Valganciclovir Therapy in Infants and Children With Congenital CMV Infection and Hearing Loss

Study Overview
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Brief Summary
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This is an international, multi-center, double-blind, placebo-controlled evaluation valganciclovir treatment for up to 54 children (up to 4 years of age) with virologically-confirmed congenital CMV infection and hearing loss. Subject participation will be over a six-month period and study subjects will be stratified according to age. The primary objective is to assess whether a six-week course of oral valganciclovir can stabilize the hearing of children with congenital CMV infection who present with hearing loss.

Detailed Description
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Congenital cytomegalovirus (CMV) infection is the most frequent known viral cause of mental retardation, and is the leading non-genetic cause of sensorineural hearing loss in many countries including the United States. This is a Phase II international, multi-center, double-blind, placebo-controlled evaluation of 6 weeks of oral valganciclovir treatment or 6 weeks of placebo for fifty-four male and female infants/toddlers 1 month through 3 years of age (up to 4 years of age) with virologically-confirmed congenital CMV infection and hearing loss. Patient who are between 1 month and 4 years of age and who have SNHL (Sensorineural Hearing Loss) and are eligible for enrollment. The expected study duration is 3.5 years from enrollment of first study subject. The primary objective is to assess whether a six week course of oral valganciclovir can stabilize the hearing of children with congenital CMV infection who present with hearing loss. The secondary objective is to define the following responses as a function of systemic exposure to ganciclovir (active metabolite of valganciclovir): CMV viral load in blood; CMV viral load in urine; and CMV viral load in saliva. Also, to define the safety and tolerability of valganciclovir in enrolled subjects. The tertiary objective is to define the pharmacokinetics of ganciclovir (metabolite) following administration of valganciclovir (prodrug) in enrolled subjects.

Official Title
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A Phase II Randomized and Controlled Investigation of Six Weeks of Oral Valganciclovir Therapy in Infants and Children With Congenital Cytomegalovirus Infection and Hearing Loss

Conditions
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Cytomegalovirus Infection

Intervention / Treatment
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* Other: Placebo
* Drug: Valganciclovir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent from parent(s) or legal guardian(s) Sensorineural hearing loss (>/= 21dB in one or both ears, documented within 12 weeks prior to study entry) Children from 1 month through 3 years of age (up to the 4th birthday) Exclusion Criteria: Imminent demise Profound sensorineural hearing loss (> 90dB) in both ears Patients receiving other antiviral agents or immune globulin Gastrointestinal abnormality which might preclude absorption of an oral medication (e.g., a history of necrotizing enterocolitis) Documented renal insufficiency, as noted by a creatinine clearance < 10 mL/min/1.73m2 at time of study enrollment Breastfeeding from mother who is receiving ganciclovir, valganciclovir, foscarnet, cidofovir, or maribavir Infants known to be born to women who are HIV positive (but HIV testing is not required for study entry). Current receipt of other investigational drugs Previous receipt of ganciclovir or valganciclovir Known hypersensitivity to ganciclovir, valganciclovir, or components of the product Inability to attend follow-up hearing and clinical assessments Infants with Auditory neuropathy/dyssynchrony. Children with another known etiology for SNHL (e.g. connexin 26, syndrome or metabolic disorder associated with SNHL, inner ear malformation and widened vestibular aqueducts, meningitis). Exclusion of each of these conditions is not required for trial enrollment.

