Clinical trial NCT06339892: HCMV Breakthrough Infections During Letermovir Prophylaxis
Official title: Comparison of Two Strategies for Monitoring HCMV Breakthrough Infections During Letermovir Prophylaxis. a Multicenter, Randomized, Open-label Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Cytomegalovirus Infections
Cytomegalovirus Viremia
Hematopoietic Stem Cell Transplantation
Lead sponsor: Fondazione IRCCS Policlinico San Matteo di Pavia
Sponsor class: OTHER
Collaborators: name: Ministero della Salute, Italy
First posted: 2024-04-01
Enrollment: 140
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: DIAGNOSTIC

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.

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 (1:1) 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 GCV/VGCV/FOS pre-emptive therapy in case of positive HCMV DNAemia confirmed in two consecutive samples.
* In the Study arm, patients will stop LTV shifting to GCV/VGCV/FOS 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 \>10,000 copies/ml whole blood in two consecutive samples, even if DNAse-resistant HCMV plasma DNAemia is negative.

GCV/VGCV/FOS pre-emptive therapy will be stopped in all cases after detection of a negative HCMV DNAemia (i.e. 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 and/or alteration in plasma electrolytes will be observed without an increase of HCMV diseases.

Study definitions

* Positive HCMV DNAemia will be defined as HCMV DNAemia \>1,500 copies/ml whole blood (or \>150 copies/ml plasma) for high-risk patients and \>3,000 copies/ml whole blood (or \>300 copies/ml 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 \< 1000/mmc (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 \>2.0 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 patient's 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.

Eligibility criteria: Inclusion Criteria:

* Age\>18 years.
* Allogeneic hematopoietic stem cell transplant.
* HCMV IgG seropositivity before transplant
* Written informed consent.
* LTV prophylaxis administration

Exclusion Criteria:

* Age \<18 years.
* Inability to comply with the requirements of the protocol.

Primary outcomes:
measure: - Proportion of patients with positive HCMV DNAemia developing antiviral drug-related toxicity.
timeFrame: Day 100
Secondary outcomes:
measure: Proportion of patients developing HCMV DNAemia during LTV prophylaxis.
timeFrame: Day 100
measure: Proportion of patients developing HCMV disease within day 100 and between day 100 and 360 from transplant (key secondary endpoint)
timeFrame: Day 100 and day 360
measure: Proportion of patients stopping LTV prophylaxis and shifting to GCV/VGCV/FOS therapy.
timeFrame: Day 100
measure: Proportion of patients requiring GCV/VGCV/FOS therapy between day 100 and 360.
timeFrame: Day 360
measure: Proportion of patients with persisting HCMV DNAemia.
timeFrame: Day 360
measure: Proportion of patients developing neutropenia between day 100 and 360.
timeFrame: Day 360
measure: Proportion of patients developing HCMV-specific T-cell response at day 100, 180, and 360.
timeFrame: Day 100, day 180 and day 360
measure: Proportion of patients developing LTV-resistant HCMV strains.
timeFrame: Day 100
measure: Cumulative incidence of acute or chronic GvHD.
timeFrame: Day 100 and day 360
measure: Transplant related mortality (TRM), underlying disease relapse, and 1-year survival.
timeFrame: Day 360
Other outcomes:
Locations:
city: Brescia
country: Italy
facility: ASST-Spedali Civili
state: BS
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo
state: PV
city: Bergamo
country: Italy
facility: ASST-Ospedale Papa Giovanni XXIII
city: Bologna
country: Italy
facility: IRCCS Azienda Ospedaliero-Universitaria di Bologna
city: Milano
country: Italy
facility: ASST Grande Ospedale Metropolitano Niguarda
city: Reggio Calabria
country: Italy
facility: Grande Ospedale Metropolitano "Bianchi-Melacrino-Morelli"
city: Roma
country: Italy
facility: AOU Policlinico Umberto I
city: Roma
country: Italy
facility: Policlinico Universitario Agostino Gemelli
Study officials:
affiliation: Fondazione IRCCS Policlinico San Matteo
name: Fausto Baldanti, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Marty FM, Ljungman P, Chemaly RF, Maertens J, Dadwal SS, Duarte RF, Haider S, Ullmann AJ, Katayama Y, Brown J, Mullane KM, Boeckh M, Blumberg EA, Einsele H, Snydman DR, Kanda Y, DiNubile MJ, Teal VL, Wan H, Murata Y, Kartsonis NA, Leavitt RY, Badshah C. Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation. N Engl J Med. 2017 Dec 21;377(25):2433-2444. doi: 10.1056/NEJMoa1706640. Epub 2017 Dec 6.
citation: Ljungman P, Boeckh M, Hirsch HH, Josephson F, Lundgren J, Nichols G, Pikis A, Razonable RR, Miller V, Griffiths PD; Disease Definitions Working Group of the Cytomegalovirus Drug Development Forum. Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials. Clin Infect Dis. 2017 Jan 1;64(1):87-91. doi: 10.1093/cid/ciw668. Epub 2016 Sep 28.