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

Cytomegalovirus Infection Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01649869
• Other study ID #: 11-0069
• Secondary ID: HHSN272201100035
• Status: Completed
• Phase: Phase 2
• Start date: February 24, 2015
• Est. completion date: December 24, 2019

Study information

• Verified date: March 22, 2018
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 54
• Est. completion date: December 24, 2019
• Est. primary completion date: December 24, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Month to 4 Years

Eligibility

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.

Related Conditions & MeSH terms

• Communicable Diseases
• Cytomegalovirus Infection
• Cytomegalovirus Infections
• Deafness
• Hearing Loss
• Infection

Intervention

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.

Locations

Country	Name	City	State
United Kingdom	Birmingham Heartlands Hospital	Birmingham
United Kingdom	Bristol Royal Hospital for Children - Paediatric Immunology	Bristol	Bristol, City Of
United Kingdom	Pennine Acute Hospitals NHS Trust, North Manchester General Hospital - Children's and Adolescent Services	Crumpsall
United Kingdom	John Radcliffe Hospital - Children's Hospital - Paediatric Infectious Disease and Immunology	Headington, Oxford
United Kingdom	Great Ormond Street Hospital - Infectious Diseases	London	London, City Of
United Kingdom	Saint George's Hospital - Pediatric Infectious Diseases	London	London, City Of
United Kingdom	The Great North Children's Hospital - Paediatric Immunology	Newcastle Upon Tyne
United Kingdom	Sheffield Children's Hospital - Immunology	Sheffield
United Kingdom	Southampton Children's Hospital - Allergy, Immunology and Infection	Southampton, Hampshire
United States	University of Alabama - Children's of Alabama - Clinical Virology	Birmingham	Alabama
United States	Carolinas Medical Center - Pediatrics - Infectious Diseases	Charlotte	North Carolina
United States	Nationwide Children's Hospital - Neonatology - Center for Perinatal Research	Columbus	Ohio
United States	Texas Medical Center - Texas Children's Hospital	Houston	Texas
United States	Steven and Alexandra Cohen Childrens Medical Center of New York - New Hyde Park - Infectious Disease	Manhasset	New York
United States	Rhode Island Hospital - Pediatrics	Providence	Rhode Island
United States	University of Rochester Medical Center - Golisano Children's Hospital - Infectious Diseases	Rochester	New York
United States	Washington University School of Medicine in St. Louis - Center for Clinical Studies	Saint Louis	Missouri
United States	Children's National Medical Center - Sheikh Zayed Campus - Infectious Disease	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)

