HCMV Breakthrough Infections During Letermovir Prophylaxis

NCT06339892 | Recruiting

• 1 other identifier: 2022-3.11/451
• Study Type: interventional
• Target: 140
• Locations: 1 country
• Sites: 8

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.

Conditions

Cytomegalovirus Infections; Cytomegalovirus Viremia; Hematopoietic Stem Cell Transplantation

Outcome Measures

Primary Outcomes (1)

• - Proportion of patients with positive HCMV DNAemia developing antiviral drug-related toxicity.

  Antiviral drug-related toxicity will be considered as neutrophil impairment or kidney injury. Patients who exit before day 100 for death, underlying disease relapse, or transplant rejection after detection of HCMV-positive DNAemia will be considered as failures and counted along with antiviral drug-related toxicities for the analysis of the primary end-point occurring at least 5 days after start of preemptive antiviral therapy

  Day 100

Secondary Outcomes (10)

• Proportion of patients developing HCMV DNAemia during LTV prophylaxis.

  Day 100

• Proportion of patients developing HCMV disease within day 100 and between day 100 and 360 from transplant (key secondary endpoint)

  Day 100 and day 360

• Proportion of patients stopping LTV prophylaxis and shifting to GCV/VGCV/FOS therapy.

  Day 100

• Proportion of patients requiring GCV/VGCV/FOS therapy between day 100 and 360.

  Day 360

• Proportion of patients with persisting HCMV DNAemia.

  Day 360

Study Arms (2)

Study

EXPERIMENTAL

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.

Diagnostic Test: Determination of HCMV DNA in plasma after DNAse digestion.

Control

ACTIVE COMPARATOR

Patients will stop LTV shifting to GCV/VGCV/FOS pre-emptive therapy in case of positive HCMV DNAemia confirmed in two consecutive samples.

Diagnostic Test: Determination of HCMV DNA in blood or plasma.

Interventions

Determination of HCMV DNA in plasma after DNAse digestion. DIAGNOSTIC_TEST

Plasma will be tested after DNAse digestion for quantification of virion-associated HCMV DNA (defined as true breakthrough HCMV productive infection).

Study

Determination of HCMV DNA in blood or plasma. DIAGNOSTIC_TEST

HCMV DNA will be determined in blood or plasma without DNAse digestion, as per current clinical practice.

Control

Eligibility Criteria

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

You may qualify if:

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

You may not qualify if:

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

Sponsors & Collaborators

• Fondazione IRCCS Policlinico San Matteo di Pavia: lead
• Ministero della Salute, Italy: collaborator

Study Sites (8)

ASST-Spedali Civili

Brescia, BS, Italy

RECRUITING

Fondazione IRCCS Policlinico San Matteo

Pavia, PV, 27100, Italy

RECRUITING

ASST-Ospedale Papa Giovanni XXIII

Bergamo, Italy

NOT YET RECRUITING

IRCCS Azienda Ospedaliero-Universitaria di Bologna

Bologna, Italy

NOT YET RECRUITING

ASST Grande Ospedale Metropolitano Niguarda

Milan, Italy

NOT YET RECRUITING

Grande Ospedale Metropolitano "Bianchi-Melacrino-Morelli"

Reggio Calabria, Italy

NOT YET RECRUITING

AOU Policlinico Umberto I

Roma, Italy

NOT YET RECRUITING

Policlinico Universitario Agostino Gemelli

Roma, Italy

NOT YET RECRUITING

Related Publications (2)

• 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.

  PMID: 29211658 BACKGROUND

• 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.

  PMID: 27682069 BACKGROUND

Related Links

• Common Terminology Criteria for Adverse Events (CTCAE)

MeSH Terms

Conditions

Cytomegalovirus Infections

Interventions

Blood Specimen Collection

Condition Hierarchy (Ancestors)

Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Fausto Baldanti, MD

  Fondazione IRCCS Policlinico San Matteo

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Daniele Lilleri, MD

CONTACT

+39 0382 502420; d.lilleri@smatteo.pv.it

Irene Cassaniti, PhD

CONTACT

+39 0382 502420; i.cassaniti@smatteo.pv.it

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Medical staff

Study Record Dates

• First Submitted: March 25, 2024
• First Posted: April 1, 2024
• Study Start: January 9, 2023
• Primary Completion: June 1, 2025
• Study Completion: March 1, 2026
• Last Updated: November 6, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

IT (8)