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NCT Number: NCT04690933

AntiCMV molécules Monitoring in Real-life in Stem Cell Recipients

Cytomegalovirus (CMV) is a ubiquitous herpesvirus that represent a major cause of morbidity in haematopoietic stem cell transplants (HSCT) recipients, mostly through reactivation of the recipient's virus.

If left untreated, 40 to 80% of patients will develop CMV infection, leading to CMV disease in 30 to 35 % patients, and associated with considerable morbi-mortality. Interstitial pneumonia is the most severe and specific manifestation, although CMV replication by itself has also indirect effects such as triggering graft versus host disease and increasing immunosuppression. The current burden of CMV infection increases by 25 to 30% the cost of the graft in France. This also includes the burden for refractory - infections, that represent up to 13% of recipients with CMV infection, including 3% of cases with virological resistance in France (data from the Reference Center cohorts).

Ganciclovir, or valganciclovir preemptive treatment, guided by CMV viral load follow-up allowed significant reduction of CMV disease to 2-6% but did not prevent CMV indirect effects. In addition, hematotoxicity can compromise post-transplant haematological reconstitution, thus preventing its use as prophylaxis in France. Foscarnet, iv-administered and nephrotoxic, remains less used. There is thus a high expectation from less toxic molecules for prophylaxis The development letermovir recently available for prophylaxis of CMV infection in high risk patients will modify the patients care and follow-up. This new molecule targeting CMV terminases (developed by Merck) was recently marketed in France (Jan 2020). However, the analysis of the letermovir phase III study and further publications show that the risk of emergence of resistance is low, but may occur in case of breakthrough and thus post AMM monitoring is required.

A "real-life" evaluation of these new molecules in terms of efficacy, emergence of resistance, tolerance and morbimortality related to CMV infection, is useful, to propose recommendations on management strategies, in particular for the most at-risk patients i.e. CMV-seropositive recipients. To this purpose, the National Reference Center in collaboration with the French Society for marrow graft and cell therapy (SFGMTC) set up a cohort of surveillance of allografted patients, receiving, in prevention or treatment, old and new molecules.

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Key information

Conditions

Hematopoietic Stem Cell Transplantation Antiviral Drug Resistance Antivirals Cytomegalovirus Infections DNA Virus Infections Herpesviridae Infections Infections Virus Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Observational

Primary location

CHU de LIMOGES, Limoges, France

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About this study

Cytomegalovirus (CMV) is a ubiquitous herpesvirus that represent a major cause of morbidity in haematopoietic stem cell transplants (HSCT) recipients, mostly through reactivation of the recipient's virus.

If left untreated, 40 to 80% of patients will develop CMV infection, leading to CMV disease in 30 to 35 % patients, and associated with considerable morbi-mortality. Interstitial pneumonia is the most severe and specific manifestation, although CMV replication by itself has also indirect effects such as triggering graft versus host disease and increasing immunosuppression. The current burden of CMV infection increases by 25 to 30% the cost of the graft in France. This also includes the burden for refractory - infections, that represent up to 13% of recipients with CMV infection, including 3% of cases with virological resistance in France (data from the Reference Center cohorts).

Ganciclovir, or valganciclovir preemptive treatment, guided by CMV viral load follow-up allowed significant reduction of CMV disease to 2-6% but did not prevent CMV indirect effects. In addition, hematotoxicity can compromise post-transplant haematological reconstitution, thus preventing its use as prophylaxis in France. Foscarnet, iv-administered and nephrotoxic, remains less used. There is thus a high expectation from less toxic molecules for prophylaxis The development letermovir recently available for prophylaxis of CMV infection in high risk patients will modify the patients care and follow-up. This new molecule targeting CMV terminases (developed by Merck) was recently marketed in France (Jan 2020). However, the analysis of the letermovir phase III study and further publications show that the risk of emergence of resistance is low, but may occur in case of breakthrough and thus post AMM monitoring is required.

A "real-life" evaluation of these new molecules in terms of efficacy, emergence of resistance, tolerance and morbimortality related to CMV infection, is useful, to propose recommendations on management strategies, in particular for the most at-risk patients i.e. CMV-seropositive recipients. To this purpose, the National Reference Center in collaboration with the French Society for marrow graft and cell therapy (SFGMTC) set up a cohort of surveillance of allografted patients, receiving, in prevention or treatment, old and new molecules.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Candidate (adult) for an allograft of hematopoietic stem cells for which a decision of transplant is made and willing to participate in the cohort.