Countries where clinical trial is conducted

United States,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Ears That Had (1) Improved Hearing or no Change in Hearing (2) Worsened Hearing.	A single, independent study audiologist who is masked (blinded) to treatment assignment will assess the audiology test battery for each subject and assign the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications will be assigned by ear (one for the left ear and one for the right ear), giving "total ear" classifications. At the analyses stage, the "best ear" classification for the subject at that study visit will be determined; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the "best ear" classification will be mild hearing loss. Not both ears are evaluable for all subjects. In some subjects, only one ear is evaluable.	Day 1 through Day 180
Secondary	Number of Best Ear That Had (1) Improved Hearing or no Change in Hearing (2) Worsened Hearing [ex. Improved+ no Change (Normal to Normal) Versus Other].	A single, independent study audiologist who is masked (blinded) to treatment assignment will assess the audiology test battery for each subject and assign the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications will be assigned by ear (one for the left ear and one for the right ear), giving "total ear" classifications. At the analyses stage, the "best ear" classification for the subject at that study visit will be determined; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the "best ear" classification will be mild hearing loss. For this outcome, we combine the improved hearing and no change for the special case only of normal to normal. Other category include worsened and no change from (1) mild to mild hearing loss, (2) moderate to moderate hearing loss, or (3) severe to severe hearing loss.	Day 1 through Day 180
Secondary	Change in Best Ear Hearing Assessments [Improved Versus Other] Between Baseline and Study Month 6.	A single, independent study audiologist who is masked (blinded) to treatment assignment will assess the audiology test battery for each subject and assign the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications will be assigned by ear (one for the left ear and one for the right ear), giving "total ear" classifications. At the analyses stage, the "best ear" classification for the subject at that study visit will be determined; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the "best ear" classification will be mild hearing loss.	Day 1 through Day 180
Secondary	Change in Best Ear Hearing Assessments [Worse + no Change (Abnormal to Abnormal) Versus Other] Between Baseline and Study Month 6.	A single, independent study audiologist who is masked (blinded) to treatment assignment will assess the audiology test battery for each subject and assign the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications will be assigned by ear (one for the left ear and one for the right ear), giving "total ear" classifications. At the analyses stage, the "best ear" classification for the subject at that study visit will be determined; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the "best ear" classification will be mild hearing loss.	Day 1 through Day 180
Secondary	Change in Best Ear Hearing Assessments [Worse Versus Other] Between Baseline and Study Month 6.	A single, independent study audiologist who is masked (blinded) to treatment assignment will assess the audiology test battery for each subject and assign the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications will be assigned by ear (one for the left ear and one for the right ear), giving "total ear" classifications. At the analyses stage, the "best ear" classification for the subject at that study visit will be determined; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the "best ear" classification will be mild hearing loss.	Day 1 through Day 180
Secondary	Change in Total Ear Hearing Assessments [Improved Versus Other] Between Baseline and Study Month 6.	A single, independent study audiologist who is masked (blinded) to treatment assignment will assess the audiology test battery for each subject and assign the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications will be assigned by ear (one for the left ear and one for the right ear), giving "total ear" classifications. At the analyses stage, the "best ear" classification for the subject at that study visit will be determined; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the "best ear" classification will be mild hearing loss.	Day 1 through Day 180
Secondary	Change in Total Ear Hearing Assessments [Worse+ no Change (Abnormal to Abnormal) Versus Other] Between Baseline and Study Month 6.	A single, independent study audiologist who is masked (blinded) to treatment assignment will assess the audiology test battery for each subject and assign the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications will be assigned by ear (one for the left ear and one for the right ear), giving "total ear" classifications. At the analyses stage, the "best ear" classification for the subject at that study visit will be determined; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the "best ear" classification will be mild hearing loss.	Day 1 through Day 180
Secondary	Change in Total Ear Hearing Assessments [Worse Versus Other] Between Baseline and Study Month 6.	A single, independent study audiologist who is masked (blinded) to treatment assignment will assess the audiology test battery for each subject and assign the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications will be assigned by ear (one for the left ear and one for the right ear), giving "total ear" classifications. At the analyses stage, the "best ear" classification for the subject at that study visit will be determined; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the "best ear" classification will be mild hearing loss.	Day 1 through Day 180
Secondary	Association of Change in Viral Load (Blood) With Change in Total Ear Hearing at 6 Months	Analysis of actual viral load was done using log base 10 transformation. Undetectable viral load value was replaced by a value of 10. A summary measure of the viral load over time considers all time points available by calculating the average area under the curve (AUC) (trapezoidal rule) applied to the log base 10 viral load. Average is based on the maximum period of time with viral load data for a given subject. The average or standardize AUC units is therefore the original AUC units of log 10 copies/ml*days divided by days in study which equals log 10 copies/ml.	At 6 months
