VIROMARKERS GA n.101194735 - CMV and TTV Biomarkers Study Protocol

NCT07286461 | Not Yet Recruiting

• 1 other identifier: 101194735-CMV-TTV
• Study Type: observational
• Target: 290
• Locations: 1 country
• Sites: 1

Brief Summary

The study is one of the researches carried out in the VIROMARKERS Project. The project VIROMARKERS is supported by the Innovative Health Initiative Joint Undertaking (IHI JU) under grant agreement No 101194735. The JU receives support from the European Union's Horizon Europe research and innovation programme and COCIR, EFPIA, Europa Bio, MedTech Europe, Vaccines Europe, and Roboscreen. To date, the virological surveillance for CMV replication relies basically on the quantification of CMV-DNA in blood or plasma by using Real-Time PCR assays, and CMV-DNAemia is known to correlate with both CMV-related disease and non-relapse mortality \[Ljungman, 2025\]. However, the detection of CMV-DNAemia is not always associated with an active CMV replication, particularly in patients exposed to letermovir. Therefore, the identification of new virological markers to accurately monitor CMV activity in the early and late post-HSCT phases, remains a crucial issue especially in individuals receiving letermovir as prophylaxis to ensure a proper diagnosis of CMV infection/disease and to guide prophylactic and pre-emptive antiviral treatment. In this setting, the quantification of CMV-RNA represents a potential candidate marker capable of better reflecting the presence of complete, infectious CMV virions than CMV-DNAemia. Despite several data support a correlation of CMV UL21.5-mRNA with viral activity \[Nicastro, 2025\], studies investigating the kinetics of this viral mRNA among immune-suppressed patients at risk of CMV re-uptake are largely missing, especially in the setting of patients receiving antiviral prophylaxis with letermovir after HSCT. TTV-DNA load was mostly investigated in solid organ transplant patients (SOT), where it showed a good correlation of high viral load and degree of immunosuppression. In HSCT patients the interaction of the immune system, which is under reconstitution, and clinically relevant CMV infection is more complex. First data have been reported by our group \[Gilles et al., 2017\] showing high TTV load as a prognostic marker for risk of complications after HSCT. Little information is available for HSCT patients under letermovir prophylaxis. Specific primary objectives related to CMV monitoring in the HSCT setting are the following: Primary In participants who received HSCT, to estimate the rate of initiation of anti-CMV therapy during letermovir-based prophylaxis and the rate of CMV re-activation (based on symptoms, signs of organ dysfunction and CMV-DNAemia) after suspension of letermovir. To evaluate the kinetics of CMV-RNAemia, CMV-DNAemia and TTV-DNAemia and their correlation during prophylaxis with letermovir. To establish whether early quantitative CMV-RNA level or the early kinetics of CMV-RNAemia and TTV-DNAemia during prophylaxis can predict initiation of anti-CMV therapy. In participants not initiating anti-CMV therapy during prophylaxis, to establish whether quantitative CMV-RNA level at time of letermovir suspension or the kinetics of CMV-RNAemia and TTV-DNAemia during prophylaxis can predict CMV re-activation (based on symptoms signs of organ dysfunction and CMV-DNAemia) after suspension of letermovir. Secondary objectives include to establish a cut-off for CMV-RNAemia and TTV DNAemia to maximize the accuracy of prediction of CMV re-activation after suspension of prophylaxis; to explore the kinetics of CMV-RNAemia and TTV-DNAemia in participants treated with anti CMV drugs. The information used from this study on participants in the HSCT setting will be rapidly analyzed and shared broadly to guide policymakers for the use and monitoring of CMV-DNAemia, CMV-RNAemia and TTV-DNAemia in CMV disease and to design future studies. For exact plans regarding the expected date of study completion and plans for dissemination please refer to separate documents produced within the WP5 of VIROMARKERS.

Conditions

CMV; Allogeneic Hematopoietic Stem Cell Transplantation Recipient

Keywords

CMV; TTV

Outcome Measures

Primary Outcomes (1)

• CMV-DNA

  plasma samples will be collected at the following time-points for CMV-RNA quantification

  Italy: 0 , 7, 15, 30, 45, 60, 75, 90,100 107 115,130, 145, 160, 175, 190 day post HSCT). Germany:0, 7, 15, 30, 60, 90, 120, 150, 180 , 200 , 207 230, 260, 290 day post HSCT

Study Arms (1)

receiving HSCT and being seropositive for CMV, receiving HSCT from a donor CMV positive

The sibjects going to be enrolled are: Having received or due to receive HSCT; HSCT recipient is seropositive for CMV, or receiving HSCT from a CMV seropositive donor

Drug: letermovir prophylaxis

Interventions

letermovir prophylaxis DRUG

quantification of CMV-DNA in blood or plasma by using Real-Time PCR assays

receiving HSCT and being seropositive for CMV, receiving HSCT from a donor CMV positive

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

This observational study will include at least 290 consecutive patients undergoing HSCT at risk of CMV infection. Clinical management of participants will be carried out according to international and local guidelines, without any modification due to the current study. Participants will be followed for the entire duration of prophylaxis treatment followed by a minimum of 3 months after suspension.

