A Safety Assessment of Oral Letermovir in Infants With Symptomatic Congenital Cytomegalovirus

July 30, 2026 updated by: National Institute of Allergy and Infectious Diseases (NIAID)

A Phase I Pharmacokinetic and Safety Assessment of Oral Letermovir in Infants With Symptomatic Congenital Cytomegalovirus Disease

This is a Phase 1 single-arm open-label study of letermovir in neonates with symptomatic congenital Cytomegalovirus (CMV) disease. There will be two groups enrolled. Group 1 will be comprised of 4 subjects. Following documentation study inclusion and signing of informed consent, Group 1 subjects will receive one dose of oral letermovir (Study Day 0), using the dose bands. A full pharmacokinetics (PK) profile will then be obtained over the next 24 hours, and blood specimens will be shipped immediately to the University of Alabama at Birmingham (UAB) Pharmacokinetic Lab and processed in real time. Within = 7 days, pharmacokinetics (PK) results will be conveyed to the study site. If the Area Under the Curve (AUC24) is =100,000 ngxhr/mL (see footnote a in Table 1), the subject will initiate a 14-day course of once-daily oral letermovir at the same dose as utilized on Dose Finding Day. This duration of letermovir therapy was selected based upon our earlier observation in this population that patients with symptomatic congenital Cytomegalovirus (CMV) disease who achieve viral suppression to =2.5 log by day 14 of valganciclovir therapy and then maintain it over the next 4 months are statistically more likely to have improved hearing across the first two years of life (22). If the observed letermovir exposure of the subject is > 100,000 ngxhr/mL, the once-daily oral letermovir dose that will be used will be adjusted down in 2.5 mg increments. Oral valganciclovir (16 mg/kg/dose BID) will begin within the first month of life, as standard of care; initiation of valganciclovir can be concomitant with or prior to initiation of the 14-day course of letermovir (but will not start before obtaining the pharmacokinetics (PK) specimens following the single dose of letermovir on the Dose Finding Day). This is similar to the intensification approach that has been evaluated in the management of patients infected with human immunodeficiency virus (23-25). The day that the 14-day course of letermovir begins for Group 1 subjects will be known as Study Day 1. Serial blood samples will be obtained on Study Days 1, 5, 10, and 14 for safety chemistry and hematology labs and for Cytomegalovirus (CMV) viral loads. Cytomegalovirus (CMV) viral load will be followed as well on Study Days 21 and 42 to assess for rebound in Cytomegalovirus (CMV) following cessation of letermovir treatment on Study Day 14. Saliva and urine viral loads will be followed at these timepoint as well. Full pharmacokinetics (PK) profiles for both letermovir and ganciclovir will be obtained on Study Day 10. In addition, sparse pharmacokinetics (PK) sampling will be obtained on Study Days 1, 5, and 14. Adverse events will be assessed at each study visit during treatment, and at Study Days 21 and 42 (4 weeks after the last study drug dose). Subjects then will continue on oral valganciclovir as routine clinical care to complete an anticipated 6 month duration of total therapy. The primary objective is to determine the systemic exposure (AUC24) of letermovir following administration of oral letermovir granules in infants with symptomatic congenital CMV disease.

