OPEN-LABEL, RANDOMIZED STUDY TO ASSESS THE SAFETY AS WELL AS THE PHARMACOKINETIC PROFILE AND TO INVESTIGATE THE EFFICACY TRENDS ON BIOMARKERS IN TYPE 2 DIABETES MELLITUS PATIENTS OF A SUSTAINED RELEASE FORMULATION OF EXENATIDE BASED ON MEDUSA* TECHNOLOGY

Exenatide is a registered medication that has been developed for the treatment
of Diabetes Mellitus Type 2. It concerns a synthetic form of a naturally
occurring gut hormone, GLP-1 (Glucagon-Like Peptide 1), a protein that is
administered by a subcutaneous injection. Exenatide is used to lower the blood
sugar level in patients with Diabetes Mellitus Type 2 where the conventional
oral medication does not provide sufficient reduction of the blood sugar level.
It stimulates the production of insulin in response to increased levels of
glucose in the blood.

Exenatide MPF (MicroParticles Formulation) is a new formulation of Exenatide
that will aim for a sustained and prolonged release of the original drug
substance, allowing patients themselves less frequent injections to administer
and to experience fewer side effects.

The purpose of the study is to investigate to what extent Exenatide MPF is
tolerated.
It will also be investigated how quickly and to what extent Exenatide, when
administered as Exenatide MPF, is absorbed and eliminated from the body (this
is called pharmacokinetics). In addition, the effect of the compound on blood
levels and body weight will be investigated (this is called pharmacodynamics).

Part A:
The actual study will consist of 2 periods. During Period 1, you will stay in
the clinical research center in Groningen for 5 days (4 nights) followed by 3
ambulant visits during which you will visit the clinical research center in
Groningen, or you will stay in the clinical research center in Groningen for 3
days (2 nights), depending on the treatment sequence (see *How much of the
study compound will I receive?*). If you will receive Byetta® during Period 1,
your stay will be shorter as the clearance of the product is significantly
shorter than that of Exenatide MPF. During Period 2, you will stay in the
clinical research center in Groningen for 5 days (4 nights) followed by 5
ambulant visits.
During the study you will receive Exenatide MPF or Byetta® within 60 minutes
prior to a standardized breakfast, and in case of Byetta®, you will receive a
second dose within 60 minutes prior to a standardized dinner. Exenatide MPF and
Byetta® will be given as a subcutaneous injection in the abdominal wall.

Part B:
Visit schedule:
Week 1: from Day 2 to Day 4, followed by 2 ambulant visits on Day 5 and Day 6
Week 2: from Day 7 to Day 8, followed by 2 ambulant visits on Days 10 and 12
Week 3: from Day 14 to Day 15
Week 4: from Day 21 to Day 25, followed by 1 ambulant visit on Day 26
from Day 27 to Day 28, followed by 5 ambulant visits on Days 29, 31,
33, 36 and 39, and a post study screening on Day 43
During the study you will receive Exenatide MPF within 60 minutes prior to a
breakfast. Exenatide MPF will be given as a subcutaneous injection.

Part A of the study will consist of 2 periods. During Period 1, you will
receive a single dose of Exenatide MPF or two doses of Byetta® at a 12-hour
interval. Byetta® is the existing and registered formulary of Exenatide that
acts shorter. It will be administered in order to compare the pharmacokinetics
and tolerability of the new agent to that of the existing compound. During
Period 2, you will receive a single dose of Exenatide MPF. Exenatide MPF and
Byetta® will be given in the form of a subcutaneous injection.

The following treatment sequences are planned:

Sequence 1 (n=10) Period 1: two subcutaneous doses of 5 µg Byetta® at 12-hour
interval
Period 2: a single subcutaneous dose of 70 µg Exenatide MPF

Sequence 2 (n=10) Period 1: two subcutaneous doses of 5 µg Byetta® at 12-hour
interval
Period 2: a single subcutaneous dose of 140 µg Exenatide MPF

Sequence 3 (n=10) Period 1: a single subcutaneous dose of 10 µg Exenatide MPF
Period 2: a single subcutaneous dose of 70 µg Exenatide MPF

Sequence 4 (n=10) Period 1: a single subcutaneous dose of 10 µg Exenatide MPF
Period 2: a single subcutaneous dose of 140 µg Exenatide MPF


Whether you will receive treatment sequence 1, 2, 3 or 4 will be determined by
chance.


Part B of the study will consist of 1 period during which you will receive
Exenatide MPF once-a-week for 4 weeks. Exenatide MPF will be given in the form
of a subcutaneous injection in the abdominal wall.

Subjects will receive:
140 µg or 180 µg Exenatide MPF once-a-week for 4 weeks

Procedures: pain, light bleeding, heamatoma, possibly an infection.

As Exenatide MPF will be administered to man for the first time in this study,
adverse effects of Exenatide MPF in man have not been reported to date.
However, the most important possible adverse effects of the current formulation
of Exenatide (Byetta®) are nausea and vomiting; in addition, diarrhea,
constipation, reactions at the injection site, loss of appetite and weight
loss. A rare complication is pancreatitis.