Secondary	Association of Change in Viral Load (Saliva) With Change in Total Ear Hearing at 6 Months	Analysis of actual viral load was done using log base 10 transformation. Undetectable viral load value was replaced by a value of 10. A summary measure of the viral load over time considers all time points available by calculating the average area under the curve (AUC) (trapezoidal rule) applied to the log base 10 viral load. Average is based on the maximum period of time with viral load data for a given subject. The average or standardize AUC units is therefore the original AUC units or log 10 copies/ml*days divided by days in study which equals log 10 copies/ml.	At 6 months
Secondary	Association of Change in Viral Load (Urine) With Change in Total Ear Hearing at 6 Months	Analysis of actual viral load was done using log base 10 transformation. Undetectable viral load value was replaced by a value of 10. A summary measure of the viral load over time considers all time points available by calculating the average area under the curve (AUC) (trapezoidal rule) applied to the log base 10 viral load. Average is based on the maximum period of time with viral load data for a given subject. The average or standardize AUC units is therefore the original AUC units of log 10 copies/ml*days divided by days in study which equals log 10 copies/ml.	At 6 months
Secondary	Association of Change in Viral Load (Blood) With Change in Best Ear Hearing at 6 Months	Analysis of actual viral load was done using log base 10 transformation. Undetectable viral load value was replaced by a value of 10. A summary measure of the viral load over time considers all time points available by calculating the average area under the curve (AUC) (trapezoidal rule) applied to the log base 10 viral load. Average is based on the maximum period of time with viral load data for a given subject. The average or standardize AUC units is therefore the original AUC units of log 10 copies/ml*days divided by days in study which equals log 10 copies/ml.	At 6 months
Secondary	Association of Change in Viral Load (Saliva) With Change in Best Ear Hearing at 6 Months	Analysis of actual viral load was done using log base 10 transformation. Undetectable viral load value was replaced by a value of 10. A summary measure of the viral load over time considers all time points available by calculating the average area under the curve (AUC) (trapezoidal rule) applied to the log base 10 viral load. Average is based on the maximum period of time with viral load data for a given subject. The average or standardize AUC units is therefore the original AUC units of log 10 copies/ml*days divided by days in study which equals log 10 copies/ml.	At 6 months
Secondary	Association of Change in Viral Load (Urine) With Change in Best Ear Hearing at 6 Months	Analysis of actual viral load was done using log base 10 transformation. Undetectable viral load value was replaced by a value of 10. A summary measure of the viral load over time considers all time points available by calculating the average area under the curve (AUC) (trapezoidal rule) applied to the log base 10 viral load. Average is based on the maximum period of time with viral load data for a given subject. The average or standardize AUC units is therefore the original AUC units of log 10 copies/ml*days divided by days in study which equals log 10 copies/ml.	At 6 months
Secondary	Detection of Viruria (Urine) by PCR Six Weeks After Trial Entry	Each subject either has positive or negative PCR results. Virus is detected if the PCR is positive.	At 6 weeks (Day 42)
Secondary	Detection of Viruria (Urine) by PCR Six Month After Trial Entry	Each subject either has positive or negative PCR results. Virus is detected if the PCR is positive.	At 6 months
Secondary	Detection of Viremia (Blood) by PCR Six Weeks After Trial Entry	Each subject either has positive or negative PCR results. Virus is detected if the PCR is positive.	At 6 weeks (Day 42)
Secondary	Detection of Viremia (Blood) by PCR Six Month After Trial Entry	Each subject either has positive or negative PCR results. Virus is detected if the PCR is positive.	At 6 months
Secondary	Detection of CMV in Saliva by PCR Six Weeks After Trial Entry	Each subject either has positive or negative PCR results. Virus is detected if the PCR is positive.	At 6 weeks (Day 42)
Secondary	Detection of CMV in Saliva PCR Six Month After Trial Entry	Each subject either has positive or negative PCR results. Virus is detected if the PCR is positive.	At 6 months
Secondary	The Quantitative Log Change in Viremia From Baseline to Month 6.	The quantitative change (Month 6 minus baseline) in viremia (blood) Quantitative viral load by PCR in log 10 units measured in urine after 6 weeks of therapy; if undetectable, viral load is assigned a value of 10 (1 in log 10 units).	Baseline to month 6
Secondary	The Quantitative Log Reduction in Viruria Detected After 6 Weeks of Therapy	The quantitative log reduction in viruria (urine) detected after 6 weeks of therapy. Quantitative viral load by PCR in log 10 units measured in urine after 6 weeks of therapy; if undetectable, viral load is assigned a value of 10 (1 in log 10 units)	Baseline thru months 6
Secondary	The Quantitative Log Reduction in CMV in Saliva Detected After 6 Weeks of Therapy	The quantitative log reduction in CMV in saliva (urine) detected after 6 weeks of therapy. Quantitative viral load by PCR in log 10 units measured in urine after 6 weeks of therapy; if undetectable, viral load is assigned a value of 10 (1 in log 10 units)	Baseline thru months 6
Secondary	Number of Adverse Events in the Active Group That Resulted in Discontinuation of Valganciclovir	AE resulting in discontinuation of valganciclovir (active group only). This outcome summarizes the number of adverse events (AEs) that resulted in the discontinuation of valganciclovir in the active group only.	Day 1 thru day 70
Secondary	Adverse Event (AE) Resulting in Unresolved Outcome	Adverse event resulting in unresolved outcome. This outcome summarizes the number of adverse events (AEs) that resulted in unresolved outcome of that AE.	Day 1 thru day 70
Secondary	Adverse Event (AE) Resulting in Unanticipated Medically Attended Visit	Adverse event resulting in unanticipated medically attended visit. This outcome summarizes the number of adverse events (AEs) that resulted in the unanticipated medically attended visit.	Day 1 thru day 70