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

• 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: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): National Institute of Allergy and Infectious Diseases (NIAID)

Study Description

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.

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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.

Eligibility Criteria

• 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.

Contacts and Locations

Locations

United States, Alabama

University of Alabama - Children's of Alabama - Clinical Virology

Birmingham, Alabama, United States, 35233-1711

United States, District of Columbia

Children's National Medical Center - Sheikh Zayed Campus - Infectious Disease

Washington, District of Columbia, United States, 20010-2916

United States, Missouri

Washington University School of Medicine in St. Louis - Center for Clinical Studies

Saint Louis, Missouri, United States, 63110-1010

United States, New York

Steven and Alexandra Cohen Childrens Medical Center of New York - New Hyde Park - Infectious Disease

Manhasset, New York, United States, 11030-3816

University of Rochester Medical Center - Golisano Children's Hospital - Infectious Diseases

Rochester, New York, United States, 14642-0001

United States, North Carolina

Carolinas Medical Center - Pediatrics - Infectious Diseases

Charlotte, North Carolina, United States, 28203-5812

United States, Ohio

Nationwide Children's Hospital - Neonatology - Center for Perinatal Research

Columbus, Ohio, United States, 43205-2664

United States, Rhode Island

Rhode Island Hospital - Pediatrics

Providence, Rhode Island, United States, 02903-4923

United States, Texas

Texas Medical Center - Texas Children's Hospital

Houston, Texas, United States, 77030

United Kingdom

Bristol Royal Hospital for Children - Paediatric Immunology

Bristol, Bristol, City Of, United Kingdom, BS2 8BJ

Saint George's Hospital - Pediatric Infectious Diseases

London, London, City Of, United Kingdom, SW17 0QT

Great Ormond Street Hospital - Infectious Diseases

London, London, City Of, United Kingdom, WC1N 3JH

Birmingham Heartlands Hospital

Birmingham, United Kingdom, B9 5SS

Pennine Acute Hospitals NHS Trust, North Manchester General Hospital - Children's and Adolescent Services

Crumpsall, United Kingdom, M8 5RB

John Radcliffe Hospital - Children's Hospital - Paediatric Infectious Disease and Immunology

Headington, Oxford, United Kingdom, OX3 9DU

The Great North Children's Hospital - Paediatric Immunology

Newcastle Upon Tyne, United Kingdom, NE14LP

Sheffield Children's Hospital - Immunology

Sheffield, United Kingdom, S10 2TH

Southampton Children's Hospital - Allergy, Immunology and Infection

Southampton, Hampshire, United Kingdom, SO16 6YD

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

More Information

• 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
• Results First Posted: June 2, 2021
• Last Update Posted: June 2, 2021
• Last Verified: March 22, 2018

• 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:

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; Valganciclovir; Antiviral Agents; Anti-Infective Agents