Clinical Trial of Efficacy and Safety of the Combination of Reduced Duration Prophylaxis Followed by Immuno-guided Prophylaxis in Lung Transplant Recipients. (CYTOCOR)

Efficacy and Safety of the Combination of Reduced Duration Prophylaxis Followed by Immuno-guided Prophylaxis to Prevent Cytomegalovirus Disease in Lung Transplant Recipients (CYTOCOR STUDY): An Open-label, Randomised, Non-inferiority Clinical Trial.

To assess the efficacy of reduced duration prophylaxis followed by immuno-guided prophylaxis to prevent cytomegalovirus disease.

Study Overview

• Status: Completed
• Conditions: Cytomegalovirus Infections; Transplantation Infection
• Intervention / Treatment: Drug: Valganciclovir; Drug: Ganciclovir

Detailed Description

Prolonged use of antivirals to prevent the development of cytomegalovirus (CMV) disease in lung transplant patients has been shown to have significant side effects, for which alternatives are being sought to reduce their use. The monitoring of cell immunity against CMV could be an alternative as it has shown to be useful in identifying transplant patients at low risk of infection, who could benefit from shorter prophylaxis. The aim of the CYTOCOR study is to demonstrate that the combination of a reduced prophylaxis strategy with subsequent CMV-specific immunological monitoring would allow CMV infection to be controlled in lung transplant patients as effectively as the usual strategy (prophylaxis followed by pre-emptive therapy), while reducing the side effects of antivirals due to the shorter duration of prophylaxis.

• Study Type: Interventional
• Enrollment (Actual): 150
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Aurora Páez Vega; Phone Number: 0034957011040; Email: aurora.paez@imibic.org

Study Locations

• Spain
  • A Coruña, Spain, 15006
    • Hospital Universitario de A Coruna
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron
  • Córdoba, Spain, 14004
    • Hospital Univesitario Reina Sofía
  • Madrid, Spain, 28041
    • Hospital Universitario 12 De Octubre
  • Valencia, Spain, 46026
    • Hospital Universitario La Fé
  • Cantabria
    • Santander, Cantabria, Spain, 39008
      • Hospital Universitario Marques de Valdecilla
  • Madrid
    • Majadahonda, Madrid, Spain, 28222
      • Hospital Universitario Puerta de Hierro

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Subjects with cytomegalovirus positive serology who underwent lung transplantation.
• Subjects of 18 years of age or older.
• Expected valgancilovir prophylactic treatment of 6 months after transplantation.
• Patients who have signed the informed consent form.

Exclusion Criteria:

• HIV infected subjects.
• Subjects unable to comply with the protocolo follow-up visits.
• Subjects who underwent multivisceral transplant.
• Pregnant and/or lactating women.
• Intolerance to Valganciclovir/Ganciclovir treatment.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Control; Control Group (universal prophylaxis + pre-emptive therapy; 6+6): The recommendation of the Spanish Consensus Document will be followed according to the strategy described below: Universal prophylaxis with valganciclovir (900 mg/24h, corrected for renal function) up to month +6. The use of associated immunotherapy (e.g., anti-CMV hyperimmune immunoglobulin) will depend on each center's clinical practice. During this period, the treatment of blips of viral replication detected during the usual clinical follow-up of patients will depend oneach center's clinical practice.; Pre-emptive therapy guided by viral load from month +6 to month +12. For a viral load above> 38 copies/mL (> 35 IU/mL) and depending on each center's clinical practice, treatment with valganciclovir may be initiated (900 mg/12h, corrected for renal function).	Drug: Valganciclovir; Valganciclovir is a L-valyl ester of ganciclovir that exists as a mix of 2 diastereomers. After administration, both are converted to ganciclovir by esterases. Ganciclovir is a synthetic analogue of 2'-deoxyguanosine, it inhibits replication of cytomegalovirus. In CMV-infected cells it's phosphorylated (phosphorylation is dependent on the viral kinase and occurs preferentially in virus-infected cells). Ganciclovir activity is due to inhibition of viral DNA synthesis by ganciclovir triphosphate.; Other Names: Valcyte; Drug: Ganciclovir; Ganciclovir is a synthetic analogue of 2'-deoxyguanosine, it inhibits replication of cytomegalovirus. In CMV-infected cells it's phosphorylated (phosphorylation is dependent on the viral kinase and occurs preferentially in virus-infected cells). Ganciclovir activity is due to inhibition of viral DNA synthesis by ganciclovir triphosphate.; Other Names: Cymevene
Experimental: Experimental; Experimental Group (reduced prophylaxis + immuno-guided prophylaxis; 3+9): Universal prophylaxis with valganciclovir (900 mg/24h, corrected for renal function) up to month +3. The use of associated immunotherapy (e.g., anti-CMV hyperimmune immunoglobulin) will depend oneach center's clinical practice. During this period, the treatment of blips of viral replication detected during the usual clinical follow-up of the patients will depend on the each center's clinical practice.; Immuno-guided prophylaxis. This will consist of a monthly determination of cellular immunity by QF-CMV from month +3 to month +12.	Drug: Valganciclovir; Valganciclovir is a L-valyl ester of ganciclovir that exists as a mix of 2 diastereomers. After administration, both are converted to ganciclovir by esterases. Ganciclovir is a synthetic analogue of 2'-deoxyguanosine, it inhibits replication of cytomegalovirus. In CMV-infected cells it's phosphorylated (phosphorylation is dependent on the viral kinase and occurs preferentially in virus-infected cells). Ganciclovir activity is due to inhibition of viral DNA synthesis by ganciclovir triphosphate.; Other Names: Valcyte; Drug: Ganciclovir; Ganciclovir is a synthetic analogue of 2'-deoxyguanosine, it inhibits replication of cytomegalovirus. In CMV-infected cells it's phosphorylated (phosphorylation is dependent on the viral kinase and occurs preferentially in virus-infected cells). Ganciclovir activity is due to inhibition of viral DNA synthesis by ganciclovir triphosphate.; Other Names: Cymevene

