pre-emptive therapy according to current procedures of each center
The hypothesis is that in the Study arm due to the lower use of antiviral drugs as preemptive therapy a significant reduction of neutropenia renal failure andor alteration in plasma electrolytes will be observed without an increase of HCMV diseases
Study definitions
Positive HCMV DNAemia will be defined as HCMV DNAemia 1500 copiesml whole blood or 150 copiesml plasma for high-risk patients and 3000 copiesml whole blood or 300 copiesml plasma for low-risk patients
HCMV disease will be defined by clinical and laboratory examination Both proven and probable HCMV disease will be considered
Neutrophil impairment will be defined as delay in neutrophil engraftment and neutropenia after full engraftment will be defined by Common Terminology Criteria for Adverse Events version 4 see website link below Patients with 1 value of ANC 1000mmc grade 3 from full engraftment to day 100 will be considered to have neutropenia
Acute renal impairment will be defined by Common Terminology Criteria for Adverse Events version 4 defined as sCr 20 x baseline sCr grade 2
High risk having a related donor with at least one mismatch at one of the specified three HLA gene loci HLA-A B or DR having an unrelated donor with at least one mismatch at one of the specified four HLA gene loci HLA-A B C and DRB1 having a haploidentical donor the use of umbilical cord blood as the stem-cell source the use of ex vivo T-cell-depleted grafts and having GVHD of grade 2 or greater that led to the use of prednisone or its equivalent at a dose of 1 mg or more per kilogram of body weight per day
Low risk all the patients who did not meet the definition of being at high risk
Antiviral drug-related toxicity will be considered as neutrophil impairment or kidney injury occurring at least 5 days after start of preemptive antiviral therapy
Sample collection
Virological monitoring EDTA-treated blood for HCMV DNA quantification will be collected weekly until day 100 then monthly until day 360 unless otherwise indicated by patients clinical conditions In case of positive HCMV DNAemia virological monitoring will be performed twice a week
Immunological monitoring heparin-treated blood will be collected i at day 100 180 and 360 for determination of HCMV-specific T-cells
Neutrophil count blood will be collected at least weekly in EDTA-treated tubes for blood cell count determination according to standard local procedures of each center
In the Control arm patients will stop LTV shifting to GCVVGCVFOS pre-emptive therapy in case of positive HCMV DNAemia confirmed in two consecutive samples
In the Study arm patients will stop LTV shifting to GCVVGCVFOS pre-emptive therapy in case of positive HCMV DNA and subsequent confirmation of productive infection by detection of DNAse-resistant HCMV plasma DNAemia However for safety reasons patients of the Study arm will stop LTV and shift to pre-emptive therapy in case of HCMV DNAemia 10000 copiesml whole blood in two consecutive samples even if DNAse-resistant HCMV plasma DNAemia is negative
GCVVGCVFOS pre-emptive therapy will be stopped in all cases after detection of a negative HCMV DNAemia ie below detection level of the assay adopted in two consecutive samples
After the end of LTV prophylaxis HCMV infection will be treated with pre-emptive therapy according to current procedures of each center
The hypothesis is that in the Study arm due to the lower use of antiviral drugs as preemptive therapy a significant reduction of neutropenia renal failure andor alteration in plasma electrolytes will be observed without an increase of HCMV diseases
Study definitions
Positive HCMV DNAemia will be defined as HCMV DNAemia 1500 copiesml whole blood or 150 copiesml plasma for high-risk patients and 3000 copiesml whole blood or 300 copiesml plasma for low-risk patients
HCMV disease will be defined by clinical and laboratory examination Both proven and probable HCMV disease will be considered
Neutrophil impairment will be defined as delay in neutrophil engraftment and neutropenia after full engraftment will be defined by Common Terminology Criteria for Adverse Events version 4 see website link below Patients with 1 value of ANC 1000mmc grade 3 from full engraftment to day 100 will be considered to have neutropenia
Acute renal impairment will be defined by Common Terminology Criteria for Adverse Events version 4 defined as sCr 20 x baseline sCr grade 2
High risk having a related donor with at least one mismatch at one of the specified three HLA gene loci HLA-A B or DR having an unrelated donor with at least one mismatch at one of the specified four HLA gene loci HLA-A B C and DRB1 having a haploidentical donor the use of umbilical cord blood as the stem-cell source the use of ex vivo T-cell-depleted grafts and having GVHD of grade 2 or greater that led to the use of prednisone or its equivalent at a dose of 1 mg or more per kilogram of body weight per day
Low risk all the patients who did not meet the definition of being at high risk
Antiviral drug-related toxicity will be considered as neutrophil impairment or kidney injury occurring at least 5 days after start of preemptive antiviral therapy
Sample collection
Virological monitoring EDTA-treated blood for HCMV DNA quantification will be collected weekly until day 100 then monthly until day 360 unless otherwise indicated by patients clinical conditions In case of positive HCMV DNAemia virological monitoring will be performed twice a week
Immunological monitoring heparin-treated blood will be collected i at day 100 180 and 360 for determination of HCMV-specific T-cells
Neutrophil count blood will be collected at least weekly in EDTA-treated tubes for blood cell count determination according to standard local procedures of each center
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None