HORUS-Cytomegalovirus Open Proof-of-concept Exploratory Trial (HORUS-COPE)

HORUS-Cytomegalovirus Open Proof-of-concept Exploratory Trial (HORUS-COPE): An International Proof-of-concept Clinical Trial on Modulation of Immunosuppressive Regimen in Solid-organ Transplant Recipients With Cytomegalovirus Infection.

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.

Study Overview

• Status: Not yet recruiting
• Conditions: CMV Infection
• Intervention / Treatment: Drug: 50% reduction in the dose of MPA; Drug: Switch from MPA to a mammalian target of rapamycin inhibitor (mTORi), together with an adapted dose of tacrolimus; Drug: standard antiviral therapy along with maintenance of their initial immunosuppressive therapy.

Detailed Description

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:

1. a 50% dose reduction of an antimetabolite agent- mycophenolate mofetil [MMF, Cellcept®] or enteric-coated mycophenolate sodium [EC-MPS, Myfortic®]; hereafter referred to as mycophenolic acid [MPA])
2. a switch from MPA to a mammalian target of rapamycin inhibitor (mTORi) everolimus, together with an adapted dose of tacrolimus.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Oriol Manuel, Professor, MD; Phone Number: +41 79 556 61 36; Email: oriol.manuel@chuv.ch
• Study Contact Backup: Name: Elisa Ruiz-Arabi, MD, PhD; Phone Number: +41 79 556 5484; Email: elisa.ruiz-arabi@chuv.ch

Study Locations

• France
  • Talence Cedex
    • Bourdeaux, Talence Cedex, France, 33404
      • Centre hospitalier universitaire Bordeaux (CHU Bordeaux)
      • Contact: Hannah Kaminski, Professor, MD, PhD; Phone Number: +33 05 56 79 56 79; Email: hannah.kaminski@chu-bordeaux.fr
      • Sub-Investigator: Lionel Couzi, Professor MD, PhD
  • Toulouse
    • Toulouse, Toulouse, France, 31059
      • Centre hospitalier universitaire Toulouse (CHU Toulouse)
      • Contact: Nassim Kamar, Professor, MD, PhD; Phone Number: +33 05 61 77 22 33; Email: kamar.n@chu-toulouse.fr
• Spain
  • Catalonia
    • Barcelona, Catalonia, Spain, 08035
      • Hospital Universitari Vall d'Hebrón
      • Contact: Oriol Bestard, MD PhD; Phone Number: +34 934 893 000; Email: oriol.bestard@vallhebron.cat
• Switzerland
  • Canton of Vaud
    • Lausanne, Canton of Vaud, Switzerland, 1011
      • Centre Hospitalier Universitaire Vaudois (CHUV)
      • Contact: Oriol Manuel, Professor, MD; Phone Number: +41 79 556 61 36; Email: oriol.manuel@chuv.ch
      • Contact: Elisa Ruiz-Arabi, MD, PhD; Phone Number: +41 79 556 5484; Email: elisa.ruiz-arabi@chuv.ch
      • Sub-Investigator: Dela Golshayan, Professor, MD PhD
      • Sub-Investigator: Julien Vionnet, MD, PhD
      • Sub-Investigator: Patrick Yerly, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Clinically stable adult patients (aged 18 years or older) who have received a solid organ transplant (e.g., kidney, liver, heart, lung, pancreas) and developed clinically significant CMV infection as determined by positive CMV PCR.
• On maintenance therapy of tacrolimus, MPA, +/- steroids.
• Informed consent signed.

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:

  • Patient not affiliated to the French social security system
  • Patient under legal protection (guardianship, curatorship).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 50% reduction in the dose of MPA for a duration of minimum 21 days; with standard antiviral therapy	Drug: 50% reduction in the dose of MPA; 50% reduction in the dose of MPA with standard antiviral therapy; Other Names: Mycophenolic acid; Mycophenolate mofetil
Experimental: switch of MPA to everolimus with adapted dose of tacrolimus, for a duration of at least 56 days; with standard antiviral therapy	Drug: Switch from MPA to a mammalian target of rapamycin inhibitor (mTORi), together with an adapted dose of tacrolimus; Switch from MPA to a mammalian target of rapamycin inhibitor (mTORi), together with an adapted dose of tacrolimus, with standard antiviral therapy; Other Names: everolimus
Active Comparator: Standard antiviral therapy without modulation of immunosuppression	Drug: standard antiviral therapy along with maintenance of their initial immunosuppressive therapy.; standard antiviral therapy along with maintenance of their initial immunosuppressive therapy (control group); Other Names: control group

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Viral load decay	Differences in log CMV viral load in plasma between baseline and 3 weeks	3 weeks

Secondary Outcome Measures

Outcome Measure	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.	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

Other Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Oriol Manuel
• Collaborators: Hospital Vall d'Hebron; Centre Hospitalier Universitaire de Toulouse, FRANCE; Centre Hospitalier Universitaire Bordeaux
• Investigators: Principal Investigator: Oriol Manuel, Professor, MD, Service des maladies infectieuses, Centre hospitalier universitaire vaudois (CHUV)

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): January 1, 2028
• Study Completion (Estimated): March 1, 2028

Study Registration Dates

• First Submitted: April 23, 2026
• First Submitted That Met QC Criteria: April 29, 2026
• First Posted (Actual): May 6, 2026

Study Record Updates

• Last Update Posted (Actual): May 6, 2026
• Last Update Submitted That Met QC Criteria: April 29, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: immunosuppression; infection; cytomegalovirus; everolimus; CMV; solid organ transplantation; MPA; mTORi; immune signature
• Additional Relevant MeSH Terms: Virus Diseases; DNA Virus Infections; Herpesviridae Infections; Infections; Cytomegalovirus Infections; Organic Chemicals; Investigative Techniques; Epidemiologic Research Design; Epidemiologic Methods; Research Design; Methods; Fatty Acids; Lipids; Acids, Acyclic; Carboxylic Acids; Macrolides; Lactones; Sirolimus; Caproates; Everolimus; Mycophenolic Acid; Control Groups
• Other Study ID Numbers: 2025-02457; 2025-524845-28-00 (Ctis); HumRes (Registry Identifier: BASEC 2025-02457)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No