Asymptomatic Congenital CMV Treatment

• ClinicalTrials.gov Identifier: NCT03301415
• Recruitment Status: Terminated
• First Posted: October 4, 2017
• Results First Posted: January 26, 2023
• Last Update Posted: January 26, 2023
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): National Institute of Allergy and Infectious Diseases (NIAID)

Study Description

Brief Summary:

This is a phase II, open-label trial to evaluate valganciclovir as a treatment to prevent development of sensorineural hearing loss (SNHL) in infants with asymptomatic congenital cytomegalovirus (CMV) infection. The trial will be conducted in two phases - screening of newborns to identify eligible subjects, and treatment of those newborns who have confirmed CMV infection at birth but without outward manifestations of congenital CMV infection. 229 newborns with confirmed CMV infection but without baseline SNHL and who meet all inclusion/exclusion criteria will be enrolled into the treatment phase. Study duration is 5 years. Primary objective of this study is to estimate the proportion of subjects with asymptomatic congenital CMV infection who, following treatment with 4 months of oral valganciclovir, develop SNHL by 6 months of life.

Condition or disease	Intervention/treatment	Phase
Congenital Cytomegalovirus Infection	Drug: Valganciclovir	Phase 2

Detailed Description:

This is a phase II, open-label trial to evaluate valganciclovir as a treatment to prevent development of sensorineural hearing loss (SNHL) in infants with asymptomatic congenital cytomegalovirus (CMV) infection. The trial will be conducted in two phases - screening of newborns to identify eligible subjects, and treatment of those newborns who have confirmed CMV infection at birth but without outward manifestations of congenital CMV infection. Approximately 48,250 newborn infants with no outward manifestations of congenital CMV infection will be screened to detect approximately 241 neonates with asymptomatic congenital CMV infection; these 241 newborns then will have audiology examinations to determine baseline hearing, with approximately 229 having normal hearing in both ears. Those 229 newborns with confirmed CMV infection but without baseline SNHL and who meet all inclusion/exclusion criteria will be enrolled into the treatment phase. Enrolled subjects will be treated for four months with oral valganciclovir (16 mg/kg/dose, administered two times per day). Audiologic assessments will be made during the Screening Period and Study Months 4 (end of treatment), 6, 12, and 18. Treated infants will be followed for safety throughout the first 6 months of the study (including for 2 months post-treatment). Study duration is 5 years. Primary objective of this study is to estimate the proportion of subjects with asymptomatic congenital CMV infection who, following treatment with 4 months of oral valganciclovir, develop sensorineural hearing loss (SNHL) by 6 months of life. Secondary objectives are to: 1) define the safety and tolerability of valganciclovir in enrolled subjects, 2) estimate the proportion of subjects with asymptomatic congenital CMV infection who, following treatment with 4 months of oral valganciclovir, develop SNHL over the first 18 months of life.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 7 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II, Single Stage, Single-Arm Investigation of Oral Valganciclovir Therapy in Infants With Asymptomatic Congenital Cytomegalovirus Infection
• Actual Study Start Date: August 21, 2019
• Actual Primary Completion Date: November 5, 2020
• Actual Study Completion Date: November 5, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Confirmed congenital CMV without baseline SNHL; Valganciclovir 16 mg/kg/dose orally twice daily for four months, n=229	Drug: Valganciclovir; Valganciclovir, 16 mg/kg/dose given orally twice daily for four months

Outcome Measures

Primary Outcome Measures :

1. The Number of Participants Developing Sensorineural Hearing Loss (SNHL) in at Least One Ear Between Baseline and Study Month 6 [ Time Frame: Between baseline and study month 6 ]
   Audiologic assessments were made during the Screening Period and Study Months 4 (end of treatment), 6, 12, and 18. A single, independent study audiologist assessed the audiology test battery for each subject and assigned each ear the classifications of normal hearing, mild hearing loss, moderate hearing loss, severe hearing loss, or profound hearing loss based upon their hearing thresholds (in decibels). SNHL between baseline and Study Month 6 is defined as both ears with normal hearing at baseline, then at least one ear with sensorineural hearing loss (SNHL) at the 6 month follow-up.

