An open-label study of two single oral doses of galantamine, examining the pharmacokinetics, safety, and tolerability in children with Down syndrome

Galantamine has been approved in almost all major markets for the treatment of
mild to moderate dementia of the Alzheimer*s type. Galantamine has also been
investigated for the treatment of other diseases and in healthy volunteers and
was shown to be generally safe and well tolerated. Neuropsychological en
neurochemical similarities between Down syndrome and Alzheimer*s disease (AD)
are well established. There is a reduced cholinergic input to cortical and
limbic brain regions in both Down Syndrome and AD, which supports a rationale
for the study of cholinergic drugs in Down syndrome.
Down syndrome is the most common genetic disorder recognized at birth with
associated adaptive and cognitive impairments. The rate of cognitive
development tends to slow down as these children grow older. A study in
children rather than in adults avoids possible confusion of treatment effects
in Alzheimer*s disease(AD), since AD is widely prevalent in adults with Down
syndrome.
Drugs which specifically activate cholinergic receptors provide amelioration of
Down syndrome symptoms in studies in children and adults. Galantamine*s unique
profile of cholinergic action may offer exceptional potential for its use as a
novel treatment for Downs syndrome. It is possible that subjects with Down
syndrome show different pharmacokinetics to healthy subjects. In order to
prepare for larger controlled clinical studies in this indication,
pharmacokinetic data of galantamine in this particular population are required.

The primary objective is to determine the pharmacokinetic characteristics of
galantamine after 2 single oral doses in children with Down syndrome. Secondary
objectives are to evaluate safety and tolerability.

Open-label pharmacokinetic study in a multi center with two profile days. After
screening, eligible subjects will receive a single oral dose of galantamine on
each of the two profile days, the lower dose first. Time is allowed after the
first dose, in a sub-group of subjects, to analyze galantamine pharmacokinetics
and assess safety data before proceeding to the remaining subjects or moving to
the second dose.

Galantamine will be provided as solution. The dose will be determined per kg
body weight (mg/kg). Study medication will be administered in the morning of
the two profile days. A dose of 0.04 mg/kg will be administered in the morning
on the first profile day, and the dose will be 0.08 mg/kg on the second profile
day. The two profile days will be separated by at least 7 days and by not more
than 48 days.

The children will have to return to the clinic 5 times; for 2 hours at visit 1,
for 9 hours at visit 2, for 4 hours at visit 3 (visit 2 and 3 together cover
Profile day A), for 9 hours at visit 4 and for 4 hours at visit 5 (visit 4 and
5 together cover Profile day B). The children will be watched carefully (and
will be entertained) during the Profile days. Data of the first dose will be
analyzed from 6 subjects before the higher dose will be administered.
At visit 1, 10 ml blood will be collected, maximally 1 week later, visit 2 will
be scheduled and 6 times 2 = 12 ml blood will be collected (0, 0.5, 1, 2, 4,
and 8 hours after dosing), the subsequent day is visit 3, and 2 times 2 = 4 ml
blood will be collected (24 and 28 hours after dosing), visit 4 is scheduled 7
to 48 days later and 6 times 2 = 12 ml blood will be collected and the
subsequent day (visit 5) 2 times 2 = 4 ml blood will be collected, togather
with once more 10 ml blood.
The study has to be performed in children with Down syndrome because (a)
development of cognition decreases with age and finding an effects will be
possible only in children, (b) adults with Down syndrome have an increased risk
for Alzheimer's disease and this will omplicate the interpretation of results
and (c) it is possible that pharmocinetics differ from others in subjects with
Down syndrome.