You may qualify if:

• Be \> 18 years of age
• Sign an informed consent
• HSCT recipients seropositive to CMV, or receiving HSCs from a CMV seropositive donor
• Antiviral prophylaxis with letermovir for preventing CMV infection will be administered for 100 days in Italy (or 200 days in Germany) after HSCT to all participants according to the current guidelines

You may not qualify if:

• Individuals \<18 years old undergoing HSCT Individuals not receiving letermovir prophylaxis

Sponsors & Collaborators

• University of Rome Tor Vergata: lead
• Heinrich-Heine-Universitaet Duesseldorf: collaborator

Study Sites (1)

Heinrich-Heine-Universitaet Duesseldorf

Düsseldorf, Germany

Location

Related Publications (4)

• Gilles R, Herling M, Holtick U, Heger E, Awerkiew S, Fish I, Holler K, Sierra S, Knops E, Kaiser R, Scheid C, Di Cristanziano V. Dynamics of Torque Teno virus viremia could predict risk of complications after allogeneic hematopoietic stem cell transplantation. Med Microbiol Immunol. 2017 Oct;206(5):355-362. doi: 10.1007/s00430-017-0511-4. Epub 2017 Jul 12.

  PMID: 28702856 BACKGROUND

• Nicastro E, Severi E, Passera I, Totaro M, Matarazzo L, Fornataro L, Morotti F, Tebaldi A, Bonanomi E, Bravi M, Di Giorgio A, Covini S, Dolci M, Pinelli D, Arosio MEG, D'Antiga L. Cytomegalovirus-RNA Accurately Identifies Clinically Significant Infection Needing Preemptive Therapy in Liver Transplanted Children: A Proof-of-Concept Study. J Med Virol. 2025 Apr;97(4):e70347. doi: 10.1002/jmv.70347.

  PMID: 40232168 BACKGROUND

• Cassaniti I, Colombo AA, Bernasconi P, Malagola M, Russo D, Iori AP, Girmenia C, Greco R, Peccatori J, Ciceri F, Bonifazi F, Percivalle E, Campanini G, Piccirilli G, Lazzarotto T, Baldanti F. Positive HCMV DNAemia in stem cell recipients undergoing letermovir prophylaxis is expression of abortive infection. Am J Transplant. 2021 Apr;21(4):1622-1628. doi: 10.1111/ajt.16450. Epub 2021 Feb 8.

  PMID: 33320429 BACKGROUND

• Ljungman P, Alain S, Chemaly RF, Einsele H, Galaverna F, Hirsch HH, Sadowska-Klasa A, Navarro D, Styczynski J, de la Camara R. Recommendations from the 10th European Conference on Infections in Leukaemia for the management of cytomegalovirus in patients after allogeneic haematopoietic cell transplantation and other T-cell-engaging therapies. Lancet Infect Dis. 2025 Aug;25(8):e451-e462. doi: 10.1016/S1473-3099(25)00069-6. Epub 2025 Apr 3.

  PMID: 40188837 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

A blood sample will be obtained for all participants at enrollment to be shipped to a central repository for testing. In all samples resulting positive to CMV-DNAemia, an additional aliquot of the same sample will be pre-treated with DNase prior to DNA extraction, to exclude DNA which is not protected by a viral capsid (e.g., concatemeric DNA) from Real Time-PCR amplification, thus inducing the loss of non-infectious viral DNA. The quantification of CMV-RNA and TTV-DNAemia will be carried at T0 and every month during and after letermovir prophylaxis up to the end of study period.

Study Officials

• VALENTINA SVICHER

  UNIVERST' DI ROMA TOR VERGATA

  STUDY CHAIR

Central Study Contacts

VALENTINA SVICHER, PROFESSOR

CONTACT

+39 3332381462; valentina.svicher@uniroma2.it

ROMINA SALPINI

CONTACT

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: OTHER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: December 2, 2025
• First Posted: December 16, 2025
• Study Start: December 15, 2025
• Primary Completion (Estimated): September 30, 2027
• Study Completion (Estimated): December 30, 2027
• Last Updated: December 16, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will share

Locations

DE (1)