AntiCMV molécules Monitoring in Real-life in Stem Cell Recipients

Cytomegalovirus Infections Clinical Trial

— NAViRe  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04690933
• Other study ID #: 87RI18_0011 (NAViRe)
• Status: Recruiting
• Start date: September 24, 2020
• Est. completion date: December 31, 2024

Study information

• Verified date: September 2020
• Source: University Hospital, Limoges
• Contact: Sophie ALAIN, Pr
• Phone: 05.55.05.67.24
• Email: sophie.alain[@]chu-limoges.fr
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 400
• Est. completion date: December 31, 2024
• Est. primary completion date: September 24, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 ;

Related Conditions & MeSH terms

• Antiviral Drug Resistance
• Antivirals
• Cytomegalovirus Infections
• Hematopoietic Stem Cell Transplantation

Intervention

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.

Locations

Country	Name	City	State
France	CHU de LIMOGES	Limoges

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Limoges

Country where clinical trial is conducted

France, 

References & Publications (7)

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. Review. — View Citation

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 — View Citation

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. — View Citation

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 Transplantatio — View Citation

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. Epub 2016 Sep 28. — View Citation

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. — View Citation

Robin C, Hémery 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017).	CMV detection (CMV DNAemia or antigen detection) in any body fluid or tissue specimen	between Day-30 and Day -8
Primary	CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017).	CMV detection (CMV DNAemia or antigen detection) in any body fluid or tissue specimen	between Day-8 and Day 0
Primary	CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017).	CMV detection (CMV DNAemia or antigen detection) in any body fluid or tissue specimen	at Day20
Primary	CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017).	CMV detection (CMV DNAemia or antigen detection) in any body fluid or tissue specimen	at Day100
Primary	CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017).	CMV detection (CMV DNAemia or antigen detection) in any body fluid or tissue specimen	at Day 200 (Month 6)
Primary	CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017).	CMV detection (CMV DNAemia or antigen detection) in any body fluid or tissue specimen	Month12
Primary	CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017).	CMV detection (CMV DNAemia or antigen detection) in any body fluid or tissue specimen	Month24
Secondary	Uses of anti-CMV molecules : preemptive treatment	% of patients having received preemptive treatment	at Day200
Secondary	Uses of anti-CMV molecules : prophylaxis	% of patients having received prophylaxis	at Day200
Secondary	Uses of anti-CMV molecules : curative treatment	% of patients having received curative treatment	at Day200
Secondary	Uses of anti-CMV molecules	Cumulative duration of exposure (number of day) for each drug administered	at Day200
Secondary	Uses of anti-CMV molecules : preemptive treatment	% of patients having received preemptive treatment	at Month12
Secondary	Uses of anti-CMV molecules : prophylaxis	% of patients having received prophylaxis	at Month12
Secondary	Uses of anti-CMV molecules : curative treatment	% of patients having received curative treatment	at Month12
Secondary	Uses of anti-CMV molecules	Cumulative duration of exposure (number of day) for each drug administered	at Month12
Secondary	Uses of anti-CMV molecules : preemptive treatment	% of patients having received preemptive treatment	at Month24
Secondary	Uses of anti-CMV molecules : prophylaxis	% of patients having received prophylaxis	at Month24
Secondary	Uses of anti-CMV molecules : curative treatment	% of patients having received curative treatment	at Month24
Secondary	Uses of anti-CMV molecules	Cumulative duration of exposure (number of day) for each drug administered	at Month24
Secondary	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	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.	at Month12
Secondary	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	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.	at Month24
Secondary	Adverse effects leading to interruption of treatment	Incidence of treatment emergent adverse event as assessed by interruption of treatment	at Month12
Secondary	Adverse effects leading to interruption of treatment	Incidence of treatment emergent adverse event as assessed by interruption of treatment	at Month24
Secondary	CMV related mortality	Number of patients who died from CMV related desease	at Month12
Secondary	CMV related mortality	Number of patients who died from CMV related desease	at Month24
Secondary	CMV associated morbidity : delay engraftment	number of days bettwen graft and engraftment	at Month12
Secondary	CMV associated morbidity : GVHD	Incidence of GVHD	at Month12
Secondary	CMV associated morbidity : CMV infection/disease	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).	at Month12
Secondary	CMV associated morbidity : delay engraftment	number of days bettwen graft and engraftment	at Month24
Secondary	CMV associated morbidity : GVHD	Incidence of GVHD	at Month24
Secondary	CMV associated morbidity : CMV infection/disease	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).	at Month24