Exclusion criteria

  • CMV-seronegative patient receiving a negative CMV donor graft ;
  • Patient having signed the consent but not grafted ;
  • Patient included in a clinical study on an anti-CMV molecule ;
  • Non-insured social patient ;

Treatment and study plan

Real-life observatory of efficacy and resistance to anti CMV molecules in stem cell recipients

Other

Signing of consent at the time of the pre-transplant consultation (1 month before grafting). Inclusion of patients during conditioning (around D-8 of transplantation). Samples related to the cohort:one blood sample from the donor (only familial donors) for genetic SNPs analysis. 5 samples: D-8, D20, D100, D200 (+/-10 days), 1 year : 1 tube of 7ml of whole blood on EDTA: Biobanking of whole blood for genetic SNPs analysis (D-8) of specific transporters for GCV, and of plasma for TTV viral load at all times. In routine care:samples taken in the event of a therapeutic escape (2 x 7 ml EDTA tubes, for resistance genotype, and ganciclovir dosage, 3 x 1 ml for Quantiferon CMV, according to CNR Herpesvirus recommendations. 1 x Paxgene tube (2.5 ml) for subsequent CMV genomic and transcriptomic studies. Cell preservation plasma and whole blood for biocollection (2 tubes EDTA de 7ml). Samples stored by the centers' virology laboratories are periodically sent to the CNR for analysis.

Primary outcomes

  1. CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017).

    Time frame: between Day-30 and Day -8

    CMV detection (CMV DNAemia or antigen detection) in any body fluid or tissue specimen

  2. CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017).

    Time frame: between Day-8 and Day 0

    CMV detection (CMV DNAemia or antigen detection) in any body fluid or tissue specimen

  3. CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017).

    Time frame: at Day20

    CMV detection (CMV DNAemia or antigen detection) in any body fluid or tissue specimen

  4. CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017).

    Time frame: at Day100

    CMV detection (CMV DNAemia or antigen detection) in any body fluid or tissue specimen

  5. CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017).

    Time frame: at Day 200 (Month 6)

    CMV detection (CMV DNAemia or antigen detection) in any body fluid or tissue specimen

  6. CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017).

    Time frame: Month12

    CMV detection (CMV DNAemia or antigen detection) in any body fluid or tissue specimen

  7. CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017).

    Time frame: Month24

    CMV detection (CMV DNAemia or antigen detection) in any body fluid or tissue specimen

Secondary outcomes

  1. Uses of anti-CMV molecules : preemptive treatment

    Time frame: at Day200

    % of patients having received preemptive treatment

  2. Uses of anti-CMV molecules : prophylaxis

    Time frame: at Day200

    % of patients having received prophylaxis

  3. Uses of anti-CMV molecules : curative treatment

    Time frame: at Day200

    % of patients having received curative treatment

  4. Uses of anti-CMV molecules

    Time frame: at Day200

    Cumulative duration of exposure (number of day) for each drug administered

  5. Uses of anti-CMV molecules : preemptive treatment

    Time frame: at Month12

    % of patients having received preemptive treatment

  6. Uses of anti-CMV molecules : prophylaxis

    Time frame: at Month12

    % of patients having received prophylaxis

  7. Uses of anti-CMV molecules : curative treatment

    Time frame: at Month12

    % of patients having received curative treatment

  8. Uses of anti-CMV molecules

    Time frame: at Month12

    Cumulative duration of exposure (number of day) for each drug administered

  9. Uses of anti-CMV molecules : preemptive treatment

    Time frame: at Month24

    % of patients having received preemptive treatment

  10. Uses of anti-CMV molecules : prophylaxis

    Time frame: at Month24

    % of patients having received prophylaxis

  11. Uses of anti-CMV molecules : curative treatment

    Time frame: at Month24

    % of patients having received curative treatment

  12. Uses of anti-CMV molecules

    Time frame: at Month24

    Cumulative duration of exposure (number of day) for each drug administered

  13. Incidence of the non-response and resistance to antivirals with risk factors associated (virological, pharmacological, immunological). Criteria recently published by Chemaly et al. CID 2018 will be used to classify cases in

