CONgenital Cytomegalovirus: Efficacy of antiviral treatment in a non-Randomized Trial with historical control group

Congenital cytomegalovirus (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 a congenital CMV infection have no
symptoms at birth. Of these 85-90% asymptomatic children, 13.5% will eventually
develop complaints, such as SNHL and possibly also mental retardation and
visual defects.
Due to the wide variety in presenting signs and symptoms caused by a congenital
CMV infection, a distinction is made between symptomatic and asymptomatic
congenital CMV. Symptomatic CMV infection is defined as 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, thus also including children with SNHL. This distinction has
traditionally existed in literature because until the introduction of NHS,
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 yearly 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 bilateral 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 with hearing impairment above the screening thresholds, will be detected
by the NHS.
Several studies have shown the beneficial effect of intravenous ganciclovir
and/or oral valganciclovir on hearing preservation in newborns diagnosed with
congenital CMV. However, these studies concentrated on infants with symptomatic
congenital CMV infections (clinically apparent disease in the newborn period)
and treated, in most cases, 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 (at risk for
late-onset hearing loss) and which thus cannot be detected by NHS. It is
possible 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 (DBS).
We hypothesize that this study will show that early treatment of congenital CMV
infected children with hearing impairment 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 follow-up (age 18 * 22 months
after birth).

Secondary Objectives:
Investigate whether early valganciclovir treatment of children with SNHL of *
20 dB, unilateral or bilateral, and a confirmed congenital CMV infection can
prevent communicative and speech developmental delay and cognitive and motor
retardation.

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 after 6 weeks treatment
and one week after completion of treatment. At follow-up (18-22 months after
birth) the viral load will be determined solely in urine.

Investigate whether drug resistance has evolved.

The design of the study is an efficacy trial with a combined refusal and
historical control group. See the logistical flowcharts on pages 44 and 45 for
a schematic depiction of the trial. Two separate phases constitute the study,
also implying that parents will be asked for informed consent separately for
each phase. Phase 1 encompasses the diagnostic phase, for which informed
consent will be asked to test for congenital CMV. Phase 2 comprises inclusion
in the study (treatment and / or follow-up) for infants diagnosed with
congenital CMV and hearing loss of * 20 dB. Three groups of infants may
participate in the CONCERT study 2.0, all infants who are eligible for
inclusion will go through both phases. Infants in the treatment group and
infants in the refusal control group come into contact with the CONCERT study
2.0 after referral to the Audiological Center (AC). Generally infants are aged
approximately 4 weeks at referral. Inclusion of these infants (in the treatment
group or refusal control group) takes place before 13 weeks of age. Infants in
the historical control group will be mostly older and receive a letter with
information (including informed consent form for CMV diagnostics) when the
infant is 14-21 months of age. Inclusion of infants in the historical control
group occurs only after congenital CMV has been diagnosed and parents decide to
participate in the follow-up. Depending on the age of the infant, the follow-up
will take place shortly or several months after parents have provided consent.
Infants in the historical control group participate only in the follow-up of
phase 2.

Treatment consists of twice daily administration of 16 mg/kg valganciclovir (32
mg/kg daily) (Roche Pharmaceuticals) in an oral solution. The doses should be
administered orally just before morning and evening feeding moments.
All treated infants will be treated for a total of 6 weeks.

One of the main benefits of this trial is the chance of preventing
deterioration of hearing loss in the treated infants. Another benefit will be
extensive follow-up with laboratory tests, extra physical examinations,
developmental tests and hearing evaluation. At follow-up all children will be
physically examined, audiometric examinations will be carried out and cognitive
and motor development will be investigated. Early habilitation of hearing loss
is known to have a significant impact on the communicative, emotional,
cognitive and social development as well as the quality of life. Besides
hearing amplification, other adjustments (for example learning sign language
and special education and family intervention programs) will benefit the
infant.
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.

A possible disadvantage of 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. The blood samples will be taken
by a study group member at the infant*s home. Neutropenia may also arise as a
consequence of a congenital CMV infection itself. Hence the infants in the
refusal control group will also be monitored for neutropenia.
Another disadvantage for the treated infants and the infants in the refusal
control group are the blood samples that will be taken during the first 7 weeks
after inclusion. A study group member will visit the infant*s home to reduce
the strain on parents of traveling to a nearby hospital. The person responsible
for taking the blood samples is a well-trained physician assistant with
experience in taking blood samples from young infants. The blood sampling is
necessary to ensure the safety of the treated infants.
From inclusion until the follow-up at the age 18 * 22 months after birth, the
following data will be collected: history, physical examination, parental
questionnaire, blood tests (treatment group: at inclusion, weekly for 6 weeks
during treatment and 1 week after completion of treatment; refusal control
group: two blood samples, one at inclusion and one 6 weeks post inclusion),
urine tests with filter paper in the diaper (weekly during 7 weeks after
inclusion). At follow-up the following data will be collected at the home of
the infant (for treatment group, refusal and historical control groups): urine
test with filter paper in the diaper, hearing evaluation, developmental scores
and a developmental questionnaire.
Infants in the historical control group are expected to be around the age of 15
- 22 months at the moment that they are contacted by the study group to
participate in the historical control group. A possible disadvantage is that
parents may realize that their child might have been treated in the CONCERT 2.0
trial if the trial were started earlier. At this stage these infants are too
old to consider treatment. The possibility of follow-up with the extra physical
examination, extra developmental tests and extra hearing evaluation are evident
advantages for the children in the historical control group.