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| ID | Type | Description | Link |
|---|---|---|---|
| 2025-524845-28-00 | EU Trial (CTIS) Number | ||
| HumRes | Registry Identifier | BASEC 2025-02457 |
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| Name | Class |
|---|---|
| Centre Hospitalier Universitaire Bordeaux | UNKNOWN |
| Centre Hospitalier Universitaire de Toulouse, FRANCE | UNKNOWN |
| Hospital Vall d'Hebron | OTHER |
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Cytomegalovirus (CMV) remains a significant cause of morbidity and mortality following organ transplantation.
Cell-mediated immunity plays a crucial role in controlling CMV replication after transplantation. Immune monitoring involves the use of immune biomarkers to dynamically estimate the risk of CMV replication. This approach allows for the individualization of preventive and therapeutic strategies, improving patient outcomes.
The HORUS-COPE trial is designed to assess the effect of immune modulation on CMV replication kinetics and to explore the performance of a selected immune signature during antiviral therapy for CMV infection to stratify patients based on their risk of not responding to immune modulation.
Cytomegalovirus (CMV) remains a significant cause of morbidity and mortality following organ transplantation.
Cell-mediated immunity plays a crucial role in controlling CMV replication after transplantation. Immune monitoring involves the use of immune biomarkers-primarily those assessing cell-mediated immunity-to dynamically estimate the risk of CMV replication. This approach allows for the individualization of preventive and therapeutic strategies, improving patient outcomes.
The HORUS consortium is a comprehensive European research initiative aimed at providing an in-depth assessment of immune signatures associated with CMV immune control in SOT recipients. One of the ultimate goals of the HORUS project is to leverage these immune signatures to design and implement a clinical trial evaluating their feasibility and impact in routine clinical practice.
As part of this initiative, we introduce the HORUS-COPE trial, designed to assess the effect of immune modulation on CMV replication kinetics and to explore the performance of a selected immune signature during antiviral therapy for CMV infection to stratify patients based on their risk of not responding to immune modulation.
Specifically, immune modulation consists of either:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 50% reduction in the dose of MPA for a duration of minimum 21 days | Experimental | with standard antiviral therapy |
|
| switch of MPA to everolimus with adapted dose of tacrolimus, for a duration of at least 56 days | Experimental | with standard antiviral therapy |
|
| Standard antiviral therapy without modulation of immunosuppression | Active Comparator |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 50% reduction in the dose of MPA | Drug | 50% reduction in the dose of MPA with standard antiviral therapy |
|
| Measure | Description | Time Frame |
|---|---|---|
| Viral load decay | Differences in log CMV viral load in plasma between baseline and 3 weeks | 3 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Change in CMV-specific immune signature score | Change in the CMV-specific immune signature from baseline to week 3 and week 8, assessed using a predefined composite immune monitoring panel derived from the HORUS cohort. The panel will include CMV-specific T-cell functional assays and phenotyping, such as quantitative and qualitative measures of CD4 and CD8 CMV-specific responses, cytokine production, and selected activation/exhaustion markers. Results will be summarized as change from baseline at each time point. |
| Measure | Description | Time Frame |
|---|---|---|
| Viral load decay | Differences in log CMV viral load in plasma between baseline and 8 weeks | 8 weeks |
| Viral load eradication | Rate of patients with CMV viral load eradication, defined as the percentage of patients with a CMV PCR result below the level of quantification at 3 weeks and 8 weeks |
Inclusion Criteria:
Exclusion Criteria:
Active acute graft rejection or significant graft dysfunction requiring modification of the current immunosuppressive regimen, in the opinion of the investigator.
Receipt of more than 72 hours of antiviral therapy for CMV infection prior to enrolment, before randomization, including valganciclovir and/or IV ganciclovir therapy
Known intolerance or hypersensitivity to mTOR inhibitors or to any component of the everolimus formulation.
Any medical condition that constitutes a contraindication to everolimus use, as judged by the investigator.