Study Overview

Status

Status

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

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

This is a Phase 1 single-arm open-label study of letermovir in neonates with symptomatic congenital Cytomegalovirus (CMV) disease. There will be two groups enrolled. Group 1 will be comprised of 4 subjects. Following documentation study inclusion and signing of informed consent, Group 1 subjects will receive one dose of oral letermovir (Study Day 0), using the dose bands. A full pharmacokinetics (PK) profile will then be obtained over the next 24 hours, and blood specimens will be shipped immediately to the University of Alabama at Birmingham (UAB) Pharmacokinetic Lab and processed in real time. Within = 7 days, pharmacokinetics (PK) results will be conveyed to the study site. If the Area Under the Curve (AUC24) is =100,000 ngxhr/mL (see footnote a in Table 1), the subject will initiate a 14-day course of once-daily oral letermovir at the same dose as utilized on the Dose Finding Day. This duration of letermovir therapy was selected based upon our earlier observation in this population that patients with symptomatic congenital Cytomegalovirus (CMV) disease who achieve viral suppression to =2.5 log by day 14 of valganciclovir therapy and then maintain it over the next 4 months are statistically more likely to have improved hearing across the first two years of life (22). If the observed letermovir exposure of the subject is > 100,000 ngxhr/mL, the once-daily oral letermovir dose that will be used will be adjusted down in 2.5 mg increments. Oral valganciclovir (16 mg/kg/dose BID) will begin within the first month of life, as standard of care; initiation of valganciclovir can be concomitant with or prior to initiation of the 14-day course of letermovir (but will not start before obtaining the pharmacokinetics (PK) specimens following the single dose of letermovir on the Dose Finding Day). This is similar to the intensification approach that has been evaluated in the management of patients infected with human immunodeficiency virus (23-25). The day that the 14-day course of letermovir begins for Group 1 subjects will be known as Study Day 1. Serial blood samples will be obtained on Study Days 1, 5, 10, and 14 for safety chemistry and hematology labs and for Cytomegalovirus (CMV) viral loads. Cytomegalovirus (CMV) viral load will be followed as well on Study Days 21 and 42 to assess for rebound in Cytomegalovirus (CMV) following cessation of letermovir treatment on Study Day 14. Saliva and urine viral loads will be followed at these timepoint as well. Full pharmacokinetics (PK) profiles for both letermovir and ganciclovir will be obtained on Study Day 10. In addition, sparse pharmacokinetics (PK) sampling will be obtained on Study Days 1, 5, and 14. Adverse events will be assessed at each study visit during treatment, and at Study Days 21 and 42 (4 weeks after the last study drug dose). Subjects then will continue on oral valganciclovir as routine clinical care to complete an anticipated 6 month duration of total therapy. Following enrollment of the 4 subjects in Group 1, the Safety Monitoring Committee (SMC) will review all safety and pharmacokinetic data. If no halting rules are met and no other safety concerns are identified, then additional subjects will be enrolled in Group 2. Subjects in Group 2 will initiate a 14-day course of once-daily oral letermovir, using the dose bands listed in Table 1, at the same time that oral valganciclovir (16 mg/kg/dose BID) is initiated as standard of care; initiation of valganciclovir can be concomitant with or prior to initiation of the 14-day course of letermovir. If the median of observed letermovir exposures of subjects in Group 1 is below 34,400 ngxhr/mL (or above 100,000 ngxhr/mL), then the subjects enrolled in Group 2 will receive once-daily oral letermovir at a dose that has been adjusted upward (or downward) in 2.5 mg increments. The day that the 14-day course of letermovir begins for Group 2 will be known as Study Day 1. Serial blood samples will be obtained on Study Days 1, 5, 10, and 14 for safety chemistry and hematology labs and for Cytomegalovirus (CMV) viral loads. Cytomegalovirus (CMV) viral load will be followed as well on Study Days 21 and 42 to assess for rebound in Cytomegalovirus (CMV) following cessation of letermovir treatment on Study Day 14. Saliva and urine viral loads will be followed at these timepoint as well. Full pharmacokinetics (PK) profiles for both letermovir and ganciclovir will be obtained on Study Day 10. In addition, sparse pharmacokinetics (PK) sampling will be obtained on Study Days 1, 5, and 14. Adverse events will be assessed at each study visit during treatment, and at Study Days 21 and 42 (4 weeks after the last study drug dose). Subjects then will continue on oral valganciclovir as routine clinical care to complete an anticipated 6 month duration of total therapy. The primary objective is to determine the systemic exposure (AUC24) of letermovir following administration of oral letermovir granules in infants with symptomatic congenital CMV disease. The secondary objectives are 1.) To determine the other pharmacokinetic parameters of letermovir following administration of oral letermovir granules in infants with symptomatic congenital CMV disease; 2.) To evaluate the safety of letermovir oral granules in infants.

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.
Interventional

Enrollment (Actual)

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.
3

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 1

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 Locations

  • United States
    • Alabama
      • Birmingham, Alabama, United States, 35233-0011
        • Children's of Alabama Child Health Research Unit (CHRU)
    • Georgia
      • Atlanta, Georgia, United States, 30322-1014
        • Emory University School of Medicine
    • Wisconsin
      • Milwaukee, Wisconsin, United States, 53226
        • Medical College of Wisconsin

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

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Signed informed consent from parent(s) or legal guardian(s)
  2. Cytomegalovirus (CMV) confirmation by culture, shell vial, or Polymerase Chain Reaction (PCR) tests from a specimen obtained at </= 30 days of life from saliva, blood, or urine
  3. Symptomatic congenital CMV disease*

  4. Age at study enrollment:

    1. </= 83 days for Group 1 subjects**
    2. </= 90 days for Group 2 subjects
  5. Weight at study enrollment 2.6 kg to < 8.0 kg
  6. Gestational age >/= 32 weeks at birth

  7. Intention by patient's physician to clinically treat infant with oral valganciclovir for 6 months for symptomatic congenital CMV disease

