OPEN LABEL PHASE I STUDY TO INVESTIGATE THE EFFECT OF MULTIPLE DOSES OF RIFAMPICIN ON THE SINGLE-DOSE PHARMACOKINETICS OF TASQUINIMOD IN HEALTHY SUBJECTS

Tasquinimod is a new, investigational compound that may be used for the
treatment of prostate cancer. In addition, tasquinimod might be used for other
indications as well in the future.
Rifampicin is a registered drug for the treatment of bacterial infections, such
as tuberculosis and lepra.
Rifampicin induces the activity of the enzyme CYP3A4. Tasquinimod is broken
down by this enzyme. Induction of the activity of CYP3A4 by rifampicin may
affect the breaking down of tasquinimod, leading to decreased tasquinimod blood
concentrations.
This study will possibly clarify the potential effect of rifampicin on the
concentrations of tasquinimod in the body and possibly a change in the
concentrations of the metabolites.

Primary : To assess the effect of multiple doses of rifampicin on the
single-dose pharmacokinetics (PK) of tasquinimod
Secondary : To assess the safety and tolerability of multiple doses of
rifampicin with a single dose of tasquinimod

Design:
This is an open-label, 2-period, fixed sequence, crossover, drug interaction
study in healthy volunteers. Subjects will receive a single dose of tasquinimod
alone on Day 1 of Period 1, followed by an assessment/washout period of 7 days.
On Days 1 to 13 of Period 2, subjects will receive daily doses of rifampicin in
combination with a single dose of tasquinimod on Day 8.

Treatments:
12 healthy male or female subjects (at least 4 of each gender) will receive
treatments in 2 periods as follows:
Period 1 : single oral dose of 0.5 mg tasquinimod administered on Day 1
followed by 7 days of assessment and washout.
Period 2 : multiple oral doses of 600 mg rifampicin, administered once daily on
Days 1-13, given in combination with a single oral dose of 0.5 mg tasquinimod
on Day 8 (tasquinimod administered immediately after the rifampicin dose).
Tasquinimod and rifampicin will be administered under fasting conditions.

Procedures and assessments:
Screening : medical history, demographic data, clinical laboratory (including
clinical chemistry, haematology and urinalysis), alcohol and drug screen,
pregnancy test (females only), hepatitis B surface antigen (HBsAg),
anti-hepatitis C virus (HCV) and anti-human immunodeficiency virus (HIV), vital
signs (including supine systolic and diastolic blood pressure, pulse rate,
respiratory rate and body temperature measured with an ear thermometer), 12
lead electrocardiogram (ECG), physical examination (including body weight and
height), adverse events (AEs) from the signing of the informed consent form
(ICF) and previous and concomitant medication.

Follow-up : clinical laboratory (including clinical chemistry, haematology and
urinalysis), vital signs (including supine systolic and diastolic blood
pressure, pulse rate, respiratory rate and body temperature), 12-lead ECG,
physical examination, pregnancy test (females only), AEs and concomitant
medication.

Each admission : drug and alcohol screen, pregnancy test (females only),
clinical laboratory (including clinical chemistry, haematology and urinalysis),
vital signs (including supine systolic and diastolic blood pressure, pulse
rate, respiratory rate and body temperature), 12-lead ECG, AEs and concomitant
medication.

Observation period : 2 periods in the clinic
Period 1: In the clinic from the afternoon on Day -1 of Period 1 until the
afternoon of Day 3 and ambulant visits on Days 4, 5 and 7.
After the 144-hour blood sample on Day 7, the subjects will receive rifampicin
600 mg tablets to be taken once daily at home on Days 1 to 7 of Period 2.
During this period subjects will be contacted daily to check rifampicin dosing
and AEs.
Period 2: In the clinic from the afternoon of Day 7 of Period 2 until the
morning of Day 10 and ambulant visits on Days 11, 12 and 14. On Day 12 the
subjects will receive a rifampicin 600 mg tablet for the Day 13 dose to be
taken at home under fasting conditions. A follow-up visit will occur 7 to 10
days after the Day 13 dose of rifampicin.

Blood sampling:
for PK of tasquinimod in plasma: at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12,
24, 36, 48, 72, 96 and 144 hours after administration of tasquinimod on Day 1
of Period 1 and Day 8 of Period 2.
for PK of rifampicin in plasma: on Day 7 of Period 2 (at admission)

Safety assessments:
AEs recorded from the signing of the ICF until completion of the follow up
visit; clinical laboratory (including clinical chemistry, haematology and
urinalysis) and 12-lead ECG at screening, at admission on Day -1 of Period 1
and Day 7 of Period 2, 4 hours post-dose on Days 1 and 3 of Period 1 and Days 8
and 10 of Period 2, and at follow-up; vital signs (including supine systolic
and diastolic blood pressure, pulse rate, respiratory rate and body temperature
measured with an ear thermometer) at screening, at admission, once daily in the
morning within 2 and 4 hours after any dosing on in-clinic days (but in the
morning around 11 am when there is no dosing), and at follow up; physical
examination at screening and at follow-up.

Active substance: tasquinimod
Activity: anti-angiogenic
Strength: 0.5 mg
Dosage form: per oral capsule

Active substance: rifampicin
Activity: bactericidal antibiotic
Indication: mycobacterial infections
Strength: 600 mg tablet; a dose of 600 mg will be administered
Dosage form: per oral tablet

Risks
Procedures:
Pain, light bleeding, heamotoma, possibly an infection

Medication:
Tasquinimod: muscle or joint pain, tiredness, dizziness and headache.
Rifampicin: The most common adverse effects of rifampicin include
gastrointestinal disorders such as nausea, abdominal pain, accumulation of gas,
vomiting and diarrhea. Other adverse effects are itching, jaundice, drowsiness,
headache and dizziness. Intermittent therapy with rifampicin can cause chills,
fever, headache, general malaise, bone pain and shortness of breath.
Since rifampicin can be present in tears, soft contact lenses can colour red
and become unusable. Also, urine, saliva and sweat can turn red. This is not
harmful. In addition, rifampicin reduces the reliability of oral
contraceptives, see section *contraception*.