Additional exclusion criteria for French sites:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Oriol Manuel, Professor, MD | Contact | +41 79 556 61 36 | oriol.manuel@chuv.ch | |
| Elisa Ruiz-Arabi, MD, PhD | Contact | +41 79 556 5484 | elisa.ruiz-arabi@chuv.ch |
| Name | Affiliation | Role |
|---|---|---|
| Oriol Manuel, Professor, MD | Service des maladies infectieuses, Centre hospitalier universitaire vaudois (CHUV) | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Centre hospitalier universitaire Bordeaux (CHU Bordeaux) | Bourdeaux | Talence Cedex | 33404 | France |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 27775865 | Background | Qazi Y, Shaffer D, Kaplan B, Kim DY, Luan FL, Peddi VR, Shihab F, Tomlanovich S, Yilmaz S, McCague K, Patel D, Mulgaonkar S. Efficacy and Safety of Everolimus Plus Low-Dose Tacrolimus Versus Mycophenolate Mofetil Plus Standard-Dose Tacrolimus in De Novo Renal Transplant Recipients: 12-Month Data. Am J Transplant. 2017 May;17(5):1358-1369. doi: 10.1111/ajt.14090. Epub 2017 Jan 4. | |
| 37046380 |
| Label | URL |
|---|---|
| Related Info | View source |
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After the study is completed, de-identified individual participant data may be shared. Data will be made available only after a formal request to the Principal Investigator (PI) and approval by the study's Scientific Committee. Data sharing will be limited to use for scientific research purposes and will follow all applicable privacy and ethical regulations.
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Randomized open-label, phase IV non-comparative trial with three parallel arms
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|
| Switch from MPA to a mammalian target of rapamycin inhibitor (mTORi), together with an adapted dose of tacrolimus | Drug | Switch from MPA to a mammalian target of rapamycin inhibitor (mTORi), together with an adapted dose of tacrolimus, with standard antiviral therapy |
|
|
| standard antiviral therapy along with maintenance of their initial immunosuppressive therapy. | Drug | standard antiviral therapy along with maintenance of their initial immunosuppressive therapy (control group) |
|
|
| from enrollment to 3 and 8 weeks |
| Viral load decay according to immune signature | Difference in log CMV viral load decay between baseline and 3 and 8 weeks according to baseline immune signature | 3 and 8 weeks |
| 3 and 8 weeks |
| Refractory CMV infection | Rate of refractory CMV infection at 8 weeks, according to standard definition | 8 weeks |
| Safety outcome 1 | Episodes of biopsy-proven acute rejection within 90 days | 90 days |
| Safety Outcome 2 | Delta eGFR ml/min between baseline and day 90 | 90 days |
| Safety Outcome 3 | mTORi /MPA toxicity | 90 days |
| Centre hospitalier universitaire Toulouse (CHU Toulouse) | Toulouse | Toulouse | 31059 | France |
|
| Hospital Universitari Vall D'Hebron | Barcelona | Catalonia | 08035 | Spain |
|
| Centre hospitalier universitaire vaudois (CHUV) | Lausanne | Canton of Vaud | 1011 | Switzerland |
|
| Background |
| Viana LA, Cristelli MP, Basso G, Santos DW, Dantas MTC, Dreige YC, Requiao Moura LR, Nakamura MR, Medina-Pestana J, Tedesco-Silva H. Conversion to mTOR Inhibitor to Reduce the Incidence of Cytomegalovirus Recurrence in Kidney Transplant Recipients Receiving Preemptive Treatment: A Prospective, Randomized Trial. Transplantation. 2023 Aug 1;107(8):1835-1845. doi: 10.1097/TP.0000000000004559. Epub 2023 Jul 20. |
| 34990047 | Background | Kaminski H, Kamar N, Thaunat O, Bouvier N, Caillard S, Garrigue I, Anglicheau D, Rerolle JP, Le Meur Y, Durrbach A, Bachelet T, Savel H, Coueron R, Visentin J, Del Bello A, Pellegrin I, Dechanet-Merville J, Merville P, Thiebaut R, Couzi L. Incidence of cytomegalovirus infection in seropositive kidney transplant recipients treated with everolimus: A randomized, open-label, multicenter phase 4 trial. Am J Transplant. 2022 May;22(5):1430-1441. doi: 10.1111/ajt.16946. Epub 2022 Jan 19. |
