Congenital Cytomegalovirus: Efficacy of Antiviral Treatment in a Randomized Controlled Trial

Sensorineural Hearing Loss Clinical Trial

— CONCERT  

Official title:

Congenital Cytomegalovirus: Efficacy of Antiviral Treatment in a Randomized Controlled Trial

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01655212
• Other study ID #: CMV-MM-1
• Secondary ID: 2011-005378-44
• Status: Terminated
• Phase: Phase 3
• First received: July 13, 2012
• Last updated: June 17, 2015
• Start date: June 2012
• Est. completion date: October 2013

Study information

• Verified date: June 2015
• Source: Leiden University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial Summary

The objective of the trial is to investigate whether early treatment with oral valganciclovir of infants with both congenital cytomegalovirus infection and sensorineural hearing loss can prevent progression of hearing loss.

Description:

In the Netherlands all neonates are routinely screened for hearing during the first weeks after birth with the Otoacoustic Emissions (OAE) procedure. After the second refer an Automated Auditory Brainstem Response (AABR) is performed. The parents of all newborns, born at ≥ 37 weeks gestational age, that fail this AABR in the Netherlands (about 550 yearly) will be asked for consent for CMV-testing on the dried blood spots. Newborns diagnosed with congenital CMV and with confirmed SNHL (≥ 20 dB) are eligible for inclusion. After informed consent infants will be randomized before the age of 13 weeks to a treatment group (6 weeks valganciclovir 32 mg/kg daily dose; oral solution) or control group (no antiviral treatment). Infants will be monitored for leucopenia and liver- and kidney function. Inclusion will continue for at least 1.5 years, or until 25 infants in each treatment arm have been randomized.

At 1 year follow-up hearing and child development are assessed. Hearing will be assessed with Brainstem Evoked Response Audiometry at an audiological center. Child development will be assessed during a home visit with the Bayley Scales of Infant Development III and parents will fill in the Dutch Child Development Inventory (NCDI) which will give more detailed information on communicative development of their child. Viral loads in blood and urine will be monitored during antiviral treatment as well as twice in the control group.

This study will provide information on the percentage of infants with a congenital CMV infection who fail the neonatal hearing screening . The RCT will show whether early treatment of congenital CMV infected children with hearing impairment prevents deterioration of hearing loss and to what extent. The outcome may lead to implementation of congenital CMV testing in the neonatal hearing screening program or possibly into the newborn blood screening.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 2
• Est. completion date: October 2013
• Est. primary completion date: October 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 12 Weeks

Eligibility

Inclusion Criteria:

• Infants with congenital CMV infection and hearing loss (= 20 dB, in one or both ears).

• Age at time of inclusion is < 13 weeks after birth.

• = 37 weeks gestational age.

• Birth weight = 2500 gram.

• Parental signed informed consent.

Exclusion Criteria:

• Indications for symptomatic congenital CMV infection based on diagnostics carried out prior to the inclusion of the child in the trial.

• In case during the house visit the presence of a symptomatic CMV infection is doubted, inclusion will be discussed. Depending on the medical history taking, physical examination and laboratory tests inclusion will be decided upon.

• Treatment with other antiviral agents or immunoglobulins.

• Leucopenia < 0,5 x 10*9/L (blood sample tested at t=0).

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Congenital Cytomegalovirus Infection
• Cytomegalovirus Infections
• Deafness
• Hearing Loss
• Hearing Loss, Sensorineural
• Sensorineural Hearing Loss

Intervention

Drug:
• Valganciclovir
Infants will be treated with valganciclovir for 6 weeks, 32 mg/kg daily dose in two doses, oral solution.

Locations

Country	Name	City	State
Netherlands	Department Medical Microbiology, Leiden University Medical Center	Leiden	Zuid Holland

Sponsors (3)

Lead Sponsor	Collaborator
Dr. Ann C.T.M. Vossen	Leiden University Medical Center, Stichting Nuts Ohra

Country where clinical trial is conducted

Netherlands, 

References & Publications (16)

Amir J, Wolf DG, Levy I. Treatment of symptomatic congenital cytomegalovirus infection with intravenous ganciclovir followed by long-term oral valganciclovir. Eur J Pediatr. 2010 Sep;169(9):1061-7. doi: 10.1007/s00431-010-1176-9. Epub 2010 Mar 16. — View Citation

de Vries JJ, Korver AM, Verkerk PH, Rusman L, Claas EC, Loeber JG, Kroes AC, Vossen AC. Congenital cytomegalovirus infection in the Netherlands: birth prevalence and risk factors. J Med Virol. 2011 Oct;83(10):1777-82. doi: 10.1002/jmv.22181. — View Citation

Foulon I, Naessens A, Foulon W, Casteels A, Gordts F. A 10-year prospective study of sensorineural hearing loss in children with congenital cytomegalovirus infection. J Pediatr. 2008 Jul;153(1):84-8. doi: 10.1016/j.jpeds.2007.12.049. Epub 2008 Mar 6. — View Citation

Fowler KB, McCollister FP, Dahle AJ, Boppana S, Britt WJ, Pass RF. Progressive and fluctuating sensorineural hearing loss in children with asymptomatic congenital cytomegalovirus infection. J Pediatr. 1997 Apr;130(4):624-30. — View Citation