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cytomegalovirus disease incidence rate at 18 months after lung transplantation.	Cytomegalovirus disease incidence rate at 18 months after lung transplantation.	18 months after subject's transplantation.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
INFG cut-off point other than 0.2 IU/mL	For patients of the experimental group (3+9) in which immuno-guided prophylaxis is used based on QF-CMV Reactive (cut-off 0.2 IU/mL of IFNG) and who develop CMV disease, a secondary objective will be to assess whether an INFG cut-off point other than 0.2 IU/mL could predict protection against the disease more reliably.	18 months after subject's transplantation.

Collaborators and Investigators

• Sponsor: Maimónides Biomedical Research Institute of Córdoba
• Collaborators: Instituto de Salud Carlos III
• Investigators: Principal Investigator: Julián de la Torre Cisneros, MD, Hospital Universitario Reina Sofia

Publications and helpful links

General Publications

• Gibson L. An Interferon-gamma Release Assay for Evaluation of Cell-mediated Immunity in Infants With Congenital Cytomegalovirus Infection. Clin Infect Dis. 2021 Aug 2;73(3):374-375. doi: 10.1093/cid/ciaa700. No abstract available.
• Paez-Vega A, Cantisan S, Vaquero JM, Vidal E, Luque-Pineda A, Lobo-Acosta MA, Perez AB, Alonso-Moralejo R, Iturbe D, Monforte V, Otero-Gonzalez I, Pastor A, Ussetti P, Torre-Cisneros J. Efficacy and safety of the combination of reduced duration prophylaxis followed by immuno-guided prophylaxis to prevent cytomegalovirus disease in lung transplant recipients (CYTOCOR STUDY): an open-label, randomised, non-inferiority clinical trial. BMJ Open. 2019 Aug 15;9(8):e030648. doi: 10.1136/bmjopen-2019-030648.

Study record dates

Study Major Dates

• Study Start (Actual): April 5, 2019
• Primary Completion (Actual): May 29, 2023
• Study Completion (Actual): May 29, 2023

Study Registration Dates

• First Submitted: October 5, 2018
• First Submitted That Met QC Criteria: October 5, 2018
• First Posted (Actual): October 9, 2018

Study Record Updates

• Last Update Posted (Actual): September 15, 2023
• Last Update Submitted That Met QC Criteria: September 14, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Lung transplantation; Cytomegalovirus infection; Specific immunity
• Additional Relevant MeSH Terms: Pathologic Processes; Virus Diseases; Disease Attributes; DNA Virus Infections; Herpesviridae Infections; Infections; Communicable Diseases; Cytomegalovirus Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Valganciclovir; Ganciclovir; Ganciclovir triphosphate
• Other Study ID Numbers: CYTOCOR; 2018-003300-39 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

The individual participant data will be available.

Individual parcicipant data that underlie the results reportes in this article, after deidenttification (text, tables, figures and appendices)

The other documents that will be available: study protocol, Statistical Analysis Plan, Informed Consent Form.

The data will be available beginning 9 months and ending 36 months following article publication.

With whom? Researchers who provide a methodologically sound proposal.

For what types of analyses? for individual participant data meta-analysis.

• IPD Sharing Time Frame: The data will be available beginning 9 months and ending 36 months following article publication.
• IPD Sharing Access Criteria: To obtain the data, a proposal must be sent to uicec@imibic.org. To gain access, data requestors will need to sign a data access agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

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