| 34725108 | Background | Kaminski H, Marseres G, Yared N, Nokin MJ, Pitard V, Zouine A, Garrigue I, Loizon S, Capone M, Gauthereau X, Mamani-Matsuda M, Coueron R, Duran RV, Pinson B, Pellegrin I, Thiebaut R, Couzi L, Merville P, Dechanet-Merville J. mTOR Inhibitors Prevent CMV Infection through the Restoration of Functional alphabeta and gammadelta T cells in Kidney Transplantation. J Am Soc Nephrol. 2022 Jan;33(1):121-137. doi: 10.1681/ASN.2020121753. Epub 2021 Nov 1. |
| 22390651 | Background | Poglitsch M, Weichhart T, Hecking M, Werzowa J, Katholnig K, Antlanger M, Krmpotic A, Jonjic S, Horl WH, Zlabinger GJ, Puchhammer E, Saemann MD. CMV late phase-induced mTOR activation is essential for efficient virus replication in polarized human macrophages. Am J Transplant. 2012 Jun;12(6):1458-68. doi: 10.1111/j.1600-6143.2012.04002.x. Epub 2012 Mar 5. |
| 21307192 | Background | Clippinger AJ, Maguire TG, Alwine JC. The changing role of mTOR kinase in the maintenance of protein synthesis during human cytomegalovirus infection. J Virol. 2011 Apr;85(8):3930-9. doi: 10.1128/JVI.01913-10. Epub 2011 Feb 9. |
| 20486914 | Background | Asberg A, Jardine AG, Bignamini AA, Rollag H, Pescovitz MD, Gahlemann CC, Humar A, Hartmann A; VICTOR Study Group. Effects of the intensity of immunosuppressive therapy on outcome of treatment for CMV disease in organ transplant recipients. Am J Transplant. 2010 Aug;10(8):1881-8. doi: 10.1111/j.1600-6143.2010.03114.x. Epub 2010 May 10. |
| 35980197 | Background | Dubrawka CA, Progar KJ, January SE, Hagopian JC, Nesselhauf NM, Malone AF. Impact of antimetabolite discontinuation following cytomegalovirus or BK polyoma virus infection in kidney transplant recipients. Transpl Infect Dis. 2022 Dec;24(6):e13931. doi: 10.1111/tid.13931. Epub 2022 Aug 26. |
| 26054538 | Background | Kaminski H, Garrigue I, Couzi L, Taton B, Bachelet T, Moreau JF, Dechanet-Merville J, Thiebaut R, Merville P. Surveillance of gammadelta T Cells Predicts Cytomegalovirus Infection Resolution in Kidney Transplants. J Am Soc Nephrol. 2016 Feb;27(2):637-45. doi: 10.1681/ASN.2014100985. Epub 2015 Jun 8. |
| 38020746 | Background | Bestard O, Kaminski H, Couzi L, Fernandez-Ruiz M, Manuel O. Cytomegalovirus Cell-Mediated Immunity: Ready for Routine Use? Transpl Int. 2023 Nov 7;36:11963. doi: 10.3389/ti.2023.11963. eCollection 2023. |
| 40200403 | Background | Kotton CN, Kumar D, Manuel O, Chou S, Hayden RT, Danziger-Isakov L, Asberg A, Tedesco-Silva H, Humar A; Transplantation Society International CMV Consensus Group. The Fourth International Consensus Guidelines on the Management of Cytomegalovirus in Solid Organ Transplantation. Transplantation. 2025 Jul 1;109(7):1066-1110. doi: 10.1097/TP.0000000000005374. Epub 2025 Apr 9. No abstract available. |
| 23914796 | Background | Manuel O, Kralidis G, Mueller NJ, Hirsch HH, Garzoni C, van Delden C, Berger C, Boggian K, Cusini A, Koller MT, Weisser M, Pascual M, Meylan PR; Swiss Transplant Cohort Study. Impact of antiviral preventive strategies on the incidence and outcomes of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant. 2013 Sep;13(9):2402-10. doi: 10.1111/ajt.12388. Epub 2013 Aug 5. |
| ID | Term |
|---|---|
| D003586 | Cytomegalovirus Infections |
| D007239 | Infections |
| ID | Term |
|---|---|
| D006566 | Herpesviridae Infections |
| D004266 | DNA Virus Infections |
| D014777 | Virus Diseases |
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| ID | Term |
|---|---|
| D009173 | Mycophenolic Acid |
| D000068338 | Everolimus |
| D035061 | Control Groups |
| ID | Term |
|---|---|
| D002208 | Caproates |
| D000144 | Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D009930 | Organic Chemicals |
| D005227 | Fatty Acids |
| D008055 | Lipids |
| D020123 | Sirolimus |
| D018942 | Macrolides |
| D007783 | Lactones |
| D015340 | Epidemiologic Research Design |
| D004812 | Epidemiologic Methods |
| D008919 | Investigative Techniques |
| D012107 | Research Design |
| D008722 | Methods |
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