Evaluation of Long-term Efficacy of 4 to 6-month Course Antiviral Therapy for Neurodevelopmental Impairments Caused by Congenital Cytomegalovirus Infection

Study Identification

Brief Title: 4-month vs. 6-month Antiviral Therapy for Congenital CMV Infection: A Non-inferiority Trial (CMV-DURATION).

Official Title: Evaluation of Long-term Efficacy of 4-month versus 6-month Course Antiviral Therapy for Neurodevelopmental Impairment Caused by Congenital Cytomegalovirus Infection: A Multicenter, Randomized, Controlled, Non-inferiority Clinical Study.

Protocol Version: 1.1, January 15, 2026.

2\. Background and Rationale Congenital cytomegalovirus (cCMV) infection is the most common infectious cause of neurodevelopmental impairment and non-genetic sensorineural hearing loss (SNHL) in children worldwide. Approximately 10-15% of symptomatic infants develop long-term neurological sequelae.

The scientific premise for this study is based on two key observations:

Landmark studies (e.g., Kimberlin et al.) indicate that the long-term neurodevelopmental benefit of a 6-month course over a 6-week course may be mediated by sustained viral suppression, with viral load differences persisting until around 4 months of age.

Preliminary data from our prior multicenter study suggest that a 4-month antiviral course is significantly superior to a 6-week course in improving long-term brain function.

We hypothesize that as the neonatal immune system matures, active viral replication may transition to a latent state around 4 months of age. Therefore, a 4-month treatment course may be non-inferior to the 6-month standard course, potentially optimizing therapy by reducing duration-related risks (e.g., drug toxicity, cost, potential for resistance) while maintaining efficacy.

3\. Objectives

Primary Objective: To evaluate the non-inferiority of a 4-month course versus a 6-month course of antiviral therapy on the composite poor neurodevelopmental outcome at 12 months of age in infants with moderate-to-severe symptomatic cCMV infection.

Secondary Objectives:

To compare the long-term neurodevelopmental outcomes (both poor and mild impairment) between the two treatment groups at 12 and 24 months of age.

To identify high-risk factors associated with adverse long-term neurodevelopmental outcomes.

To compare safety profiles (e.g., hematological, hepatic, renal toxicity) between the 4-month and 6-month treatment regimens.

4\. Study Design

Trial Design: Prospective, multicenter, randomized, open-label, parallel-group, active-controlled, non-inferiority clinical trial.

Randomization: Eligible participants will be randomized in a 1:1 ratio to either the Experimental Group (4-month course) or the Active Control Group (6-month course). Randomization will be performed using a computer-generated block randomization sequence.

Blinding: This is an open-label study. Outcome assessors for key neurodevelopmental and audiological evaluations are encouraged to be blinded to treatment allocation where feasible.

Sample Size: A total of 150 subjects will be enrolled to yield 126 evaluable subjects at the final follow-up (63 per group). This calculation is based on an anticipated composite poor outcome rate of 20% at 12 months, a non-inferiority margin (Δ) of 20%, a one-sided alpha of 0.025, and 80% power, accounting for a 16% dropout rate.

5\. Participants

Inclusion Criteria:

Confirmed congenital CMV infection (CMV DNA detected in urine, blood, or serum within 21 days after birth).

Clinical disease classified as moderate or severe symptomatic cCMV infection (defined by involvement of multiple systems, including at least one neurologic finding, or two or more central nervous system findings such as microcephaly, imaging abnormalities, SNHL, chorioretinitis, or positive CMV DNA in CSF).

Age at enrollment ≤ 30 days. Written informed consent obtained from the parent(s) or legal guardian(s).

Exclusion Criteria:

Gestational age \< 32 weeks. Birth weight \< 1.8 kg. Absence of informed consent. Confirmed genetic mutations associated with hearing loss (e.g., GJB2). Coexisting major genetic or metabolic diseases known to affect neurodevelopment.

Occurrence of other intracranial infections during the neonatal period. Any condition that, in the opinion of the investigator, would make the infant unsuitable for the study or preclude evaluation.

6\. Interventions

Medications: All participants will receive standard antiviral therapy.

Intravenous Ganciclovir: 6 mg/kg per dose, administered twice daily (every 12 hours) via intravenous infusion.

Oral Valganciclovir: 16 mg/kg per dose, administered twice daily (every 12 hours).

The choice between intravenous or oral therapy will be at the treating physician's discretion based on the infant's clinical status and ability to tolerate oral medication.

Group Assignments:

Experimental Group (4-month course): Receives antiviral therapy for a total duration of 4 months (approximately 16 weeks).

Active Control Group (6-month course): Receives antiviral therapy for a total duration of 6 months (approximately 24 weeks), consistent with current international standard-of-care.

7\. Study Procedures and Assessments

Screening \& Baseline (≤21 days): Diagnosis confirmation, baseline lab tests (hematology, hepatic/renal function, blood/urine CMV DNA load), and comprehensive assessments (cranial imaging, brainstem auditory evoked potential, ophthalmologic exam, abdominal ultrasound).

Treatment Phase: Clinical \& Safety Monitoring: Follow-up every 2 weeks for infants ≤3 months old, and monthly for infants \>3 months old until the end of their assigned therapy. Assessments include physical exam, safety labs (complete blood count with differential, hepatic/renal function), and CMV DNA load monitoring.

Post-Treatment Follow-up: Scheduled Visits: All participants will be evaluated at 6, 12, and 24 months of age (chronological).

• Mild Neurodevelopmental Impairment [Срок оценки: at 12 months of age]
• Composite Poor Neurodevelopmental Outcome [Срок оценки: at 24 months of age]
• Mild Neurodevelopmental Impairment at 24 Months [Срок оценки: at 24 months of age]
• Incidence of Adverse Events (AEs) [Срок оценки: from start of treatment through 24 months of age]
• Incidence of Serious Adverse Events (SAEs) [Срок оценки: from start of treatment through 24 months of age]
• Incidence of Hematological Toxicity - Neutropenia [Срок оценки: from start of treatment through 24 months of age]
• Incidence of Hematological Toxicity - Thrombocytopenia [Срок оценки: from start of treatment through 24 months of age]
• Incidence of Hepatic Dysfunction [Срок оценки: from start of treatment through 24 months of age]
• Incidence of Renal Dysfunction [Срок оценки: from start of treatment through 24 months of age]
• Time to Undetectable CMV DNA in Blood [Срок оценки: from start of treatment through 24 months of age]
• Time to Undetectable CMV DNA in Urine [Срок оценки: from start of treatment through 24 months of age]