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 4 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active<br>27 Children between 1 month and 3 years of age (up to 4th birthday) with sensoneural hearing loss and documented CMV infection will receive valganciclovir HCl 16.0 mg/kg orally twice a day for 6 weeks | Drug: Valganciclovir<br>* Valcyte (valganciclovir hydrochloride) 50 mg of valganciclovir free base per 1 mL, oral solution: given at 16.0 mg/kg, twice a day for 6 weeks.<br>|
| Placebo Comparator: Placebo<br>27 Children between 1 month and 3 years of age (up to 4th birthday) with sensoneural hearing loss and documented CMV infection will receive placebo orally twice a day for 6 weeks | Other: Placebo<br>* Simple Syrup as 60-90% sucrose in purified water: given orally twice a day for 6 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Ears That Had (1) Improved Hearing or no Change in Hearing (2) Worsened Hearing. | A single, independent study audiologist who is masked (blinded) to treatment assignment will assess the audiology test battery for each subject and assign the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications will be assigned by ear (one for the left ear and one for the right ear), giving total ear classifications. At the analyses stage, the best ear classification for the subject at that study visit will be determined; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the best ear classification will be mild hearing loss. Not both ears are evaluable for all subjects. In some subjects, only one ear is evaluable. | Day 1 through Day 180 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Best Ear That Had (1) Improved Hearing or no Change in Hearing (2) Worsened Hearing [ex. Improved+ no Change (Normal to Normal) Versus Other]. | A single, independent study audiologist who is masked (blinded) to treatment assignment will assess the audiology test battery for each subject and assign the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications will be assigned by ear (one for the left ear and one for the right ear), giving total ear classifications. At the analyses stage, the best ear classification for the subject at that study visit will be determined; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the best ear classification will be mild hearing loss. For this outcome, we combine the improved hearing and no change for the special case only of normal to normal. Other category include worsened and no change from (1) mild to mild hearing loss, (2) moderate to moderate hearing loss, or (3) severe to severe hearing loss. | Day 1 through Day 180 | 
| Change in Best Ear Hearing Assessments [Improved Versus Other] Between Baseline and Study Month 6. | A single, independent study audiologist who is masked (blinded) to treatment assignment will assess the audiology test battery for each subject and assign the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications will be assigned by ear (one for the left ear and one for the right ear), giving total ear classifications. At the analyses stage, the best ear classification for the subject at that study visit will be determined; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the best ear classification will be mild hearing loss. | Day 1 through Day 180 | 
| Change in Best Ear Hearing Assessments [Worse + no Change (Abnormal to Abnormal) Versus Other] Between Baseline and Study Month 6. | A single, independent study audiologist who is masked (blinded) to treatment assignment will assess the audiology test battery for each subject and assign the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications will be assigned by ear (one for the left ear and one for the right ear), giving total ear classifications. At the analyses stage, the best ear classification for the subject at that study visit will be determined; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the best ear classification will be mild hearing loss. | Day 1 through Day 180 | 
| Change in Best Ear Hearing Assessments [Worse Versus Other] Between Baseline and Study Month 6. | A single, independent study audiologist who is masked (blinded) to treatment assignment will assess the audiology test battery for each subject and assign the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications will be assigned by ear (one for the left ear and one for the right ear), giving total ear classifications. At the analyses stage, the best ear classification for the subject at that study visit will be determined; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the best ear classification will be mild hearing loss. | Day 1 through Day 180 | 
| Change in Total Ear Hearing Assessments [Improved Versus Other] Between Baseline and Study Month 6. | A single, independent study audiologist who is masked (blinded) to treatment assignment will assess the audiology test battery for each subject and assign the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications will be assigned by ear (one for the left ear and one for the right ear), giving total ear classifications. At the analyses stage, the best ear classification for the subject at that study visit will be determined; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the best ear classification will be mild hearing loss. | Day 1 through Day 180 | 
| Change in Total Ear Hearing Assessments [Worse+ no Change (Abnormal to Abnormal) Versus Other] Between Baseline and Study Month 6. | A single, independent study audiologist who is masked (blinded) to treatment assignment will assess the audiology test battery for each subject and assign the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications will be assigned by ear (one for the left ear and one for the right ear), giving total ear classifications. At the analyses stage, the best ear classification for the subject at that study visit will be determined; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the best ear classification will be mild hearing loss. | Day 1 through Day 180 | 
| Change in Total Ear Hearing Assessments [Worse Versus Other] Between Baseline and Study Month 6. | A single, independent study audiologist who is masked (blinded) to treatment assignment will assess the audiology test battery for each subject and assign the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications will be assigned by ear (one for the left ear and one for the right ear), giving total ear classifications. At the analyses stage, the best ear classification for the subject at that study visit will be determined; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the best ear classification will be mild hearing loss. | Day 1 through Day 180 | 
