Asymptomatic Congenital CMV Treatment

Study Overview
=================
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.

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.

Official Title
-----------------
A Phase II, Single Stage, Single-Arm Investigation of Oral Valganciclovir Therapy in Infants With Asymptomatic Congenital Cytomegalovirus Infection

Conditions
-----------------
Congenital Cytomegalovirus Infection

Intervention / Treatment
-----------------
* Drug: Valganciclovir


Participation Criteria
=================
Eligibility 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).

Ages Eligible for Study
-----------------
Minimum Age: 1 Day
Maximum Age: 30 Days

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Confirmed congenital CMV without baseline SNHL<br>Valganciclovir 16 mg/kg/dose orally twice daily for four months, n=229 | Drug: Valganciclovir<br>* Valganciclovir, 16 mg/kg/dose given orally twice daily for four months<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Participants Developing Sensorineural Hearing Loss (SNHL) in at Least One Ear 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. | Between baseline and study month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Absolute Neutrophil Counts Below 500/mm^3 | Blood was collected for assessments of hematology and absolute neutrophil count was assessed at each study visit through Month 5 | Day 1 through Study month 5 | 
| Number of Participants With Adverse Events Leading to Permanent Discontinuation of Valganciclovir Therapy, or Any Adverse Event That is Not Recovered / Not Resolved | 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. | Day 1 through Study month 6 | 
| Number of Participants With Grade 3 or Higher Safety Laboratory Adverse Events | 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. | From day 1 through study month 6 | 
| Number of Participants With Serious Adverse Events | 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. | From day 1 through study month 6 | 
| Number of Participants With Grade 3 or Higher Unsolicited Adverse Events Assessed by Adapted From DAIDS Toxicity Tables | 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. | From day 1 through study month 6 | 
| Number of Participants With Mild Worsened Hearing, Represented by the Ear That Has the Larger Degree of Worsening | 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. | Screening and Study Months 4, 6, 8 and 12 | 
| Number of Participants With Moderate Worsened Hearing, Represented by the Ear That Has the Larger Degree of Worsening | 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. | Screening and Study Months 4, 6, 8 and 12 | 
| Number of Participants With Profound Worsened Hearing, Represented by the Ear That Has the Larger Degree of Worsening | 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. | Study Months 4, 6, 8 and 12 | 
| Number of Participants With Severe Worsened Hearing, Represented by the Ear That Has the Larger Degree of Worsening | 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. | Study Months 4, 6, 8 and 12 | 
| Number of Participants With Sensorineural Hearing Loss in at Least One Ear Through 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. | Between screening and study month 4 | 
| Number of Participants With Sensorineural Hearing Loss in at Least One Ear Through 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. | Between screening and study month 12 | 
| Number of Participants With Sensorineural Hearing Loss in at Least One Ear Through 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. | Between screening and study month 18 | 
| Number of Participants With Transaminase Elevation During Treatment > / = 2 Times the Baseline Value | 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 | Baseline, weeks 2, 4, 6, 8, 10, 12, months 4, 5 and 6. | 
| Number of Ears of Mild Worsened Hearing | 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). | Screening and Study Months 4, 6, 12, and 18 | 
| Number of Ears of Moderate Worsened Hearing | 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). | Screening and Study Months 4, 6, 12, and 18 | 
| Number of Ears of Profound Worsened Hearing | 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). | Screening and Study Months 4, 6, 12, and 18 | 
| Number of Ears of Severe Worsened Hearing | 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). | Screening and Study Months 4, 6, 12, and 18 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Asymptomatic, Congenital CMV Infection, Valganciclovir Therapy