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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Confirmed congenital CMV without baseline SNHL | Experimental | Valganciclovir 16 mg/kg/dose orally twice daily for four months, n=229 |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Valganciclovir | Drug | Valganciclovir, 16 mg/kg/dose given orally twice daily for four months |
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| 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 |
| 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 |
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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
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
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Alabama - Children's of Alabama - Clinical Virology | Birmingham | Alabama | 35233-1711 | United States | ||
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Male and female infants with asymptomatic congenital CMV infection were recruited at participating sites between 20Aug2019 and 09SEP2020.
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| ID | Title | Description |
|---|---|---|
| FG000 | Confirmed Congenital CMV Without Baseline SNHL | Valganciclovir, 16 mg/kg/dose given orally twice daily for four months |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Confirmed Congenital CMV Without Baseline SNHL | Valganciclovir, 16 mg/kg/dose given orally twice daily for four months |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | All participants who have received at least one dose of study product and with a normal baseline hearing assessment for both ears and with hearing assessment result available at Study month 6 visit. | Posted | Count of Participants | Participants | Between baseline and study month 6 |
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All AEs occurring from Study Day 1 through four weeks following the last four weeks following the last dose of study drug and laboratory AEs occurring through Study Month 6 were collected.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Confirmed Congenital CMV Without Baseline SNHL | Valganciclovir, 16 mg/kg/dose given orally twice daily for four months |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA (25.0) | Non-systematic Assessment |
The trial was stopped early due to low accrual with only 7 participants enrolled.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| David W. Kimberlin, MD | The University of Alabama at Birmingham | 205-934-5316 | dkimberlin@peds.uab.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Mar 22, 2019 | Dec 28, 2022 | Prot_SAP_002.pdf |
| ICF | No | No | Yes | Informed Consent Form | May 22, 2019 | Dec 28, 2022 | ICF_003.pdf |
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| ID | Term |
|---|---|
| D003586 | Cytomegalovirus Infections |
| ID | Term |
|---|---|
| D006566 | Herpesviridae Infections |
| D004266 | DNA Virus Infections |
| D014777 | Virus Diseases |
| D007239 | Infections |
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| ID | Term |
|---|---|
| D000077562 | Valganciclovir |
| ID | Term |
|---|---|
| D015774 | Ganciclovir |
| D000212 | Acyclovir |
| D006147 | Guanine |
| D007042 | Hypoxanthines |
| D011688 |
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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 |
| Arkansas Children's Hospital - Infectious Diseases |
| Little Rock |
| Arkansas |
| 72202 |
| United States |
| University of Louisville School of Medicine - Norton Children's Hospital - Infectious Diseases | Louisville | Kentucky | 40202 | United States |
| University of Mississippi - Children's Infectious Diseases | Jackson | Mississippi | 39216-4505 | United States |
| Washington University School of Medicine in St. Louis - Center for Clinical Studies | St Louis | Missouri | 63110-1010 | United States |
| Carolinas Medical Center - Pediatrics - Infectious Diseases | Charlotte | North Carolina | 28203-5812 | United States |
| Nationwide Children's Hospital - Neonatology - Center for Perinatal Research | Columbus | Ohio | 43205-2664 | United States |
| Children's Hospital of Pittsburgh of UPMC - Pediatric Infectious Diseases | Pittsburgh | Pennsylvania | 15224-1529 | United States |
| Texas Medical Center - Texas Children's Hospital | Houston | Texas | 77030-2303 | United States |
| Participants |
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| Age, Continuous | Mean | Standard Deviation | days |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Confirmed Congenital CMV Without Baseline SNHL |
Valganciclovir, 16 mg/kg/dose given orally twice daily for four months |
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| Secondary | 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 | Posted | Count of Participants | Participants | Day 1 through Study month 5 |
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| Secondary | 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. | All participants who have received at least one dose of study product and for whom any data on safety are available. | Posted | Count of Participants | Participants | Day 1 through Study month 6 |
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| Secondary | 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. | All participants who have received at least one dose of study product and for whom any safety data are available. | Posted | Count of Participants | Participants | From day 1 through study month 6 |
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| Secondary | 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. | All participants who have received at least one dose of study product and for whom any safety data are available. | Posted | Count of Participants | Participants | From day 1 through study month 6 |
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| Secondary | 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. | All participants who have received at least one dose of study product and for whom any safety data are available. | Posted | Count of Participants | Participants | From day 1 through study month 6 |
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| Secondary | 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. | All participants who have received at least one dose of study product and with a normal baseline hearing assessment for both ears and with hearing assessment result available at Study month 12 visit. | Posted | Count of Participants | Participants | Screening and Study Months 4, 6, 8 and 12 |
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| Secondary | 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. | All participants who have received at least one dose of study product and with a normal baseline hearing assessment for both ears and with hearing assessment result available at Study month 12 visit. | Posted | Count of Participants | Participants | Screening and Study Months 4, 6, 8 and 12 |
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| Secondary | 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. | All participants who have received at least one dose of study product and with a normal baseline hearing assessment for both ears and with hearing assessment result available at Study month 18 visit. | Posted | Count of Participants | Participants | Study Months 4, 6, 8 and 12 |
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| Secondary | 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. | All participants who have received at least one dose of study product and with a normal baseline hearing assessment for both ears and with hearing assessment result available at Study month 12 visit. | Posted | Count of Participants | Participants | Study Months 4, 6, 8 and 12 |
