Pharmacokintetics, safety and tolerability study of subcutaneous Rizatriptan (DFN-10) in healthy subjects

DFN-10 is a new investigational formulation of the registered compound
rizatriptan and may eventually be used for the treatment of acute migraine with
or without aura. Migraine is a severe, painful headache that is often
accompanied by nausea, vomiting and increased sensitivity to light and sound.
Auras are perceptual disturbances, often manifesting as the perception of a
strange light, an unpleasant smell or confusing thoughts or experiences.

Rizatriptan is an activator of the serotonin receptors called 5 HT1B and 5
HT1D. A receptor is a protein on the surface of a cell to which a molecule
(e.g., serotonin) can bind, causing a change in the activity of the cell. 5
HT1B/1D receptors are found on blood vessels and nerve tissue in the brain.
People who suffer from migraine tend to have low levels of serotonin. Because
Rizatriptan, like serotonin, activates serotonin receptors, DFN-10 is in
development for the treatment of acute migraine. This is the first time this
new formulation of Rizatriptan via this dosing route (injection under the skin)
is being given to humans. The expected advantages of a formulation that is
administered per injection are that it can be effective in case of vomiting
(which is a rather common symptom of migraine), and that the effect of the
medication may start sooner after dosing.

In Part B of the study the volunteer will also receive Maxalt®, which is drug
that is already available in the market under several dosages and formulations.
The active ingredient of Maxalt® is the same as the active ingredient of DFN-10
(Rizatriptan, an activator of the 5 HT1B/1D receptors), so the working
mechanism is comparable.

The purpose of Part A is to investigate how quickly and to what extent
Rizatriptan in DFN-10 is absorbed and eliminated from the body (this is called
pharmacokinetics). In addition, it will be investigated to what extent DFN-10
is tolerated.

In Part B of the study it will be investigated whether the pharmacokinetic
properties of DFN-10 are comparable to the pharmacokinetic properties of
Maxalt®.

Part A:
The actual study will consist of 1 period during which the volunteer will stay
in the clinical research center in Zuidlaren for 3 days (2 nights).

Part B:
The actual study will consist of 2 periods. In each period the volunteer will
stay in the clinical research center in Zuidlaren for 3 days (2 nights). The
time interval between the different periods is 4 days.

Part A:
The study will consist of 1 period during which you will receive a single dose
of DFN-10 or a single dose of placebo. A placebo is the same formulation
without the active ingredient. DFN-10 and placebo will be given as an injection
under the skin (subcutaneous injection).

Group Day Treatment How often
1 1 DFN-10 0.5 mg or placebo Once
2 1 DFN-10 1.0 mg or placebo Once
3 1 DFN-10 2.0 mg or placebo Once

Part B:
The study will consist of 2 periods. In the first period you will receive a
single dose of DFN-10 or a single dose of placebo. A placebo is the same
formulation without the active ingredient. In the second period you will
receive a single dose of 10 mg Maxalt® or a single dose of placebo. DFN-10 will
be given as an injection under the skin (subcutaneous injection). Maxalt® will
be given as a tablet.

The order in which the volunteer will be administered DFN-10 and Maxalt® will
be determined by chance.

The dose DFN 10 that will be administered to the volunteer is 3 mg. This dose
is based on the results of Part A of the study. Should, in the opinion of the
investigators, unacceptable adverse effects appear, the study will be
discontinued..

All potential drugs cause adverse events; the extent to which this occurs
differs. As DFN-10 will be administered to man for the first time in this
study, adverse effects of DFN-10 in man have not been reported to date.
However, DFN-10 has been studied in animals. The most frequently observed
adverse effect in animals was: tremors. Because the active ingredient of DFN-10
is the same as the active ingredient of the registered drug Maxalt®, similar
adverse effects, and possibly other, still unknown adverse effects, may occur.

Maxalt® is a drug that is already available in the market since 1998 under
several dosages and formulations. Maxalt® has been evaluated in 8630 adult
patients and is now being used by many patients suffering from migraine. The
most frequently observed adverse effects are: tingling sensation, headache,
decreased sensitivity of skin, decreased mental sharpness, insomnia, fast or
irregular heartbeat, flushing (redness of the face lasting a short time),
throat discomfort, nausea, dry mouth, vomiting, diarrhea, indigestion, feeling
of heaviness in parts of the body, neck pain, stiffness, pain in abdomen or
chest.