Cytomegalovirus Infection
Conditions
Keywords
CMV, Cytomegalovirus, Hearing Loss, Infants, Valganciclovir
Brief summary
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
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.
Interventions
OTHERPlacebo
Simple Syrup as 60-90% sucrose in purified water: given orally twice a day for 6 weeks
DRUGValganciclovir
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.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
1 Months to 4 Years
Healthy volunteers
No
Inclusion criteria
1. Signed informed consent from parent(s) or legal guardian(s) 2. Sensorineural hearing loss (\>/= 21dB in one or both ears, documented within 12 weeks prior to study entry) 3. Children from 1 month through 3 years of age (up to the 4th birthday)
Exclusion criteria
1. Imminent demise 2. Profound sensorineural hearing loss (\> 90dB) in both ears 3. Patients receiving other antiviral agents or immune globulin 4. Gastrointestinal abnormality which might preclude absorption of an oral medication (e.g., a history of necrotizing enterocolitis) 5. Documented renal insufficiency, as noted by a creatinine clearance \< 10 mL/min/1.73m2 at time of study enrollment 6. Breastfeeding from mother who is receiving ganciclovir, valganciclovir, foscarnet, cidofovir, or maribavir 7. Infants known to be born to women who are HIV positive (but HIV testing is not required for study entry). 8. Current receipt of other investigational drugs 9. Previous receipt of ganciclovir or valganciclovir 10. Known hypersensitivity to ganciclovir, valganciclovir, or components of the product 11. Inability to attend follow-up hearing and clinical assessments 12. Infants with Auditory neuropathy/dyssynchrony. 13. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Ears That Had (1) Improved Hearing or no Change in Hearing (2) Worsened Hearing. | Day 1 through Day 180 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Best Ear Hearing Assessments [Improved Versus Other] Between Baseline and Study Month 6. | Day 1 through Day 180 | 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. |
| Change in Best Ear Hearing Assessments [Worse + no Change (Abnormal to Abnormal) Versus Other] Between Baseline and Study Month 6. | Day 1 through Day 180 | 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. |
| Change in Best Ear Hearing Assessments [Worse Versus Other] Between Baseline and Study Month 6. | Day 1 through Day 180 | 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. |
| Change in Total Ear Hearing Assessments [Improved Versus Other] Between Baseline and Study Month 6. | Day 1 through Day 180 | 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. |
| Change in Total Ear Hearing Assessments [Worse+ no Change (Abnormal to Abnormal) Versus Other] Between Baseline and Study Month 6. | Day 1 through Day 180 | 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. |
| Change in Total Ear Hearing Assessments [Worse Versus Other] Between Baseline and Study Month 6. | Day 1 through Day 180 | 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. |
| Detection of CMV in Saliva by PCR Six Weeks After Trial Entry | At 6 weeks (Day 42) | Each subject either has positive or negative PCR results. Virus is detected if the PCR is positive. |
| Association of Change in Viral Load (Blood) With Change in Total Ear Hearing at 6 Months | 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. |
| Association of Change in Viral Load (Saliva) With Change in Total Ear Hearing at 6 Months | 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. |
| Detection of CMV in Saliva PCR Six Month After Trial Entry | At 6 months | Each subject either has positive or negative PCR results. Virus is detected if the PCR is positive. |
| Association of Change in Viral Load (Urine) With Change in Total Ear Hearing at 6 Months | 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. |
| Association of Change in Viral Load (Blood) With Change in Best Ear Hearing at 6 Months | 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. |
| 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]. | Day 1 through Day 180 | 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. |
| Association of Change in Viral Load (Urine) With Change in Best Ear Hearing at 6 Months | 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. |
| Detection of Viruria (Urine) by PCR Six Weeks After Trial Entry | At 6 weeks (Day 42) | Each subject either has positive or negative PCR results. Virus is detected if the PCR is positive. |
| Detection of Viruria (Urine) by PCR Six Month After Trial Entry | At 6 months | Each subject either has positive or negative PCR results. Virus is detected if the PCR is positive. |
| Detection of Viremia (Blood) by PCR Six Weeks After Trial Entry | At 6 weeks (Day 42) | Each subject either has positive or negative PCR results. Virus is detected if the PCR is positive. |
| Detection of Viremia (Blood) by PCR Six Month After Trial Entry | At 6 months | Each subject either has positive or negative PCR results. Virus is detected if the PCR is positive. |
| The Quantitative Log Change in Viremia From Baseline to Month 6. | 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). |
| The Quantitative Log Reduction in Viruria Detected After 6 Weeks of Therapy | Baseline thru months 6 | 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) |
| The Quantitative Log Reduction in CMV in Saliva Detected After 6 Weeks of Therapy | Baseline thru months 6 | 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) |
| Number of Adverse Events in the Active Group That Resulted in Discontinuation of Valganciclovir | Day 1 thru day 70 | 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. |
| Adverse Event (AE) Resulting in Unresolved Outcome | Day 1 thru day 70 | Adverse event resulting in unresolved outcome. This outcome summarizes the number of adverse events (AEs) that resulted in unresolved outcome of that AE. |
| Adverse Event (AE) Resulting in Unanticipated Medically Attended Visit | Day 1 thru day 70 | 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. |
| Association of Change in Viral Load (Saliva) With Change in Best Ear Hearing at 6 Months | 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. |
Countries
United Kingdom, United States
Participant flow
Recruitment details
For this study, subjects were enrolled once they signed the informed consent form (ICF). It was not until after hearing loss was confirmed by audiology testing and confirmation of congenital CMV by dried blood spot that a subject was randomized and started on study drug. This reduced protocol enrollment from 54 to 35.