Kimberlin DW, Acosta EP, Sánchez PJ, Sood S, Agrawal V, Homans J, Jacobs RF, Lang D, Romero JR, Griffin J, Cloud GA, Lakeman FD, Whitley RJ; National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Pharmacokinetic and pharmacodynamic assessment of oral valganciclovir in the treatment of symptomatic congenital cytomegalovirus disease. J Infect Dis. 2008 Mar 15;197(6):836-45. doi: 10.1086/528376. — View Citation

Kimberlin DW, Lin CY, Sánchez PJ, Demmler GJ, Dankner W, Shelton M, Jacobs RF, Vaudry W, Pass RF, Kiell JM, Soong SJ, Whitley RJ; National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial. J Pediatr. 2003 Jul;143(1):16-25. — View Citation

Korver AM, de Vries JJ, Konings S, de Jong JW, Dekker FW, Vossen AC, Frijns JH, Oudesluys-Murphy AM; DECIBEL collaborative study group. DECIBEL study: Congenital cytomegalovirus infection in young children with permanent bilateral hearing impairment in the Netherlands. J Clin Virol. 2009 Dec;46 Suppl 4:S27-31. doi: 10.1016/j.jcv.2009.09.007. — View Citation

Lackner A, Acham A, Alborno T, Moser M, Engele H, Raggam RB, Halwachs-Baumann G, Kapitan M, Walch C. Effect on hearing of ganciclovir therapy for asymptomatic congenital cytomegalovirus infection: four to 10 year follow up. J Laryngol Otol. 2009 Apr;123(4):391-6. doi: 10.1017/S0022215108003162. Epub 2008 Jun 30. — View Citation

Lanari M, Lazzarotto T, Venturi V, Papa I, Gabrielli L, Guerra B, Landini MP, Faldella G. Neonatal cytomegalovirus blood load and risk of sequelae in symptomatic and asymptomatic congenitally infected newborns. Pediatrics. 2006 Jan;117(1):e76-83. Epub 2005 Dec 1. Erratum in: Pediatrics. 2006 Apr;117(4):1467. — View Citation

Lombardi G, Garofoli F, Stronati M. Congenital cytomegalovirus infection: treatment, sequelae and follow-up. J Matern Fetal Neonatal Med. 2010 Oct;23 Suppl 3:45-8. doi: 10.3109/14767058.2010.506753. Review. — View Citation

Michaels MG, Greenberg DP, Sabo DL, Wald ER. Treatment of children with congenital cytomegalovirus infection with ganciclovir. Pediatr Infect Dis J. 2003 Jun;22(6):504-9. — View Citation

Misono S, Sie KC, Weiss NS, Huang ML, Boeckh M, Norton SJ, Yueh B. Congenital cytomegalovirus infection in pediatric hearing loss. Arch Otolaryngol Head Neck Surg. 2011 Jan;137(1):47-53. doi: 10.1001/archoto.2010.235. — View Citation

Nigro G, Scholz H, Bartmann U. Ganciclovir therapy for symptomatic congenital cytomegalovirus infection in infants: a two-regimen experience. J Pediatr. 1994 Feb;124(2):318-22. — View Citation

Oliver SE, Cloud GA, Sánchez PJ, Demmler GJ, Dankner W, Shelton M, Jacobs RF, Vaudry W, Pass RF, Soong SJ, Whitley RJ, Kimberlin DW; National Institute of Allergy, Infectious Diseases Collaborative Antiviral Study Group. Neurodevelopmental outcomes following ganciclovir therapy in symptomatic congenital cytomegalovirus infections involving the central nervous system. J Clin Virol. 2009 Dec;46 Suppl 4:S22-6. doi: 10.1016/j.jcv.2009.08.012. Epub 2009 Sep 18. — View Citation

Smets K, De Coen K, Dhooge I, Standaert L, Laroche S, Mahieu L, Logghe N, Cossey V, Boudewyns A. Selecting neonates with congenital cytomegalovirus infection for ganciclovir therapy. Eur J Pediatr. 2006 Dec;165(12):885-90. Epub 2006 Jun 20. Review. — View Citation

Whitley RJ, Cloud G, Gruber W, Storch GA, Demmler GJ, Jacobs RF, Dankner W, Spector SA, Starr S, Pass RF, Stagno S, Britt WJ, Alford C Jr, Soong S, Zhou XJ, Sherrill L, FitzGerald JM, Sommadossi JP. Ganciclovir treatment of symptomatic congenital cytomegalovirus infection: results of a phase II study. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. J Infect Dis. 1997 May;175(5):1080-6. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Hearing assessment	At 1 year follow-up hearing will be assessed with Brainstem Evoked Response Audiometry at an audiological center.	1 year follow-up	No
Secondary	Child development	At 1 year follow-up child development will be assessed during a home visit with the Bayley Scales of Infant Development III. Additionally, parents will fill in the Dutch Child Development Inventory.	1 year follow-up	No
Secondary	Viral load	Viral blood load will be monitored in the treatment group(at baseline, weekly during antiviral treatment, and one week after treatment) as well as in the control group (baseline and 7 weeks after inclusion).; Viral urine load will be monitored in the treatment group and in the control group (at baseline, weekly during 7 weeks after inclusion, and at the age of 1 year).	Baseline, weekly during 7 weeks, and at 1 year	No

External Links

•   CONCERT study website