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| Secondary | 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. | All participants who have received at least one dose of study product and with a normal baseline hearing assessment for both ears and with hearing assessment result available at Study month 4 visit. | Posted | Count of Participants | Participants | Between screening and study month 4 |
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| Secondary | 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. | All participants who have received at least one dose of study product and with a normal baseline hearing assessment for both ears and with hearing assessment result available at Study month 12 visit. | Posted | Count of Participants | Participants | Between screening and study month 12 |
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| Secondary | 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. | All participants who have received at least one dose of study product and with a normal baseline hearing assessment for both ears and with hearing assessment result available at Study month 18 visit. | Posted | Count of Participants | Participants | Between screening and study month 18 |
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| Secondary | 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 | All participants who have received at least one dose of study product and for whom with any alanine aminotransferase result available from Day 1 through Month 6. | Posted | Count of Participants | Participants | Baseline, weeks 2, 4, 6, 8, 10, 12, months 4, 5 and 6. |
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| Secondary | 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). | All participants who have received at least one dose of study product and with a normal baseline hearing assessment for both ears and with hearing assessment result available at Study months 4, 6, 12, 18. | Posted | Number | Ears | Screening and Study Months 4, 6, 12, and 18 | Ears | Ears |
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| Secondary | 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). | All participants who have received at least one dose of study product and with a normal baseline hearing assessment for both ears and with hearing assessment result available at Study months 4, 6, 12, 18. | Posted | Number | Ears | Screening and Study Months 4, 6, 12, and 18 | Ears | Ears |
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| Secondary | 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). | All participants who have received at least one dose of study product and with a normal baseline hearing assessment for both ears and with hearing assessment result available at Study months 4, 6, 12, 18. | Posted | Number | Ears | Screening and Study Months 4, 6, 12, and 18 | Ears | Ears |
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| Secondary | 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). | All participants who have received at least one dose of study product and with a normal baseline hearing assessment for both ears and with hearing assessment result available at Study months 4, 6, 12, 18. | Posted | Number | Ears | Screening and Study Months 4, 6, 12, and 18 | Ears | Ears |
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|
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| 0 |
| 7 |
| 0 |
| 7 |
| 7 |
| 7 |
| Neutropenia | Blood and lymphatic system disorders | MedDRA (25.0) | Non-systematic Assessment |
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| Abdominal pain upper | Gastrointestinal disorders | MedDRA (25.0) | Non-systematic Assessment |
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| Flatulence | Gastrointestinal disorders | MedDRA (25.0) | Non-systematic Assessment |
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| Vomiting | Gastrointestinal disorders | MedDRA (25.0) | Non-systematic Assessment |
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| Pyrexia | General disorders | MedDRA (25.0) | Non-systematic Assessment |
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| Conjunctivitis | Infections and infestations | MedDRA (25.0) | Non-systematic Assessment |
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| Oral candidiasis | Infections and infestations | MedDRA (25.0) | Non-systematic Assessment |
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| Upper respiratory tract infection | Infections and infestations | MedDRA (25.0) | Non-systematic Assessment |
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| Bilirubin conjugated increased | Investigations | MedDRA (25.0) | Non-systematic Assessment |
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| Haemoglobin decreased | Investigations | MedDRA (25.0) | Non-systematic Assessment |
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| Monocyte count increased | Investigations | MedDRA (25.0) | Non-systematic Assessment |
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| Somnolence | Nervous system disorders | MedDRA (25.0) | Non-systematic Assessment |
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| Insomnia | Psychiatric disorders | MedDRA (25.0) | Non-systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA (25.0) | Non-systematic Assessment |
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| Nasal congestion | Respiratory, thoracic and mediastinal disorders | MedDRA (25.0) | Non-systematic Assessment |
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| Rhinorrhoea | Respiratory, thoracic and mediastinal disorders | MedDRA (25.0) | Non-systematic Assessment |
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| Rash | Skin and subcutaneous tissue disorders | MedDRA (25.0) | Non-systematic Assessment |
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Not provided
| Purinones |
| D011687 | Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
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| Month 6 |
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| Month 8 |
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| Month 12 |
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| Month 6 |
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| Month 8 |
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| Month 12 |
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| Month 6 |
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| Month 8 |
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| Month 12 |
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| Month 6 |
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| Month 8 |
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| Month 12 |
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| Month 6 |
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| Month 12 |
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| Month 18 |
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| Month 6 |
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| Month 12 |
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| Month 18 |
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| Month 6 |
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| Month 12 |
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| Month 18 |
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| Month 6 |
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| Month 12 |
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| Month 18 |
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