Participants by arm
| Arm | Count |
|---|---|
| Placebo 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
Placebo: Simple Syrup as 60-90% sucrose in purified water: given orally twice a day for 6 weeks | 18 |
| Active 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
Valganciclovir: 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. | 17 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Family member illness | 1 | 0 |
| Overall Study | Required treatment outside protocol | 1 | 0 |
| Overall Study | Severe hearing loss borderline eligible | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | Active |
|---|---|---|---|
| Age, Continuous | 19.5 MONTHS STANDARD_DEVIATION 13.1 | 18.7 MONTHS STANDARD_DEVIATION 14.3 | 17.8 MONTHS STANDARD_DEVIATION 15.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants | 32 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 27 Participants | 12 Participants |
| Region of Enrollment United Kingdom | 11 participants | 24 participants | 13 participants |
| Region of Enrollment United States | 7 participants | 11 participants | 4 participants |
| Sex: Female, Male Female | 8 Participants | 14 Participants | 6 Participants |
| Sex: Female, Male Male | 10 Participants | 21 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 17 |
| other Total, other adverse events | 18 / 35 | 17 / 35 |
| serious Total, serious adverse events | 0 / 18 | 1 / 17 |
Outcome results
Primary
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.
Time frame: Day 1 through Day 180
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Ears That Had (1) Improved Hearing or no Change in Hearing (2) Worsened Hearing. | Improve + no change | 27 Ears |
| Placebo | Number of Ears That Had (1) Improved Hearing or no Change in Hearing (2) Worsened Hearing. | Worsened | 1 Ears |
| Active | Number of Ears That Had (1) Improved Hearing or no Change in Hearing (2) Worsened Hearing. | Improve + no change | 20 Ears |
| Active | Number of Ears That Had (1) Improved Hearing or no Change in Hearing (2) Worsened Hearing. | Worsened | 6 Ears |
p-value: 0.0859Generalized linear model
Secondary
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.
Time frame: Day 1 thru day 70
Population: Overall number of participants analyzed=18
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Adverse Event (AE) Resulting in Unanticipated Medically Attended Visit | No | 15 Participants |
| Placebo | Adverse Event (AE) Resulting in Unanticipated Medically Attended Visit | Yes | 3 Participants |
| Active | Adverse Event (AE) Resulting in Unanticipated Medically Attended Visit | No | 17 Participants |
| Active | Adverse Event (AE) Resulting in Unanticipated Medically Attended Visit | Yes | 0 Participants |
Secondary
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.
Time frame: Day 1 thru day 70
Population: Overall number of participants analyzed=18
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Adverse Event (AE) Resulting in Unresolved Outcome | No | 18 Participants |
| Placebo | Adverse Event (AE) Resulting in Unresolved Outcome | Yes | 0 Participants |
| Active | Adverse Event (AE) Resulting in Unresolved Outcome | No | 17 Participants |
| Active | Adverse Event (AE) Resulting in Unresolved Outcome | Yes | 0 Participants |
Secondary
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.
