Clinical trial NCT03301415: Asymptomatic Congenital CMV Treatment
Official title: A Phase II, Single Stage, Single-Arm Investigation of Oral Valganciclovir Therapy in Infants With Asymptomatic Congenital Cytomegalovirus Infection
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Congenital Cytomegalovirus Infection
Keywords: Asymptomatic
Congenital CMV Infection
Valganciclovir Therapy
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2017-10-04
Enrollment: 7
Sex: ALL
Minimum age (years): 1
Maximum age (years): 30
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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).

Primary outcomes:
measure: The Number of Participants Developing Sensorineural Hearing Loss (SNHL) in at Least One Ear Between Baseline and Study Month 6
timeFrame: Between baseline and study month 6
Secondary outcomes:
measure: Number of Participants With Absolute Neutrophil Counts Below 500/mm^3
timeFrame: Day 1 through Study month 5
measure: Number of Participants With Adverse Events Leading to Permanent Discontinuation of Valganciclovir Therapy, or Any Adverse Event That is Not Recovered / Not Resolved
timeFrame: Day 1 through Study month 6
measure: Number of Participants With Grade 3 or Higher Safety Laboratory Adverse Events
timeFrame: From day 1 through study month 6
measure: Number of Participants With Serious Adverse Events
timeFrame: From day 1 through study month 6
measure: Number of Participants With Grade 3 or Higher Unsolicited Adverse Events Assessed by Adapted From DAIDS Toxicity Tables
timeFrame: From day 1 through study month 6
measure: Number of Participants With Mild Worsened Hearing, Represented by the Ear That Has the Larger Degree of Worsening
timeFrame: Screening and Study Months 4, 6, 8 and 12
measure: Number of Participants With Moderate Worsened Hearing, Represented by the Ear That Has the Larger Degree of Worsening
timeFrame: Screening and Study Months 4, 6, 8 and 12
measure: Number of Participants With Profound Worsened Hearing, Represented by the Ear That Has the Larger Degree of Worsening
timeFrame: Study Months 4, 6, 8 and 12
measure: Number of Participants With Severe Worsened Hearing, Represented by the Ear That Has the Larger Degree of Worsening
timeFrame: Study Months 4, 6, 8 and 12
measure: Number of Participants With Sensorineural Hearing Loss in at Least One Ear Through Study Month 4
timeFrame: Between screening and study month 4
measure: Number of Participants With Sensorineural Hearing Loss in at Least One Ear Through Study Month 12
timeFrame: Between screening and study month 12
measure: Number of Participants With Sensorineural Hearing Loss in at Least One Ear Through Study Month 18
timeFrame: Between screening and study month 18
measure: Number of Participants With Transaminase Elevation During Treatment > / = 2 Times the Baseline Value
timeFrame: Baseline, weeks 2, 4, 6, 8, 10, 12, months 4, 5 and 6.
measure: Number of Ears of Mild Worsened Hearing
timeFrame: Screening and Study Months 4, 6, 12, and 18
measure: Number of Ears of Moderate Worsened Hearing
timeFrame: Screening and Study Months 4, 6, 12, and 18
measure: Number of Ears of Profound Worsened Hearing
timeFrame: Screening and Study Months 4, 6, 12, and 18
measure: Number of Ears of Severe Worsened Hearing
timeFrame: Screening and Study Months 4, 6, 12, and 18
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama - Children's of Alabama - Clinical Virology
state: Alabama
city: Little Rock
country: United States
facility: Arkansas Children's Hospital - Infectious Diseases
state: Arkansas
city: Louisville
country: United States
facility: University of Louisville School of Medicine - Norton Children's Hospital - Infectious Diseases
state: Kentucky
city: Jackson
country: United States
facility: University of Mississippi - Children's Infectious Diseases
state: Mississippi
city: Saint Louis
country: United States
facility: Washington University School of Medicine in St. Louis - Center for Clinical Studies
state: Missouri
city: Charlotte
country: United States
facility: Carolinas Medical Center - Pediatrics - Infectious Diseases
state: North Carolina
city: Columbus
country: United States
facility: Nationwide Children's Hospital - Neonatology - Center for Perinatal Research
state: Ohio
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC - Pediatric Infectious Diseases
state: Pennsylvania
city: Houston
country: United States
facility: Texas Medical Center - Texas Children's Hospital
state: Texas
Study officials:
References: