HORUS-Cytomegalovirus Open Proof-of-concept Exploratory Trial

Official title

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.

Overview

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.

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.

Interventions

• Drug 50% reduction in the dose of MPA
  50% reduction in the dose of MPA 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
• 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)

Primary outcome measures

• Viral load decay [Time frame: 3 weeks]

Secondary outcome measures (2)

• Change in CMV-specific immune signature score [Time frame: from enrollment to 3 and 8 weeks]
• Viral load decay according to immune signature [Time frame: 3 and 8 weeks]

Eligibility criteria

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).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

France · 2 centers

• Centre hospitalier universitaire Bordeaux (CHU Bordeaux) — Bourdeaux
• Centre hospitalier universitaire Toulouse (CHU Toulouse) — Toulouse

Spain · 1 center

• Hospital Universitari Vall D'Hebron — Barcelona

Switzerland · 1 center

• Centre hospitalier universitaire vaudois (CHUV) — Lausanne

Publications

• 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. PMID 27775865
• 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 20 PMID 37046380
• 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 PMID 34990047
• 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):121-13 PMID 34725108
• 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. PMID 22390651
• 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. PMID 21307192
• 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. PMID 20486914
• 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. PMID 35980197

Identifiers

NCT: NCT07570433 · 2025-02457 · 2025-524845-28-00 · HumRes

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