Trial consisting of an 8-week double-blind placebo-controlled part to evaluate efficacy, safety, tolerability and pharmacokinetics of prucalopride in paediatric subjects with functional constipation, aged ???6 months to <18 years, followed by a 16-week open-label comparator (PEG) controlled part, to document safety and tolerability up to 24 weeks

Prucalopride has been developed for chronic constipation in adults not
adequately relieved by laxative treatment (approved dose 2 mg o.d.).
Prucalopride may also be of use in paediatric patients with functional
constipation. However, limited efficacy, safety and pharmacokinetic data are
available in this population.

The current trial in functional constipation in paediatric subjects (n=210)
from 6 months to 18 years old consists of an 8-week, double-blind,
placebo-controlled period to evaluate efficacy, safety, tolerability and
pharmacokinetics of prucalopride followed by a 16-weekopen-label, active
comparator (PEG)-controlled period to evaluate long term safety and
tolerability. Thus, the total treatment duration is 24 weeks. The design is
based on a review of published data on the effect of prokinetics and/or
laxatives in children with constipation, and is in line with the paediatric
investigational plan of prucalopride as agreed with the Paediatric Committee of
the EMA.

Two double-blind, placebo-controlled studies of drugs approved for the
treatment of functional constipation in children (PEG) have been published.
Both studies had a short (2-week) treatment duration and a small sample size.
The first study (Nurko, 2008) examined 3 doses of PEG vs. placebo in
approximately 25 patients per treatment group. Response rate was defined as the
percentage of patients with *3 bowel movements in the second week of treatment.
A placebo response of approximately 40% was shown vs. 70% after treatment with
PEG. In the cross-over study of Thomson (2007), 51 children were included. No
response rates were mentioned but an increase in bowel movements vs. placebo
was observed after treatment with PEG. Both the short treatment duration and
the small sample size made it difficult to document a real benefit of existing
laxative treatment over placebo. Movetis therefore prefers the inclusion of a
placebo arm over inclusion of a control arm. A treatment period longer than 2
weeks is considered necessary, because constipation is a chronic recurring
condition. Subjects will be allowed to use rescue medication.

Limited or no pharmacokinetic information on prucalopride is available in the
various age groups to be studied. Therefore this study will also document the
pharmacokinetics of prucalopride.

The primary objective is to evaluate the efficacy of prucalopride compared to
placebo for the treatment of functional constipation in a paediatric
population, aged *6 months to <18 years.


Secondary objectives include:
1. Investigation of the individual symptoms defined by the Rome III criteria:
bowel frequency, faecal incontinence, retentive posturing or excessive
volitional stool retention, defecation pain, stool consistency, occurrence of
large diameter stools. In addition use of rescue medication, abdominal pain and
toilet training*.
2. Pharmacokinetics: sparse blood sampling at single dose and steady state to
enable population pharmacokinetic modelling.
3. Safety and tolerability: evaluation of prucalopride treatment up to 24 weeks.

*Only for older children after acquisition of toileting skills (as standard of
care).

Run-in period (1-2.5 week): After screening, eligible subjects will enter a
run-in period of 8-17 days, during which bowel habits of subjects will be
recorded in a daily diary. The run-in period will consist of 1 week control
measurements for the documentation of constipation symptoms, followed by
treatment with an enema or an oral laxative agent for 1 to 3 days to remove any
recto-faecal impaction. The subject will be randomized as soon as the removal
is finalized; the double-blind placebo controlled period should start after the
removal of the faecal impaction.
In case disallowed medication is used at screening, the intake has to be
stopped, and the run-in should take 2 weeks (allowing 1 week for wash-out of
the disallowed medication).