Secondary Outcome Measures :

1. Number of Participants With Absolute Neutrophil Counts Below 500/mm^3 [ Time Frame: Day 1 through Study month 5 ]
   Blood was collected for assessments of hematology and absolute neutrophil count was assessed at each study visit through Month 5
2. Number of Participants With Adverse Events Leading to Permanent Discontinuation of Valganciclovir Therapy, or Any Adverse Event That is Not Recovered / Not Resolved [ Time Frame: Day 1 through Study month 6 ]
   A count of participants discontinued from valganciclovir therapy due to adverse events were reported during the therapy period, and the count of participants with adverse events not recovered/not resolved were reported throughout the adverse event period.
3. Number of Participants With Grade 3 or Higher Safety Laboratory Adverse Events [ Time Frame: From day 1 through study month 6 ]
   At each study visit from the receipt of first dose of study drug and continuing through four weeks following the final dose of study drug, the participants were assessed for any adverse events. Lab parameters included ALT, creatinine, direct bilirubin, white blood cell count with differential, hemoglobin, platelets count. Abnormal laboratory values were reported as an AE if they worsened in severity from baseline, per the grading definitions provided in the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events.
4. Number of Participants With Serious Adverse Events [ Time Frame: From day 1 through study month 6 ]
   Serious adverse events were those defined as: death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, a congenital anomaly/birth defect, or were important medical events that may not result in death, be life-threatening, or require hospitalizations may be considered serious when, based upon appropriate medical judgment they may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.
5. Number of Participants With Grade 3 or Higher Unsolicited Adverse Events Assessed by Adapted From DAIDS Toxicity Tables [ Time Frame: From day 1 through study month 6 ]
   At each study visit from the receipt of first dose of study drug and continuing through four weeks following the final dose of study drug, the participants were assessed for any adverse events. Lab parameters included ALT, creatinine, direct bilirubin, white blood cell count with differential, hemoglobin, platelets count. Abnormal laboratory values were reported as an AE if they worsened in severity from baseline, per the grading definitions provided in the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events.
6. Number of Participants With Mild Worsened Hearing, Represented by the Ear That Has the Larger Degree of Worsening [ Time Frame: Screening and Study Months 4, 6, 8 and 12 ]
   Audiologic assessments were made during the Screening Period and Study Months 4 (end of treatment), 6, 12, and 18. A single, independent study audiologist assessed the audiology test battery for each participant and assigned each ear the classifications of normal hearing, mild hearing loss, moderate hearing loss, severe hearing loss, or profound hearing loss based upon their hearing thresholds (in decibels). SNHL between baseline and Study Month 18 is defined as both ears with normal hearing at baseline, then at least one ear with sensorineural hearing loss (SNHL) at the 18 month follow-up.
7. Number of Participants With Moderate Worsened Hearing, Represented by the Ear That Has the Larger Degree of Worsening [ Time Frame: Screening and Study Months 4, 6, 8 and 12 ]
   Audiologic assessments were made during the Screening Period and Study Months 4 (end of treatment), 6, 12, and 18. A single, independent study audiologist assessed the audiology test battery for each subject and assigned each ear the classifications of normal hearing, mild hearing loss, moderate hearing loss, severe hearing loss, or profound hearing loss based upon their hearing thresholds (in decibels). SNHL between baseline and Study Month 18 is defined as both ears with normal hearing at baseline, then at least one ear with sensorineural hearing loss (SNHL) at the 18 month follow-up.
8. Number of Participants With Profound Worsened Hearing, Represented by the Ear That Has the Larger Degree of Worsening [ Time Frame: Study Months 4, 6, 8 and 12 ]
   Audiologic assessments were made during the Screening Period and Study Months 4 (end of treatment), 6, 12, and 18. A single, independent study audiologist assessed the audiology test battery for each participant and assigned each ear the classifications of normal hearing, mild hearing loss, moderate hearing loss, severe hearing loss, or profound hearing loss based upon their hearing thresholds (in decibels). SNHL between baseline and Study Month 18 is defined as both ears with normal hearing at baseline, then at least one ear with sensorineural hearing loss (SNHL) at the 18 month follow-up.
9. Number of Participants With Severe Worsened Hearing, Represented by the Ear That Has the Larger Degree of Worsening [ Time Frame: Study Months 4, 6, 8 and 12 ]