    Time frame: at Month12

    Criteria recently published by Chemaly et al. CID 2018 will be used to classify cases in :

    • Refractory CMV infection CMV viremia that increases after at least 2 wk of appropriately dosed antiviral therapy.
    • Probable refractory CMV infection : persistent viral load after at least 2 wk of appropriately dosed antiviral therapy.
    • Refractory CMV end organ disease : worsening in signs and symptoms or progression into end-organ disease after at least 2 wk of appropriately dosed antiviral therapy.
    • Probable refractory CMV end-organ disease : lack of improvement in signs and symptoms after at least 2 wk of appropriately dosed antiviral drugs.
    • Antiviral drug resistance : viral genetic alteration that decreases susceptibility to one or more antiviral drugs.

    Resistance : presence of a resistance-related mutation by resistance genotyping of UL97, UL54, UL56, UL89, UL27 genes, carried out or validated by the Limoges Herpesviruses reference laboratory. In blood or any other sample.

  14. Incidence of the non-response and resistance to antivirals with risk factors associated (virological, pharmacological, immunological). Criteria recently published by Chemaly et al. CID 2018 will be used to classify cases in

    Time frame: at Month24

    Criteria recently published by Chemaly et al. CID 2018 will be used to classify cases in :

    • Refractory CMV infection CMV viremia that increases after at least 2 wk of appropriately dosed antiviral therapy.
    • Probable refractory CMV infection : persistent viral load after at least 2 wk of appropriately dosed antiviral therapy.
    • Refractory CMV end organ disease : worsening in signs and symptoms or progression into end-organ disease after at least 2 wk of appropriately dosed antiviral therapy.
    • Probable refractory CMV end-organ disease : lack of improvement in signs and symptoms after at least 2 wk of appropriately dosed antiviral drugs.
    • Antiviral drug resistance : viral genetic alteration that decreases susceptibility to one or more antiviral drugs.

    Resistance : presence of a resistance-related mutation by resistance genotyping of UL97, UL54, UL56, UL89, UL27 genes, carried out or validated by the Limoges Herpesviruses reference laboratory. In blood or any other sample.

  15. Adverse effects leading to interruption of treatment

    Time frame: at Month12

    Incidence of treatment emergent adverse event as assessed by interruption of treatment

  16. Adverse effects leading to interruption of treatment

    Time frame: at Month24

    Incidence of treatment emergent adverse event as assessed by interruption of treatment

  17. CMV related mortality

    Time frame: at Month12

    Number of patients who died from CMV related desease

  18. CMV related mortality

    Time frame: at Month24

    Number of patients who died from CMV related desease

  19. CMV associated morbidity : delay engraftment

    Time frame: at Month12

    number of days bettwen graft and engraftment

  20. CMV associated morbidity : GVHD

    Time frame: at Month12

    Incidence of GVHD

  21. CMV associated morbidity : CMV infection/disease

    Time frame: at Month12

    Incidence of CMV infection/disease (infection or disease will be combined to report this outcome).

    CMV infection : positive diagnostic test (CMV culture, antigen detection or CMV PCR), in any body fluid or tissue, in the absence of symptoms.

    CMV disease : CMV infection associated with end-organ disease (clinical signs and oriented virological diagnosis).

  22. CMV associated morbidity : delay engraftment

    Time frame: at Month24

    number of days bettwen graft and engraftment

  23. CMV associated morbidity : GVHD

    Time frame: at Month24

    Incidence of GVHD

  24. CMV associated morbidity : CMV infection/disease

    Time frame: at Month24

    Incidence of CMV infection/disease (infection or disease will be combined to report this outcome).

    CMV infection : positive diagnostic test (CMV culture, antigen detection or CMV PCR), in any body fluid or tissue, in the absence of symptoms.

    CMV disease : CMV infection associated with end-organ disease (clinical signs and oriented virological diagnosis).

Sponsors and collaborators

Lead sponsor

University Hospital, Limoges

Other

Registry information

Official study title

Real-life Observatory of Efficacy and Resistance to Anti CMV Molecules in Stem Cell Recipients

Acronym: NAViRe

Important dates

Study start
2020
Primary completion
2025
Study completion
2025
First posted
Dec 31, 2020
Registry last updated
Dec 15, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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