A two-part, randomized, two-period, two-sequence crossover and placebo-controlled parallel group, phase 1B trial to evaluate the safety and pharmacokinetics of Modafinil administered in combination with Aniracetam in elderly subjects with subjective cognitive decline

Modafinil has been on the market in Europe since 1992, and in the US since
1998. In the EU and UK, modafinil is indicated for the treatment of excessive
sleepiness in adults with narcolepsy. Aniracetam is a drug that has possible
cognition enhancing effects.

Neither of these 2 drugs alone appears potent enough on its own to alleviate
the cognitive deficits which are present in elderly adults with subjective
cognitive decline. However, by combining the 2 drugs, improvement of episodic
memory (personal important events), executive function (cognitive processes
that are necessary for the control of behavior), and motivation can be
expected. These cognitive functions are reduced among persons exhibiting
age-related cognitive decline and mild cognitive impairment.

The purpose of this study is to investigate how safe modafinil is and how well
it is tolerated when it is administered in combination with aniracetam to
generally healthy elderly volunteers with subjective cognitive decline.
Modafinil and aniracetam are not new compounds; they are already available on
the market in several dosages and formulations.

It will also be investigated how quickly and to what extent modafinil is
absorbed and eliminated from the body. In addition, the effect of modafinil
alone or in combination with aniracetam on cognitive function will be
investigated.

This study will be performed in 66 generally healthy elderly male and female
volunteers with subjective cognitive decline. The study will be performed in 2
parts, Part 1 and Part 2.

The effects of modafinil and aniracetam will be compared to the effects of a
placebo.

Part 1:
The actual study will consist of 2 periods during which the volunteer will stay
twice in the research center. In each period, they will stay in the research
center for 2 days (1 night). This will be followed by a stay in the research
center for 3 days (2 nights) in each period.

In each period, Day 1 is the first day of administration of the study
compound(s). The volunteers are expected at the research center at 14:00 h in
the afternoon prior to the day of first administration of the study compound.
They will leave the research center on Day 1. From Day 2 up to Day 6 they must
take the medication at home at a fixed time, staff from the research center
will contact them by telephone for each medication moment. The volunteers will
return to the research center on Day 6 at 14:00 h for a short stay until Day 8.

Modafinil (200 mg) will be given without or with aniracetam (1500 mg, 2 tablets
of 750 mg) as small oral tablets in a capsule with 240 milliliters (mL) of
(tap) water once daily for 7 days. The aniracetam will be taken approximately 1
hour and 25 minutes after taking Modafinil. In order to be blinded when taking
modafinil without aniracetam, the volunteers will also receive 2 empty
capsules. The study drugs should be swallowed and not be chewed.

Part 2:
The actual study will consist of 1 period during which the volunteers will stay
in the research center for 2 days (1 night). This will be followed by an
ambulatory visit on Day 7.

Day 1 is the first day of administration of the study compound(s). The
volunteers are expected at the research center at 10:00 h in the morning prior
to the day of first administration of the study compound. They will leave the
research center on Day 1. From Day 2 up to Day 6 they must take the medication
at home at a fixed time, staff from the research center will contact them by
telephone for each medication moment. The volunteers will return to the
research center on Day 6 at 14:00 h for a short stay until Day 7.

Modafinil (200 mg) with aniracetam (1500 mg, 2 tablets of 750 mg), or placebo
will be given as small oral tablets in a capsule with 240 milliliters (mL) of
(tap) water once daily for 7 days. The aniracetam will be taken approximately 1
hour and 25 minutes after taking modafinil. The study drugs should be swallowed
and not be chewed.

Part 1:

Treatment A: modafinil 200 mg and 2 empty capsules once a day for 7 days
Treatment B: modafinil 200 mg with aniracetam 1500 mg once a day for 7 days

Part 2:

Modafinil 200 mg and aniracetam 1500 mg once a day for 7 days
Placebo, once a day for 7 days

Modafinil
The most commonly observed side effect (in 10% of patients or more) is headache.

Less common side effects (in 1% to 10% of patients) are decreased appetite,
nervousness, insomnia, anxiety, depression, confusion, irritability, dizziness,
sleepiness, paresthesia, tachycardia, heart palpitations, blurred vision,
vasodilation, abdominal pain, nausea, dry mouth, diarrhea, dyspepsia (upset
stomach), constipation, chest pain, asthenia, abnormal liver function test,
dose-related increases in alkaline phosphatase and glutamyl transferase.

The following have also been reported: Stevens-Johnson syndrome, angioedema,
and anaphylactic reaction.

Aniracetam
Aniracetam is generally well tolerated by patients. The most important observed
side effects are headache, nervousness, irritability, insomnia, nausea, and
vomiting.

The study compound may also have side effects that are still unknown.

Drawing blood and/or insertion of the indwelling cannula may be painful or
cause some bruising.

There will taken about 270 mL blood for Part A and 60 mL for Part B.

To make a heart tracing, electrodes will be pasted at specific locations on
your arms, chest and legs. Prolonged use of these electrodes can cause skin
irritation.