| Association of Change in Viral Load (Blood) With Change in Total Ear Hearing at 6 Months | Analysis of actual viral load was done using log base 10 transformation. Undetectable viral load value was replaced by a value of 10. A summary measure of the viral load over time considers all time points available by calculating the average area under the curve (AUC) (trapezoidal rule) applied to the log base 10 viral load. Average is based on the maximum period of time with viral load data for a given subject. The average or standardize AUC units is therefore the original AUC units of log 10 copies/ml*days divided by days in study which equals log 10 copies/ml. | At 6 months | 
| Association of Change in Viral Load (Saliva) With Change in Total Ear Hearing at 6 Months | Analysis of actual viral load was done using log base 10 transformation. Undetectable viral load value was replaced by a value of 10. A summary measure of the viral load over time considers all time points available by calculating the average area under the curve (AUC) (trapezoidal rule) applied to the log base 10 viral load. Average is based on the maximum period of time with viral load data for a given subject. The average or standardize AUC units is therefore the original AUC units or log 10 copies/ml*days divided by days in study which equals log 10 copies/ml. | At 6 months | 
| Association of Change in Viral Load (Urine) With Change in Total Ear Hearing at 6 Months | Analysis of actual viral load was done using log base 10 transformation. Undetectable viral load value was replaced by a value of 10. A summary measure of the viral load over time considers all time points available by calculating the average area under the curve (AUC) (trapezoidal rule) applied to the log base 10 viral load. Average is based on the maximum period of time with viral load data for a given subject. The average or standardize AUC units is therefore the original AUC units of log 10 copies/ml*days divided by days in study which equals log 10 copies/ml. | At 6 months | 
| Association of Change in Viral Load (Blood) With Change in Best Ear Hearing at 6 Months | Analysis of actual viral load was done using log base 10 transformation. Undetectable viral load value was replaced by a value of 10. A summary measure of the viral load over time considers all time points available by calculating the average area under the curve (AUC) (trapezoidal rule) applied to the log base 10 viral load. Average is based on the maximum period of time with viral load data for a given subject. The average or standardize AUC units is therefore the original AUC units of log 10 copies/ml*days divided by days in study which equals log 10 copies/ml. | At 6 months | 
| Association of Change in Viral Load (Saliva) With Change in Best Ear Hearing at 6 Months | Analysis of actual viral load was done using log base 10 transformation. Undetectable viral load value was replaced by a value of 10. A summary measure of the viral load over time considers all time points available by calculating the average area under the curve (AUC) (trapezoidal rule) applied to the log base 10 viral load. Average is based on the maximum period of time with viral load data for a given subject. The average or standardize AUC units is therefore the original AUC units of log 10 copies/ml*days divided by days in study which equals log 10 copies/ml. | At 6 months | 
| Association of Change in Viral Load (Urine) With Change in Best Ear Hearing at 6 Months | Analysis of actual viral load was done using log base 10 transformation. Undetectable viral load value was replaced by a value of 10. A summary measure of the viral load over time considers all time points available by calculating the average area under the curve (AUC) (trapezoidal rule) applied to the log base 10 viral load. Average is based on the maximum period of time with viral load data for a given subject. The average or standardize AUC units is therefore the original AUC units of log 10 copies/ml*days divided by days in study which equals log 10 copies/ml. | At 6 months | 
| Detection of Viruria (Urine) by PCR Six Weeks After Trial Entry | Each subject either has positive or negative PCR results. Virus is detected if the PCR is positive. | At 6 weeks (Day 42) | 
| Detection of Viruria (Urine) by PCR Six Month After Trial Entry | Each subject either has positive or negative PCR results. Virus is detected if the PCR is positive. | At 6 months | 
| Detection of Viremia (Blood) by PCR Six Weeks After Trial Entry | Each subject either has positive or negative PCR results. Virus is detected if the PCR is positive. | At 6 weeks (Day 42) | 
| Detection of Viremia (Blood) by PCR Six Month After Trial Entry | Each subject either has positive or negative PCR results. Virus is detected if the PCR is positive. | At 6 months | 
| Detection of CMV in Saliva by PCR Six Weeks After Trial Entry | Each subject either has positive or negative PCR results. Virus is detected if the PCR is positive. | At 6 weeks (Day 42) | 
| Detection of CMV in Saliva PCR Six Month After Trial Entry | Each subject either has positive or negative PCR results. Virus is detected if the PCR is positive. | At 6 months | 
| The Quantitative Log Change in Viremia From Baseline to Month 6. | The quantitative change (Month 6 minus baseline) in viremia (blood) Quantitative viral load by PCR in log 10 units measured in urine after 6 weeks of therapy; if undetectable, viral load is assigned a value of 10 (1 in log 10 units). | Baseline to month 6 | 
| The Quantitative Log Reduction in Viruria Detected After 6 Weeks of Therapy | The quantitative log reduction in viruria (urine) detected after 6 weeks of therapy. Quantitative viral load by PCR in log 10 units measured in urine after 6 weeks of therapy; if undetectable, viral load is assigned a value of 10 (1 in log 10 units) | Baseline thru months 6 | 
| The Quantitative Log Reduction in CMV in Saliva Detected After 6 Weeks of Therapy | The quantitative log reduction in CMV in saliva (urine) detected after 6 weeks of therapy. Quantitative viral load by PCR in log 10 units measured in urine after 6 weeks of therapy; if undetectable, viral load is assigned a value of 10 (1 in log 10 units) | Baseline thru months 6 | 
| Number of Adverse Events in the Active Group That Resulted in Discontinuation of Valganciclovir | AE resulting in discontinuation of valganciclovir (active group only). This outcome summarizes the number of adverse events (AEs) that resulted in the discontinuation of valganciclovir in the active group only. | Day 1 thru day 70 | 
| Adverse Event (AE) Resulting in Unresolved Outcome | Adverse event resulting in unresolved outcome. This outcome summarizes the number of adverse events (AEs) that resulted in unresolved outcome of that AE. | Day 1 thru day 70 | 
| Adverse Event (AE) Resulting in Unanticipated Medically Attended Visit | Adverse event resulting in unanticipated medically attended visit. This outcome summarizes the number of adverse events (AEs) that resulted in the unanticipated medically attended visit. | Day 1 thru day 70 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CMV, Cytomegalovirus, Hearing Loss, Infants, Valganciclovir