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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01649869
Recruitment Status : Completed
First Posted : July 25, 2012
Results First Posted : June 2, 2021
Last Update Posted : June 2, 2021
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

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.

Condition or disease Intervention/treatment Phase
Cytomegalovirus Infection Other: Placebo Drug: Valganciclovir Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 54 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Phase II Randomized and Controlled Investigation of Six Weeks of Oral Valganciclovir Therapy in Infants and Children With Congenital Cytomegalovirus Infection and Hearing Loss
Actual Study Start Date : February 24, 2015
Actual Primary Completion Date : December 24, 2019
Actual Study Completion Date : December 24, 2019


Arm Intervention/treatment
Active Comparator: 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
Drug: 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.

Placebo Comparator: 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
Other: Placebo
Simple Syrup as 60-90% sucrose in purified water: given orally twice a day for 6 weeks




Primary Outcome Measures :
  1. Number of Ears That Had (1) Improved Hearing or no Change in Hearing (2) Worsened Hearing. [ Time Frame: 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 Outcome Measures :
  1. 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]. [ Time Frame: 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.

  2. Change in Best Ear Hearing Assessments [Improved Versus Other] Between Baseline and Study Month 6. [ Time Frame: 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.

  3. Change in Best Ear Hearing Assessments [Worse + no Change (Abnormal to Abnormal) Versus Other] Between Baseline and Study Month 6. [ Time Frame: 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.

  4. Change in Best Ear Hearing Assessments [Worse Versus Other] Between Baseline and Study Month 6. [ Time Frame: 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.

  5. Change in Total Ear Hearing Assessments [Improved Versus Other] Between Baseline and Study Month 6. [ Time Frame: 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.

  6. Change in Total Ear Hearing Assessments [Worse+ no Change (Abnormal to Abnormal) Versus Other] Between Baseline and Study Month 6. [ Time Frame: 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.

  7. Change in Total Ear Hearing Assessments [Worse Versus Other] Between Baseline and Study Month 6. [ Time Frame: 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.

  8. Association of Change in Viral Load (Blood) With Change in Total Ear Hearing at 6 Months [ Time Frame: 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.

  9. Association of Change in Viral Load (Saliva) With Change in Total Ear Hearing at 6 Months [ Time Frame: 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.

  10. Association of Change in Viral Load (Urine) With Change in Total Ear Hearing at 6 Months [ Time Frame: 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.

  11. Association of Change in Viral Load (Blood) With Change in Best Ear Hearing at 6 Months [ Time Frame: 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.

  12. Association of Change in Viral Load (Saliva) With Change in Best Ear Hearing at 6 Months [ Time Frame: 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.

  13. Association of Change in Viral Load (Urine) With Change in Best Ear Hearing at 6 Months [ Time Frame: 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.

  14. Detection of Viruria (Urine) by PCR Six Weeks After Trial Entry [ Time Frame: At 6 weeks (Day 42) ]
    Each subject either has positive or negative PCR results. Virus is detected if the PCR is positive.

  15. Detection of Viruria (Urine) by PCR Six Month After Trial Entry [ Time Frame: At 6 months ]
    Each subject either has positive or negative PCR results. Virus is detected if the PCR is positive.

  16. Detection of Viremia (Blood) by PCR Six Weeks After Trial Entry [ Time Frame: At 6 weeks (Day 42) ]
    Each subject either has positive or negative PCR results. Virus is detected if the PCR is positive.

  17. Detection of Viremia (Blood) by PCR Six Month After Trial Entry [ Time Frame: At 6 months ]
    Each subject either has positive or negative PCR results. Virus is detected if the PCR is positive.

  18. Detection of CMV in Saliva by PCR Six Weeks After Trial Entry [ Time Frame: At 6 weeks (Day 42) ]
    Each subject either has positive or negative PCR results. Virus is detected if the PCR is positive.

  19. Detection of CMV in Saliva PCR Six Month After Trial Entry [ Time Frame: At 6 months ]
    Each subject either has positive or negative PCR results. Virus is detected if the PCR is positive.

  20. The Quantitative Log Change in Viremia From Baseline to Month 6. [ Time Frame: 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).

  21. The Quantitative Log Reduction in Viruria Detected After 6 Weeks of Therapy [ Time Frame: 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)

  22. The Quantitative Log Reduction in CMV in Saliva Detected After 6 Weeks of Therapy [ Time Frame: 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)

  23. Number of Adverse Events in the Active Group That Resulted in Discontinuation of Valganciclovir [ Time Frame: 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.

  24. Adverse Event (AE) Resulting in Unresolved Outcome [ Time Frame: 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.

  25. Adverse Event (AE) Resulting in Unanticipated Medically Attended Visit [ Time Frame: 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   1 Month to 4 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01649869


Locations
Show Show 18 study locations
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
  Study Documents (Full-Text)

Documents provided by National Institute of Allergy and Infectious Diseases (NIAID):
Study Protocol  [PDF] April 28, 2016
Statistical Analysis Plan  [PDF] August 14, 2020

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Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT01649869    
Other Study ID Numbers: 11-0069
HHSN272201100035C
First Posted: July 25, 2012    Key Record Dates
Results First Posted: June 2, 2021
Last Update Posted: June 2, 2021
Last Verified: March 22, 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
CMV
Cytomegalovirus
Hearing Loss
Infants
Valganciclovir
Additional relevant MeSH terms:
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Valganciclovir
Infections
Communicable Diseases
Cytomegalovirus Infections
Hearing Loss
Deafness
Disease Attributes
Pathologic Processes
Hearing Disorders
Ear Diseases
Otorhinolaryngologic Diseases
Sensation Disorders
Neurologic Manifestations
Nervous System Diseases
Herpesviridae Infections
DNA Virus Infections
Virus Diseases
Antiviral Agents
Anti-Infective Agents