Time frame: At 6 months
Population: Analysis stratified by hearing outcome--total analyzed is the sum of the number analyzed for 2 rows below
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Association of Change in Viral Load (Blood) With Change in Best Ear Hearing at 6 Months | Improved + normal to normal | 1.396 log 10 copies/ml | Standard Deviation 0.542 |
| Placebo | Association of Change in Viral Load (Blood) With Change in Best Ear Hearing at 6 Months | No change abnormal + worsened | 1.359 log 10 copies/ml | Standard Deviation 0.668 |
p-value: 0.8675Generalized linear model
Secondary
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.
Time frame: At 6 months
Population: Analysis was stratified by hearing outcome--total analyzed is the sum of the number analyzed for 2 rows below
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Association of Change in Viral Load (Blood) With Change in Total Ear Hearing at 6 Months | Improved + normal to normal | 1.396 log 10 copies/ml | Standard Deviation 0.542 |
| Placebo | Association of Change in Viral Load (Blood) With Change in Total Ear Hearing at 6 Months | No change abnormal + worsened | 1.326 log 10 copies/ml | Standard Deviation 0.566 |
p-value: 0.8212Generalized linear model
Secondary
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.
Time frame: At 6 months
Population: Analysis stratified by hearing outcome--total analyzed is the sum of the number analyzed for 2 rows below
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Association of Change in Viral Load (Saliva) With Change in Best Ear Hearing at 6 Months | Improved + normal to normal | 2.447 log 10 copies/ml | Standard Deviation 1.715 |
| Placebo | Association of Change in Viral Load (Saliva) With Change in Best Ear Hearing at 6 Months | No change abnormal + worsened | 2.423 log 10 copies/ml | Standard Deviation 1.484 |
p-value: 0.9682Generalized linear model
Secondary
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.
Time frame: At 6 months
Population: Analysis stratified by hearing outcome--total analyzed is the sum of the number analyzed for 2 rows belos
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Association of Change in Viral Load (Saliva) With Change in Total Ear Hearing at 6 Months | Improved + normal to normal | 2.447 log 10 copies/ml | Standard Deviation 1.715 |
| Placebo | Association of Change in Viral Load (Saliva) With Change in Total Ear Hearing at 6 Months | No change abnormal + worsened | 2.290 log 10 copies/ml | Standard Deviation 1.349 |
p-value: 0.8356Generalized linear model
Secondary
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.
Time frame: At 6 months
Population: Analysis stratified by hearing outcome--total analyzed is the sum of the number of analyzed for 2 rows below
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Association of Change in Viral Load (Urine) With Change in Best Ear Hearing at 6 Months | Improved + normal to normal | 3.562 log 10 copies/ml | Standard Deviation 1.139 |
| Placebo | Association of Change in Viral Load (Urine) With Change in Best Ear Hearing at 6 Months | No change abnormal + worsened | 3.831 log 10 copies/ml | Standard Deviation 1.57 |
p-value: 0.6063Generalized linear model
Secondary
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.
Time frame: At 6 months
Population: Analysis stratified by hearing outcome--total analyzed is the sum of the number analyzed for 2 rows below
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Association of Change in Viral Load (Urine) With Change in Total Ear Hearing at 6 Months | Improved + normal to normal | 3.562 log 10 copies/ml | Standard Deviation 1.139 |
| Placebo | Association of Change in Viral Load (Urine) With Change in Total Ear Hearing at 6 Months | No change abnormal + worsened | 3.583 log 10 copies/ml | Standard Deviation 1.37 |
p-value: 0.7961Generalized linear model
Secondary
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.
Time frame: Day 1 through Day 180
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Change in Best Ear Hearing Assessments [Improved Versus Other] Between Baseline and Study Month 6. | Improved | 0 Participants |
| Placebo | Change in Best Ear Hearing Assessments [Improved Versus Other] Between Baseline and Study Month 6. | No change or worsened | 15 Participants |
| Active | Change in Best Ear Hearing Assessments [Improved Versus Other] Between Baseline and Study Month 6. | Improved | 0 Participants |
| Active | Change in Best Ear Hearing Assessments [Improved Versus Other] Between Baseline and Study Month 6. | No change or worsened | 12 Participants |
p-value: 1Fisher Exact
Secondary
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.
