Dolphin CONTINUE: A nutritional intervention aimed at improving neurodevelopmental outcome in infants at risk for or with early life brain injury

Despite advances in perinatal care, preterm born infants born < 30 weeks of
gestation still are at risk for brain injury and subsequent neurodevelopmental
delay. The likelihood of brain injury occurring depend on gestational and age
as well as on other morbidities. Depending on the cause, location and extent of
injury, adverse outcome includes epilepsy, visual impairments, cerebral palsy,
intellectual disabilities, learning and attention difficulties and
neuropsychiatric conditions. This injury occurs during a period when their
vulnerable developing brain undergoes a massive transformation and can
therefore have severe consequences. At the same time this might be a window of
opportunity for interventions to harness the brain*s intrinsic plasticity to
overcome the consequences of brain injury. It has become clear that prematurity
itself can have can have wide spread effects on the developing brain, in even
in the absence of focal injury, and can likewise affect neurodevelopmental
outcome in these infants. Preterm born infants (< 30 weeks) often show problems
at school age, including lower intelligence, attention problems and memory
deficits. There are currently no early therapies available for this group of
infants. During the last decade, nutrition has received increasing attention as
a potential intervention to promote brain development and subsequent outcome.
During critical periods of development in fetal and early postnatal life, the
brain demands high amounts of nutrients for cell proliferation, differentiation
and metabolism, specifically glucose, amino acids, iron and zinc. Several
studies have demonstrated that high protein and energy intake improves growth
fo the preterm born infant and subsequent outcome. However, there is limited
clinical evidence for the effect of nutritional intervention on long term
cognitive outcome. This might also be due to the use of single nutrients or the
use of nutrients during a brief period of time. The Dolphin concept, a
combination of several nutrients such as docosahexaenoic acid, arachidonic
acid, choline, vitamines and trace elements has demonstrated to increase the
number of synaptic proteins and phospholipids in the brain resulting in
increased dendritic spine densities and subsequent improved cognitive outcome
in rodents. In two recent clinical trials in infants and toddlers, subjects who
received the Dolphin concept also showed a trend towards a better cognitive
outcome, though this did not reach significance.

The main objective is to study the effect of the nutritional intervention
versus the control product on white matter development (as assessed using tract
based spatial statistics of fractional anisotropy) using a DTI scan at the
corrected age of three months.

Secondary objectives are
- to study the effect of the nutritional intervention versus the control
product on cognitive, speech and language, and motor development.
- to study the effect of the nutritional intervention versus the control
product on brain anatomy, defined as (sub)cortical volumes, cortical folding,
white matter integrity and MR spectroscopy
- to study safety of the study product

This is an exploratory randomized, placebo-controlled, double blind, parallel
group, multi-center, single country trial. Infants will be randomised between
the Dolphin Concept and placebo and will be given the nutritional product for
12 months.

Infants will be randomised between the Dolphin concept or placebo for a period
of 12 months. The supplement can be added to a normal diet. The Dolphin concept
consists of a combination of docosahexaenoic acid, arachidonic acid, choline,
vitamins and trace elements.

The burden for the infant is limited. It can drink and eat at the moments
he/she wants, with the nutritional supplement added.
The infant will undergo a MRI at three months of corrected age. This will take
place whilst sedated and with maximum hearing production, minimising the burden
to the infant. In our experience at the UMC Utrecht, infants undergo the MRI
without any burden whilst sedated. After the MRI they slowly awaken at the
neonatology department and will remain admitted until they're awake enough and
have had a feed. Infants will be monitored during and after the MRI using a
pulseoximeter. At this age the occurrence of desaturation due to shallow
breathing is rare and if it occurs, it can easily be restored by tactile
stimulating of the infant. However, due to the admission of the infant to the
medium care unit after the MRI, it will be a long day for parents.

For parents, the burden will be to add the supplement to the milk or diet every
day during 12 months. In addition, parents will be asked to fill in a couple of
questionnaires during the duration of the study. The other visits at 12 and 24
months are part of the standard clinical care.
Parents will be receive phone calls (7 in total) during the study. These phone
calls will be used to supply information on preparing and dosing the product,
answer any questions and ask some questions on adherence, safety, current diet
and medication.

It might be that some parents, by using the study product, will find it to be
confronting to be reminded of the previous admission of their infant to the
NICU, including the risk for a delayed outcome. However, in the previous
Dolphin study, parents reported that the found it to be comforting that they
could give something to their infant that would be potentially be beneficial
for its development.

The burden of the additional time investment is described in E4.

We don't expect that the study will involve any risk for the infants or their
parents. In the previous Dolphin study the number of adverse events was
comparable between the Dolphin and the placebo group.