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

1. Background and Rationale：Congenital cytomegalovirus (cCMV) infection is a leading cause of childhood neurodevelopmental disability and sensorineural hearing loss (SNHL). International guidelines, based on evidence from high-income countries, recommend a 6-month antiviral course for symptomatic infection. However, clinical practice in China lags significantly, still adhering to a 3-4 week regimen due to a lack of high-quality domestic evidence. Preliminary data suggest a 4-month course may be non-inferior to the 6-month standard by potentially aligning with the transition from productive to latent infection around 4 months of age. This study aims to address this critical evidence gap.2. Study Objectives：Primary: To evaluate the impact of intermediate (4-month) versus long (6-month) course antiviral therapy on long-term neurodevelopmental outcomes in infants with moderate-to-severe cCMV infection, and to establish a novel diagnostic and therapeutic framework.Secondary: To identify high-risk factors associated with adverse long-term outcomes.3. Study Design and Methods：This is a prospective, multicenter, randomized, open-label, parallel-controlled, non-inferiority clinical trial.Participants: Newborns (≤30 days old) diagnosed with moderate-to-severe cCMV infection. Key exclusion criteria include gestational age <32 weeks, birth weight <1.8 kg, and coexisting genetic/metabolic diseases.Randomization & Intervention: Eligible subjects will be block-randomized 1:1 via a computer-generated sequence.Experimental Group: Receives 4 months of antiviral therapy.Control Group: Receives 6 months of antiviral therapy (current international standard).Both groups receive either intravenous ganciclovir (6 mg/kg, twice daily) or oral valganciclovir (16 mg/kg, twice daily).Sample Size: A total of 150 subjects will be enrolled (60 from the lead center), anticipating 126 evaluable cases at study completion (2 years of age) to demonstrate non-inferiority with a margin (Δ) of 20%, 80% power, and a one-sided alpha of 0.025.4. Evaluation and Endpoints：Primary Outcome: Composite poor neurodevelopmental outcome at 12 months of age, defined as (1) death, or (2) moderate/severe impairment, including cerebral palsy, epilepsy, moderate-to-severe SNHL (>40 dB threshold and/or requiring cochlear implantation), visual impairment, or a score <-2 SD on standardized developmental scales (Griffiths, BSID-II, or Bayley-III).Secondary Outcomes: Include mild neurodevelopmental impairment at 12 months, and poor/mild neurodevelopmental outcomes at 24 months.Assessments: Scheduled follow-ups include clinical, laboratory (hepatic/renal function, CMV DNA load), and instrumental evaluations (neuroimaging, audiology, ophthalmology) during treatment and at 6, 12, and 24 months of age.5. Data Management and Ethics：Data will be managed using a multicenter Electronic Data Capture (EDC) system with double data entry. The study protocol has been approved by the Medical Ethics Committee of Children's Hospital, Zhejiang University School of Medicine. Written informed consent will be obtained from all participants' guardians. The study is scheduled from January 2026 to December 2028.This study will provide crucial high-level evidence to inform optimal antiviral therapy duration for cCMV infection in China, with the goal of improving long-term child health outcomes and reducing disease burden.

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).

Outcome Assessments: Each follow-up includes:

Neurological/Developmental: Standardized neurodevelopmental testing using the Griffiths Mental Development Scales, Bayley Scales of Infant Development-II (BSID-II), or Bayley Scales of Infant and Toddler Development-III (Bayley-III). Neurological exam for cerebral palsy, epilepsy, and behavioral disorders.

Audiological: Comprehensive hearing assessment including brainstem auditory evoked potential to define SNHL severity.

Ophthalmological: Retinal examination to detect chorioretinitis or other visual impairments.

Other: Clinical examination, safety labs, and cranial MRI at key time points.

8. Outcome Measures

Primary Outcome Measure: Composite Poor Neurodevelopmental Outcome at 12 Months: Defined as the occurrence of any one of the following:

Death.

Moderate/Severe Impairment, including:

Cerebral palsy (GMFCS level ≥ II) Behavioral disorders requiring intervention Epilepsy Moderate-to-severe SNHL (threshold >40 dB in the better ear and/or meeting criteria for cochlear implantation) Visual impairment (extensive retinal exudates, documented visual deficit, or poor fixation due to neurological abnormality) Significant developmental delay, defined as a score less than -2 standard deviations (SD) on any of the standardized developmental scales (Griffiths, BSID-II MDI/PDI, or Bayley-III Cognitive/Motor/General IQ composite).

Secondary Outcome Measures:

Rate of Mild Neurodevelopmental Impairment at 12 months (defined by specific, less severe criteria).

Composite Poor Neurodevelopmental Outcome at 24 months. Rate of Mild Neurodevelopmental Impairment at 24 months. Incidence and severity of adverse events and serious adverse events, with special attention to hematological toxicity (neutropenia, thrombocytopenia) and hepatic/renal dysfunction.

Viral kinetics (time to undetectable CMV DNA in blood/urine) during and after therapy.

9. Data Management and Monitoring Data will be collected via electronic Case Report Forms (eCRFs) within a secure, password-protected, multicenter Electronic Data Capture (EDC) system. A double data entry process with independent reconciliation by two data managers will ensure accuracy. The final database will be locked after verification and joint approval by the Principal Investigator and the lead statistician. The study will be monitored for protocol compliance and data quality.

10. Ethics and Dissemination The study protocol has been approved by the Medical Ethics Committee of Children's Hospital, Zhejiang University School of Medicine. Written informed consent will be obtained from a parent or legal guardian of every participant before any study procedures are performed. The study will be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice (GCP) guidelines. Results will be disseminated through peer-reviewed publications and presentations at scientific conferences. The dataset generated may be available from the corresponding author upon reasonable request after the primary publication.

11. Study Timeline

Anticipated Study Start Date: January 2026.

Anticipated Primary Completion Date: December 2028 (date of last follow-up for primary outcome measure).

Anticipated Study Completion Date: December 2028.

12. Contacts and Locations The study will be conducted at multiple centers in China, with Children's Hospital, Zhejiang University School of Medicine as the lead center. Contact information for the principal investigator and sponsor-investigator will be provided in the formal registration.

Inclusion Criteria:

1. Confirmed congenital CMV infection (CMV DNA detected in urine, blood, or serum within 21 days after birth).
2. 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).
3. Age at enrollment ≤ 30 days.
4. Written informed consent obtained from the parent(s) or legal guardian(s).

Exclusion Criteria:

1. Gestational age < 32 weeks.
2. Birth weight < 1.8 kg.
3. Absence of informed consent.
4. Confirmed genetic mutations associated with hearing loss (e.g., GJB2).
5. Coexisting major genetic or metabolic diseases known to affect neurodevelopment.
6. Occurrence of other intracranial infections during the neonatal period.
7. Any condition that, in the opinion of the investigator, would make the infant unsuitable for the study or preclude evaluation.