Open-label phase I study to investigate the effect of multiple doses of tasquinimod on the single-dose pharmacodynamics and pharmacokinetics of warfarin in healthy subjects

Tasquinimod is a new, investigational compound that may eventually be used for
the treatment of prostate cancer. Warfarin is a drug for treatment and
prevention of harmful blood clots and is likely to be a concomitant medication
in patients with prostate cancer, This study is conducted to determine whether
tasquinimod may influence the pharmacokinetics and thereby also the effects of
warfarin. This study is performed to learn more about the nature of this
interaction to aid in the design of future studies.

Primary:
To assess the effect of multiple doses of tasqinimod on the single-dose
pharmacodynamics (PD) of warfarin.

Secondary:
To assess the effect of multiple doses of tasqinimod on the single-dose
pharmacokinetics (PK) of warfarin.
To assess the safety and tolerability of multiple doses of tasquinimod and
single doses of warfarin.

Design
This is an open-label, fixed-sequence crossover study in healthy volunteers.
Subjects will receive a single dose of warfarin alone on Day 1 of Period 1
followed by 7 days of assessment and washout. Subjects will then receive
tasquinimod on Days 1 to 14 in Period 2 and a single dose of warfarin on Day 9.
All subjects will receive the same treatment.

Treatments
All 15 subjects will be administered the following treatments in 2 study
periods:
Period 1: a single oral dose of 25 mg warfarin on Day 1 followed by 7 days for
assessment and washout
Period 2: multiple oral doses of 0.5 mg tasquinimod once daily on Days 1 to 14
and a single oral dose of 25 mg warfarin on Day 9

Procedures and assessments
Screening: medical history, demographic data (including body weight and
height), clinical laboratory (including clinical chemistry, haematology,
coagulation 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) 1/2, 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, adverse events (AEs) from the signing of the informed
consent form (ICF), previous and concomitant medication; genotyping: for
cytochrome P (CYP) 450 2C9

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 measured with an
ear thermometer), 12-lead ECG, physical examination, pregnancy test (females
only), AEs and concomitant medication

Each admission: drug and alcohol screen, pregnancy test (females only), AEs and
concomitant medication

Observation period:
2 periods in the clinic
Period 1: from the afternoon on Day -1 until the morning of Day 3, daily
outpatient visits through Day 7 (Day 7 of Period 1 is also Day -1 of Period 2)
Period 2: from the afternoon on Day -1 until the morning of Day 15 (a follow-up
visit will occur 7 to 10 days after the Day 14 dose of tasquinimod)

Blood sampling:
for pharmacodynamics: samples for international normalised ratio (INR): 2
samples at least 10 min apart in the hour pre-dose (warfarin) and 8, 24, 36,
48, 72, 96, 120, and 144 h after warfarin doses on Day 1 of Period 1 and Day 9
of Period 2;
for pharmacokinetics of R-warfarin and S-warfarin in plasma: pre-dose and 1, 2,
4, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 h after administration of warfarin
on Day 1 of Period 1 and Day 9 of Period 2
for pharmacokinetics of tasquinimod in plasma: in Period 2, pre-dose
(tasquinimod) on Days 1, 3, 5, 6 and 14 and, on Days 8 and 9, pre-dose and 2,
4, 8, 12, and 24 h after the tasquinimod doses (analysis optional; to be
determined after treatment completion)
for genotyping of CYP2C9: once after start of dosing (preferably on Day 1)

Safety assessments:
AEs and concomitant medications: recorded from the time the ICF is signed until
completion of the final visit; clinical laboratory (including clinical
chemistry, haematology and urinalysis): screening, 4 h post-dose (warfarin) on
Days 1 and 3 in Period 1, 4 h post-dose on Days 1, 3, 9, and 11 in 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, once daily 2 to 4 h after any dosing on in
clinic days, and at follow-up; 12 lead ECG: screening, 4 h post-dose (warfarin)
on Days 1 and 3 in Period 1, 4 h post-dose on Days 1, 3, 9, and 11 in Period 2,
and at follow-up; physical examination: at screening, Day 3 of Period 1, Day 10
of Period 2, and at follow-up

Study medication
Active substance: tasquinimod
Activity: anti-angiogenic
Indication: not applicable
Strength: 0.5 mg
Dosage form: oral capsule

Active substance: warfarin
Activity: anticoagulant
Indication: not applicable
Strength: 25 mg
Dosage form: oral tablet

Treatment
All 15 subjects will be administered the following treatments in 2 study
periods:
Period 1: a single oral dose of 25 mg warfarin on Day 1 followed by 7 days for
assessment and washout
Period 2: multiple oral doses of 0.5 mg tasquinimod once daily on Days 1 to 14
and a single oral dose of 25 mg warfarin on Day 9

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

Medication:
Tasquinimod: muscle or joint pain, tiredness, dizziness and headache.

Warfarin:
The most prominent adverse effect of warfarin use is an increased risk of
haemorrhage (bleeding).