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

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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)

Tracking Information
First Submitted Date  ICMJE July 20, 2012
First Posted Date  ICMJE July 25, 2012
Results First Submitted Date  ICMJE December 23, 2020
Results First Posted Date  ICMJE June 2, 2021
Last Update Posted Date June 2, 2021
Actual Study Start Date  ICMJE February 24, 2015
Actual Primary Completion Date December 24, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 6, 2021)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: July 24, 2012)
The proportion of children whose sensorineural hearing deteriorates from baseline [ Time Frame: Baseline to 6 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 6, 2021)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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)
  • 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)
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 24, 2012)
  • The proportion of children who have viruria detected by PCR [ Time Frame: 6 weeks and six months after trial entry ]
  • The quantitative log reduction in viruria [ Time Frame: Baseline to end of 6 weeks of therapy ]
  • The proportion of children who have viremia [ Time Frame: 6 weeks and six months after trial entry ]
  • The quantitative log reduction in viremia [ Time Frame: Baseline to end of 6 weeks of therapy ]
  • The proportion of children who have CMV detected in saliva by PCR [ Time Frame: 6 weeks and six months after trial entry ]
  • The quantitative log reduction in CMV viral load in saliva [ Time Frame: Baseline to end of 6 weeks of therapy ]
  • The proportion of children whose sensorineural hearing improves or remains unchanged from baseline when measured [ Time Frame: Baseline to 6 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Valganciclovir Therapy in Infants and Children With Congenital CMV Infection and Hearing Loss
Official Title  ICMJE 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
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Cytomegalovirus Infection
Intervention  ICMJE
  • Other: Placebo
    Simple Syrup as 60-90% sucrose in purified water: given 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.
Study Arms  ICMJE
  • 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
    Intervention: Drug: Valganciclovir
  • 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
    Intervention: Other: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 24, 2012)
54
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE December 24, 2019
Actual Primary Completion Date December 24, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 1 Month to 4 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01649869
Other Study ID Numbers  ICMJE 11-0069
HHSN272201100035C
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institute of Allergy and Infectious Diseases (NIAID)
Study Sponsor  ICMJE National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account National Institute of Allergy and Infectious Diseases (NIAID)
Verification Date March 22, 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP