The CONCERT study
CONgenital Cmv: Efficacy of antiviral treatment in a Randomized controlled Trial

Congenital CMV is a common infection leading to a wide range of clinical signs
and symptoms. These include intrauterine growth retardation, microcephaly,
cerebral involvement with developmental delay, sensorineural hearing loss
(SNHL) and opthalmological disorders. Transient problems include hepatic damage
and haematological disorders (leucopenia and thrombocytopenia). One of the most
apparent, frequent and serious consequences of a congenital CMV infection is
SNHL. Most children with congenital CMV infection have no symptoms at birth. Of
these 85-90 % asymptomatic children, 13.5 % will eventually develop symptoms,
such as SNHL but possibly also mental retardation and visual defects.
Due to the wide variety in presenting symptoms caused by a congenital CMV
infection, a distinction is made between symptomatic and asymptomatic
congenital CMV. Symptomatic CMV infection is defined as a clinically apparent
disease in the newborn period including microcephaly, intracranial
calcifications, chorioretinitis and abnormal cerebrospinal fluid. Asymptomatic
congenital CMV infection includes all children with no clinically apparent
disease at birth, also including children with SNHL. This distinction has
traditionally existed in literature because hearing impairment was usually not
diagnosed until the child was much older.

CMV is the most common cause of congenital infections worldwide. To determine
the birth-prevalence of congenital CMV in the Netherlands, a random sample of
6500 dried blood spots (DBS), obtained in 2007 from neonates from all regional
screening areas, was tested for CMV. Results show a birth-prevalence of 0.54%
(95% CI 0.3-0.7%). This means that every year about 1000 neonates are born in
The Netherlands with a congenital CMV infection. Of all children with
congenital CMV infection 17-20% will have long-term permanent sequelae. Of
those children, 2/3 will be asymptomatic at birth and 1/3 will be symptomatic.
These permanent sequelae result in disabilities such as SNHL, visual impairment
and mental retardation.
Moderate to severe SNHL affects about one per 1000 newborns in the Netherlands.
Early detection of severe hearing loss and subsequent intervention before the
age of 6 months has been shown to improve cognitive, social and learning
abilities. This is the reason for the recent implementation of universal
neonatal hearing screening in the Netherlands. Congenital CMV infection is an
important cause of both early and late-onset SNHL, causing 20-30 % of cases.
Korver et al recently showed that the rate of congenital CMV among Dutch
children with permanent bilateral hearing impairment was 8%, and 23% among
children with profound hearing impairment. Only early-onset cases of SNHL will
be detected by the neonatal hearing screening.
Several studies have shown the beneficial effect of intravenous ganciclovir
and/or oral valganciclovir of hearing preservation in newborns identified with
congenital CMV. However, these studies concentrated on infants with symptomatic
congenital CMV infections and treated with intravenous ganciclovir. The
mentioned studies show a substantial effect of treatment. However, there is not
sufficient data available on the treatment of congenital CMV infections whether
being symptomatic or asymptomatic, or with the use of oral valganciclovir. Oral
treatment should be explored for the obvious reasons of it being less invasive
for the patient and without the necessity for hospital admission during the
treatment.
An effective and easy to administer treatment for congenital CMV infections may
prevent further deterioration of already existing SNHL and also prevent the
development of SNHL in a group where this is not yet apparent and thus cannot
be detected by neonatal hearing screening. It is to be expected that other
manifestations of congenital CMV infection, such as psychomotor developmental
delay might also benefit from early treatment. The diagnosis of congenital CMV
infection can be carried out using dried blood spots.
We hypothesize that this study will show that early detection of congenital CMV
infection in children with hearing impairment and treatment of infected
children, will prevent (deterioration of) hearing loss in a considerable number
of children.

Primary Objective:
Investigate whether early valganciclovir treatment of children with SNHL of >=
20 dB, unilateral or bilateral, and a confirmed congenital CMV infection can
prevent deterioration of the hearing loss at 1 year follow-up.

Secondary Objective(s):
Investigate whether early valganciclovir treatment of children with SNHL of >=
20 dB, unilateral or bilateral, and a confirmed congenital CMV infection can
prevent cognitive and motor retardation. Communicative and speech development
will be extensively assessed. Investigate whether early valganciclovir
treatment of children with SNHL of >= 20 dB, unilateral or bilateral, and a
confirmed congenital CMV infection reduces the CMV viral load in urine and
blood samples 6 weeks treatment and one week and one year after completion of
treatment. At 1 year follow-up solely the urine sample will be investigated for
the viral load.

The design of the trial is a randomized controlled trial. Before inclusion of
infants, the neonatal hearing screening program is fulfilled. All children in
the Netherlands are screened for hearing loss. First with Otoacoustic Emissions
(OAE). When this test is not passed with both ears, a second OAE is carried
out. In case the second OAE is not passed with both ears the Auditory Brainstem
Response (AABR) is conducted. An infant is referred to an Audiological Center
(AC) when the AABR is not passed for both ears. Specific for the trial, parents
of all infants referred to an AC will be asked for informed consent to test the
heel stick card (previously routinely obtained for metabolic screening in the
first week of life) for congenital CMV. The parents of the children whose test
is positive for a congenital CMV infection and who are diagnosed with hearing
loss (>=20dB) at an AC will be asked for informed consent for participation in
the RCT. After consent has been given, a home visit is planned with parents for
inclusion of their child in the RCT. The child is randomized to the treatment
or the non-treatment group. The day after inclusion treatment is started for 6
weeks in the treatment group. Children in the non-treatment group receive no
additional medication. Besides the extra care for the children in the trial,
all standard care continues (hearing aids, extra hearing evaluations and all
other standard care procedures necessary). At 1 year follow-up hearing and
child development are assessed. Hearing will be assessed at an AC, child
development will be assessed during a home visit and parents will fill in a
questionnaire concerning the development of their child. The hearing assessment
and child development testing at 1 year follow-up constitute extra
investigations on top of the standard care program. A few infants will have a
second hearing evaluation requested by the AC as standard care. When this
hearing evaluation is within 1 month prior or post the moment of 1 year
follow-up, no additional hearing evaluation will be necessary for the trial at
1 year follow-up.

Target population
In the last three years, an average of 580 infants per year were referred to an
AC. According to the literature we can expect 25% of congenital CMV infected
infants with SNHL to develop hearing loss at a later stage (late-onset hearing
loss), up to several years of age. This implies that these infants will pass
the neonatal hearing screening. When calculating the target population for this
RCT we have taken into account that 8% of infants with bilateral hearing loss
will have a congenital CMV infection. For the infants with unilateral hearing
loss approximately 20% will have a congenital CMV infection. Taking the
late-onset hearing loss into account, 6% of infants with bilateral hearing loss
will present in de neonatal hearing screening with hearing loss. For the
infants with unilateral hearing loss, 15% will present in the neonatal hearing
screening with hearing loss. The above numbers have been calculated according
to extensive literature review. A proportion of infants referred to an AC will
appear to have normal hearing after audiometry (hearing loss < 40 dB). In the
Netherlands the threshold for hearing loss is defined as >= 40 dB in the best
hearing ear. For the trial hearing loss is defined as >= 20 dB in one or both
ears. As a result, a few children diagnosed with normal hearing in the
screening program do belong to the target population of the trial. It is
unclear as of yet how many infants this will be. These infants cannot be
included in the trial as these children may never or later be diagnosed with
hearing loss.
For the years 2008 and 2009 all data has been received and summarized in a
final report. Because the results of the neonatal hearing screening program of
the years 2008 and 2009 are the only ones fully available, these will be used
in the following calculation for the target population.
In the years 2008 and 2009, 96 and 82 infants respectively were diagnosed with
unilateral hearing loss. With the 15% mentioned above when taking the
late-onset cases of hearing loss into account, it can be concluded that 12-15
infants will suffer from a congenital CMV infection. In 2008 and 2009, 136 and
163 infants respectively were diagnosed with bilateral hearing loss. Taking the
above mentioned 6%, 8-10 infants will suffer from a congenital CMV infection.
Concluding, a total of 20-25 infants referred after neonatal hearing screening
can be expected to suffer from a congenital CMV infection on a yearly basis.
Considering that for the trial hearing loss of >20dB makes the neonate eligible
for inclusion makes the number of infants suitable for inclusion higher.
Quantification of how many infants this would be is as of yet not possible due
to a lack of sufficient data concerning this specific group of infants with
hearing loss of 20 - 40dB.

Treatment group: Oral valganciclovir 32 mg/kg per day in two doses during 6
weeks.
Non-treatment group: no medical intervention besides standard care.

One of the main benefits of this trial is the chance of preventing
deterioration of hearing loss for the children treated with valganciclovir. The
benefit for the untreated as well as for the treated children diagnosed with
congenital CMV will be extensive follow-up with laboratory tests, extra
physical examinations, extra developmental tests and extra hearing evaluation.
Besides the above mentioned benefits, another benefit associated with
participation is the possibility of early recognition of a cause of SNHL in
children in whom otherwise the cause of the SNHL will most often remain
unknown. This will provide information on prognosis and chances of other
children in the family suffering from hearing impairment of having a congenital
CMV infection.

At follow-up all children will be physically examined, audiometric examination
will be carried out and the cognitive and motor development will be
investigated. Early habilitation
of hearing loss is known to have a significant impact on the communicative,
emotional, cognitive, social development and quality of life (18). Besides
correction for the hearing loss, other adjustments (such as learning sign
language and special education) will benefit the infant.
The most important possible disadvantages for participation are potential side
effects of valganciclovir, most importantly reversible neutropenia. In the
treatment group the potential side effects are carefully monitored by means of
weekly blood tests during the treatment period of six weeks, (See dosage
modifications 3.6). The blood samples will be taken by a study group member at
the home of the infants.
During the 1 year follow-up, the following examinations will be carried out:
history taking, physical examination, parental questionnaire, blood tests
(treatment group: 0-6 weeks during treatment, 1 week after completion of
treatment and 1 year follow-up; non-treatment group: two blood samples at
inclusion and 6 weeks post inclusion), urine tests with filter paper in the
diaper (weekly during 7 weeks after inclusion and at 1 year follow-up), hearing
tests at an AC (baseline and 1 year follow-up) and developmental scores at the
home and a developmental questionnaire (1 year follow-up).