A single dose study to evaluate the microdose pharmacokinetics of candidate HIV integrase
strand transfer inhibitors in healthy subjects

L-1, L-2 and L-3 are new investigational compounds that may eventually be used
for the treatment of HIV-1 viral infection. These compounds are able to inhibit
the retroviral enzyme integrase during the HIV infection process. The
retroviral enzyme integrase are proteins required for the HIV-1 virus to be
incorporated into the host cell DNA. This is the first time that these
compounds will be given to humans.

The purpose of the study is to investigate to what extent L-1, L-2 and L-3 are
tolerated when administered as micro-dose.
It will also be investigated how quickly and to what extent L-1, L-2 and L-3
are absorbed and eliminated from the body (this is called pharmacokinetics).

The actual study will consist of 1 period during which, if the volunteer is
assigned to treatment group A, he will stay in the clinical research center in
Zuidlaren for 6 days (5 nights). If the volunteer participate in group B or C
he will stay in the clinical research center in Zuidlaren for 5 days (4 nights).

During the study the volunteer will receive a single 100 *g micro-dose of
either one of the following compounds L-1, L-2 or L-3 as an intravenous
injection.

The study will consist of 1 period during which the volunteer will receive
either one of the three study drugs compounds once. The study drug will be
given in the form of an intravenous injection.

Group Dosing Day Number of subjects Treatment

A 1 6 L-1 100 *g
B 1 6 L-2 100 *g
C 1 6 L-3 100 *g

To date, L-1, L-2 and L-3 have not been given to people. L-1, L-2 and L-3 have
been tested in laboratory animals as required prior to testing in humans.
Animal studies do not always predict what will happen when the study drug is
given to people.
No side effects were seen in rats when L-1, L-2 and L-3 were given at a dose
that was many times higher than the dose of drug that you will receive.
Although L-1, L-2 and L-3 have not been given to people, it is similar to
approved drugs called raltegravir (ISENTRESS*) and dolutegravir (TIVICAY®) that
are available by prescription.

The most common adverse reactions of moderate to severe intensity (*2%) seen in
people who take ISENTRESS* are:
* difficulty falling and/or staying asleep
* headache
* dizziness
* nausea
* lack of energy

Other adverse reactions seen in people who take ISENTRESS* are:
* changes in enzyme levels that may indicate muscle and brain damage
* muscle pain and weakness
* abnormal muscle breakdown which can lead to kidney problems

The most common adverse reactions of moderate to severe intensity (*2%) seen in
people who take TIVICAY® are:
* difficulty and/or staying asleep
* lack of energy
* headache

With any drug, there is the potential for an allergic reaction. The most
commonly reported symptoms associated with allergic reactions are:
* rash
* nausea
* cough
* dizziness
* fainting
* hives
* itching
* facial flushing
* fever
* muscle aches
* chest tightness
* shortness of breath/difficulty breathing

Rarely, a more severe allergic reaction may occur and may result in death.
Additional symptoms may include:
* swelling of the face, lips, throat and tongue
* low blood pressure
* loss of consciousness

Procedures:

Registration of adverse effects:
During the entire study all adverse effects from the volunteer report will be
documented.

Blood sampling, indwelling cannula:
During this study less than 500 milliliters of blood will be drawn. An
indwelling cannula will be used regularly to sample blood on Day 1. Remaining
blood samples between pre study screening and post-study screening will be
drawn by direct puncture of the vein.

Intravenous (iv) study drug administration:
For the intravenous injection the volunteer will have an indwelling cannula
inserted specifically for this purpose in addition to the indwelling cannula
used for blood sampling on Day 1. Thus the volunteer will have a cannula
inserted in both arms during dosing. The cannula for the intravenous injection
will be removed as soon as possible after dosing.

Vital signs:
Respiratory rate, blood pressure, pulse rate and body temperature will be
measured regularly, both in supine and standing position.

Heart trace (ECG):
ECGs will be made regularly, most frequently on Day 1.