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

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

Study Description

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.

Study Design

• 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

Groups and Cohorts

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.

Outcome Measures

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.

Eligibility Criteria

• 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 ;

Contacts and Locations

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

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

• Principal Investigator: Pascal TURLURE; Service d'Hématologie Clinique et de Thérapie Cellulaire

More Information

Publications of Results:

Billat PA, Woillard JB, Essig M, Sauvage FL, Picard N, Alain S, Neely M, Marquet P, Saint-Marcoux F. Plasma and intracellular exposure to ganciclovir in adult renal transplant recipients: is there an association with haematological toxicity? J Antimicrob Chemother. 2016 Feb;71(2):484-9. doi: 10.1093/jac/dkv342. Epub 2015 Nov 3.

Kotton CN, Kumar D, Caliendo AM, Huprikar S, Chou S, Danziger-Isakov L, Humar A; The Transplantation Society International CMV Consensus Group. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation. 2018 Jun;102(6):900-931. doi: 10.1097/TP.0000000000002191.

Other Publications:

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.

Chemaly RF, Chou S, Einsele H, Griffiths P, Avery R, Razonable RR, Mullane KM, Kotton C, Lundgren J, Komatsu TE, Lischka P, Josephson F, Douglas CM, Umeh O, Miller V, Ljungman P; Resistant Definitions Working Group of the Cytomegalovirus Drug Development Forum. Definitions of Resistant and Refractory Cytomegalovirus Infection and Disease in Transplant Recipients for Use in Clinical Trials. Clin Infect Dis. 2019 Apr 8;68(8):1420-1426. doi: 10.1093/cid/ciy696.

Billat PA, Ossman T, Saint-Marcoux F, Essig M, Rerolle JP, Kamar N, Rostaing L, Kaminski H, Fabre G, Otyepka M, Woillard JB, Marquet P, Trouillas P, Picard N. Multidrug resistance-associated protein 4 (MRP4) controls ganciclovir intracellular accumulation and contributes to ganciclovir-induced neutropenia in renal transplant patients. Pharmacol Res. 2016 Sep;111:501-508. doi: 10.1016/j.phrs.2016.07.012. Epub 2016 Jul 9.

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.

Robin C, Hemery F, Dindorf C, Thillard J, Cabanne L, Redjoul R, Beckerich F, Rodriguez C, Pautas C, Toma A, Maury S, Durand-Zaleski I, Cordonnier C. Economic burden of preemptive treatment of CMV infection after allogeneic stem cell transplantation: a retrospective study of 208 consecutive patients. BMC Infect Dis. 2017 Dec 5;17(1):747. doi: 10.1186/s12879-017-2854-2.

• Responsible Party: University Hospital, Limoges
• ClinicalTrials.gov Identifier: NCT04690933
• Other Study ID Numbers: 87RI18_0011 (NAViRe)
• First Posted: December 31, 2020
• Last Update Posted: December 31, 2020
• Last Verified: September 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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:

Cytomegalovirus Infections; Infections; Herpesviridae Infections; DNA Virus Infections; Virus Diseases