A randomized, double-blind, placebo controlled, four-period, cross-over study to evaluate the cognitive effects of single oral administration of roflumilast in aging-related memory impairment

Aging is known to be accompanied by cognitive deficits including learning and
retention of new information. Several community based studies have estimated
the prevalence rates of memory complaints varying from approximately 25% to
over 50% (Jonker et al., 2000). It is important to note that people with memory
complaints may have an increased risk of progressing towards dementia,
including Alzheimer*s Disease (AD) (Dartigues et al., 1997; Elias et al., 2000;
Stephan et al., 2010). Currently there are few drugs available to attenuate
cognitive impairment in AD: four acetylcholinesterase inhibitors and one
N-Methyl-D-aspartate antagonist (Loveman et al., 2006). Even though AD
constitutes more than half of all dementias (Qiu et al., 2007), there is a
significant and growing number of non-demented people with cognitive impairment
having no claim to any form of pharmaceutical intervention.
In case the development of effective prevention strategies or treatments fail,
it is predicted that the number of dementia cases will rise to 42.3 million in
2020 and 81,1 million by 2040 (Ferri et al., 2005). The development of
goal-directed treatment is hampered by limited insight in the molecular
groundwork of memory and in the mechanisms of ageing-related impairment.
Recently, Phosphodiesterase-4 inhibitors (PDE-4i) gained more attention as a
potential goal for cognitive improvement (Prickaerts et al., 2004; Blokland et
al., 2006; Reneerkens et al., 2009).PDE-4i*s exert their actions by the
selective inhibition of PDE-4, an enzyme which degrades the second messenger
cyclic adenosine monophosphate (cAMP) (Bender and Beavo, 2006). Second
messengers translate an extracellular signal, such as the binding of a
neurotransmitter to its receptor, into structural (receptor and/or synapse
formation) and non-structural (increased neurotransmitter release) cellular
responses (Wei et al., 1998; Lu and Hawkins, 2002). Both responses increase the
efficacy of signal transduction. Counteracting the function of PDE-4 prolongs
the activity of cAMP which facilitates the transition from short-term to
long-term memory (Barad, 2003). In contrast to the existing pro cognitive
drugs, PDE-4i*s do not target a single neurotransmitter system, but exert their
effects on the level of intracellular second messenger cascades. As a result,
multiple neurotransmitter systems are affected, which might be preferable since
optimal memory function relies on the action of different neurotransmitters
(Myhrer, 2003; Rose et al., 2005).

The current study will include a battery that enables assessment of different
domains of cognition including memory, attention, and response inhibition. In
addition, electroencephalography (EEG) recordings including event-related
potential (ERP) measurements will be included. The study aims at providing
proof-of-mechanism for the pro-cognitive effects of roflumilast using cognitive
deficits associated with aging as a model in certain subject populations in
which cognitive deficits (ie, learning/memory) are well defined with screening.

Primary Objective(s):
1. To determine whether aging associated cognitive impairment can be attenuated
by roflumilast administration as assessed by cognitive battery tests.
Secondary Objective(s):
1. To determine whether brain electrical activity (ie, EEG) changes due to
cognitive impairment can be normalized by roflumilast administration as
assessed by EEG recordings.
2. To evaluate safety, tolerability, and pharmacokinetics of roflumilast and
roflumilast N-oxide.
Exploratory objectives:
1. To explore the relationship between exposure of roflumilast and the
pharmacodynamic endpoints observed on specific cognitive domains (eg, learning
and memory, executive function, attention).

The study will be a randomized, double-blind, placebo-controlled, four-period
cross-over study designed to evaluate the effect of single-dose roflumilast in
attenuating the cognitive deficits associated with aging.
The study will consist of 11 visits: (1) First screening visit (Day -28 to -7;
prior to first dose, Day 1) covering memory screening (Verbal Learning Task,
VLT) and psychiatric examination by qualified personnel (semi-structured
clinical interview, Mini International Neuropsychiatric Interview [MINI] for
the assessment of lifetime Diagnostic & Statistical Manual of Mental Disorders,
4th Edition [DSMI-V] Axis -II diagnoses), (2) Second screening visit covering
full medical and neurological examination for the subjects met VLT criteria
(Day -28 to -1), (3) Familiarization visit for cognitive testing (Day -7 to
-1), (4) Four treatment/testing visits on Day 1 of each Treatment Period (each
separated by 14 days; 2 days of testing and 12 days wash-out), and (5) Four
postdose, 24-hour testing on Day 2 of each Treatment Period. A poststudy
telephone call 12±3 days after the last treatment visit (Day 52). There is no
subject confinement in this study.

Subjects will be treated 4 times with Roflumilast 100µg, 250µg, 1000µg and a
placebo. The treatment order will be established by counterbalancing.

The burden related to the actual testing is considered light. EEG measurements
can be slightly inconvenient, but are not painful and do not limit normal
functioning within the laboratory conditions. Test days take 2.5 hr in total,
during which the subjects will actively perform cognitive tasks for 45 minutes.
A short break is foreseen after 30 minutes of active testing. It is possible
subjects will feel somewhat tired due to the test procedures.