    • Manifested by one or more of the following: thrombocytopenia; petechiae; hepatomegaly; splenomegaly; intrauterine growth restriction; hepatitis; or Central Nervous System (CNS) involvement such as microcephaly, radiographic abnormalities indicative of CMV CNS disease, abnormal cerebrospinal fluid (CSF) indices for age, chorioretinitis, hearing deficits as detected by formal brainstem evoked response, and/or positive CMV Polymerase Chain Reaction (PCR) from CSF **Group 1 subjects must enroll and receive the Dose Finding Day dose of letermovir on or before 83 days of life so that oral valganciclovir can be started prior to 12 weeks 6 days (which is 90 days) of life, as is standard of care. For this study, the date of birth is counted as day of life 0

Exclusion Criteria:

  1. Imminent demise
  2. Infants known to be born to women who are HIV positive (but HIV testing is not required for study entry)
  3. Current receipt of other investigational drugs
  4. Grade 3 or 4 alanine aminotransferase (ALT) utilizing Division of AIDS (DAIDS) Toxicity Table
  5. Grade 3 or 4 total bilirubin utilizing DAIDS Toxicity Table
  6. Gastrointestinal abnormality which might preclude absorption of an oral medication (e.g., a history of necrotizing enterocolitis)
  7. Anticipated concomitant administration of carbamazepine (Tegretol), nafcillin, phenobarbital, or phenytoin (Dilantin) during the period of study drug administration

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

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
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.
Experimental: Group 1
Neonates (</= 83 days) with symptomatic congenital Cytomegalovirus (CMV) disease will receive one dose of oral letermovir, using weight dose banding. All subjects also will receive valganciclovir as standard of care. A dose safety evaluation will occur to ensure the safety data support subjects proceeding. If the observed letermovir exposure is </= 100,000 ngxhr/mL, the subject will initiate a 14-day course of once-daily oral letermovir at the same dose as utilized on the Dose Finding Day. If the observed letermovir exposure of the subject is > 100,000 ngxhr/mL, the once-daily oral letermovir dose that will be used will be adjusted down in 2.5 mg increments from the dose utilized on the Dose Finding Day. N = 4
Drug: Letermovir
Letermovir is a novel inhibitor targeting the cytomegalovirus (CMV) viral enzyme, effectively disrupting the production of additional CMV virions. Letermovir has demonstrated potent, selective, and reversible inhibition of CMV activity in preclinical studies.
Experimental: Group 2
Neonates (</= 90 days) with symptomatic congenital Cytomegalovirus (CMV) disease will initiate a 14-day course of once-daily oral letermovir, using weight dose banding. All subjects also will receive valganciclovir as standard of care. A dose escalation safety evaluation will occur to ensure the safety data support subjects proceeding. If the median of observed letermovir exposures of subjects in Group 1 is below 34,400 ngxhr/mL (or above 100,000 ngxhr/mL), then the subjects enrolled in Group 2 will receive once-daily oral letermovir at a dose that has been adjusted upward (or downward) in 2.5 mg increments. N=8
Drug: Letermovir
Letermovir is a novel inhibitor targeting the cytomegalovirus (CMV) viral enzyme, effectively disrupting the production of additional CMV virions. Letermovir has demonstrated potent, selective, and reversible inhibition of CMV activity in preclinical studies.

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
Plasma letermovir area under the curve (AUC24) concentrations
Time Frame: Through Day 14
Determined using the linear-log trapezoidal rule. In addition, a population PK analysis may be conducted at the end of the study.
Through Day 14

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
Plasma letermovir clearance (CL)
Time Frame: Through Day 14
Through Day 14
Plasma letermovir half-life (T1/2)
Time Frame: Through Day 14
Determined using regression analysis of the terminal elimination phase concentration-time points.
Through Day 14
Plasma letermovir maximum plasma concentration (Cmax)
Time Frame: Through Day 14
Through Day 14
Plasma letermovir minimum plasma concentration (Cmin)
Time Frame: Through Day 14
Through Day 14
Plasma letermovir volume of distribution (Vd)
Time Frame: Through Day 14
Through Day 14
Frequency of serious adverse events (SAEs)
Time Frame: Through Day 42
Through Day 42
Frequency of grade 3 adverse events (AEs)
Time Frame: Through Day 42
Grade 3 is defined as severe symptoms causing inability to perform usual social & functional activities with intervention or hospitalization indicated
Through Day 42
Frequency of grade 4 adverse events (AEs)
Time Frame: Through Day 42
Grade 4 is defined as Potentially life-threatening symptoms causing inability to perform basic self-care functions with intervention indicated to prevent permanent impairment, persistent disability, or death
Through Day 42

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.
National Institute of Allergy and Infectious Diseases (NIAID)

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.
February 19, 2025

Primary Completion (Actual)

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.
April 7, 2026

Study Completion (Actual)

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.
May 4, 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).
November 1, 2023

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.
November 1, 2023

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.
November 7, 2023

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.
August 3, 2026

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.
July 30, 2026

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.
July 18, 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.
  • 21-0027
  • 5U54AI150225-05 (U.S. NIH Grant/Contract)

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

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