   Audiologic assessments were made during the Screening Period and Study Months 4 (end of treatment), 6, 12, and 18. A single, independent study audiologist assessed the audiology test battery for each participant and assigned each ear the classifications of normal hearing, mild hearing loss, moderate hearing loss, severe hearing loss, or profound hearing loss based upon their hearing thresholds (in decibels). SNHL between baseline and Study Month 18 is defined as both ears with normal hearing at baseline, then at least one ear with sensorineural hearing loss (SNHL) at the 18 month follow-up.
10. Number of Participants With Sensorineural Hearing Loss in at Least One Ear Through Study Month 4 [ Time Frame: Between screening and study month 4 ]
    Audiologic assessments were made during the Screening Period and Study Months 4 (end of treatment), 6, 12, and 18. A single, independent study audiologist assessed the audiology test battery for each participant and assigned each ear the classifications of normal hearing, mild hearing loss, moderate hearing loss, severe hearing loss, or profound hearing loss based upon their hearing thresholds (in decibels). SNHL between baseline and Study Month 4 is defined as both ears with normal hearing at baseline, then at least one ear with sensorineural hearing loss (SNHL) at the 4 month follow-up.
11. Number of Participants With Sensorineural Hearing Loss in at Least One Ear Through Study Month 12 [ Time Frame: Between screening and study month 12 ]
    Audiologic assessments were made during the Screening Period and Study Months 4 (end of treatment), 6, 12, and 18. A single, independent study audiologist assessed the audiology test battery for each participant and assigned each ear the classifications of normal hearing, mild hearing loss, moderate hearing loss, severe hearing loss, or profound hearing loss based upon their hearing thresholds (in decibels). SNHL between baseline and Study Month 12 is defined as both ears with normal hearing at baseline, then at least one ear with sensorineural hearing loss (SNHL) at the 12 month follow-up.
12. Number of Participants With Sensorineural Hearing Loss in at Least One Ear Through Study Month 18 [ Time Frame: Between screening and study month 18 ]
    Audiologic assessments were made during the Screening Period and Study Months 4 (end of treatment), 6, 12, and 18. A single, independent study audiologist assessed the audiology test battery for each participant and assigned each ear the classifications of normal hearing, mild hearing loss, moderate hearing loss, severe hearing loss, or profound hearing loss based upon their hearing thresholds (in decibels). SNHL between baseline and Study Month 18 is defined as both ears with normal hearing at baseline, then at least one ear with sensorineural hearing loss (SNHL) at the 18 month follow-up.
13. Number of Participants With Transaminase Elevation During Treatment > / = 2 Times the Baseline Value [ Time Frame: Baseline, weeks 2, 4, 6, 8, 10, 12, months 4, 5 and 6. ]
    Blood was collected for assessments of clinical chemistry and alanine aminotransferase (ALT) was assessed at screening, week 2, Week 4, Week 6, Week 8, Week 10, Week 12, Month 4, Month 5, and Month 6
14. Number of Ears of Mild Worsened Hearing [ Time Frame: Screening and Study Months 4, 6, 12, and 18 ]
    Audiologic assessments were made during the Screening Period and Study Months 4 (end of treatment), 6, 12, and 18. A single, independent study audiologist assessed the audiology test battery for each participant and assigned each ear the classifications of normal hearing, mild hearing loss, moderate hearing loss, severe hearing loss, or profound hearing loss based upon their hearing thresholds (in decibels).
15. Number of Ears of Moderate Worsened Hearing [ Time Frame: Screening and Study Months 4, 6, 12, and 18 ]
    Audiologic assessments were made during the Screening Period and Study Months 4 (end of treatment), 6, 12, and 18. A single, independent study audiologist assessed the audiology test battery for each participant and assigned each ear the classifications of normal hearing, mild hearing loss, moderate hearing loss, severe hearing loss, or profound hearing loss based upon their hearing thresholds (in decibels).
16. Number of Ears of Profound Worsened Hearing [ Time Frame: Screening and Study Months 4, 6, 12, and 18 ]
    Audiologic assessments were made during the Screening Period and Study Months 4 (end of treatment), 6, 12, and 18. A single, independent study audiologist assessed the audiology test battery for each participant and assigned each ear the classifications of normal hearing, mild hearing loss, moderate hearing loss, severe hearing loss, or profound hearing loss based upon their hearing thresholds (in decibels).
17. Number of Ears of Severe Worsened Hearing [ Time Frame: Screening and Study Months 4, 6, 12, and 18 ]
    Audiologic assessments were made during the Screening Period and Study Months 4 (end of treatment), 6, 12, and 18. A single, independent study audiologist assessed the audiology test battery for each participant and assigned each ear the classifications of normal hearing, mild hearing loss, moderate hearing loss, severe hearing loss, or profound hearing loss based upon their hearing thresholds (in decibels).

