MyCyFAPP Work Package 3: Development of the enzyme replacement predictive model

In the paediatric age, secondary malnutrition to Cystic Fibrosis (CF) has a
negative impact in the patients* clinical evolution for its repercussion, among
others, on the digestive and absorptive functions and the appetite. Maintaining
an adequate nutritional status is an indispensable aspect of the CF treatment,
since it directly affects the quality of life, the lung function and the
survival.Pancreatic insufficient patients require supplementation with
exogenous pancreatic enzyme therapy (PERT), with the aim to reduce the fecal
losses of fat, protein and biliary acids and the deficit of fat-soluble
vitamins associated to this disease. It is crucial that the administration of
pancreatic extracts is in the correct dose and, moreover, adapted to each
moment and each meal.

It is a two-step approach study: The main objective in the first approach is to
obtain a mathematical predictive model (MPM) adapted to each patient*s
gastrointestinal conditions that calculates the optimal amount of enzymatic
supplements for the optimal fat digestion of any food or meal. So for each
patient an individual correction factor (ICF) will be obtained. Afterwards, in
a second step, the objective is to validate the MPM by assessing how much the
final fat in stools after applying the ICF deviates from the optimal value (<6g
of fat/24h).
The MPM would be eventually implemented into a mobile APP, and together with an
enzyme requirements database for different food products and meals digestion,
will be able to, through a calculation algorithm, predict the amount of PERD
required for a specific meal, and taking into account individual needs for
correction of the dose. This will allow the patients* self-management of this
essential therapy regardless of time and place.

A prospective multicentre interventional study among paediatric CF patients in
five reference paediatric CF units of the European Union: Valencia (Spain;
Hospital Universitari i Politècnic La Fe), Madrid (Spain; Hospital
Universitario Ramón y Cajal), Rotterdam (the Netherlands, Erasmus Medical
Center), Leuven (Belgium; University Hospitals Gasthuisberg) and Milano (Italy;
Ospedale Maggiore Policlínico).

The study consists of 3 parts
Part A:
- Follow a test diet with a fixed PERT dose (theoretical dose).
- Collection of feces that is marked by intake of color capsules.
- Keeping a nutritional diary.

After results of part A were analyzed, it was concluded that only one weekend
was necessary in the coming stages, since in those patients that were compliant
with the protocol, no differences were found between the two weekends.

Part B)
During the second part (February * March 2017), initially, patients would
repeat the process with a different study dose, which would have been
re-adjusted according to the results of faecal fat amount obtained during the
first stage. However, due to the low degree of compliance with the test menu
and with the stool collection schedule in stage A, results did not allow for a
robust calculation system of the individual correction factor.
Therefore it was agreed upon conducting stage B with the theoretical optimal
doses again including some amendments:
* Change in the test meals ( more appealing)
* a *wash-out* period before and after the colorimetric markers intake
* Change in the stools collection schedule: to make it easier for the
participants all the stools will be collected, in individual plastic bags
instead of in one container.
All these updates are expected to increase adherence and compliance with the
protocol and therefore, to enhance the quality of the samples and the accuracy
of the analyses. After updated stage B, the model to calculate the individual
correction factor will be constructed. It will be used to run the mathematical
predictive model in Stage C.

Part C)
Finally, during the third stage (April * May 2017) patients will follow a semi
ad-libitum diet while they complete a food record during one weekend. The diet
will consist of a set of foods that will be characterized for TOD. The PERT
study doses will correspond to the dose predicted by the individual MPM. Dyed
feces will again be collected, as described above. If the ICF can not be
calculated by any means after the end of the present study, the model will be
simplified and only the TOD will be used to predict the optimal dose of
enzymatic supplement.

The 3 parts will take place during a period of 9 months.

The interventions consist of following a test diet, the use of PERT (own
capsules, test dose), the collection of feces that is marked by the intake of
color capsules and keeping a nutritional diary. .

The burden of the study for participating patients consists of following a test
menu ( 1 x 1 weekend for part B) and a semi free menu (1x 1 weekend for part C)
adjusted to age and nutritional habits of the child and the collection of
feces after taking color capsules to mark the feces corresponding to the menu.
(can take up to 2 days after following the test menu before last colored feces
are produced)

The participation in the present pilot study supposes no risk for the patient,
provided that it does not include any additional medicament or treatment, but a
slight change in the enzymatic supplements dose as compared to the current
patterns.
Participation kan give more insight into the current use do food and PERT. The
personal dose of PERT that we obtain in this study can lead to a decrease in
abdominal pain, flatulence and diarrhea and may improve growth, nutritional
status and quality of life in the longer term. We believe that the results of
this study can contribute to improve the treatment both for participating
patients and other patients with the same disease.