Immunoglobiulin-specific Prophylaxis of Citomegalovirus Infections in Immunocompromised Children Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

June 2, 2025 updated by: Antonello Di Paolo, M.D., Ph.D.

Immunoglobulin-specific Prophylaxis Against Citomegalovirus Infections in Immunocompromised Children Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Human cytomegalovirus (CMV) is a globally prevalent, human-specific herpesvirus characterised by a lifelong latency after primary infection, an often asymptomatic reactivation and affecting up to 100% of adults based on region and age. CMV reactivation has serious risks for immunocompromised patients, especially those undergoing allogeneic hematopoietic stem cell transplantation (HSCT). In these patients, CMV can lead to graft failure, multiorgan disease, increased risk of other infections, GVHD, post-transplant lymphoproliferative disorders, and higher transplant-related mortality (TRM). Although antiviral prophylaxis, CMV infection occurs in 38-80% of HSCT recipients, but current antiviral drugs are insufficiently effective and they are associated with adverse effects. Furthermore, treatment failure is due to the high genetic variability of CMV. The protective role of virus-specific antibodies remains under debate. Some studies suggest that high neutralizing antibody titers protect transplant recipients from CMV, while others highlight the importance of T-cell responses. However, recent animal studies showed that humoral immunity alone can prevent CMV reactivation, even without T or NK cells. In solid-organ transplant patients, antibody titers ≥480 have been linked to reduced infection, shorter treatment, and full protection from CMV disease. Although the use of anti-CMV immunoglobulin remains controversial, the IRCCS Burlo Garofolo has used it as post-transplant prophylaxis and second-line treatment for over a decade.

The main objective of their study was to assess whether CMV-specific immunoglobulin prophylaxis reduces CMV incidence and severity in pediatric HSCT patients. Secondary goals included evaluating its effect on transplant outcomes and its efficacy across different ethnic groups. A population pharmacokinetic (POP/PK) study was also conducted to better understand the drug's distribution and elimination and to identify factors influencing its pharmacokinetics in patients.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

The study will enroll all patients who received standard myeloablative conditioning. GVHD prophylaxis consisting of tacrolimus and, for unrelated donors, rabbit ATG and mycophenolate mofetil. Haploidentical transplants initially used in vivo T-cell depletion with post-transplant cyclophosphamide, later replaced by ex vivo αβ+/CD19+ T-cell depletion.

Outcomes included overall survival (OS), relapse-related mortality (RRM), and GVHD, defined by standard grading systems. Immune reconstitution was measured by CD4+ T-lymphocyte counts, with ≥500 cells/μL in two readings within 100 days post-HSCT considered adequate. Follow-up continued until death or last contact, with a minimum duration of 12 months for survivors.

Viral Load Detection

CMV DNAemia was quantified in whole blood using real-time PCR (CMV ELITe MGB Kit). Monitoring occurred twice weekly during hospitalization, then weekly in outpatient visits until immune reconstitution and end of immunosuppression.

CMV-Specific Immunoglobulin Prophylaxis and Treatment

Prophylaxis was administered using Cytomegatect® (Biotest Pharma GmbH), beginning on day 3 of conditioning and continued biweekly during hospitalization. Post-discharge, it was given at each hospital admission until CD4+ normalization. If DNAemia appeared, a 3-5 day "boost" treatment was given based on risk assessment. Non-responders (based on viral load behavior) discontinued treatment. In cases of CMV disease, dosing and treatment duration were tailored. Cytomegatect was dosed by weight: 1000 U (<10 kg), 2000 U (10-25 kg), 3000 U (25-50 kg), and 4000 U (>50 kg).

Foscarnet was used as first-line therapy within the first post-transplant month. Ganciclovir or valganciclovir was introduced after engraftment. Second-line options included cidofovir, letermovir, and maribavir. Advanced therapies involved NK or CD45RO+ lymphocyte infusions. CMV IgG levels were monitored 24-72 hours after each infusion for inpatients and before administration for outpatients.

CMV-Related Complications

CMV-related complications were classified per Ljungman et al.'s updated definitions. CMV infection referred to virus detection in body fluids or tissues. DNAemia denoted CMV DNA presence in blood. Primary infection was the first detection in previously unexposed patients; recurrent infections occurred after a 4-week CMV-negative interval. Refractory infections showed persistent or increasing viral load despite at least two weeks of treatment. CMV disease followed existing consensus criteria.

Statistical and POP/PK Analyses

Continuous variables were summarized by means or medians with interquartile ranges, depending on distribution (tested via Shapiro-Wilk). Categorical variables were presented as counts and percentages. Group comparisons were performed using chi-square tests for qualitative variables and Wilcoxon tests for continuous ones. Kaplan-Meier curves and log-rank tests assessed survival outcomes. Differences in pharmacokinetics between occasions were evaluated with ANOVA.

Plasma concentrations of anti-CMV immunoglobulin were analyzed using a nonlinear mixed-effects modeling approach via Monolix 2023.1. Mono-, bi-, and tri-compartmental models with various error structures were evaluated. Covariates (age, weight, creatinine clearance) were assessed for influence on model performance, which was judged based on objective function value (OFV), standard errors, and residual distributions. Individual elimination half-lives were calculated as t½ = (0.693 × Vi) / Cli, where Vi and Cli are individual volume of distribution and clearance values

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
150

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Child
  • Adult

Accepts Healthy Volunteers

No

Sampling Method

Probability Sample

Study Population

Children who underwent allogeneic HSCT due to any condition

Description

Inclusion Criteria:

  • Children who underwent allogeneic HSCT due to any condition

Exclusion Criteria:

  • Positive personal records of immunoglobulin-related adverse reactions
  • CMV reactivation before the CMV-specific immunoglobulin prophylaxis onset
  • adoptive cellular post-HSCT immunotherapy for any indication

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Control Group
Pediatric allo-HSCT recipients who have not received CMV-specific immunoglobulin prophylaxis after transplantation.
Immunoprophylaxis Group
Pediatric allo-HSCT recipients who received an anti-CMV prophylaxis with immunoglobulin (Megalotect)
Biological: Anti-CMV immunoglobulins [Megalotect (R)]
Children received an anti-CMV immunoglobulin to prevent viral infections

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
CMV reactivation and infection
Time Frame: 12 months since allo-HSCT
The rate of viral reactivation and infection in children undergoing all-HSCT
12 months since allo-HSCT

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Overall Survival
Time Frame: 12 months since allo-HSCT
The rate of overall survival since allo-HSCT
12 months since allo-HSCT
Hospital stay
Time Frame: 12 months since allo-HSCT
The lenght of hospital stay after allo-HSCT
12 months since allo-HSCT
Immunological recovery
Time Frame: 12 months since allo-HSCT
The percentage of patients in who the function of CD4+ lymphocytes was restored
12 months since allo-HSCT
GVHD incidence
Time Frame: 12 months since allo-HSCT
The percentage of patients who experienced a GVHD
12 months since allo-HSCT

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Antonello Di Paolo, M.D., Ph.D.

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
IRCCS Burlo Garofolo

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Natalia Maximova, MD, IRCCS Burlo Garofolo - Trieste - ITALY

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
June 2, 2025

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 31, 2025

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
June 2, 2026

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
June 2, 2025

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 2, 2025

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
June 10, 2025

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
June 10, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 2, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
June 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 1105/2015_BG

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

IPD Plan Description

Data sharing will be discussed case by case upon reasonable request and after local IRB approval.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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