Eligibility Criteria

• Ages Eligible for Study: 1 Day to 30 Days (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Parent(s)/legal guardian(s) have signed informed consent documents*
• Confirmation of cytomegalovirus (CMV) by urine polymerase chain reaction (PCR) testing
• Infant </= 30 days of age at initiation of study drug
• Weight at study enrollment >/= 1775 grams

• Gestational age >/= 32 weeks at birth

  • There is a screening informed consent for screening phase of study participation, and a treatment informed consent for treatment phase of study participation.

Exclusion Criteria:

• Symptomatic congenital cytomegalovirus (CMV) disease*
• Sensorineural hearing deficits as detected by formal brainstem evoked response (not a screening auditory brainstem response (abr)) of known etiology other than CMV
• Prior or current receipt of ganciclovir, valganciclovir, foscarnet, cidofovir, brincidofovir, maribavir, or letermovir
• Maternal receipt of CMV hyperimmune globulin during pregnancy
• Breastfeeding from mother who is receiving ganciclovir, valganciclovir, foscarnet, cidofovir, brincidofovir, maribavir, or letermovir
• Gastrointestinal abnormality which might preclude absorption of an oral medication (e.g., a history of necrotizing enterocolitis)
• Infants known to be born to women who are HIV positive (HIV testing is not required for study entry)

• Current receipt of other investigational drugs

  • Symptomatic disease is defined as one or more of the following: 1) thrombocytopenia, if known; 2) petechiae; 3) hepatomegaly; 4) splenomegaly; 5) intrauterine growth restriction; 6) hepatitis (elevated transaminases and/or direct bilirubin), if known; 7) central nervous system involvement of the CMV disease (such as microcephaly; radiographic abnormalities indicative of CMV CNS disease, if known; abnormal CSF indices for age, if known; chorioretinitis, if known; and/or positive CMV PCR from CSF, if known).

Contacts and Locations

Locations

United States, Alabama

University of Alabama - Children's of Alabama - Clinical Virology

Birmingham, Alabama, United States, 35233-1711

United States, Arkansas

Arkansas Children's Hospital - Infectious Diseases

Little Rock, Arkansas, United States, 72202

United States, Kentucky

University of Louisville School of Medicine - Norton Children's Hospital - Infectious Diseases

Louisville, Kentucky, United States, 40202

United States, Mississippi

University of Mississippi - Children's Infectious Diseases

Jackson, Mississippi, United States, 39216-4505

United States, Missouri

Washington University School of Medicine in St. Louis - Center for Clinical Studies

Saint Louis, Missouri, United States, 63110-1010

United States, North Carolina

Carolinas Medical Center - Pediatrics - Infectious Diseases

Charlotte, North Carolina, United States, 28203-5812

United States, Ohio

Nationwide Children's Hospital - Neonatology - Center for Perinatal Research

Columbus, Ohio, United States, 43205-2664

United States, Pennsylvania

Children's Hospital of Pittsburgh of UPMC - Pediatric Infectious Diseases

Pittsburgh, Pennsylvania, United States, 15224-1529

United States, Texas

Texas Medical Center - Texas Children's Hospital

Houston, Texas, United States, 77030-2303

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

  Study Documents (Full-Text)

Documents provided by National Institute of Allergy and Infectious Diseases (NIAID):

Study Protocol and Statistical Analysis Plan  [PDF] March 22, 2019

Informed Consent Form  [PDF] May 22, 2019

More Information

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT03301415
• Other Study ID Numbers: 16-0095
• First Posted: October 4, 2017
• Results First Posted: January 26, 2023
• Last Update Posted: January 26, 2023
• Last Verified: October 2018

• 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

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):

Asymptomatic; Congenital CMV Infection; Valganciclovir Therapy

Additional relevant MeSH terms:

Infections; Cytomegalovirus Infections; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Valganciclovir; Antiviral Agents; Anti-Infective Agents