Time frame: Day 1 through Day 180
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Change in Best Ear Hearing Assessments [Worse + no Change (Abnormal to Abnormal) Versus Other] Between Baseline and Study Month 6. | No change abnormal to abnormal + worsened | 6 Participants |
| Placebo | Change in Best Ear Hearing Assessments [Worse + no Change (Abnormal to Abnormal) Versus Other] Between Baseline and Study Month 6. | Improved + normal to normal | 9 Participants |
| Active | Change in Best Ear Hearing Assessments [Worse + no Change (Abnormal to Abnormal) Versus Other] Between Baseline and Study Month 6. | No change abnormal to abnormal + worsened | 6 Participants |
| Active | Change in Best Ear Hearing Assessments [Worse + no Change (Abnormal to Abnormal) Versus Other] Between Baseline and Study Month 6. | Improved + normal to normal | 6 Participants |
p-value: 0.7068Fisher Exact
Secondary
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.
Time frame: Day 1 through Day 180
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Change in Best Ear Hearing Assessments [Worse Versus Other] Between Baseline and Study Month 6. | Worsened | 0 Participants |
| Placebo | Change in Best Ear Hearing Assessments [Worse Versus Other] Between Baseline and Study Month 6. | Other | 15 Participants |
| Active | Change in Best Ear Hearing Assessments [Worse Versus Other] Between Baseline and Study Month 6. | Worsened | 3 Participants |
| Active | Change in Best Ear Hearing Assessments [Worse Versus Other] Between Baseline and Study Month 6. | Other | 9 Participants |
p-value: 0.0752Fisher Exact
Secondary
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.
Time frame: Day 1 through Day 180
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Change in Total Ear Hearing Assessments [Improved Versus Other] Between Baseline and Study Month 6. | Improved | 0 Ears |
| Placebo | Change in Total Ear Hearing Assessments [Improved Versus Other] Between Baseline and Study Month 6. | Other | 28 Ears |
| Active | Change in Total Ear Hearing Assessments [Improved Versus Other] Between Baseline and Study Month 6. | Improved | 0 Ears |
| Active | Change in Total Ear Hearing Assessments [Improved Versus Other] Between Baseline and Study Month 6. | Other | 26 Ears |
Secondary
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.
Time frame: Day 1 through Day 180
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Change in Total Ear Hearing Assessments [Worse+ no Change (Abnormal to Abnormal) Versus Other] Between Baseline and Study Month 6. | worse + no change (abnormal to abnormal) | 19 Ears |
| Placebo | Change in Total Ear Hearing Assessments [Worse+ no Change (Abnormal to Abnormal) Versus Other] Between Baseline and Study Month 6. | Other | 9 Ears |
| Active | Change in Total Ear Hearing Assessments [Worse+ no Change (Abnormal to Abnormal) Versus Other] Between Baseline and Study Month 6. | worse + no change (abnormal to abnormal) | 20 Ears |
| Active | Change in Total Ear Hearing Assessments [Worse+ no Change (Abnormal to Abnormal) Versus Other] Between Baseline and Study Month 6. | Other | 6 Ears |
p-value: 0.4823Generalized linear model
Secondary
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.
Time frame: Day 1 through Day 180
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Change in Total Ear Hearing Assessments [Worse Versus Other] Between Baseline and Study Month 6. | Worsened | 1 Ears |
| Placebo | Change in Total Ear Hearing Assessments [Worse Versus Other] Between Baseline and Study Month 6. | Other | 27 Ears |
| Active | Change in Total Ear Hearing Assessments [Worse Versus Other] Between Baseline and Study Month 6. | Worsened | 6 Ears |
| Active | Change in Total Ear Hearing Assessments [Worse Versus Other] Between Baseline and Study Month 6. | Other | 20 Ears |
p-value: 0.0859Generalized linear model
Secondary
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.
Time frame: At 6 weeks (Day 42)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Detection of CMV in Saliva by PCR Six Weeks After Trial Entry | Positive | 9 Participants |
| Placebo | Detection of CMV in Saliva by PCR Six Weeks After Trial Entry | Negative | 7 Participants |
| Active | Detection of CMV in Saliva by PCR Six Weeks After Trial Entry | Positive | 3 Participants |
| Active | Detection of CMV in Saliva by PCR Six Weeks After Trial Entry | Negative | 13 Participants |
p-value: 0.0659Fisher Exact
Secondary
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.
Time frame: At 6 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Detection of CMV in Saliva PCR Six Month After Trial Entry | Positive | 8 Participants |
| Placebo | Detection of CMV in Saliva PCR Six Month After Trial Entry | Negative | 8 Participants |
| Active | Detection of CMV in Saliva PCR Six Month After Trial Entry | Positive | 7 Participants |
| Active | Detection of CMV in Saliva PCR Six Month After Trial Entry | Negative | 9 Participants |
p-value: 1Fisher Exact
Secondary
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.
