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AntiCMV molécules Monitoring in Real-life in Stem Cell Recipients (NAViRe)

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ClinicalTrials.gov Identifier: NCT04690933
Recruitment Status : Recruiting
First Posted : December 31, 2020
Last Update Posted : December 31, 2020
Sponsor:
Information provided by (Responsible Party):
University Hospital, Limoges

Brief Summary:

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.


Condition or disease Intervention/treatment
Hematopoietic Stem Cell Transplantation Cytomegalovirus Infections Antivirals Antiviral Drug Resistance Other: Real-life observatory of efficacy and resistance to anti CMV molecules in stem cell recipients

Detailed Description:

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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Study Type : Observational
Estimated Enrollment : 400 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Real-life Observatory of Efficacy and Resistance to Anti CMV Molecules in Stem Cell Recipients
Actual Study Start Date : September 24, 2020
Estimated Primary Completion Date : September 24, 2022
Estimated Study Completion Date : December 31, 2024

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
Multicentric NAViRe cohort with biocollection
The National Reference Center (CNR) for cytomegalovirus with the French Society for Medullary Transplantation and Cell Therapy (SFGM-TC) has set up a surveillance cohort of allografted patients (NAViRe cohort) receiving, as prevention or treatment, Anti-Cytomegalovirus (Anti-CMV) molecules, "new or less recent", thus allowing the development of a new observatory evaluating in real life the potentials of these drugs in terms of efficacy, emergence of resistance, tolerance and morbidity and mortality associated with CMV infection.This work is useful to propose recommendations on management strategies, in particular for the most at-risk patients i.e. CMV-seropositive recipients and allows the emergence of an real-life observatory of efficacy and resistance to anti CMV molecules in stem cell recipients.
Other: Real-life observatory of efficacy and resistance to anti CMV molecules in stem cell recipients
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 Outcome Measures :
  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 Outcome Measures :
  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).



Biospecimen Retention:   Samples With DNA

Samples related to the cohort :

One blood sample from the donor (only familial donors) for genetic SNPs analysis.

5 samples: D-8 (conditioning), D20, D100 (+/- 10 days), 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. Conservation of viral load monitoring remnants at the center's virology laboratory.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
Candidate (adult) for an allograft of hematopoietic stem cells for which a decision of transplant is made and willing to participate in the cohort.
Criteria

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 ;

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04690933


Contacts
Layout table for location contacts
Contact: Sophie ALAIN, Pr 05.55.05.67.24 sophie.alain@chu-limoges.fr
Contact: Françoise GARNIER-GEOFFROY, CRA Francoise.GARNIER-GEOFFROY@chu-limoges.fr

Locations
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France
CHU de LIMOGES Recruiting
Limoges, France, 87045
Contact: Sophie Alain, Pr    33 5 55 05 67 28    sophie.alain@unilim.fr   
Contact: Françoise Geoffroy-Garnier, ING       françoise.garnier-geoffroy@chu-limoges.fr   
Sponsors and Collaborators
University Hospital, Limoges
Investigators
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Principal Investigator: Pascal TURLURE Service d'Hématologie Clinique et de Thérapie Cellulaire
Publications of Results:
Other Publications:

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Responsible Party: University Hospital, Limoges
ClinicalTrials.gov Identifier: NCT04690933    
Other Study ID Numbers: 87RI18_0011 (NAViRe)
First Posted: December 31, 2020    Key Record Dates
Last Update Posted: December 31, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University Hospital, Limoges:
Hematopoietic Stem Cell Transplantation
Cytomegalovirus Infections
Antivirals
Antiviral Drug Resistance
Additional relevant MeSH terms:
Layout table for MeSH terms
Cytomegalovirus Infections
Infections
Herpesviridae Infections
DNA Virus Infections
Virus Diseases