Double-blind placebo-controlled period (8 weeks): Subjects will be randomized
at Day 1 to placebo or prucalopride (1:1). Randomization will be stratified by
country and age group (<4 years; 4 to <12 years; *12 years).
* Subjects with weight *50 kg will receive placebo or a dose of 0.04 mg/kg body
weight prucalopride once daily given as an oral solution of 0.4 mg/mL
(prucalopride succinate equivalent to 0.4 mg/mL prucalopride). After 4 weeks of
treatment the dose might be adjusted:

1) a dose increase to 0.06 mg prucalopride/kg should occur in case of no safety
concerns and insufficient response (i.e. average frequency of < 3 spontaneous*
defecations per week and/or on average >1 episodes of faecal incontinence# per
2 weeks (based on diary data)). Irrespective of body weight the maximum dose
per intake will be 2 mg prucalopride (i.e max. intake 5 mL).
2) a dose decrease to 0.02 mg prucalopride/kg should occur if the subject has
safety/tolerability concerns (e.g. diarrhea) that are likely related to
treatment with prucalopride AND is a responder (i.e. an average frequency of
*3 spontaneous* defecations per week and an average *1 episode of faecal
incontinence# per 2 weeks).
Subjects with a dose adjustment will remain on this dose for the remaining 4
weeks of the double-blind treatment period.

*A spontaneous bowel movement (SBM) is defined as a non-laxative induced BM,
i.e. not preceded within a period of 24 hours by the intake of a laxative agent
or by the use of an enema.
#Faecal incontinence will only be taken into account in children after
acquisition of toileting skills.

* Subjects with weight >50 kg will receive placebo or a tablet of 2 mg
prucalopride once daily.

An interim analysis will be performed to evaluate the possible effects of the
dose adjustments when approximately 70 subjects completed the double-blind
treatment phase.
Use of rescue medication is allowed during the double-blind period as explained
in Section 4.6.2. Concomitant medication.

Open-label active controlled period (16 weeks):
Subjects who have completed the 8-week double-blind treatment phase will be
re-randomised in a 1:1 ratio to receive 16-week open-label treatment with
prucalopride once daily or active control (PEG 4000 (Forlax Junior® <8 years
and Forlax® *8 years)). This randomisation will be stratified by the preceding
treatment (prucalopride or placebo), by country and age group (<4 years; 4 to
<12 years; *12 years).
Subjects with weight *50 kg as measured at start of trial, assigned to the
prucalopride arm, will be dosed with 0.04 mg/kg body weight. After the interim
analysis this dose might be adjusted to 0.06 mg prucalopride/kg once daily when
the 0.06 mg/kg results in substantially higher response rate for efficacy and
when there are no safety concerns. In case of safety/tolerability concerns and
a sufficient response rate for efficacy it might be decided to decrease the
dose to 0.02 mg/kg .
Subjects with weight >50 kg as measured at start of trial, assigned to the
prucalopride arm, will be dosed with 2 mg prucalopride as tablet.
Use of rescue medication is recommended during this period as explained in
Section 4.6.2. Concomitant medication.

For subjects with weight *50 kg, as measured at start of trial, prucalopride
will be administered, as an oral solution of 0.4 mg/mL (prucalopride succinate
equivalent to 0.4 mg/mL prucalopride). Subjects who are *50 kg at onset will
remain on treatment with the oral solution for the remainder of the treatment
period.

Other excipients: Sucralose, methylparaben, propylparaben, hydrochloric acid,
sodium hydroxide and purified water.

Dosing will be based on body weight (dose 0.04 mg/kg body weight=0.1mL/kg). The
dosing volume will be indicated by the investigator at every visit based on
body weight (max. daily dose of 2 mg). Daily dosing will occur before the
evening meal.

The taste and appearance of the placebo solution will be identical to the
prucalopride solution.



For subjects with weight >50 kg, as measured at start of trial, prucalopride
will be administered, as a 2 mg film-coated tablet (prucalopride succinate
equivalent to 2.0 mg prucalopride) for the remainder of the trial. Daily dosing
will occur before the evening meal.

Other excipients: lactose monohydrate, microcrystalline cellulose, colloidal
silicon dioxide, magnesium stearate and coating powder pink.

Placebo tablets are identical in appearance and taste to the prucalopride
tablets.

The most common side effects of the study drug are headacje, nausea, diarrhea
and abdominal pain.
Blood sampling can cause pain, swelling, bruising or infection.
In total there will be 8 study visits.

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