Time frame: At 6 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Detection of Viremia (Blood) by PCR Six Month After Trial Entry | Positive | 4 Participants |
| Placebo | Detection of Viremia (Blood) by PCR Six Month After Trial Entry | Negative | 11 Participants |
| Active | Detection of Viremia (Blood) by PCR Six Month After Trial Entry | Positive | 3 Participants |
| Active | Detection of Viremia (Blood) by PCR Six Month After Trial Entry | Negative | 12 Participants |
p-value: 1Fisher Exact
Secondary
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.
Time frame: At 6 weeks (Day 42)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Detection of Viremia (Blood) by PCR Six Weeks After Trial Entry | Positive | 4 Participants |
| Placebo | Detection of Viremia (Blood) by PCR Six Weeks After Trial Entry | Negative | 11 Participants |
| Active | Detection of Viremia (Blood) by PCR Six Weeks After Trial Entry | Positive | 2 Participants |
| Active | Detection of Viremia (Blood) by PCR Six Weeks After Trial Entry | Negative | 12 Participants |
p-value: 0.6513Fisher Exact
Secondary
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.
Time frame: At 6 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Detection of Viruria (Urine) by PCR Six Month After Trial Entry | Positive | 10 Participants |
| Placebo | Detection of Viruria (Urine) by PCR Six Month After Trial Entry | Negative | 1 Participants |
| Active | Detection of Viruria (Urine) by PCR Six Month After Trial Entry | Positive | 11 Participants |
| Active | Detection of Viruria (Urine) by PCR Six Month After Trial Entry | Negative | 3 Participants |
p-value: 0.6043Fisher Exact
Secondary
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.
Time frame: At 6 weeks (Day 42)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Detection of Viruria (Urine) by PCR Six Weeks After Trial Entry | Positive | 11 Participants |
| Placebo | Detection of Viruria (Urine) by PCR Six Weeks After Trial Entry | Negative | 1 Participants |
| Active | Detection of Viruria (Urine) by PCR Six Weeks After Trial Entry | Positive | 1 Participants |
| Active | Detection of Viruria (Urine) by PCR Six Weeks After Trial Entry | Negative | 11 Participants |
p-value: 0.0001Fisher Exact
Secondary
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.
Time frame: Day 1 thru day 70
Population: No participants in the active group were discontinued due to adverse event.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Adverse Events in the Active Group That Resulted in Discontinuation of Valganciclovir | No | 17 Participants |
| Placebo | Number of Adverse Events in the Active Group That Resulted in Discontinuation of Valganciclovir | Yes | 0 Participants |
Secondary
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.
Time frame: Day 1 through Day 180
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | 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]. | Improved + normal to normal | 9 Participants |
| Placebo | 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]. | No change abnormal or worsened | 6 Participants |
| Active | 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]. | Improved + normal to normal | 6 Participants |
| Active | 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]. | No change abnormal or worsened | 6 Participants |
p-value: 0.7068Fisher Exact
Secondary
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).
Time frame: Baseline to month 6
Population: Overall number of participants analyzed=34: 17 active and 17 placebo
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo | The Quantitative Log Change in Viremia From Baseline to Month 6. | Active | 0.4908 log10 IU/ml |
| Placebo | The Quantitative Log Change in Viremia From Baseline to Month 6. | Placebo | -0.1528 log10 IU/ml |
Secondary
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)
Time frame: Baseline thru months 6
Population: Overall number of participants analyzed=34
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo | The Quantitative Log Reduction in CMV in Saliva Detected After 6 Weeks of Therapy | Active | 1.3202 log10 IU/ml |
| Placebo | The Quantitative Log Reduction in CMV in Saliva Detected After 6 Weeks of Therapy | Placebo | 0.0057 log10 IU/ml |
Secondary
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)
Time frame: Baseline thru months 6
Population: Overall number of participants analyzed=28: 15 active and 13 placebo
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo | The Quantitative Log Reduction in Viruria Detected After 6 Weeks of Therapy | Active | 1.2152 log10 IU/ml |
| Placebo | The Quantitative Log Reduction in Viruria Detected After 6 Weeks of Therapy | Placebo | 0.8390 log10 IU/ml |